ISSN 1866-8836
Клеточная терапия и трансплантация
Change template to: announce
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Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.<br> Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.<br> Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.<br> Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».<br> Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.<br> Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(37) "Редакционная статья" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(37) "Редакционная статья" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(37) "Редакционная статья" ["SECTION_META_TITLE"]=> string(37) "Редакционная статья" ["SECTION_META_KEYWORDS"]=> string(37) "Редакционная статья" ["SECTION_META_DESCRIPTION"]=> string(37) "Редакционная статья" ["SECTION_PICTURE_FILE_ALT"]=> string(37) "Редакционная статья" ["SECTION_PICTURE_FILE_TITLE"]=> string(37) "Редакционная 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"Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19958" ["VALUE"]=> array(2) { ["TEXT"]=> string(445) "Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)<br> Профессор Аксель Р. Цандер, Со-редактор журнала СТТ (Германия)<br> Профессор Герард Вагемакер, Со-редактор журнала СТТ (Нидерланды)<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(427) "Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)
Профессор Аксель Р. Цандер, Со-редактор журнала СТТ (Германия)
Профессор Герард Вагемакер, Со-редактор журнала СТТ (Нидерланды)
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19959" ["VALUE"]=> array(2) { ["TEXT"]=> string(4561) "<p style="text-align: justify;"> Уважаемые авторы и рецензенты журнала СТТ!<br> Прежде всего, мы бы хотели выразить нашу глубокую благодарность за ваш труд по подготовке и отправке статей в наш журнал, а также за рецензирование рукописей, что обеспечило важную поддержку журналу СТТ за прошедшие годы. Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.<br> Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.<br> Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.<br> Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».<br> Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.<br> Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4503) "

Уважаемые авторы и рецензенты журнала СТТ!
Прежде всего, мы бы хотели выразить нашу глубокую благодарность за ваш труд по подготовке и отправке статей в наш журнал, а также за рецензирование рукописей, что обеспечило важную поддержку журналу СТТ за прошедшие годы. Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.
Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.
Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.
Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».
Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.
Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19960" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-4-10-12" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-4-10-12" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19961" ["VALUE"]=> array(2) { ["TEXT"]=> string(248) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation<br> Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal<br> Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(236) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation
Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal
Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19962" ["VALUE"]=> array(2) { ["TEXT"]=> string(2358) "<p style="text-align: justify;"> Dear CTT authors and reviewers,<br> First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.<br> Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.<br> The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.<br> Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.<br> Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2306) "

Dear CTT authors and reviewers,
First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.
Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.
The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.
Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.
Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy.

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Zander (Germany), Co-Editor-in Chief, CTT Journal<br> Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(236) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation
Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal
Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(236) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation
Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal
Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19962" ["VALUE"]=> array(2) { ["TEXT"]=> string(2358) "<p style="text-align: justify;"> Dear CTT authors and reviewers,<br> First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.<br> Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.<br> The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.<br> Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.<br> Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2306) "

Dear CTT authors and reviewers,
First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.
Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.
The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.
Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.
Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2306) "

Dear CTT authors and reviewers,
First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.
Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.
The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.
Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.
Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy.

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Профессор Аксель Р. Цандер, Со-редактор журнала СТТ (Германия)
Профессор Герард Вагемакер, Со-редактор журнала СТТ (Нидерланды)
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Профессор Аксель Р. Цандер, Со-редактор журнала СТТ (Германия)
Профессор Герард Вагемакер, Со-редактор журнала СТТ (Нидерланды)
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19959" ["VALUE"]=> array(2) { ["TEXT"]=> string(4561) "<p style="text-align: justify;"> Уважаемые авторы и рецензенты журнала СТТ!<br> Прежде всего, мы бы хотели выразить нашу глубокую благодарность за ваш труд по подготовке и отправке статей в наш журнал, а также за рецензирование рукописей, что обеспечило важную поддержку журналу СТТ за прошедшие годы. Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.<br> Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.<br> Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.<br> Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».<br> Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.<br> Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4503) "

Уважаемые авторы и рецензенты журнала СТТ!
Прежде всего, мы бы хотели выразить нашу глубокую благодарность за ваш труд по подготовке и отправке статей в наш журнал, а также за рецензирование рукописей, что обеспечило важную поддержку журналу СТТ за прошедшие годы. Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.
Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.
Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.
Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».
Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.
Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии.

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Уважаемые авторы и рецензенты журнала СТТ!
Прежде всего, мы бы хотели выразить нашу глубокую благодарность за ваш труд по подготовке и отправке статей в наш журнал, а также за рецензирование рукописей, что обеспечило важную поддержку журналу СТТ за прошедшие годы. Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.
Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.
Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.
Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».
Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.
Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии.

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Figure 1. The Great Persky also considers transplants.pngProfessor [Joseph] Munro reminded him of an old saying which he rather reluctantly proposed, in that company, to repeat. It was to the eff ect that there were three gradations of inveracity – there were lies, there were d-d lies, and there were statistics.
Arthur James Balfour, 1st Earl of Balfour (Manchester Guardian, 29th June 1892)
If everyone in the world with acute myeloid leukaemia (AML) in 1st remission received a haematopoietic cell transplant we would know precisely how they fared. Forget statistics, confi dence intervals, p-values, meta-analyses and the like, the  outcome is the outcome. Th e problem is we do not have these data but data only from a subset of persons receiving a transplant and no data on many did not receiving a transplant in 1st remission. So, we need statistics applied to a small, selected sample of transplant recipients to try to estimate a larger truth: what would be the outcome where everyone with AML in 1st remission received a transplant. And with this approach come many assumptions, limitations and substantial uncertainty. As it turns out, people generally hate statistics but they hate uncertainty even more. How can we rationally decide who should receive a transplant in 1st remission and who not. Th e answer hinges to a great extent on accuratly estimating the probability of relapse in a person with AML in 1st remission. To make this estimate haematologists use prognostic and predictive variables, alone or combined into a score such as high-, intermediate- or low risk. Accuracy of this approach is best evaluated using a receiver- operator characteristic (ROC) curve with accuracy expressed as a concordance or C-statistic. Th e C-statistic is derived from the area under the curve (AUC) derived from the ROC curve. A C-statistic of 0.5 indicates no predictive accuracy and a value of 1, perfect predictive accuracy (i.e. no false-positives nor -negatives). However, the C-statistic has limitations. For example, its value depends on the prevalence and/or distribution of covariates in the population being studied. Other estimators of accuracy include positive and negative predictive indices and net reclassifi cation index. Many variables and co-variates are associated with likelihood of relapse in someone with AML in 1st remission such as cytogenetics, WBC, numbers of cycles of induction therapy to achieve a complete remission, duration of complete remission at the time of assessment, results of measurable residual disease (MRD)-testing, expression of so-called leukaemia stem cell (LSC) associated genes etc. However, scores derived from these variables alone or combined explain only about one half of the variance in outcomes with C-statistics of about 0.65-075. Th e question is what accounts for the remaining unexplained variance. Th ere are 3 sources: (1) unknown but potentially knowable (latent) co-variates; (2) measurement error; and (3) chance. The issue of whether a person with AML in 1st remission should receive a haematopoietic cell transplant hinges on several assumptions: (1) we can predict which persons will relapse with reasonable accuracy; (2) a transplant can overcome the adverse biological features of high-risk AML; (3) there is an advantage to doing a transplant before relapse rather than waiting to see if a person relapses and then doing it if needed; and (4) we cause no harm if we predict leukaemia relapse incorrectly and transplant someone already cured by chemotherapy. One demon confounding our estimates of outcomes and applicability of conclusions from a small sample to a wider population is selection bias. Selection bias sounds terrible, politically incorrect, like racial profi ling. Perhaps something Donald Trump might suggest. However, selection biases operate in every aspect of our lives. For example, our old clothes dryer recently began making terrible noises. Death seemed imminent and a do not resuscitate order was written. I rushed online to read the Consumer Reports analysis of new dryers, let’s say the universe of dryers (you would be amazed what’s out there; forget targeted therapy). However, my wife Laura quickly ended my research. She wanted a Maytag (which was, sadly for me, expensive and low-rated by Consumer Reports). But she had a reason. Her mother wanted a Maytag but her father, a mechanical engineer, said he found a cheaper, better-rated brand in Popular Mechanics. According to Laura’s mother (an involuntary but not impartial participant in the dryer experiment) the non-Maytag was a loser. She complained for the rest of her life, especially after the substitute dryer met an untimely end. It never worked right she pronounced. Who am I to argue; happy wife, happy life. Our Maytag is working great (6 months old; fingers crossed) and based on these data Laura pronounced the Maytag the greatest dryer in Earth. Reasonable? No, but happy Wife, happy life. A more statistically-orientated defi nition of selection bias is a bias which occurs when the association between exposure (for example, an allotransplant) and a disease or condition (for example, AML) is diff erent for those who complete a study compared with those in the target population, the overall population for which the measure of eff ect size is being calculated and from which study members are selected. What do you do with these limitations? My advice: Be humble. I am reminded of a line from a Woody Allen article in the New Yorker [1]. Kugelmass, an English professor at City University of New York (CCNY), is married to the now overweight Daphne and is seeing a psychiatrist, Dr. Mandel. He tells Mandel he is unhappy and dreams of romance, perhaps an aff air with Emma Bovary. Th e psychiatrist thinks awhile and says: Kugelmass, you need a magician, not a psychiatrist. Viola! Enter the Great Persky, a Coney Island magician who accomplishes the task (but with a few amusing twists and turns. Strongly recommended). Statisticians, like magicians, have lots of tricks up their sleeves. One is to analyze the data you have rather than the data you don’t have. Terms like heterogeneity, random- and fixed-eff ects models, Cochran Q test, I2 statistic, funnel plots, Egger test etc. magically appear. Th ese manipulations, of course, greatly impress the non-statistician much like rabbits appearing in a hat or seeming to saw a beautiful woman in half. However, there is always a need for another non-statistical and imperfect but useful test: common sense (which, oddly, is distinctly uncommon). Can we rely on data from a very small sample of selected subjects to impute a higher truth? Does this make sense? Does it ring true? Psychologists and philosophers refer to this process as thin slicing [2]. Usually, your 1st impression is correct. Sometimes it’s not, something referred to as the Herbert Hoover eff ect. This type of mistake can have tragic consequences: witness President Donald Trump. Which brings us to the ability of physicians to predict how their patients will do. Prediction is imperfect, as Niels Bohr pointed out: especially about the future. Consider Field Marshal Ferdinand Foch in 1914: Airplanes are interesting toys but of no military value. However, physicians are somewhat better than Foch in predictions. Above I have discussed uses and limitations of analyses of prediction accuracy using a ROC curve and C-statistic. However, physicians claim to have the 6th sense, a bit like umami, which we cannot quantify, at least not yet, and which they think allows them to add something to these predictive scores. Unfortunately, this seems wrong. When formally-tested the C-statistic for physicians’ estimates is only about 0.6, substantially worse than objective prognostic and predictive scores (Estey; unpublished). So much for MSG. Let’s return to the assumptions underlying the consideration of whether to do a transplant with someone with AML in 1st remission and see how many are proved: (1) We can predict which persons will relapse with reasonable accuracy. As discussed above our ability to accurately predict whether someone with mission will relapse is accurate only about one half other time. For example, results of MRD-testing are associated with about 30 percent false-positives and 30 percent – negatives. So, the answer hinges on how comfortable an haematologist is in being wrong in about 1 in every 3 people he/she treats. If an intervention is not dangerous, say giving aspirin, these error rates might be acceptable. Whether they are acceptable in the context of a transplant is more complex. (2) A transplant can overcome the adverse biological features of high-risk AML. This is unproved and requires a clinical trial in which persons predicted to be at substantial relapse risk are randomly-assigned to conventional therapy or a transplant. No such data are reported but a trial with this design is underway in the UK. However, generally the poor outcomes associated with adverse biological features are only modestly overcome by more intensive interventions. (3) There is an advantage to doing a transplant before relapse rather than waiting to see if someone relapses and then doing it if needed. This is also unproved requiring data from a randomized clinical trial. However, data from controlled, non-randomized trials suggest waiting for relapse and transplanting only persons who relapse results in the same survival as transplanting larger numbers of persons in 1st remission. Whether persons who relapse and are in god clinical condition need to receive therapy to try to achieve a 2nd remission before proceeding to a transplant is also unproved and unlikely to be correct. (4) We cause no harm if we predict leukaemia relapse inaccurately and transplant someone already cured by chemotherapy. Obviously wrong. A transplant can kill someone already cured by chemotherapy. The bottom line is most assumptions underlying doing a transplant for persons with AML in 1st remission are unproved and/or wrong. How do we then explain why so many of these persons receive a transplant in 1st remission? Perhaps we need to ask the Great Persky who got Kugelmass from Coney Island to Charles and Emma Bovary’s bedroom in Yonville, France where before him was a beautiful woman, standing alone with her back turned to him as she folded some linen. I can’t believe this, thought Kugelmass, staring at the doctor’s ravishing wife. His caution was warranted.

Acknowledgement

RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Conflict of interest

No conflict of interest is declared.

References

1. Allen W. Th e Kugelmass Episode, New Yorker, May 2, 1977; p. 34 and thereon. 2. Gladwell M. Blink: Th e power of thinking without thinking. New York, NY. Back Bay Books, Little Brown and Company, 2005.

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Figure 1. The Great Persky also considers transplants.pngProfessor [Joseph] Munro reminded him of an old saying which he rather reluctantly proposed, in that company, to repeat. It was to the eff ect that there were three gradations of inveracity – there were lies, there were d-d lies, and there were statistics.
Arthur James Balfour, 1st Earl of Balfour (Manchester Guardian, 29th June 1892)
If everyone in the world with acute myeloid leukaemia (AML) in 1st remission received a haematopoietic cell transplant we would know precisely how they fared. Forget statistics, confi dence intervals, p-values, meta-analyses and the like, the  outcome is the outcome. Th e problem is we do not have these data but data only from a subset of persons receiving a transplant and no data on many did not receiving a transplant in 1st remission. So, we need statistics applied to a small, selected sample of transplant recipients to try to estimate a larger truth: what would be the outcome where everyone with AML in 1st remission received a transplant. And with this approach come many assumptions, limitations and substantial uncertainty. As it turns out, people generally hate statistics but they hate uncertainty even more. How can we rationally decide who should receive a transplant in 1st remission and who not. Th e answer hinges to a great extent on accuratly estimating the probability of relapse in a person with AML in 1st remission. To make this estimate haematologists use prognostic and predictive variables, alone or combined into a score such as high-, intermediate- or low risk. Accuracy of this approach is best evaluated using a receiver- operator characteristic (ROC) curve with accuracy expressed as a concordance or C-statistic. Th e C-statistic is derived from the area under the curve (AUC) derived from the ROC curve. A C-statistic of 0.5 indicates no predictive accuracy and a value of 1, perfect predictive accuracy (i.e. no false-positives nor -negatives). However, the C-statistic has limitations. For example, its value depends on the prevalence and/or distribution of covariates in the population being studied. Other estimators of accuracy include positive and negative predictive indices and net reclassifi cation index. Many variables and co-variates are associated with likelihood of relapse in someone with AML in 1st remission such as cytogenetics, WBC, numbers of cycles of induction therapy to achieve a complete remission, duration of complete remission at the time of assessment, results of measurable residual disease (MRD)-testing, expression of so-called leukaemia stem cell (LSC) associated genes etc. However, scores derived from these variables alone or combined explain only about one half of the variance in outcomes with C-statistics of about 0.65-075. Th e question is what accounts for the remaining unexplained variance. Th ere are 3 sources: (1) unknown but potentially knowable (latent) co-variates; (2) measurement error; and (3) chance. The issue of whether a person with AML in 1st remission should receive a haematopoietic cell transplant hinges on several assumptions: (1) we can predict which persons will relapse with reasonable accuracy; (2) a transplant can overcome the adverse biological features of high-risk AML; (3) there is an advantage to doing a transplant before relapse rather than waiting to see if a person relapses and then doing it if needed; and (4) we cause no harm if we predict leukaemia relapse incorrectly and transplant someone already cured by chemotherapy. One demon confounding our estimates of outcomes and applicability of conclusions from a small sample to a wider population is selection bias. Selection bias sounds terrible, politically incorrect, like racial profi ling. Perhaps something Donald Trump might suggest. However, selection biases operate in every aspect of our lives. For example, our old clothes dryer recently began making terrible noises. Death seemed imminent and a do not resuscitate order was written. I rushed online to read the Consumer Reports analysis of new dryers, let’s say the universe of dryers (you would be amazed what’s out there; forget targeted therapy). However, my wife Laura quickly ended my research. She wanted a Maytag (which was, sadly for me, expensive and low-rated by Consumer Reports). But she had a reason. Her mother wanted a Maytag but her father, a mechanical engineer, said he found a cheaper, better-rated brand in Popular Mechanics. According to Laura’s mother (an involuntary but not impartial participant in the dryer experiment) the non-Maytag was a loser. She complained for the rest of her life, especially after the substitute dryer met an untimely end. It never worked right she pronounced. Who am I to argue; happy wife, happy life. Our Maytag is working great (6 months old; fingers crossed) and based on these data Laura pronounced the Maytag the greatest dryer in Earth. Reasonable? No, but happy Wife, happy life. A more statistically-orientated defi nition of selection bias is a bias which occurs when the association between exposure (for example, an allotransplant) and a disease or condition (for example, AML) is diff erent for those who complete a study compared with those in the target population, the overall population for which the measure of eff ect size is being calculated and from which study members are selected. What do you do with these limitations? My advice: Be humble. I am reminded of a line from a Woody Allen article in the New Yorker [1]. Kugelmass, an English professor at City University of New York (CCNY), is married to the now overweight Daphne and is seeing a psychiatrist, Dr. Mandel. He tells Mandel he is unhappy and dreams of romance, perhaps an aff air with Emma Bovary. Th e psychiatrist thinks awhile and says: Kugelmass, you need a magician, not a psychiatrist. Viola! Enter the Great Persky, a Coney Island magician who accomplishes the task (but with a few amusing twists and turns. Strongly recommended). Statisticians, like magicians, have lots of tricks up their sleeves. One is to analyze the data you have rather than the data you don’t have. Terms like heterogeneity, random- and fixed-eff ects models, Cochran Q test, I2 statistic, funnel plots, Egger test etc. magically appear. Th ese manipulations, of course, greatly impress the non-statistician much like rabbits appearing in a hat or seeming to saw a beautiful woman in half. However, there is always a need for another non-statistical and imperfect but useful test: common sense (which, oddly, is distinctly uncommon). Can we rely on data from a very small sample of selected subjects to impute a higher truth? Does this make sense? Does it ring true? Psychologists and philosophers refer to this process as thin slicing [2]. Usually, your 1st impression is correct. Sometimes it’s not, something referred to as the Herbert Hoover eff ect. This type of mistake can have tragic consequences: witness President Donald Trump. Which brings us to the ability of physicians to predict how their patients will do. Prediction is imperfect, as Niels Bohr pointed out: especially about the future. Consider Field Marshal Ferdinand Foch in 1914: Airplanes are interesting toys but of no military value. However, physicians are somewhat better than Foch in predictions. Above I have discussed uses and limitations of analyses of prediction accuracy using a ROC curve and C-statistic. However, physicians claim to have the 6th sense, a bit like umami, which we cannot quantify, at least not yet, and which they think allows them to add something to these predictive scores. Unfortunately, this seems wrong. When formally-tested the C-statistic for physicians’ estimates is only about 0.6, substantially worse than objective prognostic and predictive scores (Estey; unpublished). So much for MSG. Let’s return to the assumptions underlying the consideration of whether to do a transplant with someone with AML in 1st remission and see how many are proved: (1) We can predict which persons will relapse with reasonable accuracy. As discussed above our ability to accurately predict whether someone with mission will relapse is accurate only about one half other time. For example, results of MRD-testing are associated with about 30 percent false-positives and 30 percent – negatives. So, the answer hinges on how comfortable an haematologist is in being wrong in about 1 in every 3 people he/she treats. If an intervention is not dangerous, say giving aspirin, these error rates might be acceptable. Whether they are acceptable in the context of a transplant is more complex. (2) A transplant can overcome the adverse biological features of high-risk AML. This is unproved and requires a clinical trial in which persons predicted to be at substantial relapse risk are randomly-assigned to conventional therapy or a transplant. No such data are reported but a trial with this design is underway in the UK. However, generally the poor outcomes associated with adverse biological features are only modestly overcome by more intensive interventions. (3) There is an advantage to doing a transplant before relapse rather than waiting to see if someone relapses and then doing it if needed. This is also unproved requiring data from a randomized clinical trial. However, data from controlled, non-randomized trials suggest waiting for relapse and transplanting only persons who relapse results in the same survival as transplanting larger numbers of persons in 1st remission. Whether persons who relapse and are in god clinical condition need to receive therapy to try to achieve a 2nd remission before proceeding to a transplant is also unproved and unlikely to be correct. (4) We cause no harm if we predict leukaemia relapse inaccurately and transplant someone already cured by chemotherapy. Obviously wrong. A transplant can kill someone already cured by chemotherapy. The bottom line is most assumptions underlying doing a transplant for persons with AML in 1st remission are unproved and/or wrong. How do we then explain why so many of these persons receive a transplant in 1st remission? Perhaps we need to ask the Great Persky who got Kugelmass from Coney Island to Charles and Emma Bovary’s bedroom in Yonville, France where before him was a beautiful woman, standing alone with her back turned to him as she folded some linen. I can’t believe this, thought Kugelmass, staring at the doctor’s ravishing wife. His caution was warranted.

Acknowledgement

RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Conflict of interest

No conflict of interest is declared.

References

1. Allen W. Th e Kugelmass Episode, New Yorker, May 2, 1977; p. 34 and thereon. 2. Gladwell M. Blink: Th e power of thinking without thinking. New York, NY. Back Bay Books, Little Brown and Company, 2005.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19970" ["VALUE"]=> array(2) { ["TEXT"]=> string(2569) "<p style="text-align: justify;"> В статье обсуждается многообразие факторов, влияющих на отбор пациентов с острым миелобластным лейкозом (ОМЛ) для трансплантации гемопоэтических клеток. Чтобы уточнить расчеты вероятности рецидива в 1-й ремиссии ОМЛ, оцениваются соответствующие прогностические и предиктивные переменные величины, например, применяется построение и анализ кривых ROC с точностью, выражаемой в виде конкордантности или С-статистики. Вопрос состоит в том, за счет чего возникает остающаяся необъяснимой изменчивость результатов. У нее есть 3 источника: (1) неизвестные, но потенциально выявляемые (скрытые) переменные; (2) ошибка измерений; и (3) случайность. Поэтому мы не можем сейчас с достаточной точностью предсказать, у кого из больных разовьется рецидив.<br> Например, результаты тестирования минимальной остаточной болезни ассоциированы примерно с 30% ложно-позитивных и ложно-негативных ответов. Также невозможно заключить о том, есть ли выгода от проведения трансплантации до рецидива, или же ждать развития рецидива, а потом выполнять трансплантацию по необходимости. Некоторые из этих посылок нужно доказать в рандомизированных клинических исследованиях. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, острый миелобластный лейкоз, риск рецидива, выбор лечения, статистика, ROC-анализ. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2497) "

В статье обсуждается многообразие факторов, влияющих на отбор пациентов с острым миелобластным лейкозом (ОМЛ) для трансплантации гемопоэтических клеток. Чтобы уточнить расчеты вероятности рецидива в 1-й ремиссии ОМЛ, оцениваются соответствующие прогностические и предиктивные переменные величины, например, применяется построение и анализ кривых ROC с точностью, выражаемой в виде конкордантности или С-статистики. Вопрос состоит в том, за счет чего возникает остающаяся необъяснимой изменчивость результатов. У нее есть 3 источника: (1) неизвестные, но потенциально выявляемые (скрытые) переменные; (2) ошибка измерений; и (3) случайность. Поэтому мы не можем сейчас с достаточной точностью предсказать, у кого из больных разовьется рецидив.
Например, результаты тестирования минимальной остаточной болезни ассоциированы примерно с 30% ложно-позитивных и ложно-негативных ответов. Также невозможно заключить о том, есть ли выгода от проведения трансплантации до рецидива, или же ждать развития рецидива, а потом выполнять трансплантацию по необходимости. Некоторые из этих посылок нужно доказать в рандомизированных клинических исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, острый миелобластный лейкоз, риск рецидива, выбор лечения, статистика, ROC-анализ.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19973" ["VALUE"]=> array(2) { ["TEXT"]=> string(585) " The article concerns multiple factors infl uencing selection of patients with acute myeloid leukemia (AML) for hematopoietic stem cell transplantation. A number of prognostic and predictive variables may determine better probability of AML relapse, i.e., ROC analysis, thus allowing more accurate evaluation expressed in terms of concordance, or C-statistics. Th e fi nal results are, however, subject to unexplainable variance. <h2>Keywords</h2> Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(573) " The article concerns multiple factors infl uencing selection of patients with acute myeloid leukemia (AML) for hematopoietic stem cell transplantation. A number of prognostic and predictive variables may determine better probability of AML relapse, i.e., ROC analysis, thus allowing more accurate evaluation expressed in terms of concordance, or C-statistics. Th e fi nal results are, however, subject to unexplainable variance.

Keywords

Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis." 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Gale MD, PhD DSc(hc), FACP, FRSM" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(42) "Robert P. Gale MD, PhD DSc(hc), FACP, FRSM" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(42) "Robert P. Gale MD, PhD DSc(hc), FACP, FRSM" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19973" ["VALUE"]=> array(2) { ["TEXT"]=> string(585) " The article concerns multiple factors infl uencing selection of patients with acute myeloid leukemia (AML) for hematopoietic stem cell transplantation. A number of prognostic and predictive variables may determine better probability of AML relapse, i.e., ROC analysis, thus allowing more accurate evaluation expressed in terms of concordance, or C-statistics. Th e fi nal results are, however, subject to unexplainable variance. <h2>Keywords</h2> Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(573) " The article concerns multiple factors infl uencing selection of patients with acute myeloid leukemia (AML) for hematopoietic stem cell transplantation. A number of prognostic and predictive variables may determine better probability of AML relapse, i.e., ROC analysis, thus allowing more accurate evaluation expressed in terms of concordance, or C-statistics. Th e fi nal results are, however, subject to unexplainable variance.

Keywords

Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(573) " The article concerns multiple factors infl uencing selection of patients with acute myeloid leukemia (AML) for hematopoietic stem cell transplantation. A number of prognostic and predictive variables may determine better probability of AML relapse, i.e., ROC analysis, thus allowing more accurate evaluation expressed in terms of concordance, or C-statistics. Th e fi nal results are, however, subject to unexplainable variance.

Keywords

Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis." } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19966" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-4-10-12" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-4-10-12" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-4-10-12" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19967" ["VALUE"]=> string(102) "Transplants for аcute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(102) "Transplants for аcute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(102) "Transplants for аcute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19972" ["VALUE"]=> array(2) { ["TEXT"]=> string(141) "Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK SW7 2AZ<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(135) "Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK SW7 2AZ
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" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19968" ["VALUE"]=> array(2) { ["TEXT"]=> string(25) "Роберт П. Гэйл" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(25) "Роберт П. Гэйл" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(25) "Роберт П. Гэйл" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19970" ["VALUE"]=> array(2) { ["TEXT"]=> string(2569) "<p style="text-align: justify;"> В статье обсуждается многообразие факторов, влияющих на отбор пациентов с острым миелобластным лейкозом (ОМЛ) для трансплантации гемопоэтических клеток. Чтобы уточнить расчеты вероятности рецидива в 1-й ремиссии ОМЛ, оцениваются соответствующие прогностические и предиктивные переменные величины, например, применяется построение и анализ кривых ROC с точностью, выражаемой в виде конкордантности или С-статистики. Вопрос состоит в том, за счет чего возникает остающаяся необъяснимой изменчивость результатов. У нее есть 3 источника: (1) неизвестные, но потенциально выявляемые (скрытые) переменные; (2) ошибка измерений; и (3) случайность. Поэтому мы не можем сейчас с достаточной точностью предсказать, у кого из больных разовьется рецидив.<br> Например, результаты тестирования минимальной остаточной болезни ассоциированы примерно с 30% ложно-позитивных и ложно-негативных ответов. Также невозможно заключить о том, есть ли выгода от проведения трансплантации до рецидива, или же ждать развития рецидива, а потом выполнять трансплантацию по необходимости. Некоторые из этих посылок нужно доказать в рандомизированных клинических исследованиях. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, острый миелобластный лейкоз, риск рецидива, выбор лечения, статистика, ROC-анализ. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2497) "

В статье обсуждается многообразие факторов, влияющих на отбор пациентов с острым миелобластным лейкозом (ОМЛ) для трансплантации гемопоэтических клеток. Чтобы уточнить расчеты вероятности рецидива в 1-й ремиссии ОМЛ, оцениваются соответствующие прогностические и предиктивные переменные величины, например, применяется построение и анализ кривых ROC с точностью, выражаемой в виде конкордантности или С-статистики. Вопрос состоит в том, за счет чего возникает остающаяся необъяснимой изменчивость результатов. У нее есть 3 источника: (1) неизвестные, но потенциально выявляемые (скрытые) переменные; (2) ошибка измерений; и (3) случайность. Поэтому мы не можем сейчас с достаточной точностью предсказать, у кого из больных разовьется рецидив.
Например, результаты тестирования минимальной остаточной болезни ассоциированы примерно с 30% ложно-позитивных и ложно-негативных ответов. Также невозможно заключить о том, есть ли выгода от проведения трансплантации до рецидива, или же ждать развития рецидива, а потом выполнять трансплантацию по необходимости. Некоторые из этих посылок нужно доказать в рандомизированных клинических исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, острый миелобластный лейкоз, риск рецидива, выбор лечения, статистика, ROC-анализ.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2497) "

В статье обсуждается многообразие факторов, влияющих на отбор пациентов с острым миелобластным лейкозом (ОМЛ) для трансплантации гемопоэтических клеток. Чтобы уточнить расчеты вероятности рецидива в 1-й ремиссии ОМЛ, оцениваются соответствующие прогностические и предиктивные переменные величины, например, применяется построение и анализ кривых ROC с точностью, выражаемой в виде конкордантности или С-статистики. Вопрос состоит в том, за счет чего возникает остающаяся необъяснимой изменчивость результатов. У нее есть 3 источника: (1) неизвестные, но потенциально выявляемые (скрытые) переменные; (2) ошибка измерений; и (3) случайность. Поэтому мы не можем сейчас с достаточной точностью предсказать, у кого из больных разовьется рецидив.
Например, результаты тестирования минимальной остаточной болезни ассоциированы примерно с 30% ложно-позитивных и ложно-негативных ответов. Также невозможно заключить о том, есть ли выгода от проведения трансплантации до рецидива, или же ждать развития рецидива, а потом выполнять трансплантацию по необходимости. Некоторые из этих посылок нужно доказать в рандомизированных клинических исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, острый миелобластный лейкоз, риск рецидива, выбор лечения, статистика, ROC-анализ.

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Introduction

Early infections caused by opportunistic microorganisms are quite common aft er allo-HSCT, thus requiring massive and expensive anti-infectious therapy. Massive cytoreductive therapy in cancer is followed by pronounced neutropenia and exhaustion of most lymphoid cell populations [1]. Hence, a total defi ciency of immune response is evident since 1-2 weeks aft er conditioning therapy and HSCT.
The immune failure is characterized by exhaustion of specific humoral factors, e.g., serum immunoglobulins, and decreased counts of immune subpopulations (granulocytes, monocytes, T- and B cell subsets, NKs). Th ese immune indexes reflect general drop and recovery of immune system which may continue for months and years [1]. However, these cellular and humoral markers alone cannot accurately predict clinical risk of local infections at epithelial and mucosal surfaces (pneumonia, cystitis, stomatitis et.). The most hazardous terms for development of bacterial, fungal and viral infections are shown in Fig. 1. Post-transplant deficiencies of certain leukocyte populations seem to correlate with viral, bacterial and fungal infections [2]. Hence, the immune failure may, in principle, assessed via detection of multiple microorganisms which normally live and grow on skin and external mucous surfaces (i.e., oral cavity, pharynx, urethral ways etc). These opportunistic pathogens are normally controlled by the host immune surveillance. However, within weeks aft er HSCT, they tend to colonize deeper sites and areas (e.g., respiratory ways, urogenital tract etc.) causing different aff ections of internal organs. Hence, posttransplant detection of microfl ora in bloodstream and, especially, at local inflammation sites refl ects the degree of immune failure. Appropriate clinical experience was translated into numerous clinical recommendations based on empiric antibiotic treatment during early hematopoietic recovery and febrile neutropenia [3-6]. However, despite routine protection of the post-HSCT patients by broad-spectrum antibiotics, and antiviral treatment for a period of myelopoiesis reconstitution (up to 4 weeks), the rates of local post-transplant infections (e.g., pneumonia) may reach 25% of the HSCT patients [7].
Moreover, unusual sites of infection (typhlitis, perirectal infections and atypical forms of cellulitis) in neutropenic patients were noted decades ago [8]. About 60% of febrile neutropenia in early posttransplant period are classified as fever of unknown origin without distinct infectious pathogen, yet most respond to antibacterial therapy. Unusual sites of infection include typhlitis, perirectal infections and atypical forms of cellulitis.
Later on, a number of immunosuppressive drugs are routinely used after allogeneic HSCT (allo-HSCT) in order to prevent graft -versus-host disease (GvHD). In fact, some
immune populations, especially, adaptive immunity cells, may recover at several months and years post-transplant [1,9]. Hence, a long-term immune defi ciency after SCT is a chronic condition predisposing for opportunistic infections, fungal invasions and activation of endogenous viruses. Such infectious markers could be registered, and the co-infection rates may be used for assessing the grade of immune deficiency in the patient.

Figure_1_Terms_of_the_most_common_infectious_complications_in_HSCT__10.png

Severity and clinical signifi cance of the post-HSCT immune deficiency depends on dosage and expected immunotoxic effects of drugs used in the conditioning protocol, i.e., myeloablative or nonmyeloablative regimen. However, individual damage to the patient’s immune system is modified by the following factors:
• Intensity and number of preceding cytoreductive treatments exhausting the myelo-and lymphopoiesis system;
• Pharmacokinetics of cytotoxic drugs which strongly depends on its administration route, altered liver and kidney functions, and genetic variants aff ecting activation or inactivation of the given drug(s);
• Recipient/donor immune conflict, i.e., partial HLA mismatch, severe graft -versus-host disease [11]. Therefore, personalized evaluation of selected pathogen-specific markers, their multiplicity and biodiversity seems to be an efficient tool for specifying degree of immune defi ciency observed at early and later terms post-transplant.
Hence, the aim of our review is to propose the sets (panels) of latent/opportunistic marker microorganisms as potential markers of immune defi ciency, especially, in post-transplant patients. A number of species- and genus-specifi c multiplex PCR kits, as well as some integral microbial markers could be used for severity evaluation of immune defi ciency when testing peripheral blood samples and locally infected sites.

Table_1_List_of_opportunistic_flora_activated_in_immunocompromised_patients_combined_of_different_studies.png

Incidence and sites of opportunistic infections

The list of opportunistic infections in immunocompromised patients is rather broad, however, limited by distinct microbial, fungal and viral species (see Table 1).
Most bacterial species revealed in immunocompromised patients proved to be opportunistic microorganisms, i.e., those which are present in normal human skin or inhabit normal gut mucosa. The main prerequisites for growth and cytopathic/ infl ammatory effects of opportunistic fl ora are as follows: (1) Penetrating skin barrier; (2) Passing mucosal surfaces; (3) Remote dissemination via bloodstream to lymph nodes, spleen, liver, kidney, lungs; (4) Passing blood/brain barrier. As a result, posttransplant patients develop opportunistic infections of lower respiratory ways, brain, urinary tract, as well as deep abscesses caused by skin or intestinal microorganisms. Moreover, the skin microorganisms may colonize catheter lumen, then proceeding into a bloodstream infection.

Incidence of bacterial pathogens in blood cultures from immunocompromised patients

Detection of bacterial pathogens is normally performed in blood cultures, now using automatic incubation/detection systems. Blood is normally regarded as a sterile medium. However, some episodes of septicemia may occur due to occasional microbial contamination, e.g., major purulent surgery, dental extraction etc. Fungal pathogens may be detected in blood both by beta-galactomannan immunoassay, or by DNA diagnostics. Viral infection/reactivation is routinely detected in whole blood or plasma by means of PCR.
Blood screening for bacterial infections may be an efficient tool of infection monitoring. Blood culture done at a regular interval of at least 5 days. Studies on surveillance blood cultures in HSCT are routinely practicized at many centers. E.g., this approach was tested by for 205 patients admitted for auto- or allo-HSCTs [12]. Bloodstream infection was detected in 14.1% of these patients, which is at lower limits of previously reported rates (12.5-40%). Suprisingly, none of the patients who developed bloodstream infection were diagnosed by surveillance blood cultures. Blood cultures taken in presence of clinical infectious symptoms were much more informative. The most common organisms isolated were coagulasenegative staphylococci, 41/84 (49%) in pure culture and an additional 10 (12%) in mixed cultures. Klebsiella spp. and Enterococci each accounted for 5 episodes (6%) of positive cultures; Viridans group streptococci accounted for 2 episodes (2.4%); and the remaining 25% were caused by different organisms.
In some other countries, the spectrum of cultured bloodborne bacteria is shift ed towards Gram-negative microbes, i.e., Pseudomonas aeruginosa, Klebsiella pneumonia, Esherichia coli, Acinetobacter spp, Enterobacter spp. as reported by an Indian team who analyzed data from 653 pediatric cancer patients undergoing chemotherapy [13].
In a Belarus study, the incidence (top-10) of cultivable bacterial pathogens during the early period aft er HSCT, their culture and identifi cation was assessed with BacT/ALERT-Vitec technique [14]. Th e following rating of microbial detection was obtained (Table 2), with Klebsiella pneumonia and Escherichia coli. making >40% of all clinical microbial isolates.
In immunocompromised patients, herpesviruses, fungal infections,
hepatitis B and C are taken into scope.

Table_2_Detection_rates_for_different_bacterial_pathogens_in_blood_of_HSCT_patients_14.png

A comprehensive randomized analysis of posttransplant infections which occured during 2 years aft er HSCT was reported by Young et al. [15] being performed in the patients from USA BMT centers. A total of 499 patients were under study exhibiting 1347 infection episodes of severe or life-threatening grade documented in 384 (77%) patients. 249 (81%) of these patients had received a BM graft and 183/250 (73%) had received a PBSC graft , at a cumulative two-year incidence of infections of 80-85%. Th e majority of these episodes, 810 (60%), were due to bacteria, with a twoyear cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bacterial infections during the first 100 days was 44.8% for BM vs. 35.0% for PBSC (P= 0.027). The infection rates were slightly more often after BM transplantation than following peripheral PBSCT (Table 3).

Local microbiotes as a source of opportunistic flora

Skin surface

Normal skin harbors hundreds of opportunistic or commensal microorganisms including bacteria, fungi and viruses that compose skin microbiome [16]. T e skin cell populations (keratinocytes, dermal cells, fi broblast, macrophages etc.) release a lot of protective factors and molecules (antimicrobial peptides etc.), to limit excessive microbial growth and colonization [17]. Therefore, survival of the microorganisms on the skin surface suffi ciently depends on their ability to resist the host defense mechanisms [18].
The major fraction is represented by coagulase-negative staphylococci such as S.epidermidis [19, 20] as well as more pathogenic S.aureus [21]. Sebaceous glands are colonized by Propionibacterium acne [22]. Candida yeasts also colonize skin surface, being, however, controlled by appropriate defense mechanisms [23]. In immunocompetent organism, these microflora interact with keratinocytes and local immune cells, thus supporting limiting local growth of skin microflora. However, in immunocompromised and elderly patients, the commensal skin staphylococci, Candida yeasts etc. may be isolated from the sites of extradermal opportunistic infections, like catheter- or pacemaker-associated infl ammatory conditions [24]. Clinical studies show that all the mentioned skin microfl ora could be revealed in blood of the immunocompromised patients (see tables 2, 3).

Oral mucosa

Hundreds microbial and viral species, of them – only up to 5-10 marker microbes, Candida yeasts and viruses (EBV). Dental flora could be revealed in bloodstream, and, especially, in heart valves [25], thus demonstrating a wide opportunity of a distant microbial contamination with opportunistic oral microflora.
Oral mucosa is protected by innate immunity factors, playing a crucial role in the regulation of oral health. E.g., epithelial cells lining oral mucosal surfaces provide not only a physical barrier but also produce diff erent antimicrobial peptides, including human β-defensins (hBDs), lactoferrin, secretory leukocyte protease inhibitor (SLPI), and various cytokines [26]. Specific IgA’s provide specifi c immune response. There are a lot of oral co-infections revealed in HIV-infected patients, such as human herpesvirus 6 and 8 (HHV-6, HHV-8), herpes simplex virus 1/2 (HSV-1/2), EBV, and human papilloma virus (HPV). Colonization with Candida species is also quite common in these patients. Oral hairy leukoplakia caused by Epstein Barr virus is a typical infection associated with immune suppression [27].
Non-tuberculosis mycobacteria (non-MBT) are also common among oral microfl ora [28]. When examining healthy persons, the non-MBT DNA was detected in the nostrils of all 10 subjects, in buccal mucosa of 8 subjects, in the oropharynx of 7 subjects, and in the dental plaques of 5 subjects.

Table_3_Incidence_of_infectious_pathogens_revealed_over_2_years_after_allo-HSCT_15.png

Oropharyngeal mucosa

In a group of 82 patients with head-and-neck cancer treated by chemo/radiotherapy, the authors studied subgingival biofilm samples, oral lavages and whole saliva samples obtained to microbiologically analyze the eff ects of cancer treatments (1-year follow-up). As compared to surgically treated patients, an increased prevalence of P. gingivalis, T. forsythia, S. mutans and Candida species was observed in the treated areas, thus demonstrating immunosuppressive action of the cytotoxic therapy [29]. Signifi cance of these fi ndings in oncohematology was evaluated by Schuurhuis et al. [30] after cytostatic treatment of 28 leukaemic and 35 auto-HSCT patients. Acute oral foci of infection were found in 2 leukaemic (7%) and 2 ASCT patients (6%), and chronic oral foci of infection in 24 leukaemic (86%) and 22 ASCT patients (63%). Positive blood cultures with microorganisms potentially originating from the oral cavity occurred in 7 patients during treatment, but did not correlate with development of infectious complications.
Nasopharyngeal area is characterized by interactions between adenoid microorganisms [31]. Adenoid microbiota plays an important role in the development of various infectious and non-infectious diseases of the upper airways, such as otitis media, adenotonsillitis, rhinosinusitis and adenoid hypertrophy. Studies have suggested that adenoids could act as a potential reservoir of opportunistic pathogens. However, previous bacterial surveys of adenoids were mainly culture based and therefore might only provide an incomplete and potentially biased assessment of the microbial diversity. To develop an in-depth and comprehensive understanding of the adenoid microbial communities and test the ‘pathogen reservoir hypothesis’, we carried out a 16S rRNA based, culture-independent survey of bacterial communities on 67 human adenoids removed by surgery. Our survey revealed highly diverse adenoid bacterial communities distinct from those of other body habitats. Despite large interpersonal variations, adenoid microbiota shared a core set of taxa and can be classified into at least five major types based on its bacterial species composition.

Broncho-alveolar mucosa

Colonization of mucosal surfaces with autofl ora (cocci, yeast fungi and molds, latent viruses), has an important stimulatory effect on whole-body development of immune responses [32]. However, the opportunistic local microfl ora in immunocompromised patients may extensively grow on the mucous surfaces in association with more or less severe clinical symptoms, e.g., opportunistic gramnegative bacilli (Enterobacteriaceae, Pseudomonas, Acinetobacter spp.). Moreover, relatively virulent serovars of M. avium complex, like as other non-MBT bacteria, may colonize the bronchial and intestinal mucosal surfaces of healthy individuals in immunocompromised conditions [33]. The same could be found with fungal outgrowth and Toxoplasma activation.

Gastrointestinal tract (GIT)

Extensive gut microbiota contains hundreds of microbial species of which only few are able to grow on media used in clinical laboratories. Th e most detectable opportunistic infectious pathogens are: E.coli, C. diffi cile, Enterococcus fecalis/faecium, etc. Meanwhile, most microorganisms (up to 70%) are fastidious or non-culturable species which may be revealed only by DNA or protein diagnostics.
As reviewed by Callejas-Díaz and Gea-Banacloche [34], the C. difficile infection (CDI) is very frequent at early terms aft er hematopoietic stem cell transplantation (HSCT) – between 6 % and 20% of HSCT recipients during the first year mostly aft er allo (allo-HSCT), thus being a promising bacterial marker of intestinal dysbiosis. For diagnostics, molecular testing for the toxin genes by (PCR) is performed, along enzyme immunoassays (EIA). It correlates with worsening of bowel graft versus host disease (GVHD).
Early after cytoreductive therapy one may observe severe damage of chemosensitive intestinal mucosa [35]. Intestinal microflora undergoes sufficient changes within several days aft er intensive chemotherapy and/or HSCT. At present time, these shift s in microfl ora subsets are eff ectively detected by means of multiplex high-throughput PCR followed by sequencing of the obtained genome fragments and computer-assisted differentiation of these genome segments. The mentioned mucosal damage and infl ammation is associated with a reduced biodiversity of intestinal microfl ora developing aft er HSCT (see a review by [36] Kucher et al., 2017). In turn, altered intestinal microbiota aft er HSCT is shown to be an important risk factor of severe GVHD [37]. Hence, the interactions between gut microbial antigens and immune cells are enhanced early aft er cytotoxic chemotherapy.

Gut bacterial translocation: lessons from HIV infection

A gradually developing immune defi ciency in HIV infection, while bearing other pathogenetic features, is known to be associated with a number of concomitant infectious complications (HCV, tuberculosis etc.) and a variety of somatic comorbidities [38] (Currier, Havlir 2005). Opportunistic infections are commonly associated with HIV infection. E.g., some malignant lymphomas in HIV patients may occur due to activation of latent Epstein-Barr virus and, probably, HHV8 [39], like as secondary lymphomas in post-transplant immunocompromised patients. Bacterial opportunistic infections, such as Pneumocystis jiroveci, Toxoplasma gondii, and Mycobacterium avium threaten the patients at CD4+ T cell counts below 200 cells/mcL [40]. However, exact critical levels for CD4+ cells are quite varying. Th erefore, a multiplex detection of opportunistic pathogens would be performed, in order to assess real individual degree of clinical immunodeficiency.
In HIV-infection, the intestinal damage and microflora changes are followed by activation of monocytes and residual T cells, due to the so-called bacterial translocation, i.e., penetration of gut bacterial cell components from injured intestinal wall to bloodstream [41]. Th e bacterial translocation is registered as endotoxin or soluble monocyte (CD14) antigen detected in blood serum. Th is “subseptic” condition is recognizable in HIV-infected patients, especially, those receiving suboptimal antiretroviral therapy. According to this opinion, the damaged gut epithelium allows diff usion of bacterial antigens which stimulate monocytes, IL-17 and IL-22-secreting cells.
The mentioned markers of microbial translocation in HIV infection showed some pathogenetic links with quantitative shift s in gut microfl ora, as shown by next-generation sequencing of bacterial 16S rRNAs which identifies hundreds of intestinal microbial species [42]. The analysis of gut microbial diversity showed a more restricted microbiota spectrum, both at baseline and aft er antiretroviral therapy (ART). Th e skewed biodiversity of gut flora correlated with decreased CD4 T-cell counts and increased markers of microbial translocation and monocyte activation. Moreover, bacterial lipopolysaccharide (LPS) and soluble CD14 (monocyte antigen) concentrations in blood plasma are shown to predict mortality and disease progression in subjects with HIV infection [41]. Intestinal epithelial damage and altered gut microfl ora in allogeneic HSCT are also well proven [36]. Hence, the markers of bacterial translocation may be potentially eff ective in diagnostics of any immune deficiency, aiming to evaluate possible damage to the gut mucosa and altered immune response aft er HSCT.

Urine and urogenital ways

The urine is sterile in healthy children. Normally, the urinary epithelium is protected by specifi c antibacterial factors, e.g., Tamm-Horsfall protein, lactoferrin, defensins etc [43]. With age, however, the urinary system is colonized in ascending manner with microfl ora from skin (Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococci, Candida) and gut (Escherichia coli, Enterobacter, Enterococcus, Proteus mirabilis). However, hematogenic infections are also possible due to Staph. aureus, Haemophilus infl uenza etc., thus causing chronic cystitis and pyelitis oft en complicated by infectious kidney stone formation [44].
Protozoic infections, e.g.., Toxoplasma gondii, may be also
revealed in urogenital ways over 1st month aft er HSCT [45], with rapid disappearance from urine cells upon hematopoiesis reconstitution.
Early after hematopoietic transplantation, hemorrhagic cystitis is developing in most cases, mainly, due to urothelial damage by toxic cytostatic treatment. Meanwhile, activation of BK and JC viruses (latent polyomaviruses in urothelial cells) are additional markers of hemorrhagic cystitis at the terms of 1-2 months which are found in urine at early terms post HSCT [46].

Catheter-associated urinary infection is a special issue in immunodeficient patients. It may be caused by P.mirabilis migrating from gut [47], or other urease-positive microbes migrating, mainly, from skin. Multiple bacterial species co-exist in microbial biofilms growing on the bladder epithelium and in catheter lumen [48].

Mixed infections in immunocompromised patients

Bacterial/fungal co-infections

Combined infections with bacterial and/or fungal agents after cytotoxic treatment in post-transplant patients were described in many works. However, the mechanisms of their simultaneous emergence are not clear yet. Acute failure of protective immune mechanisms could be the most plausible explanation for these posttransplant conditions. Moreover, multiple occurence of several pathogens in a single biological sample (i.e., blood, urine, or saliva) in HSCT patients may be promoted by a symbiotic microbial growth, thus causing a co-infection. Polymicrobial complexes grown as biofilms are regularly observed in local infections, such as dental caries and parodontitis, otitis media, diabetic foot wounds etc. [49]. Similar growth of bacterial associations is typical to blood catheter-associated infections, or urinary catheter
contamination. Hence, bacterial co-infections are not rare and should be detected in HSCT setting.
The incidence of bacterial and/or fungal infections was assessed in a group of 901 stem cell transplant recipients [50]. Of them, 237 patients (27%) had microbiologically documented microorganisms isolated, including 34 patients (14%) simultaneously infected with multiple microorganisms. Th e co-infected patients seem to be at an increased risk for aGvHD and delayed graft functioning.
The same workers evaluated infection by Clostridium difficile, a common opportunistic microbe, and its association with other infectious agents [51]. Among 822 consecutive autologous and allogeneic HCST recipients, 85 cases (10.3%) of C.diffi cile-associated disease were identified. Significant associations were found between C.diffi cile detection, and neutropenic fever, as well as with bacterial coinfection, and presence of vancomycin-resistant Enterococcus faecium (VRE) colonization. Allo-HSCT patients with C.diffi cile-associated disease showed higher rates of severe gastrointestinal aGvHD.

Viral co-infections

Combined post-transplant viral co-infections are also quite common, thus suggesting their treatment by injection of the virus-specifi c immune lymphocytes [52]. Simultaneous activation of several common endogenous viruses was shown by a multiplex PCR system for 13 common viral species in some patients before allo-HSCT, while being increased within 1st month aft er transplant [53].
Simultaneous co-activation of herpesviruses is a regular finding. E.g., in a Polish study [54] 142 allo-HSCT recipients were tested for 3 herpesviruses (CMV, HHV-6 and HHV-7) for the fi rst 3 months. Reactivation of more than one virus was identifi ed in 31% of analysed patients, with CMV being most common, thus increasing risk of specifi c complications posttransplant.
In a recent study by Koskenvuo et al. [55] the authors studied 23 viruses in 53 paediatric patients up to 3 months aft er allo- HSCT. Interestingly, polyomaviruses predominated over herpesviruses thus showing their common incidence in the immunodefi cient cohort. Of them, 13 patients (25%) had viraemias by multiple viruses. Presence of viral co-infections was signifi cantly associated with aGvHD and steroid use, the factors known to suppress immune functions.
There are specific combinations of certain viral species in post-HSCT patients. According to results obtained by Jeulin et al. [56], HHV6 infection did not correlate with CMV, HSV, EBV. Meanwhile, adenovirus infection and HHV-6 activation seemed to be related in their posttransplant replication.

Mixed infectious pathogens

A large meta-analysis was performed by Klein et al. [57] based on a systematic search of different medical databases on infl uenza virus-associated infections. It covered 27 studies including 3215 participants, with widely varying coinfection rates ranging from 2% to 65%. Most common coinfecting species were S. pneumoniae and Staph. aureus, which accounted for 35% and 28% of infections followed by P.aeruginosa, S. pyogenes, H. infl uenzae,.K. pneumoniae, and M. pneumoniae.
A study by Chebotkevitch et al. [58] has revealed that cytostatic treatment was associated with higher CMV and EBV activation rates if the patients had concomitant bacterial infections, thus confi rming a potentially common reason for mixed-type infections in this cohort (Table 5).
To confirm a need for multiplex studies of infectious agents in local samples, we would like to refer our previous study concerning incidence of diff erent opportunistic pathogens in the tissues of heart valves surgically obtained from cardiosurgery patients subjected to valve replacement (Table 4). Of course, this group comprised patients with a story of septic episodes before the valve disorder had developed. However, a number of DNA species (both microbes and viruses) was revealed in 72% of the heart valves from the patients with septic endocarditis thus showing their high rates of exposure to infectious agents. Moreover, a number of the samples tested has shown positivity for both bacterial and herpesvirus DNA, thus suggesting high probability of mixed valves contamination from the circulating blood. Th e enlisted microbial species may originate from skin (Staphylococci, Streptococci, Candida spp), gut (E.Coli), oral cavity (P.Gingivalis, Actinobacillus actinomycetemcomitans, T.Forsythus), then bacteremia.
Similar data on heart valve contamination by multiple bacteria were obtained by Miller et al. [59] using broad-range 16S rDNA PCR and Sanger sequencing on a specifi c fragment of ribosomal DNA extracted from HV tissues. Hence, the existing diagnostic approach to detection of mixed microbial and viral infections in post-transplant patients seems to be rational and feasible. Multiplicity of infectious agents should then correlate with grade of anti-infectious response and risk of severe GvHD. Th is issue may be resolved by detection of group-specifi c microbial and viral markers.

Multiple infections and post-transplant mortality risk

Some previous results suggest increased mortality of HSCT patients with diagnosed multiple bacterial infections. E.g., Trifi lio et al. [50] have reviewed clinical and laboratory data of 901 HSCT recipients (675 auto- and 226, allo-HSCTs). When studying diff erent biomaterials, the authors have identified 179 patients with proven monomicrobial infection and 59 patients (24%) with multiple microorganisms, of which 34 (14%) were classifi ed as polymicrobial infection (PI), and 25 (10%) as multiple distinct episodes of infection (MDE).
Table_4_Incidence_of_infectious_pathogens_in_heart_valves_excised_from_the_patients_with_septic_endocarditis_25.png
Table_5_Incidence_of_herpesvirus_DNA_in_leukemia_patients_with_without_bacteremia_58.png
There were no significant connections between the infection multiplicity, and age, gender, diagnosis, time to engraft ment, response to therapy, etc. However, overall mortality at day +100 post transplant was higher in patients with multiple infectious episodes (P =0.02 in the Kaplan–Meier analysis). These patients also proved to be at an increased risk for acute GVHD and graft failure. In particular, early and frequently presenting Gram-negative infections, and fungal (mostly, Candida) infections were associated with high mortality rates.
Common endogenous viruses (4 herpesviruses, BK polyomavirus, and adenovirus) were studied in allo-HSCT setting by Hill et al. (2017) [60]. Th e workers performed weekly quantitative PCR of blood plasma for viral DNA from 404 allo-HSCT patients. CMV was the most common virus (65% of patients), followed by BKV (54%), HHV-6B (46%), AdV (10%), and EBV (9%). CMV, BKV, and HHV-6B were the viruses most frequently seen in combination. Detection of multiple viruses until day +100 was quite common: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Acute GVHD grade 3-4 was associated with detection of ≥2 viruses. Myeloablative conditioning was associated with a signifi cantly higher risk for ≥3 and ≥4 viruses. Age ≤21 was associated with detection of ≥4 viruses (aHR 2.65). In general, activation of multiple dsDNA viruses had a dose-dependent association with increased mortality aft er allo-HSCT, being independent on immune reconstitution rates and acute GVHD. These data suggest opportunities to improve outcomes with better preventive antiviral strategies.

Prototype test systems for detection of multiple marker pathogens

1. Rapid blood cultures performed by several approved systems, i.e., BD BACTEC, BacT/ALERT 3D, VersaTREK and similar automated devices. They use standard aerobic and anaerobic broth media for samples and provide results within few days and even hours. The data are read by colorimetry, fl uorimetry, or redox changes of the media [61]. Th is approach allows to obtain clinical isolates for the most opportunistic bacteria listed in Table 1.
2. Manual and automated multiplex PCR was proposed by several firms, e.g., Roche, Interlabservice. To systhematize this search, a number of diagnostic panels are developed for detection of commensal/opportunistic infectious pathogens. An example of such multiplex diagnostics was developed by Roche (SeptiFast), as shown in Table 6. Appropriate systemic review and meta-analysis of SeptiFast diagnostic kits in septic patients was performed by Chang et al. (2013) [62]. A total of 34 studies enrolling 6012 patients of suspected sepsis were included. In general, sensitivity and specifi city estimates for combined bacteremia and fungemia outcome were 0.75, and 0.92, respectively. However, the mentioned multiplex PCR system covers only some opportunistic bacteria and fungi, thus missing viruses which are prone for reactivation post-HSCT. Mixed bacterial/ viral PCR assays are still under development. E.g., such multiplex real-time PCR was recently used in order to evaluate CNS infection in infants [63].
Moreover, a diagnostic panel for combined opportunistic infections should include multiplex system for detection of infectious agents in the given local sample (urine, BAL, spinal liquor etc. Such panel should detect the most common bacterial, fungal and viral pathogens (up to 15-20), in order to detect immune defi ciency and its degree (by the number of positive fi ndings per sample). It may be based either on multiplex PCR, or on microarray detection mode.
3. A more general, genus-specifi c PCR assays have been developed, e.g., in Russia. Th ese multiplex real-time PCR systems are aimed for diagnostics of vaginal or gut dysbiosis (resp., Femofl or, and ColonoFlor) detecting up to 16 microbial classes in appropriate biological samples. The ratios of diff erent microbiota members in complex biological materials are calculated, thus allowing quantify the balance of typical microbiota species in, urogenital or intestinal specimens.
4. Looking for endotoxin and surrogate markers in blood plasma, a search for microbial translocation via bloodstream (endotoxin, sCD14) may be applied, using the strategy previously used for studies of HIV infection. 
Table_6_The_SeptiFast_diagnostic_panel_multiplex_PCR_detection.png
5. Detection of total microbial contamination in blood and other normally sterile media. One may use currently developed methods for detection of total microbial DNA, or specific genes for detecting Gram+ and Gram-negative microorganisms [64]. However, most workers use in-house systems for these studies, thus being allowed for research only.
6. Moreover, some antigenic tests are commonly applied in order to detect opportunistic fungal invasions (betagalactomannan) in blood and bronchoalveolar lavage. A search for mixed infections in posttransplant patients should make diagnostics of immune defi ciency more adapted for the needs of medical practice. Detection of severe-grade immune failure may justify usage of some known treatments in order to enhance innate and adaptive immunity in the patient. E.g., detection of polymicrobial infection may be a indication for usage of immunostimulatory cytokines and hemopoietic growth factors in oncohematological patients [65]. Moreover, fi nding of mixed infection in the patient could be a proven indication for G-SF-primed granulocyte transfusions, at least during posttransplant febrile neutropenia [66].

Conclusion

1) A variety of microbes and viruses normally exists on skin and mucosal surfaces of gastrointestinal and urogenital tract.
2) In cases of immune defi ciency of either type, some of the microorganisms extend or activate at other body sites, thus causing opportunistic infections, e.g., interstitial skin abscesses, pneumonias, septicemias, catheter-associated infections. Activation of endogenous viruses (e.g. CMV) is shown to cause local lesions of diff erent organs and tissues.
3) Hence, multiplicity assessment of common infectious biomarkers (bacteria, fungi and viruses) in blood and other unusual body sites may be used to assess grade of immune deficiency in posttransplant patients at early (cytopenic) and late time periods (chronic immune defi ciency).
4) In view of low culture effi ciency for many microorganisms in humans, the panels for common marker infections are developed which will reflect grade of immune defi ciency. It could be based on express bacterial diagnostics, but, mostly, on multiplex real-time PCR of distinct pathogenic species. SeptiFast could be applied to these purposes, with addition of some multiplex PCR tests for detection of viruses, in order to detect combined viral infections. Some antigenic markers (e.g., endotoxin, beta-galactomannan) could be also screened in the HSCT patients, being complementary to the battery of microbiological tests for specifying grade of the patients’ immunodeficiency.

References

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Introduction

Early infections caused by opportunistic microorganisms are quite common aft er allo-HSCT, thus requiring massive and expensive anti-infectious therapy. Massive cytoreductive therapy in cancer is followed by pronounced neutropenia and exhaustion of most lymphoid cell populations [1]. Hence, a total defi ciency of immune response is evident since 1-2 weeks aft er conditioning therapy and HSCT.
The immune failure is characterized by exhaustion of specific humoral factors, e.g., serum immunoglobulins, and decreased counts of immune subpopulations (granulocytes, monocytes, T- and B cell subsets, NKs). Th ese immune indexes reflect general drop and recovery of immune system which may continue for months and years [1]. However, these cellular and humoral markers alone cannot accurately predict clinical risk of local infections at epithelial and mucosal surfaces (pneumonia, cystitis, stomatitis et.). The most hazardous terms for development of bacterial, fungal and viral infections are shown in Fig. 1. Post-transplant deficiencies of certain leukocyte populations seem to correlate with viral, bacterial and fungal infections [2]. Hence, the immune failure may, in principle, assessed via detection of multiple microorganisms which normally live and grow on skin and external mucous surfaces (i.e., oral cavity, pharynx, urethral ways etc). These opportunistic pathogens are normally controlled by the host immune surveillance. However, within weeks aft er HSCT, they tend to colonize deeper sites and areas (e.g., respiratory ways, urogenital tract etc.) causing different aff ections of internal organs. Hence, posttransplant detection of microfl ora in bloodstream and, especially, at local inflammation sites refl ects the degree of immune failure. Appropriate clinical experience was translated into numerous clinical recommendations based on empiric antibiotic treatment during early hematopoietic recovery and febrile neutropenia [3-6]. However, despite routine protection of the post-HSCT patients by broad-spectrum antibiotics, and antiviral treatment for a period of myelopoiesis reconstitution (up to 4 weeks), the rates of local post-transplant infections (e.g., pneumonia) may reach 25% of the HSCT patients [7].
Moreover, unusual sites of infection (typhlitis, perirectal infections and atypical forms of cellulitis) in neutropenic patients were noted decades ago [8]. About 60% of febrile neutropenia in early posttransplant period are classified as fever of unknown origin without distinct infectious pathogen, yet most respond to antibacterial therapy. Unusual sites of infection include typhlitis, perirectal infections and atypical forms of cellulitis.
Later on, a number of immunosuppressive drugs are routinely used after allogeneic HSCT (allo-HSCT) in order to prevent graft -versus-host disease (GvHD). In fact, some
immune populations, especially, adaptive immunity cells, may recover at several months and years post-transplant [1,9]. Hence, a long-term immune defi ciency after SCT is a chronic condition predisposing for opportunistic infections, fungal invasions and activation of endogenous viruses. Such infectious markers could be registered, and the co-infection rates may be used for assessing the grade of immune deficiency in the patient.

Figure_1_Terms_of_the_most_common_infectious_complications_in_HSCT__10.png

Severity and clinical signifi cance of the post-HSCT immune deficiency depends on dosage and expected immunotoxic effects of drugs used in the conditioning protocol, i.e., myeloablative or nonmyeloablative regimen. However, individual damage to the patient’s immune system is modified by the following factors:
• Intensity and number of preceding cytoreductive treatments exhausting the myelo-and lymphopoiesis system;
• Pharmacokinetics of cytotoxic drugs which strongly depends on its administration route, altered liver and kidney functions, and genetic variants aff ecting activation or inactivation of the given drug(s);
• Recipient/donor immune conflict, i.e., partial HLA mismatch, severe graft -versus-host disease [11]. Therefore, personalized evaluation of selected pathogen-specific markers, their multiplicity and biodiversity seems to be an efficient tool for specifying degree of immune defi ciency observed at early and later terms post-transplant.
Hence, the aim of our review is to propose the sets (panels) of latent/opportunistic marker microorganisms as potential markers of immune defi ciency, especially, in post-transplant patients. A number of species- and genus-specifi c multiplex PCR kits, as well as some integral microbial markers could be used for severity evaluation of immune defi ciency when testing peripheral blood samples and locally infected sites.

Table_1_List_of_opportunistic_flora_activated_in_immunocompromised_patients_combined_of_different_studies.png

Incidence and sites of opportunistic infections

The list of opportunistic infections in immunocompromised patients is rather broad, however, limited by distinct microbial, fungal and viral species (see Table 1).
Most bacterial species revealed in immunocompromised patients proved to be opportunistic microorganisms, i.e., those which are present in normal human skin or inhabit normal gut mucosa. The main prerequisites for growth and cytopathic/ infl ammatory effects of opportunistic fl ora are as follows: (1) Penetrating skin barrier; (2) Passing mucosal surfaces; (3) Remote dissemination via bloodstream to lymph nodes, spleen, liver, kidney, lungs; (4) Passing blood/brain barrier. As a result, posttransplant patients develop opportunistic infections of lower respiratory ways, brain, urinary tract, as well as deep abscesses caused by skin or intestinal microorganisms. Moreover, the skin microorganisms may colonize catheter lumen, then proceeding into a bloodstream infection.

Incidence of bacterial pathogens in blood cultures from immunocompromised patients

Detection of bacterial pathogens is normally performed in blood cultures, now using automatic incubation/detection systems. Blood is normally regarded as a sterile medium. However, some episodes of septicemia may occur due to occasional microbial contamination, e.g., major purulent surgery, dental extraction etc. Fungal pathogens may be detected in blood both by beta-galactomannan immunoassay, or by DNA diagnostics. Viral infection/reactivation is routinely detected in whole blood or plasma by means of PCR.
Blood screening for bacterial infections may be an efficient tool of infection monitoring. Blood culture done at a regular interval of at least 5 days. Studies on surveillance blood cultures in HSCT are routinely practicized at many centers. E.g., this approach was tested by for 205 patients admitted for auto- or allo-HSCTs [12]. Bloodstream infection was detected in 14.1% of these patients, which is at lower limits of previously reported rates (12.5-40%). Suprisingly, none of the patients who developed bloodstream infection were diagnosed by surveillance blood cultures. Blood cultures taken in presence of clinical infectious symptoms were much more informative. The most common organisms isolated were coagulasenegative staphylococci, 41/84 (49%) in pure culture and an additional 10 (12%) in mixed cultures. Klebsiella spp. and Enterococci each accounted for 5 episodes (6%) of positive cultures; Viridans group streptococci accounted for 2 episodes (2.4%); and the remaining 25% were caused by different organisms.
In some other countries, the spectrum of cultured bloodborne bacteria is shift ed towards Gram-negative microbes, i.e., Pseudomonas aeruginosa, Klebsiella pneumonia, Esherichia coli, Acinetobacter spp, Enterobacter spp. as reported by an Indian team who analyzed data from 653 pediatric cancer patients undergoing chemotherapy [13].
In a Belarus study, the incidence (top-10) of cultivable bacterial pathogens during the early period aft er HSCT, their culture and identifi cation was assessed with BacT/ALERT-Vitec technique [14]. Th e following rating of microbial detection was obtained (Table 2), with Klebsiella pneumonia and Escherichia coli. making >40% of all clinical microbial isolates.
In immunocompromised patients, herpesviruses, fungal infections,
hepatitis B and C are taken into scope.

Table_2_Detection_rates_for_different_bacterial_pathogens_in_blood_of_HSCT_patients_14.png

A comprehensive randomized analysis of posttransplant infections which occured during 2 years aft er HSCT was reported by Young et al. [15] being performed in the patients from USA BMT centers. A total of 499 patients were under study exhibiting 1347 infection episodes of severe or life-threatening grade documented in 384 (77%) patients. 249 (81%) of these patients had received a BM graft and 183/250 (73%) had received a PBSC graft , at a cumulative two-year incidence of infections of 80-85%. Th e majority of these episodes, 810 (60%), were due to bacteria, with a twoyear cumulative incidence of 72.1% and 62.9% in BM versus PBSC recipients, respectively (P = .003). The cumulative incidence of bacterial infections during the first 100 days was 44.8% for BM vs. 35.0% for PBSC (P= 0.027). The infection rates were slightly more often after BM transplantation than following peripheral PBSCT (Table 3).

Local microbiotes as a source of opportunistic flora

Skin surface

Normal skin harbors hundreds of opportunistic or commensal microorganisms including bacteria, fungi and viruses that compose skin microbiome [16]. T e skin cell populations (keratinocytes, dermal cells, fi broblast, macrophages etc.) release a lot of protective factors and molecules (antimicrobial peptides etc.), to limit excessive microbial growth and colonization [17]. Therefore, survival of the microorganisms on the skin surface suffi ciently depends on their ability to resist the host defense mechanisms [18].
The major fraction is represented by coagulase-negative staphylococci such as S.epidermidis [19, 20] as well as more pathogenic S.aureus [21]. Sebaceous glands are colonized by Propionibacterium acne [22]. Candida yeasts also colonize skin surface, being, however, controlled by appropriate defense mechanisms [23]. In immunocompetent organism, these microflora interact with keratinocytes and local immune cells, thus supporting limiting local growth of skin microflora. However, in immunocompromised and elderly patients, the commensal skin staphylococci, Candida yeasts etc. may be isolated from the sites of extradermal opportunistic infections, like catheter- or pacemaker-associated infl ammatory conditions [24]. Clinical studies show that all the mentioned skin microfl ora could be revealed in blood of the immunocompromised patients (see tables 2, 3).

Oral mucosa

Hundreds microbial and viral species, of them – only up to 5-10 marker microbes, Candida yeasts and viruses (EBV). Dental flora could be revealed in bloodstream, and, especially, in heart valves [25], thus demonstrating a wide opportunity of a distant microbial contamination with opportunistic oral microflora.
Oral mucosa is protected by innate immunity factors, playing a crucial role in the regulation of oral health. E.g., epithelial cells lining oral mucosal surfaces provide not only a physical barrier but also produce diff erent antimicrobial peptides, including human β-defensins (hBDs), lactoferrin, secretory leukocyte protease inhibitor (SLPI), and various cytokines [26]. Specific IgA’s provide specifi c immune response. There are a lot of oral co-infections revealed in HIV-infected patients, such as human herpesvirus 6 and 8 (HHV-6, HHV-8), herpes simplex virus 1/2 (HSV-1/2), EBV, and human papilloma virus (HPV). Colonization with Candida species is also quite common in these patients. Oral hairy leukoplakia caused by Epstein Barr virus is a typical infection associated with immune suppression [27].
Non-tuberculosis mycobacteria (non-MBT) are also common among oral microfl ora [28]. When examining healthy persons, the non-MBT DNA was detected in the nostrils of all 10 subjects, in buccal mucosa of 8 subjects, in the oropharynx of 7 subjects, and in the dental plaques of 5 subjects.

Table_3_Incidence_of_infectious_pathogens_revealed_over_2_years_after_allo-HSCT_15.png

Oropharyngeal mucosa

In a group of 82 patients with head-and-neck cancer treated by chemo/radiotherapy, the authors studied subgingival biofilm samples, oral lavages and whole saliva samples obtained to microbiologically analyze the eff ects of cancer treatments (1-year follow-up). As compared to surgically treated patients, an increased prevalence of P. gingivalis, T. forsythia, S. mutans and Candida species was observed in the treated areas, thus demonstrating immunosuppressive action of the cytotoxic therapy [29]. Signifi cance of these fi ndings in oncohematology was evaluated by Schuurhuis et al. [30] after cytostatic treatment of 28 leukaemic and 35 auto-HSCT patients. Acute oral foci of infection were found in 2 leukaemic (7%) and 2 ASCT patients (6%), and chronic oral foci of infection in 24 leukaemic (86%) and 22 ASCT patients (63%). Positive blood cultures with microorganisms potentially originating from the oral cavity occurred in 7 patients during treatment, but did not correlate with development of infectious complications.
Nasopharyngeal area is characterized by interactions between adenoid microorganisms [31]. Adenoid microbiota plays an important role in the development of various infectious and non-infectious diseases of the upper airways, such as otitis media, adenotonsillitis, rhinosinusitis and adenoid hypertrophy. Studies have suggested that adenoids could act as a potential reservoir of opportunistic pathogens. However, previous bacterial surveys of adenoids were mainly culture based and therefore might only provide an incomplete and potentially biased assessment of the microbial diversity. To develop an in-depth and comprehensive understanding of the adenoid microbial communities and test the ‘pathogen reservoir hypothesis’, we carried out a 16S rRNA based, culture-independent survey of bacterial communities on 67 human adenoids removed by surgery. Our survey revealed highly diverse adenoid bacterial communities distinct from those of other body habitats. Despite large interpersonal variations, adenoid microbiota shared a core set of taxa and can be classified into at least five major types based on its bacterial species composition.

Broncho-alveolar mucosa

Colonization of mucosal surfaces with autofl ora (cocci, yeast fungi and molds, latent viruses), has an important stimulatory effect on whole-body development of immune responses [32]. However, the opportunistic local microfl ora in immunocompromised patients may extensively grow on the mucous surfaces in association with more or less severe clinical symptoms, e.g., opportunistic gramnegative bacilli (Enterobacteriaceae, Pseudomonas, Acinetobacter spp.). Moreover, relatively virulent serovars of M. avium complex, like as other non-MBT bacteria, may colonize the bronchial and intestinal mucosal surfaces of healthy individuals in immunocompromised conditions [33]. The same could be found with fungal outgrowth and Toxoplasma activation.

Gastrointestinal tract (GIT)

Extensive gut microbiota contains hundreds of microbial species of which only few are able to grow on media used in clinical laboratories. Th e most detectable opportunistic infectious pathogens are: E.coli, C. diffi cile, Enterococcus fecalis/faecium, etc. Meanwhile, most microorganisms (up to 70%) are fastidious or non-culturable species which may be revealed only by DNA or protein diagnostics.
As reviewed by Callejas-Díaz and Gea-Banacloche [34], the C. difficile infection (CDI) is very frequent at early terms aft er hematopoietic stem cell transplantation (HSCT) – between 6 % and 20% of HSCT recipients during the first year mostly aft er allo (allo-HSCT), thus being a promising bacterial marker of intestinal dysbiosis. For diagnostics, molecular testing for the toxin genes by (PCR) is performed, along enzyme immunoassays (EIA). It correlates with worsening of bowel graft versus host disease (GVHD).
Early after cytoreductive therapy one may observe severe damage of chemosensitive intestinal mucosa [35]. Intestinal microflora undergoes sufficient changes within several days aft er intensive chemotherapy and/or HSCT. At present time, these shift s in microfl ora subsets are eff ectively detected by means of multiplex high-throughput PCR followed by sequencing of the obtained genome fragments and computer-assisted differentiation of these genome segments. The mentioned mucosal damage and infl ammation is associated with a reduced biodiversity of intestinal microfl ora developing aft er HSCT (see a review by [36] Kucher et al., 2017). In turn, altered intestinal microbiota aft er HSCT is shown to be an important risk factor of severe GVHD [37]. Hence, the interactions between gut microbial antigens and immune cells are enhanced early aft er cytotoxic chemotherapy.

Gut bacterial translocation: lessons from HIV infection

A gradually developing immune defi ciency in HIV infection, while bearing other pathogenetic features, is known to be associated with a number of concomitant infectious complications (HCV, tuberculosis etc.) and a variety of somatic comorbidities [38] (Currier, Havlir 2005). Opportunistic infections are commonly associated with HIV infection. E.g., some malignant lymphomas in HIV patients may occur due to activation of latent Epstein-Barr virus and, probably, HHV8 [39], like as secondary lymphomas in post-transplant immunocompromised patients. Bacterial opportunistic infections, such as Pneumocystis jiroveci, Toxoplasma gondii, and Mycobacterium avium threaten the patients at CD4+ T cell counts below 200 cells/mcL [40]. However, exact critical levels for CD4+ cells are quite varying. Th erefore, a multiplex detection of opportunistic pathogens would be performed, in order to assess real individual degree of clinical immunodeficiency.
In HIV-infection, the intestinal damage and microflora changes are followed by activation of monocytes and residual T cells, due to the so-called bacterial translocation, i.e., penetration of gut bacterial cell components from injured intestinal wall to bloodstream [41]. Th e bacterial translocation is registered as endotoxin or soluble monocyte (CD14) antigen detected in blood serum. Th is “subseptic” condition is recognizable in HIV-infected patients, especially, those receiving suboptimal antiretroviral therapy. According to this opinion, the damaged gut epithelium allows diff usion of bacterial antigens which stimulate monocytes, IL-17 and IL-22-secreting cells.
The mentioned markers of microbial translocation in HIV infection showed some pathogenetic links with quantitative shift s in gut microfl ora, as shown by next-generation sequencing of bacterial 16S rRNAs which identifies hundreds of intestinal microbial species [42]. The analysis of gut microbial diversity showed a more restricted microbiota spectrum, both at baseline and aft er antiretroviral therapy (ART). Th e skewed biodiversity of gut flora correlated with decreased CD4 T-cell counts and increased markers of microbial translocation and monocyte activation. Moreover, bacterial lipopolysaccharide (LPS) and soluble CD14 (monocyte antigen) concentrations in blood plasma are shown to predict mortality and disease progression in subjects with HIV infection [41]. Intestinal epithelial damage and altered gut microfl ora in allogeneic HSCT are also well proven [36]. Hence, the markers of bacterial translocation may be potentially eff ective in diagnostics of any immune deficiency, aiming to evaluate possible damage to the gut mucosa and altered immune response aft er HSCT.

Urine and urogenital ways

The urine is sterile in healthy children. Normally, the urinary epithelium is protected by specifi c antibacterial factors, e.g., Tamm-Horsfall protein, lactoferrin, defensins etc [43]. With age, however, the urinary system is colonized in ascending manner with microfl ora from skin (Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococci, Candida) and gut (Escherichia coli, Enterobacter, Enterococcus, Proteus mirabilis). However, hematogenic infections are also possible due to Staph. aureus, Haemophilus infl uenza etc., thus causing chronic cystitis and pyelitis oft en complicated by infectious kidney stone formation [44].
Protozoic infections, e.g.., Toxoplasma gondii, may be also
revealed in urogenital ways over 1st month aft er HSCT [45], with rapid disappearance from urine cells upon hematopoiesis reconstitution.
Early after hematopoietic transplantation, hemorrhagic cystitis is developing in most cases, mainly, due to urothelial damage by toxic cytostatic treatment. Meanwhile, activation of BK and JC viruses (latent polyomaviruses in urothelial cells) are additional markers of hemorrhagic cystitis at the terms of 1-2 months which are found in urine at early terms post HSCT [46].

Catheter-associated urinary infection is a special issue in immunodeficient patients. It may be caused by P.mirabilis migrating from gut [47], or other urease-positive microbes migrating, mainly, from skin. Multiple bacterial species co-exist in microbial biofilms growing on the bladder epithelium and in catheter lumen [48].

Mixed infections in immunocompromised patients

Bacterial/fungal co-infections

Combined infections with bacterial and/or fungal agents after cytotoxic treatment in post-transplant patients were described in many works. However, the mechanisms of their simultaneous emergence are not clear yet. Acute failure of protective immune mechanisms could be the most plausible explanation for these posttransplant conditions. Moreover, multiple occurence of several pathogens in a single biological sample (i.e., blood, urine, or saliva) in HSCT patients may be promoted by a symbiotic microbial growth, thus causing a co-infection. Polymicrobial complexes grown as biofilms are regularly observed in local infections, such as dental caries and parodontitis, otitis media, diabetic foot wounds etc. [49]. Similar growth of bacterial associations is typical to blood catheter-associated infections, or urinary catheter
contamination. Hence, bacterial co-infections are not rare and should be detected in HSCT setting.
The incidence of bacterial and/or fungal infections was assessed in a group of 901 stem cell transplant recipients [50]. Of them, 237 patients (27%) had microbiologically documented microorganisms isolated, including 34 patients (14%) simultaneously infected with multiple microorganisms. Th e co-infected patients seem to be at an increased risk for aGvHD and delayed graft functioning.
The same workers evaluated infection by Clostridium difficile, a common opportunistic microbe, and its association with other infectious agents [51]. Among 822 consecutive autologous and allogeneic HCST recipients, 85 cases (10.3%) of C.diffi cile-associated disease were identified. Significant associations were found between C.diffi cile detection, and neutropenic fever, as well as with bacterial coinfection, and presence of vancomycin-resistant Enterococcus faecium (VRE) colonization. Allo-HSCT patients with C.diffi cile-associated disease showed higher rates of severe gastrointestinal aGvHD.

Viral co-infections

Combined post-transplant viral co-infections are also quite common, thus suggesting their treatment by injection of the virus-specifi c immune lymphocytes [52]. Simultaneous activation of several common endogenous viruses was shown by a multiplex PCR system for 13 common viral species in some patients before allo-HSCT, while being increased within 1st month aft er transplant [53].
Simultaneous co-activation of herpesviruses is a regular finding. E.g., in a Polish study [54] 142 allo-HSCT recipients were tested for 3 herpesviruses (CMV, HHV-6 and HHV-7) for the fi rst 3 months. Reactivation of more than one virus was identifi ed in 31% of analysed patients, with CMV being most common, thus increasing risk of specifi c complications posttransplant.
In a recent study by Koskenvuo et al. [55] the authors studied 23 viruses in 53 paediatric patients up to 3 months aft er allo- HSCT. Interestingly, polyomaviruses predominated over herpesviruses thus showing their common incidence in the immunodefi cient cohort. Of them, 13 patients (25%) had viraemias by multiple viruses. Presence of viral co-infections was signifi cantly associated with aGvHD and steroid use, the factors known to suppress immune functions.
There are specific combinations of certain viral species in post-HSCT patients. According to results obtained by Jeulin et al. [56], HHV6 infection did not correlate with CMV, HSV, EBV. Meanwhile, adenovirus infection and HHV-6 activation seemed to be related in their posttransplant replication.

Mixed infectious pathogens

A large meta-analysis was performed by Klein et al. [57] based on a systematic search of different medical databases on infl uenza virus-associated infections. It covered 27 studies including 3215 participants, with widely varying coinfection rates ranging from 2% to 65%. Most common coinfecting species were S. pneumoniae and Staph. aureus, which accounted for 35% and 28% of infections followed by P.aeruginosa, S. pyogenes, H. infl uenzae,.K. pneumoniae, and M. pneumoniae.
A study by Chebotkevitch et al. [58] has revealed that cytostatic treatment was associated with higher CMV and EBV activation rates if the patients had concomitant bacterial infections, thus confi rming a potentially common reason for mixed-type infections in this cohort (Table 5).
To confirm a need for multiplex studies of infectious agents in local samples, we would like to refer our previous study concerning incidence of diff erent opportunistic pathogens in the tissues of heart valves surgically obtained from cardiosurgery patients subjected to valve replacement (Table 4). Of course, this group comprised patients with a story of septic episodes before the valve disorder had developed. However, a number of DNA species (both microbes and viruses) was revealed in 72% of the heart valves from the patients with septic endocarditis thus showing their high rates of exposure to infectious agents. Moreover, a number of the samples tested has shown positivity for both bacterial and herpesvirus DNA, thus suggesting high probability of mixed valves contamination from the circulating blood. Th e enlisted microbial species may originate from skin (Staphylococci, Streptococci, Candida spp), gut (E.Coli), oral cavity (P.Gingivalis, Actinobacillus actinomycetemcomitans, T.Forsythus), then bacteremia.
Similar data on heart valve contamination by multiple bacteria were obtained by Miller et al. [59] using broad-range 16S rDNA PCR and Sanger sequencing on a specifi c fragment of ribosomal DNA extracted from HV tissues. Hence, the existing diagnostic approach to detection of mixed microbial and viral infections in post-transplant patients seems to be rational and feasible. Multiplicity of infectious agents should then correlate with grade of anti-infectious response and risk of severe GvHD. Th is issue may be resolved by detection of group-specifi c microbial and viral markers.

Multiple infections and post-transplant mortality risk

Some previous results suggest increased mortality of HSCT patients with diagnosed multiple bacterial infections. E.g., Trifi lio et al. [50] have reviewed clinical and laboratory data of 901 HSCT recipients (675 auto- and 226, allo-HSCTs). When studying diff erent biomaterials, the authors have identified 179 patients with proven monomicrobial infection and 59 patients (24%) with multiple microorganisms, of which 34 (14%) were classifi ed as polymicrobial infection (PI), and 25 (10%) as multiple distinct episodes of infection (MDE).
Table_4_Incidence_of_infectious_pathogens_in_heart_valves_excised_from_the_patients_with_septic_endocarditis_25.png
Table_5_Incidence_of_herpesvirus_DNA_in_leukemia_patients_with_without_bacteremia_58.png
There were no significant connections between the infection multiplicity, and age, gender, diagnosis, time to engraft ment, response to therapy, etc. However, overall mortality at day +100 post transplant was higher in patients with multiple infectious episodes (P =0.02 in the Kaplan–Meier analysis). These patients also proved to be at an increased risk for acute GVHD and graft failure. In particular, early and frequently presenting Gram-negative infections, and fungal (mostly, Candida) infections were associated with high mortality rates.
Common endogenous viruses (4 herpesviruses, BK polyomavirus, and adenovirus) were studied in allo-HSCT setting by Hill et al. (2017) [60]. Th e workers performed weekly quantitative PCR of blood plasma for viral DNA from 404 allo-HSCT patients. CMV was the most common virus (65% of patients), followed by BKV (54%), HHV-6B (46%), AdV (10%), and EBV (9%). CMV, BKV, and HHV-6B were the viruses most frequently seen in combination. Detection of multiple viruses until day +100 was quite common: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Acute GVHD grade 3-4 was associated with detection of ≥2 viruses. Myeloablative conditioning was associated with a signifi cantly higher risk for ≥3 and ≥4 viruses. Age ≤21 was associated with detection of ≥4 viruses (aHR 2.65). In general, activation of multiple dsDNA viruses had a dose-dependent association with increased mortality aft er allo-HSCT, being independent on immune reconstitution rates and acute GVHD. These data suggest opportunities to improve outcomes with better preventive antiviral strategies.

Prototype test systems for detection of multiple marker pathogens

1. Rapid blood cultures performed by several approved systems, i.e., BD BACTEC, BacT/ALERT 3D, VersaTREK and similar automated devices. They use standard aerobic and anaerobic broth media for samples and provide results within few days and even hours. The data are read by colorimetry, fl uorimetry, or redox changes of the media [61]. Th is approach allows to obtain clinical isolates for the most opportunistic bacteria listed in Table 1.
2. Manual and automated multiplex PCR was proposed by several firms, e.g., Roche, Interlabservice. To systhematize this search, a number of diagnostic panels are developed for detection of commensal/opportunistic infectious pathogens. An example of such multiplex diagnostics was developed by Roche (SeptiFast), as shown in Table 6. Appropriate systemic review and meta-analysis of SeptiFast diagnostic kits in septic patients was performed by Chang et al. (2013) [62]. A total of 34 studies enrolling 6012 patients of suspected sepsis were included. In general, sensitivity and specifi city estimates for combined bacteremia and fungemia outcome were 0.75, and 0.92, respectively. However, the mentioned multiplex PCR system covers only some opportunistic bacteria and fungi, thus missing viruses which are prone for reactivation post-HSCT. Mixed bacterial/ viral PCR assays are still under development. E.g., such multiplex real-time PCR was recently used in order to evaluate CNS infection in infants [63].
Moreover, a diagnostic panel for combined opportunistic infections should include multiplex system for detection of infectious agents in the given local sample (urine, BAL, spinal liquor etc. Such panel should detect the most common bacterial, fungal and viral pathogens (up to 15-20), in order to detect immune defi ciency and its degree (by the number of positive fi ndings per sample). It may be based either on multiplex PCR, or on microarray detection mode.
3. A more general, genus-specifi c PCR assays have been developed, e.g., in Russia. Th ese multiplex real-time PCR systems are aimed for diagnostics of vaginal or gut dysbiosis (resp., Femofl or, and ColonoFlor) detecting up to 16 microbial classes in appropriate biological samples. The ratios of diff erent microbiota members in complex biological materials are calculated, thus allowing quantify the balance of typical microbiota species in, urogenital or intestinal specimens.
4. Looking for endotoxin and surrogate markers in blood plasma, a search for microbial translocation via bloodstream (endotoxin, sCD14) may be applied, using the strategy previously used for studies of HIV infection. 
Table_6_The_SeptiFast_diagnostic_panel_multiplex_PCR_detection.png
5. Detection of total microbial contamination in blood and other normally sterile media. One may use currently developed methods for detection of total microbial DNA, or specific genes for detecting Gram+ and Gram-negative microorganisms [64]. However, most workers use in-house systems for these studies, thus being allowed for research only.
6. Moreover, some antigenic tests are commonly applied in order to detect opportunistic fungal invasions (betagalactomannan) in blood and bronchoalveolar lavage. A search for mixed infections in posttransplant patients should make diagnostics of immune defi ciency more adapted for the needs of medical practice. Detection of severe-grade immune failure may justify usage of some known treatments in order to enhance innate and adaptive immunity in the patient. E.g., detection of polymicrobial infection may be a indication for usage of immunostimulatory cytokines and hemopoietic growth factors in oncohematological patients [65]. Moreover, fi nding of mixed infection in the patient could be a proven indication for G-SF-primed granulocyte transfusions, at least during posttransplant febrile neutropenia [66].

Conclusion

1) A variety of microbes and viruses normally exists on skin and mucosal surfaces of gastrointestinal and urogenital tract.
2) In cases of immune defi ciency of either type, some of the microorganisms extend or activate at other body sites, thus causing opportunistic infections, e.g., interstitial skin abscesses, pneumonias, septicemias, catheter-associated infections. Activation of endogenous viruses (e.g. CMV) is shown to cause local lesions of diff erent organs and tissues.
3) Hence, multiplicity assessment of common infectious biomarkers (bacteria, fungi and viruses) in blood and other unusual body sites may be used to assess grade of immune deficiency in posttransplant patients at early (cytopenic) and late time periods (chronic immune defi ciency).
4) In view of low culture effi ciency for many microorganisms in humans, the panels for common marker infections are developed which will reflect grade of immune defi ciency. It could be based on express bacterial diagnostics, but, mostly, on multiplex real-time PCR of distinct pathogenic species. SeptiFast could be applied to these purposes, with addition of some multiplex PCR tests for detection of viruses, in order to detect combined viral infections. Some antigenic markers (e.g., endotoxin, beta-galactomannan) could be also screened in the HSCT patients, being complementary to the battery of microbiological tests for specifying grade of the patients’ immunodeficiency.

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Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.<br> В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. 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государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
2Университетский госпиталь Тампере, Финляндия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20001" ["VALUE"]=> array(2) { ["TEXT"]=> string(4147) "<p style="text-align: justify;"> Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.<br> В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4075) "

Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.
В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита.

Ключевые слова

Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы.

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2Tampere University Hospital, Tampere, Finland" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20005" ["VALUE"]=> array(2) { ["TEXT"]=> string(2111) "<p style="text-align: justify;"> Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.<br> Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms. </p> <h2 style="text-align: justify;"></h2>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2017) "

Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.
Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade.

Keywords

Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms.

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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20005" ["VALUE"]=> array(2) { ["TEXT"]=> string(2111) "<p style="text-align: justify;"> Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.<br> Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms. </p> <h2 style="text-align: justify;"></h2>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2017) "

Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.
Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade.

Keywords

Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2017) "

Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.
Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade.

Keywords

Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms.

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" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20001" ["VALUE"]=> array(2) { ["TEXT"]=> string(4147) "<p style="text-align: justify;"> Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.<br> В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4075) "

Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.
В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита.

Ключевые слова

Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы.

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Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.
В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита.

Ключевые слова

Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы.

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Introduction

At the present time, WHO Classifi cation of Myeloid Neoplasms includes a range of myeloproliferative Neoplasms (MPN). Of them, most common are: (1) chronic myeloid leukemia (CML, BCR-ABL1+); (2) chronic neutrophilic leukemia (CNL); (3) polycythemia vera (PV); (4) primary myelofi brosis (PMF); (5) essential thrombocythemia (ET), mastocytosis. A group of myelodysplastic/myeloproliferative
Neoplasms (MDS/MPN) includes chronic myelomonocytic leukemia (CMML); atypical CML (aCML, BCR-ABL1-); juvenile myelomonocytic leukemia (JMML). Some MDS/MPN cases remain unclassifiable.
According to EBMT statistics 2015, 39% of allo HSCTs are performed in acute myeloid leukemia (AML), and 15%, for MDS/MPN (8000 transplants per year) [1]. Only 2% of BMTs are made in chronic myeloid leukemia (CML), mostly, in advanced clinical forms, thus showing increasing efficiency of tyrosine kinase inhibitors (TKI) therapy in chronic phase CML. Th erefore, current challenges for allogeneic SCT in CML in the era of TK inhibitors are worth of discussion. The present review summarizes current strategies for treatment of different myeloid neoplasias.

Current strategies of CML treatment

Previously, allo-HSCT was the only curative treatment for CML, and CML was the most frequent indication for Allo SCT. With Imatinib, TKI became the frontline therapy for newly diagnosed CML. E.g. the IRIS Program “International Randomized Study of Interferon and STI571”, has demonstrated superiority of Imatinib versus interferon treatment in CML therapy [2]. Th erefore, transplant activities in this field dropped quickly, and allo-SCT moved from frontline to second, third-line therapy. In some special situations, the reasons for allo-SCT are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis, BC).
Efficiency of allogeneic HSCT (Allo SCT) in chronic myeloid leukemia in the Imatinib era was evaluated in a subgroup of the Randomized German CML Study IV. Appropriate survival probability was evaluated showing that the patients with elective allo-SCT in fi rst CP (n=20; group I) and those who underwent transplantation aft er Imatinib failure in first CP (n=36; group II) had a comparable 3-year survival probability of 88% and 94%, respectively (CI: 69.3-98.7 and 83.9-99.4). The patients who underwent transplantation in advanced disease (n=28; group III) had a 3-year survival probability of only 59% (CI: 38.6-77.5). Matched pair analysis for 53 patients who underwent transplantation compared to 106 matched Imatinib-treated patients also did not show any differences thus suggesting similar effi ciency of the both treatment strategies [3].
Management of CML blast crisis and TKI usage could be dependent on some proven facts [4]:
• TKI moderately improves OS median survival for <1 year.
• Choice of TKI should be directed by mutational profi le.
• Best prognosis is suggested in patients who achieve 2nd CP.
• In general, allo-SCT improved survival.
As shown by Hehlmann et al [4], the CML IV study with Imatinib treatment in patients with blast crisis CML has shown a survival of ca. 20% over 10 years, as compared to <5% survival in pre-Imatinib era. Distinct improvement in OS and event-free survival (EFS) was shown in BC CML patients when using combination of allo-SCT and TKIs compared to only TKIs. E.g., the median OS in the TKI+allo-HSCT group (20 months, 95% CI 1-74 months) was signifi cantly longer than that in the TKIs group (4.5 months; 95% CI 3.5-5.5 months). Similarly, the 4-year OS rates in the TKIs+allo-HSCT group were signifi cantly higher than those in the TKI group (50.0 vs 10.0%, P=0.016). (b) Th e median EFS in the TKIs+allo-HSCT group (18 months, 95% CI 1-72.7 months) was also signifi cantly longer than in the TKIs group (3 months; 95% CI 1.9-4.0 months). The 4-year EFS rates in the TKIs+allo-HSCT group were signifi cantly higher than those in the TKIs group (50.0 vs 10.0%, P=0.002) (Jiang H 2014). It should be noted that 2/3 of the donors were haploidentical.
Improved progression-free survival (up to 60%) was registered in the patients with advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors [5]. Th us, the donor type may infl uence survival for transplanted patients with advanced CML.

Primary Myelofibrosis

To take into account variable clinical course of a myeloproliferative disorder, the Lille scoring system provides some prognostic criteria, as mentioned:
• The “low” group (Hb-level > 10 g/dL and WBC between 4 and 30 /nL (median OS 93 months);
• The “intermediate” group (Hb-level < 10 g/dL or WBC > 30/< 4 nL (median OS 26 months);
• The “high” group (Hb-level < 10 g/dL and WBC < 4 /nL or > 30 /nL (median OS 13 months).

Table_1_Summary_of_IPSS_criteria.png
Table_2_Clinical_outcomes_of_reduced-intensity_conditioning_RIC_regimens_in_MF_patients.png

Reduced conditioning regimen when transplanting the MF patients yielded good results in terms of non-relapse-related mortality (NRM) and OS levels (Table 2).

Figure_1_Survival_probabilities_for_the_4_risk_subgroups_in_MF_DIPSS_risk_low_int-1_int-2_high__DIPSS_score_is_taken_at.png

Efficiency of SCT proved to depend on initial risk score, e.g., assessed by DIPSS. As seen from Fig. 1, SCT in advanced disease prolongs survival in high-risk patients. Allogeneic SCT option for myelofi brosis with leukemic transformation was evaluated in EBMT study. Th is involved 1048 cases in allo SCT; 46 patients, with leukemic transformation [11]. The cumulative incidence of treatment-related mortality at 1 year was 28%, and of relapse at 3 years was 47%. The 3-year progression-free (PFS) and overall survival (OS) rates were 26% and 33%, respectively. Hence, allogeneic SCT can cure myelofi brosis patients transformed to leukemia.
Molecular genetic markers, i.e., multiple gene expression profile of leukemic cells may be predictive for the outcome in myelofi brosis patients aft er allogeneic transplantation, especially overexpression of JAK2 and ASXL1 gene, as shown by Kröger et al. [12].
Our previous studies concerned treatment of the myelofibrosis patients who relapsed aft er fi rst allo-SCT [13]. The following treatment consisted of either donor lymphocyte infusions, or second allo-SCT from an alternative donor. A group of 30 patients with relapsed myelofi brosis treated by donor lymphocyte infusions and/or second allo-SCT showed good 5-year overall survival rates. I.e., 2nd SCT caused complete remission in 14 out of 17 patients (82%).
Ruxolitinib, a JAK2 inhibitor, is a promising therapeutic option for MF patients during peritransplant period [14]. Feasibility and safety of Ruxolitinib treatment was tested in Hamburg-Eppendorf clinic and Ruxolitinib was used in 12 patients at a dose of 10+10 mg. Severe GVHD was observed only in 1 case of 12; overall survival was 100% after short follow-up (a mean of 163 days) [15].

Chronic Myelomonocytic Leukemia (CMML)

CMML is another chronic myeloproliferative disorder. Different prognostic scores for CMML were developed in MD Anderson, Mayo Clinics, a Düsseldorf scoring etc. CMML-specifi c prognostic scoring system was the subject to external validation being tested in 578 patients, as seen from Table 3.
Progression-free survival (PFS) in CMML was assessed by a group from the MD Anderson Cancer Center [17]. Th e study was performed in 83 CMML patients. In 78 cases a pre-transplant induction treatment was applied, with 37 patients receiving hypomethylating agents and cytotoxic chemotherapy in 41 cases. Patients treated with a hypomethylating agent had a lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P=.03), improved progression-free survival (PFS), with no detectable diff erence in treatment-related mortality at 1 year post-HST. In summary, their data support the value of hypomethylating agents administered before allo-SCT, in order to achieve morphologic remission.
Results in CMML patients treated with allo-HSCT depend on the pre-transplant risk scores (HCT-specifi c CPSS), as shown by IBMTR group in 209 patients [16]. I.e., adjusted disease-free survival, starting at the time of transplant, at a median follow-up of 51 months. CPSS score, Karnofsky performance status, and graft source proved to be signifi cant predictors of survival. Th e patients with intermediate-2/high risk had a nearly 2-fold increased risk of death aft er relapse compared to those with low/intermediate-1 CPSS scores.
Table_3_Prognostic_scales_in_CMML_a_summary_of_different_studies_16.png
An EBMT study of relapse-free survival (left ) and overall survival (right) according to disease stage (CR versus no-CR) at transplantation was performed in a group of 513 CMML patients The subjects transplanted in CR had lower probability for non-relapse death (P=0·002) and longer relapse-free and OS (P=0·001 and P=0·005, respectively). In multivariate analysis the only signifi cant prognostic factor for survival was the presence of CR at transplantation (P= 0·005). Hence, patients transplanted in CR had signifi cantly longer relapse-free survival and significantly longer overall survival [18].
Moreover, both RFS and OS diff ered according to transplantation within 12 months or aft er 12 months aft er diagnosis of CMML. Early transplant was associated with significantly higher survival rates.

Systemic mastocytosis

Systemic mastocytosis (SM) is a myeloproliferative disorder with clonal expansion of mast cell precursors in various organs [19]. It is a heterogeneous group by the clinical course and malignant precursor biology: it may indolent do not shorten life expectancy. Advanced SM may proceed as Mast Cell Leukemia (MCL), SM with associated hematologic nonmast cell lineage diseases, or aggressive systemic mastocytosis (ASM). Survival rates from months to a few years despite cytoreductive therapy were not too high.
I.e., the 3-year OS and PFS in the total group of mastocytic malignancies are about 50-60% etc. [20]. Allo-SCT is a method of choice in advanced systemic mastocytosis. However, some somatic mutations predispose for inferior clinical outcome in this disorder, i.e., ASXL1 or CBL mutations (Fig. 2). Th ese molecular markers comprise a distinct risk factor when treating ASM [21].
Atypical chronic myeloid leukemia (aCML) with BCR-ABL1-negativity is considered a special clinical entity characterized by leukocytosis, aff ected granulocyte myeloid precursors, dysgranulopoiesis, PH-negativity, SETBP1 expression. Mutated RAS was found in some cases (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]). Compared with unclassifi ed MDS/MPN-U, patients with aCML showed a significant inferior OS (12.4 months, 95% CI [9.0-16.1] vs 21.8 months, 95% CI [17.6-28.8]) and ACL-free survival (11.2 months, 95% CI [7.0-13.5] vs 18.9 months, 95% CI [12.3-26.3]), as reported by Wang et al. [22].
Age- and risk-score dependent survival in atypical CML were assessed as fi ve-year overall survival following allogeneic transplantation in 42 patients from an EBMT study [23]. As expected, the older age of aCML patients (<45 years) was associated with suffi ciently lower 5-year survival (<40%) as compared to younger patients.
Figure_2_Molecular_risk_factors_determine_survival_rates_in_systemis_mastocytosis.png

Summary

As based on clinical experience and current multicentric studies, some recommendations may be given on WHOM and WHEN to transplant, as follows:
In CML:
HSCT: in 1st complete remission – TKI failure, TKI intolerance, acceleration phase, blast crisis: TKI ± chemoinduction is performed
In Myelofi brosis:
HSCT at DIPPS INTERMED 2 and high risk scores at INTERMED 1 and with high risk features
In CMML:
Early HST, pre-treatment with hypomethylating agents
In Mastocytosis:
HSCT: in systemic mastocytosis, AHNMD (SM with associated non-mast cell)
in ASM (Aggressive Systemic Mastocytosis)
in MCL (Mast Cell Leukemia)

Conflict of interest

No conflict of interest is declared.

References

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18. Symeonidis A, van Biezen A, de Wreede L, Piciocchi A, Finke J, Beelen D, Bornhäuser M, Cornelissen J, Volin L, Muft i G, Chalandon Y, Ganser A, Bruno B, Niederwieser D, Kobbe G, Schwerdtfeger R, de Witte T, Robin M, Kröger N; Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Br J Haematol. 2015 Jul 26. doi: 10.1111/bjh.13576.
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Introduction

At the present time, WHO Classifi cation of Myeloid Neoplasms includes a range of myeloproliferative Neoplasms (MPN). Of them, most common are: (1) chronic myeloid leukemia (CML, BCR-ABL1+); (2) chronic neutrophilic leukemia (CNL); (3) polycythemia vera (PV); (4) primary myelofi brosis (PMF); (5) essential thrombocythemia (ET), mastocytosis. A group of myelodysplastic/myeloproliferative
Neoplasms (MDS/MPN) includes chronic myelomonocytic leukemia (CMML); atypical CML (aCML, BCR-ABL1-); juvenile myelomonocytic leukemia (JMML). Some MDS/MPN cases remain unclassifiable.
According to EBMT statistics 2015, 39% of allo HSCTs are performed in acute myeloid leukemia (AML), and 15%, for MDS/MPN (8000 transplants per year) [1]. Only 2% of BMTs are made in chronic myeloid leukemia (CML), mostly, in advanced clinical forms, thus showing increasing efficiency of tyrosine kinase inhibitors (TKI) therapy in chronic phase CML. Th erefore, current challenges for allogeneic SCT in CML in the era of TK inhibitors are worth of discussion. The present review summarizes current strategies for treatment of different myeloid neoplasias.

Current strategies of CML treatment

Previously, allo-HSCT was the only curative treatment for CML, and CML was the most frequent indication for Allo SCT. With Imatinib, TKI became the frontline therapy for newly diagnosed CML. E.g. the IRIS Program “International Randomized Study of Interferon and STI571”, has demonstrated superiority of Imatinib versus interferon treatment in CML therapy [2]. Th erefore, transplant activities in this field dropped quickly, and allo-SCT moved from frontline to second, third-line therapy. In some special situations, the reasons for allo-SCT are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis, BC).
Efficiency of allogeneic HSCT (Allo SCT) in chronic myeloid leukemia in the Imatinib era was evaluated in a subgroup of the Randomized German CML Study IV. Appropriate survival probability was evaluated showing that the patients with elective allo-SCT in fi rst CP (n=20; group I) and those who underwent transplantation aft er Imatinib failure in first CP (n=36; group II) had a comparable 3-year survival probability of 88% and 94%, respectively (CI: 69.3-98.7 and 83.9-99.4). The patients who underwent transplantation in advanced disease (n=28; group III) had a 3-year survival probability of only 59% (CI: 38.6-77.5). Matched pair analysis for 53 patients who underwent transplantation compared to 106 matched Imatinib-treated patients also did not show any differences thus suggesting similar effi ciency of the both treatment strategies [3].
Management of CML blast crisis and TKI usage could be dependent on some proven facts [4]:
• TKI moderately improves OS median survival for <1 year.
• Choice of TKI should be directed by mutational profi le.
• Best prognosis is suggested in patients who achieve 2nd CP.
• In general, allo-SCT improved survival.
As shown by Hehlmann et al [4], the CML IV study with Imatinib treatment in patients with blast crisis CML has shown a survival of ca. 20% over 10 years, as compared to <5% survival in pre-Imatinib era. Distinct improvement in OS and event-free survival (EFS) was shown in BC CML patients when using combination of allo-SCT and TKIs compared to only TKIs. E.g., the median OS in the TKI+allo-HSCT group (20 months, 95% CI 1-74 months) was signifi cantly longer than that in the TKIs group (4.5 months; 95% CI 3.5-5.5 months). Similarly, the 4-year OS rates in the TKIs+allo-HSCT group were signifi cantly higher than those in the TKI group (50.0 vs 10.0%, P=0.016). (b) Th e median EFS in the TKIs+allo-HSCT group (18 months, 95% CI 1-72.7 months) was also signifi cantly longer than in the TKIs group (3 months; 95% CI 1.9-4.0 months). The 4-year EFS rates in the TKIs+allo-HSCT group were signifi cantly higher than those in the TKIs group (50.0 vs 10.0%, P=0.002) (Jiang H 2014). It should be noted that 2/3 of the donors were haploidentical.
Improved progression-free survival (up to 60%) was registered in the patients with advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors [5]. Th us, the donor type may infl uence survival for transplanted patients with advanced CML.

Primary Myelofibrosis

To take into account variable clinical course of a myeloproliferative disorder, the Lille scoring system provides some prognostic criteria, as mentioned:
• The “low” group (Hb-level > 10 g/dL and WBC between 4 and 30 /nL (median OS 93 months);
• The “intermediate” group (Hb-level < 10 g/dL or WBC > 30/< 4 nL (median OS 26 months);
• The “high” group (Hb-level < 10 g/dL and WBC < 4 /nL or > 30 /nL (median OS 13 months).

Table_1_Summary_of_IPSS_criteria.png
Table_2_Clinical_outcomes_of_reduced-intensity_conditioning_RIC_regimens_in_MF_patients.png

Reduced conditioning regimen when transplanting the MF patients yielded good results in terms of non-relapse-related mortality (NRM) and OS levels (Table 2).

Figure_1_Survival_probabilities_for_the_4_risk_subgroups_in_MF_DIPSS_risk_low_int-1_int-2_high__DIPSS_score_is_taken_at.png

Efficiency of SCT proved to depend on initial risk score, e.g., assessed by DIPSS. As seen from Fig. 1, SCT in advanced disease prolongs survival in high-risk patients. Allogeneic SCT option for myelofi brosis with leukemic transformation was evaluated in EBMT study. Th is involved 1048 cases in allo SCT; 46 patients, with leukemic transformation [11]. The cumulative incidence of treatment-related mortality at 1 year was 28%, and of relapse at 3 years was 47%. The 3-year progression-free (PFS) and overall survival (OS) rates were 26% and 33%, respectively. Hence, allogeneic SCT can cure myelofi brosis patients transformed to leukemia.
Molecular genetic markers, i.e., multiple gene expression profile of leukemic cells may be predictive for the outcome in myelofi brosis patients aft er allogeneic transplantation, especially overexpression of JAK2 and ASXL1 gene, as shown by Kröger et al. [12].
Our previous studies concerned treatment of the myelofibrosis patients who relapsed aft er fi rst allo-SCT [13]. The following treatment consisted of either donor lymphocyte infusions, or second allo-SCT from an alternative donor. A group of 30 patients with relapsed myelofi brosis treated by donor lymphocyte infusions and/or second allo-SCT showed good 5-year overall survival rates. I.e., 2nd SCT caused complete remission in 14 out of 17 patients (82%).
Ruxolitinib, a JAK2 inhibitor, is a promising therapeutic option for MF patients during peritransplant period [14]. Feasibility and safety of Ruxolitinib treatment was tested in Hamburg-Eppendorf clinic and Ruxolitinib was used in 12 patients at a dose of 10+10 mg. Severe GVHD was observed only in 1 case of 12; overall survival was 100% after short follow-up (a mean of 163 days) [15].

Chronic Myelomonocytic Leukemia (CMML)

CMML is another chronic myeloproliferative disorder. Different prognostic scores for CMML were developed in MD Anderson, Mayo Clinics, a Düsseldorf scoring etc. CMML-specifi c prognostic scoring system was the subject to external validation being tested in 578 patients, as seen from Table 3.
Progression-free survival (PFS) in CMML was assessed by a group from the MD Anderson Cancer Center [17]. Th e study was performed in 83 CMML patients. In 78 cases a pre-transplant induction treatment was applied, with 37 patients receiving hypomethylating agents and cytotoxic chemotherapy in 41 cases. Patients treated with a hypomethylating agent had a lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P=.03), improved progression-free survival (PFS), with no detectable diff erence in treatment-related mortality at 1 year post-HST. In summary, their data support the value of hypomethylating agents administered before allo-SCT, in order to achieve morphologic remission.
Results in CMML patients treated with allo-HSCT depend on the pre-transplant risk scores (HCT-specifi c CPSS), as shown by IBMTR group in 209 patients [16]. I.e., adjusted disease-free survival, starting at the time of transplant, at a median follow-up of 51 months. CPSS score, Karnofsky performance status, and graft source proved to be signifi cant predictors of survival. Th e patients with intermediate-2/high risk had a nearly 2-fold increased risk of death aft er relapse compared to those with low/intermediate-1 CPSS scores.
Table_3_Prognostic_scales_in_CMML_a_summary_of_different_studies_16.png
An EBMT study of relapse-free survival (left ) and overall survival (right) according to disease stage (CR versus no-CR) at transplantation was performed in a group of 513 CMML patients The subjects transplanted in CR had lower probability for non-relapse death (P=0·002) and longer relapse-free and OS (P=0·001 and P=0·005, respectively). In multivariate analysis the only signifi cant prognostic factor for survival was the presence of CR at transplantation (P= 0·005). Hence, patients transplanted in CR had signifi cantly longer relapse-free survival and significantly longer overall survival [18].
Moreover, both RFS and OS diff ered according to transplantation within 12 months or aft er 12 months aft er diagnosis of CMML. Early transplant was associated with significantly higher survival rates.

Systemic mastocytosis

Systemic mastocytosis (SM) is a myeloproliferative disorder with clonal expansion of mast cell precursors in various organs [19]. It is a heterogeneous group by the clinical course and malignant precursor biology: it may indolent do not shorten life expectancy. Advanced SM may proceed as Mast Cell Leukemia (MCL), SM with associated hematologic nonmast cell lineage diseases, or aggressive systemic mastocytosis (ASM). Survival rates from months to a few years despite cytoreductive therapy were not too high.
I.e., the 3-year OS and PFS in the total group of mastocytic malignancies are about 50-60% etc. [20]. Allo-SCT is a method of choice in advanced systemic mastocytosis. However, some somatic mutations predispose for inferior clinical outcome in this disorder, i.e., ASXL1 or CBL mutations (Fig. 2). Th ese molecular markers comprise a distinct risk factor when treating ASM [21].
Atypical chronic myeloid leukemia (aCML) with BCR-ABL1-negativity is considered a special clinical entity characterized by leukocytosis, aff ected granulocyte myeloid precursors, dysgranulopoiesis, PH-negativity, SETBP1 expression. Mutated RAS was found in some cases (7/20 [35%] vs 4/29 [14%]) and less JAK2p.V617F (3/42 [7%] vs 10/52 [19%]). Compared with unclassifi ed MDS/MPN-U, patients with aCML showed a significant inferior OS (12.4 months, 95% CI [9.0-16.1] vs 21.8 months, 95% CI [17.6-28.8]) and ACL-free survival (11.2 months, 95% CI [7.0-13.5] vs 18.9 months, 95% CI [12.3-26.3]), as reported by Wang et al. [22].
Age- and risk-score dependent survival in atypical CML were assessed as fi ve-year overall survival following allogeneic transplantation in 42 patients from an EBMT study [23]. As expected, the older age of aCML patients (<45 years) was associated with suffi ciently lower 5-year survival (<40%) as compared to younger patients.
Figure_2_Molecular_risk_factors_determine_survival_rates_in_systemis_mastocytosis.png

Summary

As based on clinical experience and current multicentric studies, some recommendations may be given on WHOM and WHEN to transplant, as follows:
In CML:
HSCT: in 1st complete remission – TKI failure, TKI intolerance, acceleration phase, blast crisis: TKI ± chemoinduction is performed
In Myelofi brosis:
HSCT at DIPPS INTERMED 2 and high risk scores at INTERMED 1 and with high risk features
In CMML:
Early HST, pre-treatment with hypomethylating agents
In Mastocytosis:
HSCT: in systemic mastocytosis, AHNMD (SM with associated non-mast cell)
in ASM (Aggressive Systemic Mastocytosis)
in MCL (Mast Cell Leukemia)

Conflict of interest

No conflict of interest is declared.

References

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19988" ["VALUE"]=> array(2) { ["TEXT"]=> string(108) "Онкологический Центр Хантсмана, Университет штата Юта, США" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(108) "Онкологический Центр Хантсмана, Университет штата Юта, США" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19989" ["VALUE"]=> array(2) { ["TEXT"]=> string(4153) "<p style="text-align: justify;"> Значительная часть аллогенных трансплантаций гемопоэтических стволовых клеток (алло-ТГСК) сейчас проводится по поводу миелодиспластического синдрома или миелопролиферативных заболеваний, тогда как хронический миелоидный лейкоз (ХМЛ) лечат, в основном, ингибиторами тирозинкиназ (ИТК). В некоторых особых ситуациях, есть следующие причины для алло-ТГСК при ХМЛ: токсичность препаратов ИТК, резистентность к обычной лекарственной терапии и прогрессия болезни (фаза акселерации или бластный криз). Однако повышения выживаемости без прогрессии можно добиться в продвинутой фазе ХМЛ после гаплоидентичной ТГСК, по сравнению с пересадкой от HLA-совместимого родственного или неродственного донора.<br> При планировании терапии первичного миелофиброза (ПМФ) следует учитывать различия в клиническом течении заболевания, применяя, например, Лилльскую систему оценок, которая дает прогностические критерии, а также молекулярно-генетические маркеры, в особенности, гиперэкспрессию гена JAK2, что дает основания к применению рук солитиниба. Алло-ТГСК может излечивать больных с ПМФ при трансформации его в лейкоз. В случаях рецидива, вторая алло-ТГСК или инфузия лимфоцитов донора может привести к удлинению продолжительности жизни пациентов.<br> Результаты терапии больных с хроническим миеломоноцитарным лейкозом, леченных алло-ТГСК, зависят от оценок их клинического риска до пересадки. Пациенты, трансплантированные в полной ремиссии, имеют большую длительность общей и безрецидивной выживаемости. Раннее выполнение трансплантации коррелирует с более высокими цифрами выживаемости пациентов. В случаях атипичного ХМЛ следует проводить раннюю трансплантацию. Алло-ТГСК является методом выбора при обширном системном мастоцитозе. Она проводится в случаях, ассоциированных с вовлечением других клеток, кроме мастоцитов, при агрессивном системном мастоцитозе и при мастоцитарной форме лейкоза. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Миелопролиферативные заболевания, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназ, хронический миелоидный лейкоз, первичный миелофиброз, хронический миеломоноцитарный лейкоз, системный мастоцитоз. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4075) "

Значительная часть аллогенных трансплантаций гемопоэтических стволовых клеток (алло-ТГСК) сейчас проводится по поводу миелодиспластического синдрома или миелопролиферативных заболеваний, тогда как хронический миелоидный лейкоз (ХМЛ) лечат, в основном, ингибиторами тирозинкиназ (ИТК). В некоторых особых ситуациях, есть следующие причины для алло-ТГСК при ХМЛ: токсичность препаратов ИТК, резистентность к обычной лекарственной терапии и прогрессия болезни (фаза акселерации или бластный криз). Однако повышения выживаемости без прогрессии можно добиться в продвинутой фазе ХМЛ после гаплоидентичной ТГСК, по сравнению с пересадкой от HLA-совместимого родственного или неродственного донора.
При планировании терапии первичного миелофиброза (ПМФ) следует учитывать различия в клиническом течении заболевания, применяя, например, Лилльскую систему оценок, которая дает прогностические критерии, а также молекулярно-генетические маркеры, в особенности, гиперэкспрессию гена JAK2, что дает основания к применению рук солитиниба. Алло-ТГСК может излечивать больных с ПМФ при трансформации его в лейкоз. В случаях рецидива, вторая алло-ТГСК или инфузия лимфоцитов донора может привести к удлинению продолжительности жизни пациентов.
Результаты терапии больных с хроническим миеломоноцитарным лейкозом, леченных алло-ТГСК, зависят от оценок их клинического риска до пересадки. Пациенты, трансплантированные в полной ремиссии, имеют большую длительность общей и безрецидивной выживаемости. Раннее выполнение трансплантации коррелирует с более высокими цифрами выживаемости пациентов. В случаях атипичного ХМЛ следует проводить раннюю трансплантацию. Алло-ТГСК является методом выбора при обширном системном мастоцитозе. Она проводится в случаях, ассоциированных с вовлечением других клеток, кроме мастоцитов, при агрессивном системном мастоцитозе и при мастоцитарной форме лейкоза.

Ключевые слова

Миелопролиферативные заболевания, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназ, хронический миелоидный лейкоз, первичный миелофиброз, хронический миеломоноцитарный лейкоз, системный мастоцитоз.

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In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.<br> When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.<br> Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis. </p> <h2 style="text-align: justify;"></h2>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1989) "

A sufficient part of allo-HSCT is now performed for myelodysplastic syndromes and myeloproliferative neoplasms (MPN), whereas chronic myeloid leukemia is mostly treated by tyrosine kinase inhibitors (TKI). In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.
When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.
Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia.

Keywords

Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis.

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In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.<br> When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.<br> Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis. </p> <h2 style="text-align: justify;"></h2>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1989) "

A sufficient part of allo-HSCT is now performed for myelodysplastic syndromes and myeloproliferative neoplasms (MPN), whereas chronic myeloid leukemia is mostly treated by tyrosine kinase inhibitors (TKI). In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.
When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.
Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia.

Keywords

Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis.

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A sufficient part of allo-HSCT is now performed for myelodysplastic syndromes and myeloproliferative neoplasms (MPN), whereas chronic myeloid leukemia is mostly treated by tyrosine kinase inhibitors (TKI). In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.
When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.
Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia.

Keywords

Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis.

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Значительная часть аллогенных трансплантаций гемопоэтических стволовых клеток (алло-ТГСК) сейчас проводится по поводу миелодиспластического синдрома или миелопролиферативных заболеваний, тогда как хронический миелоидный лейкоз (ХМЛ) лечат, в основном, ингибиторами тирозинкиназ (ИТК). В некоторых особых ситуациях, есть следующие причины для алло-ТГСК при ХМЛ: токсичность препаратов ИТК, резистентность к обычной лекарственной терапии и прогрессия болезни (фаза акселерации или бластный криз). Однако повышения выживаемости без прогрессии можно добиться в продвинутой фазе ХМЛ после гаплоидентичной ТГСК, по сравнению с пересадкой от HLA-совместимого родственного или неродственного донора.
При планировании терапии первичного миелофиброза (ПМФ) следует учитывать различия в клиническом течении заболевания, применяя, например, Лилльскую систему оценок, которая дает прогностические критерии, а также молекулярно-генетические маркеры, в особенности, гиперэкспрессию гена JAK2, что дает основания к применению рук солитиниба. Алло-ТГСК может излечивать больных с ПМФ при трансформации его в лейкоз. В случаях рецидива, вторая алло-ТГСК или инфузия лимфоцитов донора может привести к удлинению продолжительности жизни пациентов.
Результаты терапии больных с хроническим миеломоноцитарным лейкозом, леченных алло-ТГСК, зависят от оценок их клинического риска до пересадки. Пациенты, трансплантированные в полной ремиссии, имеют большую длительность общей и безрецидивной выживаемости. Раннее выполнение трансплантации коррелирует с более высокими цифрами выживаемости пациентов. В случаях атипичного ХМЛ следует проводить раннюю трансплантацию. Алло-ТГСК является методом выбора при обширном системном мастоцитозе. Она проводится в случаях, ассоциированных с вовлечением других клеток, кроме мастоцитов, при агрессивном системном мастоцитозе и при мастоцитарной форме лейкоза.

Ключевые слова

Миелопролиферативные заболевания, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназ, хронический миелоидный лейкоз, первичный миелофиброз, хронический миеломоноцитарный лейкоз, системный мастоцитоз.

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Значительная часть аллогенных трансплантаций гемопоэтических стволовых клеток (алло-ТГСК) сейчас проводится по поводу миелодиспластического синдрома или миелопролиферативных заболеваний, тогда как хронический миелоидный лейкоз (ХМЛ) лечат, в основном, ингибиторами тирозинкиназ (ИТК). В некоторых особых ситуациях, есть следующие причины для алло-ТГСК при ХМЛ: токсичность препаратов ИТК, резистентность к обычной лекарственной терапии и прогрессия болезни (фаза акселерации или бластный криз). Однако повышения выживаемости без прогрессии можно добиться в продвинутой фазе ХМЛ после гаплоидентичной ТГСК, по сравнению с пересадкой от HLA-совместимого родственного или неродственного донора.
При планировании терапии первичного миелофиброза (ПМФ) следует учитывать различия в клиническом течении заболевания, применяя, например, Лилльскую систему оценок, которая дает прогностические критерии, а также молекулярно-генетические маркеры, в особенности, гиперэкспрессию гена JAK2, что дает основания к применению рук солитиниба. Алло-ТГСК может излечивать больных с ПМФ при трансформации его в лейкоз. В случаях рецидива, вторая алло-ТГСК или инфузия лимфоцитов донора может привести к удлинению продолжительности жизни пациентов.
Результаты терапии больных с хроническим миеломоноцитарным лейкозом, леченных алло-ТГСК, зависят от оценок их клинического риска до пересадки. Пациенты, трансплантированные в полной ремиссии, имеют большую длительность общей и безрецидивной выживаемости. Раннее выполнение трансплантации коррелирует с более высокими цифрами выживаемости пациентов. В случаях атипичного ХМЛ следует проводить раннюю трансплантацию. Алло-ТГСК является методом выбора при обширном системном мастоцитозе. Она проводится в случаях, ассоциированных с вовлечением других клеток, кроме мастоцитов, при агрессивном системном мастоцитозе и при мастоцитарной форме лейкоза.

Ключевые слова

Миелопролиферативные заболевания, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназ, хронический миелоидный лейкоз, первичный миелофиброз, хронический миеломоноцитарный лейкоз, системный мастоцитоз.

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Introduction

The only curative treatment for chronic myeloid leukemia (CML) was previously allogenous hemopoietic cell transplantation (HCT) [1]. With the introduction of the tyrosine kinase inhibitor (TKI) imatinib into CML management 15 years ago and the stunning response and survival results, treatment strategy of CML has profoundly changed. TKI became the first line treatment of choice for CML.

Long term survival

Meanwhile several long-term observational and randomized studies have matured and 10-year survival outcomes are available. An overview is shown in Table 1. 5-year survival ranges around 90%, 10-year survival around 83% and 10-year relative survival compared to the general population is more than 90% [2, 3]. Similar results have been observed in population based registries [4, 5, 6]. More patients died of comorbidities than of CML [7].
Deep molecular responses are achieved in up to 80% aft er 5 to 10 years (Figure 1) suggesting that treatment discontinuation should be possible in these patients [8].
Table_1_Long-term_survival_rates_of_CML_patients_treated_with_TKI.png
Figure_1_Molecular_response_achieved_by_imatinib_8.png

First-line treatment

Current fi rst-line options with TKI are shown in Table 2. Whereas imatinib has been proven to be safe both at 400 and the faster acting 800 mg daily even aft er prolonged periods of time, the also faster acting 2nd generation (2G-)TKI require risk assessment due to rare but serious, potentially life threatening adverse drug reactions. As seen from Fig. 2, no survival advantage has been observed with any treatment option [3, 16, 17]. The lower progression rate to blast crisis observed with 2G-TKI is off set by more deaths due to adverse drug reactions. Variables to be considered in choosing first-line therapy are:
– Risk score;
– Cytogenetics (major-route ACA at diagnosis, high-risk
ACA in the course of CML);
– Comorbidities;
– Costs.
The impact of karyotype at diagnosis was demonstrated by Fabarius et al. [18]. Patients with major route ACA which occur in 1-2% of cases at diagnosis have a much poorer prognosis. Comorbidities do not infl uence progression of CML, but impact survival more than CML. Generic imatinib has become available recently. It decreases treatment costs at equal effi cacy and adds to the advantages of matinib over 2G-TKI.
Figure_2_10-year_survival_in_CML_study_IV__3.png

Second-line therapy

2nd-line therapy is needed in cases of refractoriness to imatinib. Table 3 summarizes comparative efficacy and safety of 2nd-line treatment options. The variables to be considered for second line therapy are:
– Response milestones (Table 4);
– Adherence to therapy;
– Resistance mutations (Table 5);
– Clonal evolution;
– Intolerance;
– Drug safety;
– Health care setting.
The criteria for assessing TKI-response were proposed by the European LeukemiaNet (ELN) for newly diagnosed CML [13] and are depicted in Table 4. Before changing treatment due to resistance, non-adherence to drug-treatment has to be excluded. Non-adherence has been reported as the most frequent reason for treatment failure [19].
When changing treatment due to confi rmed resistance a mutation analysis should be initiated. This can be done simultaneously with changing to the new drug. If the new drug still does not work, the mutation analysis will give a rational basis for selecting the right drug. Table 5 lists the most important mutations and there sensitivity to the currently available TKI.
Adverse TKI reactions have recently been reviewed on behalf of ELN by [20]. Table 6 gives an overview over the most frequently observed adverse TKI reactions.
Table_2_First-line_therapy_options_Efficacy_and_safety.png
Table_3_Second_line_treatment_options_Efficacy_and_safety.png
Table_4_ELN_response_milestones_for_newly_diagnosed_CML_13.png
Table_5_Impact_of_TKI_resistance_mutations_of_the_BCR_ABL_kinase_domain_21__permission_of_reproduction_by_M_Deininger.png

Table_6_Adverse_TKI_reactions_types_and_severity_20.png

CML Studies IIIA and IV

CML study IIIA is a geneticly randomized study comparing allogenous HCT with best available drug treatment. It recruited 662 patients, randomized 427 eligible patients (family donor available vs not available) and was published after a median observation time of 12.1 years [15]. Th e key result was equivalence of outcome for low risk patients after transplantion, if performed within one year of diagnosis, and imatinib.
CML study IV is a randomized 5-arm treatment optimization study to explore whether treatment with imatinib 400mg can be improved by doubling the dose, combining imatinib with cytarabine or interferon α (IFN) or applying imatinib aft er IFN failure. 1551 newly diagnosed patients in chronic phase where recruited and the study published after a median observation time of 9.5 years [3]. The key outcome was no superiority of survival of any treatment option (Fig. 2) in spite of signifi cantly faster responses with imatinib 800 mg and the recognition of determinants of survival independent of treatment by multivariate analysis (Table 7).
Table_7_Determinants_of_survival_by_multivariate_analysis_n_1252.png
A comparison of long-term survival aft er HCT or drug treatment showed that low risk patients had similar survival with both options (Fig. 3) [22, 23].
Figure_3_HCT_Group_A_in_blue_vs_drug_treatment_Group_B_in_red_by_transplant_EBMT_score__and_disease-_risks_EURO_sco.png
After progression to blast crisis HCT did not provide a significant survival advantage (Fig. 4), although long-term observations of 699 blast crises from the German CML studies showed that most long-term survivors (72%) were patients who received a transplant [24].
Figure_4_Effects_of_hematopoietic_stem_cell_transplantation_upon_survival_of_CML_patients_with_blast_crisis_22.png

Conclusion

• Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients.
• Survival is independent of time to response.
• Outcome of CML is currently more determined by disease and patients’ factors e.g. comorbidities and smoking, and by center effects than by initial treatment selection.
• In low risk patients survival aft er imatinib and transplantation may be similar.
• Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival.
• The 10-year deep molecular remission rates of 70%–80% indicate that the majority of imatinib treated patients are candidates for treatment discontinuation.

Conflict of interest

The author has no conflicts of interest to declare.

References

1. Goldman JM. Chronic myeloid leukemia: reversing the chronic phase. J Clin Oncol. 2010;28(3):363-365.
2. Pfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, Ossenkoppele G, Hoff mann VS, Castagnetti F, Hasford J, Hehlmann R, Simonsson B. Prognosis of long-term survival considering disease-specifi c death in patients with chronic myeloid leukemia. Leukemia. 2016;30(1):48-56.
3. Hehlmann R, Lauseker M, Saußele S, Pfi rrmann M, Krause S, Kolb HJ, Neubauer A, Hossfeld DK, Nerl C, Gratwohl A, Baerlocher GM, Heim D, Brümmendorf TH, Fabarius A, Haferlach C, Schlegelberger B, Müller MC, Jeromin S, Proetel U, Kohlbrenner K, Voskanyan A, Rinaldetti S, Seifarth W, Spieß B, Balleisen L, Goebeler MC, Hänel M, Ho A, Dengler J, Falge C, Kanz L, Kremers S, Burchert A, Kneba M, Stegelmann F, Köhne CA, Lindemann HW, Waller CF, Pfreundschuh M, Spiekermann K, Berdel WE, Müller L, Edinger M, Mayer J, Beelen DW, Bentz M, Link H, Hertenstein B, Fuchs R, Wernli M, Schlegel F, Schlag R, de Wit M, Trümper L, Hebart H, Hahn M, Thomalla J, Scheid C, Schafhausen P, Verbeek W, Eckart MJ, Gassmann W, Pezzutto A, Schenk M, Brossart P, Geer T, Bildat S, Schäfer E, Hochhaus A, Hasford J. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017;31(11):2398-2406.
4. Höglund M, Sandin F, Hellström K, Björeman M, Björkholm M, Brune M, Dreimane A, Ekblom M, Lehmann S, Ljungman P, Malm C, Markevärn B, Myhr-Eriksson K, Ohm L, Olsson-Strömberg U, Själander A, Wadenvik H, Simonsson B, Stenke L, Richter J. Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry. Blood. 2013;122(7):1284-1292.
5. Thielen N, Visser O, Ossenkoppele G, Janssen J. Chronic myeloid leukemia in the Netherlands: a population-based study on incidence, treatment, and survival in 3585 patients from 1989 to 2012. Eur J Haematol. 2016;97(2):145-154. 6. Bower H, Björkholm M, Dickmann P, Höglund M, Lambert PC, Andersson TM. Life expectancy of patients with CML approaches the life expectancy of the general population. J Clin Oncol 2016;34(24): 2851-2858.
7. Saussele S, Krauss MP, Hehlmann R, Lauseker M, Proetel U, Kalmanti L, Hanfstein B, Fabarius A, Kraemer D, Berdel WE, Bentz M, Staib P, de Wit M, Wernli M, Zettl F, Hebart HF, Hahn M, Heymanns J, Schmidt-Wolf I, Schmitz N, Eckart MJ, Gassmann W, Bartholomäus A, Pezzutto A, Leibundgut EO, Heim D, Krause SW, Burchert A, Hofmann WK, Hasford J, Hochhaus A, Pfirrmann M, Müller MC; Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung and the German CML Study Group. Impact of comorbidities on overall survival in patients with chronic myeloid leukemia: results of the randomized CML study IV. Blood 2015;126(1):42-49.
8. Kalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L, Hanfstein B, Proetel U, Fabarius A, Krause SW, Rinaldetti S, Dengler J, Falge C, Oppliger-Leibundgut E, Burchert A, Neubauer A, Kanz L, Stegelmann F, Pfreundschuh M, Spiekermann K, Scheid C, Pfi rrmann M, Hochhaus A, Hasford J, Hehlmann R. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.Leukemia. 2015; 29(5):1123-1132.
9. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O’Brien SG, Druker BJ; IRIS Investigators. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017;376(10):917-927.
10. Palandri F, Castagnetti F, Alimena G, Testoni N, Breccia M, Luatti S, Rege-Cambrin G, Stagno F, Specchia G, Martino B, Levato L, Merante S, Liberati AM, Pane F, Saglio G, Alberti D, Martinelli G, Baccarani M, Rosti G. Th e long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica. 2009;94(2):205-12.
11. de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, Szydlo R, Olavarria E, Kaeda J, Goldman JM, Marin D. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26(20):3358-3363.
12. Cervantes F, López-Garrido P, Montero MI, Jonte F, Martínez J, Hernández-Boluda JC, Calbacho M, Sureda A, Pérez-Rus G, Nieto JB, Pérez-López C, Román-Gómez J, González M, Pereira A, Colomer D. Early intervention during imatinib therapy in patients with newly diagnosed chronic- phase chronic myeloid leukemia: a study of the Spanish PETHEMA group. Haematologica. 2010 Aug;95(8):1317- 1324.
13. Baccarani M, Druker BJ, Branford S, Kim DW, Pane F, Mongay L, Mone M, Ortmann CE, Kantarjian HM, Radich JP, Hughes TP, Cortes JE, Guilhot F. Long-term response to imatinib is not aff ected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: fi nal update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol. 2014;99(5):616-624.
14. Jain P, Kantarjian H, Alattar ML, Jabbour E, Sasaki K, Nogueras Gonzalez G, Dellasala S, Pierce S, Verstovsek S, Wierda W, Borthakur G, Ravandi F, O’Brien S, Cortes J. Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from fi ve clinical trials. Lancet Haematol. 2015;2(3):e118-28.
15. Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D’Emilio A, Stagno F, le Coutre P, Hurtado- Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiff ers J, Piazza, Valsecchi MG, Kim DW. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103(7):553-561.
16. Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre PD, Etienne G, Dorlhiac-Llacer PE, Clark RE, Flinn IW, Nakamae H, Donohue B, Deng W, Dalal D, Menssen HD, Kantarjian HM. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016 May;30(5):1044-1054.
17. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A.Final 5-Year Study Results of DASISION: Th e Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34(20):2333-2340.
18. Fabarius A, Kalmanti L, Dietz CT, Lauseker M, Rinaldetti S, Haferlach C, Göhring G, Schlegelberger B, Jotterand M, Hanfstein B, Seifarth W, Hänel M, Köhne CH, Lindemann HW, Berdel WE, Staib P, Müller MC, Proetel U, Balleisen L, Goebeler ME, Dengler J, Falge C, Kanz L, Burchert A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Brümmendorf TH, Edinger M, Hofmann WK, Pfi rrmann M, Hasford J, Krause S, Hochhaus A, Saußele S, Hehlmann R; SAKK and the German CML Study Group. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol. 2015;94(12):2015-2024.
19. Noens L, Hensen M, Kucmin-Bemelmans I, Lofgren C, Gilloteau I, Vrijens B. Measurement of adherence to BCRABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges. Haematologica. 2014; 99(3):437-447.
20. Steegmann JL, Baccarani M, Breccia M, Casado LF, García-Gutiérrez V, Hochhaus A, Kim DW, Kim TD, Khoury HJ, Le Coutre P, Mayer J, Milojkovic D, Porkka K, Rea D, Rosti G, Saussele S, Hehlmann R, Clark RE. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia.Leukemia. 2016;30(8):1648-1671. 
21. Eiring AM, Deininger MW. Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia. Genome Biol. 2014 Sep 17;15(9):461. doi: 10.1186/ s13059-014-0461-8.
22. Gratwohl A, Pfi rrmann M, Zander A, Kröger N, Beelen D, Novotny J, Nerl C, Scheid C, Spiekermann K, Mayer J, Sayer HG, Falge C, Bunjes D, Döhner H, Ganser A, Schmidt-Wolf I, Schwerdtfeger R, Baurmann H, Kuse R, Schmitz N, Wehmeier A, Fischer JT, Ho AD, Wilhelm M, Goebeler ME, Lindemann HW, Bormann M, Hertenstein B, Schlimok G, Baerlocher GM, Aul C, Pfreundschuh M, Fabian M, Staib P, Edinger M, Schatz M, Fauser A, Arnold R, Kindler T, Wulf G, Rosselet A, Hellmann A, Schäfer E, Prümmer O, Schenk M, Hasford J, Heimpel H, Hossfeld DK, Kolb HJ, Büsche G, Haferlach C, Schnittger S, Müller MC, Reiter A, Berger U, Saußele S, Hochhaus A, Hehlmann R; SAKK; German CML Study Group. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016 Mar;30(3):562-569.
23. Saussele S, Lauseker M, Müller MC, Gratwohl A, Beelen D, Bunjes DW et al. Allogeneic hematopoietic stem cell transplantation (HSCT) in the imatinib-era: update on the survival outcome following allogeneic HSCT after imatinib failure; results of the German CML study IV. Blood. 2014;124 (ASH Meeting abstract No. 2567).
24. Hehlmann R, Saussele S. Treatment of chronic myeloid leukemia in blast crisis. Haematologica 2008; 93:1765-1769.

" ["~DETAIL_TEXT"]=> string(19938) "

Introduction

The only curative treatment for chronic myeloid leukemia (CML) was previously allogenous hemopoietic cell transplantation (HCT) [1]. With the introduction of the tyrosine kinase inhibitor (TKI) imatinib into CML management 15 years ago and the stunning response and survival results, treatment strategy of CML has profoundly changed. TKI became the first line treatment of choice for CML.

Long term survival

Meanwhile several long-term observational and randomized studies have matured and 10-year survival outcomes are available. An overview is shown in Table 1. 5-year survival ranges around 90%, 10-year survival around 83% and 10-year relative survival compared to the general population is more than 90% [2, 3]. Similar results have been observed in population based registries [4, 5, 6]. More patients died of comorbidities than of CML [7].
Deep molecular responses are achieved in up to 80% aft er 5 to 10 years (Figure 1) suggesting that treatment discontinuation should be possible in these patients [8].
Table_1_Long-term_survival_rates_of_CML_patients_treated_with_TKI.png
Figure_1_Molecular_response_achieved_by_imatinib_8.png

First-line treatment

Current fi rst-line options with TKI are shown in Table 2. Whereas imatinib has been proven to be safe both at 400 and the faster acting 800 mg daily even aft er prolonged periods of time, the also faster acting 2nd generation (2G-)TKI require risk assessment due to rare but serious, potentially life threatening adverse drug reactions. As seen from Fig. 2, no survival advantage has been observed with any treatment option [3, 16, 17]. The lower progression rate to blast crisis observed with 2G-TKI is off set by more deaths due to adverse drug reactions. Variables to be considered in choosing first-line therapy are:
– Risk score;
– Cytogenetics (major-route ACA at diagnosis, high-risk
ACA in the course of CML);
– Comorbidities;
– Costs.
The impact of karyotype at diagnosis was demonstrated by Fabarius et al. [18]. Patients with major route ACA which occur in 1-2% of cases at diagnosis have a much poorer prognosis. Comorbidities do not infl uence progression of CML, but impact survival more than CML. Generic imatinib has become available recently. It decreases treatment costs at equal effi cacy and adds to the advantages of matinib over 2G-TKI.
Figure_2_10-year_survival_in_CML_study_IV__3.png

Second-line therapy

2nd-line therapy is needed in cases of refractoriness to imatinib. Table 3 summarizes comparative efficacy and safety of 2nd-line treatment options. The variables to be considered for second line therapy are:
– Response milestones (Table 4);
– Adherence to therapy;
– Resistance mutations (Table 5);
– Clonal evolution;
– Intolerance;
– Drug safety;
– Health care setting.
The criteria for assessing TKI-response were proposed by the European LeukemiaNet (ELN) for newly diagnosed CML [13] and are depicted in Table 4. Before changing treatment due to resistance, non-adherence to drug-treatment has to be excluded. Non-adherence has been reported as the most frequent reason for treatment failure [19].
When changing treatment due to confi rmed resistance a mutation analysis should be initiated. This can be done simultaneously with changing to the new drug. If the new drug still does not work, the mutation analysis will give a rational basis for selecting the right drug. Table 5 lists the most important mutations and there sensitivity to the currently available TKI.
Adverse TKI reactions have recently been reviewed on behalf of ELN by [20]. Table 6 gives an overview over the most frequently observed adverse TKI reactions.
Table_2_First-line_therapy_options_Efficacy_and_safety.png
Table_3_Second_line_treatment_options_Efficacy_and_safety.png
Table_4_ELN_response_milestones_for_newly_diagnosed_CML_13.png
Table_5_Impact_of_TKI_resistance_mutations_of_the_BCR_ABL_kinase_domain_21__permission_of_reproduction_by_M_Deininger.png

Table_6_Adverse_TKI_reactions_types_and_severity_20.png

CML Studies IIIA and IV

CML study IIIA is a geneticly randomized study comparing allogenous HCT with best available drug treatment. It recruited 662 patients, randomized 427 eligible patients (family donor available vs not available) and was published after a median observation time of 12.1 years [15]. Th e key result was equivalence of outcome for low risk patients after transplantion, if performed within one year of diagnosis, and imatinib.
CML study IV is a randomized 5-arm treatment optimization study to explore whether treatment with imatinib 400mg can be improved by doubling the dose, combining imatinib with cytarabine or interferon α (IFN) or applying imatinib aft er IFN failure. 1551 newly diagnosed patients in chronic phase where recruited and the study published after a median observation time of 9.5 years [3]. The key outcome was no superiority of survival of any treatment option (Fig. 2) in spite of signifi cantly faster responses with imatinib 800 mg and the recognition of determinants of survival independent of treatment by multivariate analysis (Table 7).
Table_7_Determinants_of_survival_by_multivariate_analysis_n_1252.png
A comparison of long-term survival aft er HCT or drug treatment showed that low risk patients had similar survival with both options (Fig. 3) [22, 23].
Figure_3_HCT_Group_A_in_blue_vs_drug_treatment_Group_B_in_red_by_transplant_EBMT_score__and_disease-_risks_EURO_sco.png
After progression to blast crisis HCT did not provide a significant survival advantage (Fig. 4), although long-term observations of 699 blast crises from the German CML studies showed that most long-term survivors (72%) were patients who received a transplant [24].
Figure_4_Effects_of_hematopoietic_stem_cell_transplantation_upon_survival_of_CML_patients_with_blast_crisis_22.png

Conclusion

• Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients.
• Survival is independent of time to response.
• Outcome of CML is currently more determined by disease and patients’ factors e.g. comorbidities and smoking, and by center effects than by initial treatment selection.
• In low risk patients survival aft er imatinib and transplantation may be similar.
• Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival.
• The 10-year deep molecular remission rates of 70%–80% indicate that the majority of imatinib treated patients are candidates for treatment discontinuation.

Conflict of interest

The author has no conflicts of interest to declare.

References

1. Goldman JM. Chronic myeloid leukemia: reversing the chronic phase. J Clin Oncol. 2010;28(3):363-365.
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Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. 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Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. 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["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "19978" ["VALUE"]=> array(2) { ["TEXT"]=> string(4891) "<p style="text-align: justify;"> Стратегия лечения хронического миелолейкоза (ХМЛ) сильно изменилась после внедрения иматиниба – ингибитора тирозинкиназы (ИТК). Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.<br> В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4819) "

Стратегия лечения хронического миелолейкоза (ХМЛ) сильно изменилась после внедрения иматиниба – ингибитора тирозинкиназы (ИТК). Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.
В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии.

Ключевые слова

Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость.

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TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.<br> CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2231) "

With introduction of the tyrosine kinase inhibitor (TKI) imatinib, the treatment strategy of CML has profoundly changed. TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.
CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation.

Keywords

Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival.

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strategy of CML has profoundly changed. TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.<br> CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2231) "

With introduction of the tyrosine kinase inhibitor (TKI) imatinib, the treatment strategy of CML has profoundly changed. TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.
CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation.

Keywords

Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival.

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With introduction of the tyrosine kinase inhibitor (TKI) imatinib, the treatment strategy of CML has profoundly changed. TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.
CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation.

Keywords

Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival.

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Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.<br> В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4819) "

Стратегия лечения хронического миелолейкоза (ХМЛ) сильно изменилась после внедрения иматиниба – ингибитора тирозинкиназы (ИТК). Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.
В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии.

Ключевые слова

Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость.

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Стратегия лечения хронического миелолейкоза (ХМЛ) сильно изменилась после внедрения иматиниба – ингибитора тирозинкиназы (ИТК). Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.
В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии.

Ключевые слова

Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость.

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Introduction

Infection with human immunodefi ciency virus (HIV) is associated with a signifi cantly increased risk of cancer, including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) even when patients are treated successfully with contemporary antiretroviral therapy [1, 2]. AIDS related malignancies remain a leading cause of mortality [3]. Before the introduction of highly active anti-retroviral therapy (HAART), HIV-infected patients were not candidates for standard, combination chemotherapeutic regimens because of the signifi cant risk of opportunistic infection and poor malignancy response rates [4]. Th erapy outcome in patients with HIV-related malignancies have improved since the improvement of HAART availability [5-8]. In the HAART era, treatment of HIV-related lymphomas with standard doses of chemotherapy became possible for HIV positive patients [9-14].
The role of autologous hematopoietic stem cell transplantation (ASCT) in the care of patients with HIV-related lymphoma, however, remains unclear. In the non-HIV setting, patients with relapsed refractory NHL and HL have benefits from treatment with high-dose chemotherapy and ASCT [15, 16]. Early pivotal studies come from Europe and the United States demonstrated safety and effi cacy the use of ASCT in the care of patients with high-risk, relapsed refractory HIV-related lymphoma [17, 18]. Th ese initial experiences were encouraging and spurred other investigators to study the use of ASCT for patients with lymphoma and HIV. Th e summary of the studies of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma adapted from the Serrano et al. [19] is outlined in Table 1. Th e limitation of these studies is their retrospective nature with a large variety in patient population, status of the disease, conditioning regimen and HAART strategy. Th at is why the role of high-dose chemotherapy followed by ASCT in lymphoma patients with HIV is still a subject of controversy.
There is an urgent need for prospective comparative matched case-controlled studies to prove the safety and efficacy of ASCT in HIV-related lymphoma and their number is limited. There are three studies have been published that in one way or another meet the criteria prospective, comparative, matched case-controlled studies [26, 27, 28]. Here we report the early results of a single institution, EBMT center CIC725, matched case-control study. Th is was an observational trial designed to prospectively evaluate the safety and effectiveness of ASCT for patients with HIV-related lymphoma.

Patients and methods

Study design

Between January 2016 and October 2017, an observational study was conducted at Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University of St. Petersburg (CIC725). Seven patients with HIV-related NHL or HL were enrolled in a trial. An approval for the trial was issued by the University Institutional Review Board. All the patients signed an approved informed consent, in accordance with the Declaration of Helsinki. The data on twenty-eight non-HIV-infected lymphoma patients who underwent ASCT at the same time period (control group, n=28) were also collected to compare the effi cacy and safety of the procedure (1:4). The patients were matched for age at ASCT, disease status at ASCT, number of prior regimens of chemotherapy, time from lymphoma diagnosis to ASCT, conditioning regimen and tumor histology.

Eligibility criteria

The indications for ASCT included NHL or HL if they met standard transplant criteria. HIV positive patients were required to exhibit a viral load of <50,000 copies/ml, being free of overt opportunistic infections at the time of ASCT, and receiving HAART for more than 6 months.

Stem cell mobilization and conditioning regimen

For stem cell mobilization, the patients received cyclophosphamide (CY) at 4000 mg/m2 with hydration, and Mesna (15 mg/kg) before and 3, 6, and 9 hours aft er CY for uroprotection, or an alternative salvage chemotherapy to which the lymphoma was responding. Granulocyte colonystimulating factor (G-CSF) was administered at a dose of 10 μg/kg/day starting 2 days aft er the chemotherapy. Leukapheresis was performed since the white blood count (WBC) reached ≥0.5×109/L, a maximum of 3 harvests, until an intended number of 2×106 CD34+ cells/kg has been collected. In cases of poor stem cell mobilization (failed leukapheresis), bone marrow (BM) served as a source of hematopoietic stem cells (HSC) using a standard surgical procedure. Patients who met trial eligibility criteria underwent ASCT following a preparative regimen that consisted of modifi ed BEAM to BeEAM treatment where the carmustine 300 mg/m2 (day -6) was replaced by Bendamustine 160 mg/ m2/day at day -7, day -6. Etoposide 100 mg/m2 daily (days -5 to -2), cytarabine200 mg/m2 twice daily (days -5 to -2), and melphalan 140 mg/m2 (day -1) [29]. Patients underwent ASCT on day 0 and received growth factor, transfusion, and antimicrobial supportive care as per the respective institutional standards.
Autologous peripheral stem cells were thawed in a 37°C water bath and infused through the patient’s central venous catheter on transplantation day 0.

Clinical endpoints

This study was designed to assess the safety and tolerability of intensive chemotherapy and ASCT for the treatment of HIV-related NHL and HL. Th e primary end point for the trial was one-year OS aft er ASCT. The secondary endpoints were as follows: hematopoietic recovery and organ toxicity, transplant-related mortality (TRM), progression free survival (PFS), the cumulative incidence of relapse/progressionat 12 months aft er ASCT.
The patients underwent daily routine post-transplant blood tests from day 0 through the period of neutrophil recovery, and as per the respective institutional standards. The time to hematopoietic recovery was defi ned as the fi rst of day of >500 neutrophils/μL following nadir and time to platelet count >20,000/μL at the fi rst of day with no platelet transfusions for 2 preceding days. Post-AHCT toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4. Microbiologically documented infections were classifi ed by clinical site, date of onset, and severity of the disease. Th e disease status was assessed in the patients before ASCT, at day +100 or earlier if signs of the disease re-appeared, and 1 year aft er ASCT. Responses of lymphoma to therapy were assessed using the Cheson criteria for determination of complete remission (CR), and CR+ partial remission (PR) rates at day +100 [30]. Th e data of tests for HIV status (CD4+ cells, viral load) were collected from the HIV Department where the patients were assigned and observed.
Table_1_Summary_of_reported_studies_autologous_HSCT_for_non-Hodgkin_s_and_Hodgkin_s_lymphoma_in_HIV-infected_patients.png

Statistical analysis

Survival estimates were calculated based on the Kaplan-Meier method. Differences between survival curves were assessed by the log-rank test. Potential baseline diff erences between the two groups were examined using the Mann-Whitney test for continuous variables or Fisher’s exact test for categorical variables. Patients who were alive at the time of analysis were censored at the last contact date. Overall survival was defi ned as the interval from day 0 ASCT to the death from any cause. Transplant-related mortality was defi ned as death occurring in a patient from causes other than relapse/progression. Progression free survival was defined as the  interval from day 0 ASCT to death, disease relapse, or progression.
The cumulative incidence of relapse/progressionwas defined as relapse or progressionoccurring in a patient the interval from day 0 ASCT to 12 months.

Results

Patient characteristics

A consecutive case-series of 7 HIV-group patients and 28 matched control group treated with ASCT between January 2016 and October 2017 were included. Patient, disease, and treatment characteristics for both groups are provided in Table 2. Both groups were comparable for all clinical and transplantation characteristics except for the higher proportion of male sex (p=0.03) in HIV-group, misbalance in type of lymphoma: presence of non-Hodgkin T-cell lymphoma and prevalence of Hodgkin lymphoma in control group.
Table_2_Patients_under_study_clinical_features_and_treatment_characteristics.png
One patient was diagnosed with HIV infection concomitant with the lymphoma diagnosis and started on antiretroviral therapy together with chemo. Meanwhile, six patients in HIV group had a long history of HIV infection before the lymphoma was diagnosed. Median time from the registration of HIV-positive status to lymphoma diagnosis was 1734 days (57.8 months). HIV status in study group at the moment of transplantation was as follows: HIV viral load was undetectable (100%); the median number of CD4+ cells was 265 cells/mcl; all the subjects received HAART. Neither patient had any planned or needed interruptions in their HAART during ASCT. All individual patient and HAART regimen have been consulted with the HIV specialist and changed the regimen before ASCT taking into account drug-drug interactions. Only in two patients before ASCT the modifi cation of the scheme HAART was required.
Six patients in HIV group received peripheral blood stem cell graft s, and BM was transfused in one case. The median transplanted HSC dose was 3.9×106 CD34+ cells/kg (range, 1.6-11.0). A median of 2 apheresis collections was performed (range, 1-3). A median of 3.4×106 CD34+ cells/kg (range, 2.6-6.0×106/kg) was transfused to the patients.

Engraftment

The median time to achievement of an absolute neutrophil count (ANC) of ≥0.5×109/L was similar for both groups: 14 days (range, 11-30 days) in HIV-infected group and 16 days (range, 10-30 days) in control group (Fig. 1a). The median time to achievement of an unsupported platelet count of ≥20×109/L was 15 days (range, 11-30 days) in HIV-infected group and 14 days (range, 11-30 days) in control group (Fig. 1b).

Toxicities

No fatal regimen-related toxicity occurred. Neither patient developed grade III or IV nausea or vomiting. Three patients developed oropharyngeal mucositis (3 cases – grade I-II, no one grade III). Tree patients experienced febrile neutropenia. Three patients had a documented bacteremia within 100 days post-ASCT (1 coagulase-negative staphylococcus, 2 Klebsiella pneumoniae). Comparative characteristics of non-hematologic toxicities (≤100 days post-ASCT) are listed
in Table 3.
Figure_1_Time_to_hematopoietic_recovery_for_neutrophils_1a__and_platelets_1b_from_day_0_of_ASCT_in_HIV_group_versus_cont.png
Table_3_Comparative_characteristics_of_non-hematologic_toxicities_in_the_patients.png

Outcomes

With a median follow-up of 12 months (range, 1.2-20.7 months) in HIV group and 8 (1-20) months in control group, 2 patients died in control group; one of them died within 1 year of transplant. Relapse of the underlying disease was a cause of death in both cases. There were no registered events classifi ed as transplant-related mortality. Th e overall one-year survival (n=35) was 97.1%. Overall survival at 1 year was 100% in HIV group, 96.4% – control group, and were not significantly diff erent between the groups (Fig. 2a). At the time of transplant, 4 (57%) patients in HIV group and 17 (60.7%) patients in control group were in CR, three patients (42.8%) in HIV group and 8 (28.5%) patients in control group were in PR, whereas three (10.7%) patient in control group had active diseaseat the moment of ASCT after achieving a PR to salvage therapy. During the first year aft er ASCT, 1 (3.6%) patient in control group had relapse of the disease and died on day +73 and 1 patient (14.2%) in HIV group with HL where the anticancer immunotherapy was initiated. Th e probability of 1-year PFS for all patients was 88.6%, in HIV group – 85.7% and 89.3% for control group (p=0.98) (Fig. 2b). Th e cumulative incidence of relapse/progression at 1 year was 11.4%. Th e cumulative incidence of relapse/ progression was 14,3% in HIV group and did not differ from the control group 10.7% (p=0.98).
Figure_2_Overall_survival_2a__and_progression-free_survival_2b_at_the_term_of_1_year_in_HIV_group_versus_control_patient.png

Discussion

Wide application of effective anti-HIV therapy allowed patients with HIV-related lymphoma to benefi t from standard chemotherapeutic regimens [9-14]. Clinical outcomes after treatment of these patients, including OS and PFS of treatment these patients similar comparable with those of non–HIV-infected individuals both in NHL and HL cases [7, 11, 13, 14, 31].
In the early 90’s clinical studies established ASCT as the standard of care for managing patients with chemotherapy-sensitive, relapsed/refractory NHL and HL [15-16, 32]. HIV infection historically has been considered as a contraindication to ASCT. With the improvement of supportive care, and the accumulation of experience in ASCT, as well as long-term results of the use of HAART there was an opportunity to extend implementation of high-dose chemotherapy followed by ASCT to HIV-infected patients. Series of the studies has been reported ASCT as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients [19, 20-26].
Alvarnas JC et al. highlighted that published ASCT studies were largely limited to centers with signifi cant HIV-related expertise. Th is has prevented full acceptance of ASCT as the standard of care for patients with relapsed and resistant HIV-related lymphoma [26]. We cannot disagree with the statement of Dr. Alvarnas. Our transplant activity confirms the fact that ASCT for patients with lymphoma and HIV remain largely limited to centers with signifi cant HIV-specifi c expertise [33].
Today we need prospective comparative matched case-controlled studies in order to confi rm safety and effi cacy of ASCT in HIV-related lymphoma. Th ree studies that in one way or another meet these criteria were published. One study is a single-institution one, from the City of Hope – the United States center that pioneered the use of hematopoietic stem cell transplantation for HIV positive patients [27]. Two other comparative trials represent a registry-based studies from the EBMT and CIBMTR databases [26, 28]. Table 4 presents a summary of trials with appropriate comparative analyses of HIV-infected patients and matched cohorts from non–HIV-infected patients who underwent ASCT for treatment of NHL and HL. Th e well-designed single center and multicenter studies have shown that HIV status does not affect the outcome of ASCT performed for NHL and HL. Such a conclusion is based on a total group of 122 HIV-infected individuals with lymphoma observed in the three studies.
This study and early-stage data confi rm some previously published statements that high-dose chemotherapy with ASCT is a safe and eff ective procedure in patients with highrisk, relapsed refractory HIV-related lymphoma. The issues of ASCT safety in this category of patients become actual given that HSCT is a platform for development and application of gene therapy, both with classic and more advanced genome editing techniques aimed to eradicate HIV infection [34-37]. In the last few years with a development of the genome editing technology based on autologous hematopoietic stem cell transplantation is becoming one of the most promising methods of HIV one shot therapy procedure. Hematopoietic stem cells are one of the most popular and promising target for gene therapy protocols for the treatment of numerous disease and conditions, due to their tissue-specific homing, ability for diff erentiation and production of various blood cells, as well as broad clinical experience with their transplantation [38, 39].
Table_4_Summary_of_trials_with_comparative_analysis_of_HIV-infected_patients_versus_matched_cohort_of_non_HIV-infected_patie.png
There is no doubt that further research in this field and every new patient treated with ASCT procedure is of great value, and multicenter prospective comparative matched case-controlled studies are required. Our pilot study involved a modest number of patients observed for limited terms. However, it contributes to the solution of an urgent problem. Our preliminary data provide further evidence that HIV status does not aff ect the outcome of ASCT for lymphoma. Patients with HIV-related lymphoma should be considered candidates for ASCT if they meet standard transplant criteria.

Acknowledgments

The authors would like to acknowledge all medical staff at our University’ BMT clinic CIC725. Special thanks to our transplant nurses for their particular care of our patients. Many thanks to the HIV specialists at the First Pavlov State Medical University of Saint-Petersburg, especially to Prof. Lioznov D. A., Chief of the Department, and to entire medical staff of St. Petersburg HIV Center for detailed clinical and laboratory data provided for the patients.

Conflict of interest

No conflict of interests is declared.

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33. Afanasyev BV, Popova MO, Bondarenko SN, Zyuzgin I., Babenko EV, Alyanskiy AL, Morsch S, van Lunzen I, Fehse B, Zander AR, Zubarovskaya LS. St. Petersburg experience of allogeneic hematopoietic stem cell transplantation in patients with acute leukemia and human immunodefi ciency virus. Cell Ther Transplant; 4(1-2):24-30.
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35. Mock U., Machowicz R., Hauber I., Horn S, Abramowski P, Berdien B, Hauber J, Fehse B. mRNA transfection of a novel TAL eff ector nuclease (TALEN) facilitates effi cient knockout of HIV co-receptor CCR5. Nucl Acids Res. 2015 DOI: 10.1093/nar/gkv469.
36. Wang CX, Cannon PM. Th e clinical applications of genome editing in HIV. Blood. 2016;127(21):2546-2552.
37. Popova MО, Sergeev VS, Lepik KV, Shakirova AI, Potter AY, Barkhatov IM, Fehse B, Afanasyev BV. Gene-cell therapy of HIV and hematological malignances based on hematopoietic stem cell transplantation and site-specifi c genome editing. J Infectology. 2017; 9(1):31-39 (In Russian).
38. Lepik KV, Popova MO, Shakirova, AI, Sergeev VS, Potter AY, Barkhatov IM, Fehse B, Afanasyev BV. Site-specific genome editing for hematopoetic stem cells transplantation- based on gene therapy approaches. Genes and Cells. 2016;11(2):21-29.
39. Popova MO, Lepik KV, Sergeev VS, Shakirova AI, Potter AY, Muslimov AR, Barkhatov IM, Afanasyev BV. Clinical implementation of genome editing for correction of human diseases. Cell Th er Transplant. (2017). 6(1), 37-43.

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Introduction

Infection with human immunodefi ciency virus (HIV) is associated with a signifi cantly increased risk of cancer, including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) even when patients are treated successfully with contemporary antiretroviral therapy [1, 2]. AIDS related malignancies remain a leading cause of mortality [3]. Before the introduction of highly active anti-retroviral therapy (HAART), HIV-infected patients were not candidates for standard, combination chemotherapeutic regimens because of the signifi cant risk of opportunistic infection and poor malignancy response rates [4]. Th erapy outcome in patients with HIV-related malignancies have improved since the improvement of HAART availability [5-8]. In the HAART era, treatment of HIV-related lymphomas with standard doses of chemotherapy became possible for HIV positive patients [9-14].
The role of autologous hematopoietic stem cell transplantation (ASCT) in the care of patients with HIV-related lymphoma, however, remains unclear. In the non-HIV setting, patients with relapsed refractory NHL and HL have benefits from treatment with high-dose chemotherapy and ASCT [15, 16]. Early pivotal studies come from Europe and the United States demonstrated safety and effi cacy the use of ASCT in the care of patients with high-risk, relapsed refractory HIV-related lymphoma [17, 18]. Th ese initial experiences were encouraging and spurred other investigators to study the use of ASCT for patients with lymphoma and HIV. Th e summary of the studies of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma adapted from the Serrano et al. [19] is outlined in Table 1. Th e limitation of these studies is their retrospective nature with a large variety in patient population, status of the disease, conditioning regimen and HAART strategy. Th at is why the role of high-dose chemotherapy followed by ASCT in lymphoma patients with HIV is still a subject of controversy.
There is an urgent need for prospective comparative matched case-controlled studies to prove the safety and efficacy of ASCT in HIV-related lymphoma and their number is limited. There are three studies have been published that in one way or another meet the criteria prospective, comparative, matched case-controlled studies [26, 27, 28]. Here we report the early results of a single institution, EBMT center CIC725, matched case-control study. Th is was an observational trial designed to prospectively evaluate the safety and effectiveness of ASCT for patients with HIV-related lymphoma.

Patients and methods

Study design

Between January 2016 and October 2017, an observational study was conducted at Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First State I. Pavlov Medical University of St. Petersburg (CIC725). Seven patients with HIV-related NHL or HL were enrolled in a trial. An approval for the trial was issued by the University Institutional Review Board. All the patients signed an approved informed consent, in accordance with the Declaration of Helsinki. The data on twenty-eight non-HIV-infected lymphoma patients who underwent ASCT at the same time period (control group, n=28) were also collected to compare the effi cacy and safety of the procedure (1:4). The patients were matched for age at ASCT, disease status at ASCT, number of prior regimens of chemotherapy, time from lymphoma diagnosis to ASCT, conditioning regimen and tumor histology.

Eligibility criteria

The indications for ASCT included NHL or HL if they met standard transplant criteria. HIV positive patients were required to exhibit a viral load of <50,000 copies/ml, being free of overt opportunistic infections at the time of ASCT, and receiving HAART for more than 6 months.

Stem cell mobilization and conditioning regimen

For stem cell mobilization, the patients received cyclophosphamide (CY) at 4000 mg/m2 with hydration, and Mesna (15 mg/kg) before and 3, 6, and 9 hours aft er CY for uroprotection, or an alternative salvage chemotherapy to which the lymphoma was responding. Granulocyte colonystimulating factor (G-CSF) was administered at a dose of 10 μg/kg/day starting 2 days aft er the chemotherapy. Leukapheresis was performed since the white blood count (WBC) reached ≥0.5×109/L, a maximum of 3 harvests, until an intended number of 2×106 CD34+ cells/kg has been collected. In cases of poor stem cell mobilization (failed leukapheresis), bone marrow (BM) served as a source of hematopoietic stem cells (HSC) using a standard surgical procedure. Patients who met trial eligibility criteria underwent ASCT following a preparative regimen that consisted of modifi ed BEAM to BeEAM treatment where the carmustine 300 mg/m2 (day -6) was replaced by Bendamustine 160 mg/ m2/day at day -7, day -6. Etoposide 100 mg/m2 daily (days -5 to -2), cytarabine200 mg/m2 twice daily (days -5 to -2), and melphalan 140 mg/m2 (day -1) [29]. Patients underwent ASCT on day 0 and received growth factor, transfusion, and antimicrobial supportive care as per the respective institutional standards.
Autologous peripheral stem cells were thawed in a 37°C water bath and infused through the patient’s central venous catheter on transplantation day 0.

Clinical endpoints

This study was designed to assess the safety and tolerability of intensive chemotherapy and ASCT for the treatment of HIV-related NHL and HL. Th e primary end point for the trial was one-year OS aft er ASCT. The secondary endpoints were as follows: hematopoietic recovery and organ toxicity, transplant-related mortality (TRM), progression free survival (PFS), the cumulative incidence of relapse/progressionat 12 months aft er ASCT.
The patients underwent daily routine post-transplant blood tests from day 0 through the period of neutrophil recovery, and as per the respective institutional standards. The time to hematopoietic recovery was defi ned as the fi rst of day of >500 neutrophils/μL following nadir and time to platelet count >20,000/μL at the fi rst of day with no platelet transfusions for 2 preceding days. Post-AHCT toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4. Microbiologically documented infections were classifi ed by clinical site, date of onset, and severity of the disease. Th e disease status was assessed in the patients before ASCT, at day +100 or earlier if signs of the disease re-appeared, and 1 year aft er ASCT. Responses of lymphoma to therapy were assessed using the Cheson criteria for determination of complete remission (CR), and CR+ partial remission (PR) rates at day +100 [30]. Th e data of tests for HIV status (CD4+ cells, viral load) were collected from the HIV Department where the patients were assigned and observed.
Table_1_Summary_of_reported_studies_autologous_HSCT_for_non-Hodgkin_s_and_Hodgkin_s_lymphoma_in_HIV-infected_patients.png

Statistical analysis

Survival estimates were calculated based on the Kaplan-Meier method. Differences between survival curves were assessed by the log-rank test. Potential baseline diff erences between the two groups were examined using the Mann-Whitney test for continuous variables or Fisher’s exact test for categorical variables. Patients who were alive at the time of analysis were censored at the last contact date. Overall survival was defi ned as the interval from day 0 ASCT to the death from any cause. Transplant-related mortality was defi ned as death occurring in a patient from causes other than relapse/progression. Progression free survival was defined as the  interval from day 0 ASCT to death, disease relapse, or progression.
The cumulative incidence of relapse/progressionwas defined as relapse or progressionoccurring in a patient the interval from day 0 ASCT to 12 months.

Results

Patient characteristics

A consecutive case-series of 7 HIV-group patients and 28 matched control group treated with ASCT between January 2016 and October 2017 were included. Patient, disease, and treatment characteristics for both groups are provided in Table 2. Both groups were comparable for all clinical and transplantation characteristics except for the higher proportion of male sex (p=0.03) in HIV-group, misbalance in type of lymphoma: presence of non-Hodgkin T-cell lymphoma and prevalence of Hodgkin lymphoma in control group.
Table_2_Patients_under_study_clinical_features_and_treatment_characteristics.png
One patient was diagnosed with HIV infection concomitant with the lymphoma diagnosis and started on antiretroviral therapy together with chemo. Meanwhile, six patients in HIV group had a long history of HIV infection before the lymphoma was diagnosed. Median time from the registration of HIV-positive status to lymphoma diagnosis was 1734 days (57.8 months). HIV status in study group at the moment of transplantation was as follows: HIV viral load was undetectable (100%); the median number of CD4+ cells was 265 cells/mcl; all the subjects received HAART. Neither patient had any planned or needed interruptions in their HAART during ASCT. All individual patient and HAART regimen have been consulted with the HIV specialist and changed the regimen before ASCT taking into account drug-drug interactions. Only in two patients before ASCT the modifi cation of the scheme HAART was required.
Six patients in HIV group received peripheral blood stem cell graft s, and BM was transfused in one case. The median transplanted HSC dose was 3.9×106 CD34+ cells/kg (range, 1.6-11.0). A median of 2 apheresis collections was performed (range, 1-3). A median of 3.4×106 CD34+ cells/kg (range, 2.6-6.0×106/kg) was transfused to the patients.

Engraftment

The median time to achievement of an absolute neutrophil count (ANC) of ≥0.5×109/L was similar for both groups: 14 days (range, 11-30 days) in HIV-infected group and 16 days (range, 10-30 days) in control group (Fig. 1a). The median time to achievement of an unsupported platelet count of ≥20×109/L was 15 days (range, 11-30 days) in HIV-infected group and 14 days (range, 11-30 days) in control group (Fig. 1b).

Toxicities

No fatal regimen-related toxicity occurred. Neither patient developed grade III or IV nausea or vomiting. Three patients developed oropharyngeal mucositis (3 cases – grade I-II, no one grade III). Tree patients experienced febrile neutropenia. Three patients had a documented bacteremia within 100 days post-ASCT (1 coagulase-negative staphylococcus, 2 Klebsiella pneumoniae). Comparative characteristics of non-hematologic toxicities (≤100 days post-ASCT) are listed
in Table 3.
Figure_1_Time_to_hematopoietic_recovery_for_neutrophils_1a__and_platelets_1b_from_day_0_of_ASCT_in_HIV_group_versus_cont.png
Table_3_Comparative_characteristics_of_non-hematologic_toxicities_in_the_patients.png

Outcomes

With a median follow-up of 12 months (range, 1.2-20.7 months) in HIV group and 8 (1-20) months in control group, 2 patients died in control group; one of them died within 1 year of transplant. Relapse of the underlying disease was a cause of death in both cases. There were no registered events classifi ed as transplant-related mortality. Th e overall one-year survival (n=35) was 97.1%. Overall survival at 1 year was 100% in HIV group, 96.4% – control group, and were not significantly diff erent between the groups (Fig. 2a). At the time of transplant, 4 (57%) patients in HIV group and 17 (60.7%) patients in control group were in CR, three patients (42.8%) in HIV group and 8 (28.5%) patients in control group were in PR, whereas three (10.7%) patient in control group had active diseaseat the moment of ASCT after achieving a PR to salvage therapy. During the first year aft er ASCT, 1 (3.6%) patient in control group had relapse of the disease and died on day +73 and 1 patient (14.2%) in HIV group with HL where the anticancer immunotherapy was initiated. Th e probability of 1-year PFS for all patients was 88.6%, in HIV group – 85.7% and 89.3% for control group (p=0.98) (Fig. 2b). Th e cumulative incidence of relapse/progression at 1 year was 11.4%. Th e cumulative incidence of relapse/ progression was 14,3% in HIV group and did not differ from the control group 10.7% (p=0.98).
Figure_2_Overall_survival_2a__and_progression-free_survival_2b_at_the_term_of_1_year_in_HIV_group_versus_control_patient.png

Discussion

Wide application of effective anti-HIV therapy allowed patients with HIV-related lymphoma to benefi t from standard chemotherapeutic regimens [9-14]. Clinical outcomes after treatment of these patients, including OS and PFS of treatment these patients similar comparable with those of non–HIV-infected individuals both in NHL and HL cases [7, 11, 13, 14, 31].
In the early 90’s clinical studies established ASCT as the standard of care for managing patients with chemotherapy-sensitive, relapsed/refractory NHL and HL [15-16, 32]. HIV infection historically has been considered as a contraindication to ASCT. With the improvement of supportive care, and the accumulation of experience in ASCT, as well as long-term results of the use of HAART there was an opportunity to extend implementation of high-dose chemotherapy followed by ASCT to HIV-infected patients. Series of the studies has been reported ASCT as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients [19, 20-26].
Alvarnas JC et al. highlighted that published ASCT studies were largely limited to centers with signifi cant HIV-related expertise. Th is has prevented full acceptance of ASCT as the standard of care for patients with relapsed and resistant HIV-related lymphoma [26]. We cannot disagree with the statement of Dr. Alvarnas. Our transplant activity confirms the fact that ASCT for patients with lymphoma and HIV remain largely limited to centers with signifi cant HIV-specifi c expertise [33].
Today we need prospective comparative matched case-controlled studies in order to confi rm safety and effi cacy of ASCT in HIV-related lymphoma. Th ree studies that in one way or another meet these criteria were published. One study is a single-institution one, from the City of Hope – the United States center that pioneered the use of hematopoietic stem cell transplantation for HIV positive patients [27]. Two other comparative trials represent a registry-based studies from the EBMT and CIBMTR databases [26, 28]. Table 4 presents a summary of trials with appropriate comparative analyses of HIV-infected patients and matched cohorts from non–HIV-infected patients who underwent ASCT for treatment of NHL and HL. Th e well-designed single center and multicenter studies have shown that HIV status does not affect the outcome of ASCT performed for NHL and HL. Such a conclusion is based on a total group of 122 HIV-infected individuals with lymphoma observed in the three studies.
This study and early-stage data confi rm some previously published statements that high-dose chemotherapy with ASCT is a safe and eff ective procedure in patients with highrisk, relapsed refractory HIV-related lymphoma. The issues of ASCT safety in this category of patients become actual given that HSCT is a platform for development and application of gene therapy, both with classic and more advanced genome editing techniques aimed to eradicate HIV infection [34-37]. In the last few years with a development of the genome editing technology based on autologous hematopoietic stem cell transplantation is becoming one of the most promising methods of HIV one shot therapy procedure. Hematopoietic stem cells are one of the most popular and promising target for gene therapy protocols for the treatment of numerous disease and conditions, due to their tissue-specific homing, ability for diff erentiation and production of various blood cells, as well as broad clinical experience with their transplantation [38, 39].
Table_4_Summary_of_trials_with_comparative_analysis_of_HIV-infected_patients_versus_matched_cohort_of_non_HIV-infected_patie.png
There is no doubt that further research in this field and every new patient treated with ASCT procedure is of great value, and multicenter prospective comparative matched case-controlled studies are required. Our pilot study involved a modest number of patients observed for limited terms. However, it contributes to the solution of an urgent problem. Our preliminary data provide further evidence that HIV status does not aff ect the outcome of ASCT for lymphoma. Patients with HIV-related lymphoma should be considered candidates for ASCT if they meet standard transplant criteria.

Acknowledgments

The authors would like to acknowledge all medical staff at our University’ BMT clinic CIC725. Special thanks to our transplant nurses for their particular care of our patients. Many thanks to the HIV specialists at the First Pavlov State Medical University of Saint-Petersburg, especially to Prof. Lioznov D. A., Chief of the Department, and to entire medical staff of St. Petersburg HIV Center for detailed clinical and laboratory data provided for the patients.

Conflict of interest

No conflict of interests is declared.

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35. Mock U., Machowicz R., Hauber I., Horn S, Abramowski P, Berdien B, Hauber J, Fehse B. mRNA transfection of a novel TAL eff ector nuclease (TALEN) facilitates effi cient knockout of HIV co-receptor CCR5. Nucl Acids Res. 2015 DOI: 10.1093/nar/gkv469.
36. Wang CX, Cannon PM. Th e clinical applications of genome editing in HIV. Blood. 2016;127(21):2546-2552.
37. Popova MО, Sergeev VS, Lepik KV, Shakirova AI, Potter AY, Barkhatov IM, Fehse B, Afanasyev BV. Gene-cell therapy of HIV and hematological malignances based on hematopoietic stem cell transplantation and site-specifi c genome editing. J Infectology. 2017; 9(1):31-39 (In Russian).
38. Lepik KV, Popova MO, Shakirova, AI, Sergeev VS, Potter AY, Barkhatov IM, Fehse B, Afanasyev BV. Site-specific genome editing for hematopoetic stem cells transplantation- based on gene therapy approaches. Genes and Cells. 2016;11(2):21-29.
39. Popova MO, Lepik KV, Sergeev VS, Shakirova AI, Potter AY, Muslimov AR, Barkhatov IM, Afanasyev BV. Clinical implementation of genome editing for correction of human diseases. Cell Th er Transplant. (2017). 6(1), 37-43.

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При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). 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Попова, Юлия A. Рогачева, Анастасия В. Некрасова, Иван В. Циганков, Али Базахел, Кирилл В. Лепик, Ольга В. Пирогова, Елена И. Дарская, Лилия В. Стельмах, Юрий Р. Залялов, Иван С. Моисеев, Сергей Н. Бондаренко, Наталья Б. Михайлова, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(456) "Марина O. Попова, Юлия A. Рогачева, Анастасия В. Некрасова, Иван В. Циганков, Али Базахел, Кирилл В. Лепик, Ольга В. Пирогова, Елена И. Дарская, Лилия В. Стельмах, Юрий Р. Залялов, Иван С. Моисеев, Сергей Н. Бондаренко, Наталья Б. Михайлова, Борис В. Афанасьев
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20011" ["VALUE"]=> array(2) { ["TEXT"]=> string(429) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова (CIC725)<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(423) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова (CIC725)
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20012" ["VALUE"]=> array(2) { ["TEXT"]=> string(3939) "<p style="text-align: justify;"> Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль». </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3873) "

Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль».

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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantation, Th e St. Petersburg First State Medical I. Pavlov University (CIC725)" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(222) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantation, Th e St. Petersburg First State Medical I. Pavlov University (CIC725)" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20016" ["VALUE"]=> array(2) { ["TEXT"]=> string(2428) "<p style="text-align: justify;"> Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2362) "

Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials.

Keywords

Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study.

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Popova, Yulia A. Rogacheva, Anastasia V. Nekrasova, Ivan V. Tsygankov, Ali Basahel, Kirill V. Lepik, Olga V. Pirogova, Elena I. Darskaya, Lilia V. Stelmakh, Yurii R. Zalyalov, Ivan S. Moiseev, Sergey N. Bondarenko, Natalia B. Mikhailova, Boris V. Afanasyev<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(270) "Marina O. Popova, Yulia A. Rogacheva, Anastasia V. Nekrasova, Ivan V. Tsygankov, Ali Basahel, Kirill V. Lepik, Olga V. Pirogova, Elena I. Darskaya, Lilia V. Stelmakh, Yurii R. Zalyalov, Ivan S. Moiseev, Sergey N. Bondarenko, Natalia B. Mikhailova, Boris V. Afanasyev
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(270) "Marina O. Popova, Yulia A. Rogacheva, Anastasia V. Nekrasova, Ivan V. Tsygankov, Ali Basahel, Kirill V. Lepik, Olga V. Pirogova, Elena I. Darskaya, Lilia V. Stelmakh, Yurii R. Zalyalov, Ivan S. Moiseev, Sergey N. Bondarenko, Natalia B. Mikhailova, Boris V. Afanasyev
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20016" ["VALUE"]=> array(2) { ["TEXT"]=> string(2428) "<p style="text-align: justify;"> Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2362) "

Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials.

Keywords

Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study.

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Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials.

Keywords

Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(456) "Марина O. Попова, Юлия A. Рогачева, Анастасия В. Некрасова, Иван В. Циганков, Али Базахел, Кирилл В. Лепик, Ольга В. Пирогова, Елена И. Дарская, Лилия В. Стельмах, Юрий Р. Залялов, Иван С. Моисеев, Сергей Н. Бондаренко, Наталья Б. Михайлова, Борис В. Афанасьев
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20012" ["VALUE"]=> array(2) { ["TEXT"]=> string(3939) "<p style="text-align: justify;"> Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль». </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3873) "

Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль».

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Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль».

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Introduction

Graft-versus-host disease (GVHD) prophylaxis based on calcineurin inhibitors (CNI), namely cyclosporin A and tacrolimus, was developed in 1980s by Donald Th omas group [1] and is still the standard of care in the majority of European centers [2]. Although tacrolimus and cyclosporin A have some diff erences in the effi cacy aft er unrelated hematopoietic stem cell transplantation (HSCT), there are no signifi cant differences between these two agents for matched related graft s in the majority of studies [3,4]. Th is type of prophylaxis results in grade II-IV acute GVHD and chronic GVHD in about 20-40% of patients undergoing HSCT from matched related donors (MRD) [5-7].
A recent study by Luznik et al. demonstrated that post-transplant cyclophosphamide (PTCy) could be used as single-agent GVHD prophylaxis for matched bone marrow graft s with relatively low incidence of acute and chronic GVHD [8]. Th is fi nding was subsequently confi rmed in a multicenter study [9]. Th e single-agent PTCy regimen is associated with low immunosuppression burden and relatively fast immunologic recovery, so it is anticipated to reduce the rate of infectious complications and potentiate graft -versus-leukemia (GVL) eff ect [10, 11]. However, no studies were published with direct comparison of the prophylaxis with CNIs and PTCy as the single agent. Th is retrospective study compares patients transplanted for malignant diseases with these two types of GVHD prophylaxis.

Patients and methods

Patients and transplantation procedures

183 patients transplanted in 2006-2016 at the First St.Petersburg State I. Pavlov Medical University were enrolled in the study. Only first allogeneic transplantations were included. All patients received 10/10 HLA-matched bone marrow graft from related donor. Th e Ethical Committee of Pavlov First St. Petersburg State Medical University approved the usage of PTCy as a single-agent for GVHD prophylaxis. All patients signed informed consent for the use of their medical data to research purposes. 78 subjects received PTCy, and 105 were administered either cyclosporine A or tacrolimus combined with a second immunosuppressive agent. 49% of patients had acute myeloid leukemia; 31%, acute lymphoblastic leukemia (ALL); 8%, chronic myeloid leukemia; 3%, myelodysplastic syndrome, and 8%, malignant lymphomas. 27% of patients underwent salvage transplantation, defi ned as acute leukemia without hematologic remission, chronic myeloid leukemia in blast crisis and lymphomas in less than partial remission status. Comparative clinical characteristics of the two groups are presented in Table 1. PTCy group comprised less ALL patients, less salvage patients and a significantly later year of transplant. Th e other characteristics were comparable. Median follow-up in the control group was 50 months (range 8 to 111); in the PTCy group, 24 months (range 5 to 41).

Table_1_Characteristics_of_patients_and_transplantation_conditions.png

Transplantation procedures

Myeloablative conditioning (MAC) was performed with oral busulfan at a dose of 16 mg/kg and cyclophosphamide (100-120 mg/kg). Reduced intensity conditioning (RIC) was performed with fl udarabine (180 mg/m2), and busulfan (8 mg/kg). Patients were assigned to RIC if they were 40 years or older, had HSCT-specifi c comorbidity index (HCTCI)≥ 2, grade >3 hepatic toxicity during induction therapy, or uncontrolled infection at the start of conditioning.
GVHD prophylaxis in the PTCy group consisted of single-agent cyclophosphamide (50 mg/kg) administered at days +3, +4. Mesna (50 mg/kg/day) was administered during the days of PTCy infusion. Glucocorticoid administration was prohibited from day -5 until day +5, except of cases with anaphylaxia and severe respiratory failure. In the groups with conventional prophylaxis, the patients received either tacrolimus with target concentrations of 5-15 ng/ml, or cyclosporine A, starting from the day -1, with target concentrations of 150-350 ng/ml. Th e second agent in the prophylaxis regimen was methotrexate administered as a short course (10-15 mg/m2) at days +1,+3,+6, or mycophenolate mofetil (MMF) 30 mg/kg from day -1 to day +30.
Supportive care included omeprasole 40 mg/day, acyclovir 600 mg/day, trimetoprim/sulfamethaxazole 960 mg/day, allopurinol and unfractionated heparin (100 IU/kg/day) starting day -7. In patients without previous history of invasive fungal infection, prophylaxis was done with fl uconazole (400 mg/day) starting on day 0, in patients with history or evidence of invasive aspergillosis, with voriconazole (400 mg/day) starting on day 0. Premedication before graft transfusion in the PTCy group was performed with metamesole 2 g and diphenhydramine 20 mg and steroids 1 mg/kg were added in the conventional prophylaxis group.

Clinical definitions

Time to disease relapse, acute GVHD (GVHD), moderate to severe chronic GVHD (cGVHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GVHD-relapse free survival (GRFS) were defi ned as the time from transplantation to the event. All these parameters were calculated for the two-year interval. Incidence of aGVHD was calculated at 125 days aft er HSCT, and the time frame for the other outcomes was three years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grade III-IV acute GVHD or systemic therapy-requiring chronic GVHD. Th e Consensus Conference criteria and NIH criteria were used for aGVHD and cGVHD grading, respectively [12, 13]. Primary graft failure was defined as a complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraft ment was calculated as a time period from HSCT to unsupported neutrophil count of >500/μl and white blood cell count >1000/μl for 3  onsecutive days. Toxicity was assessed with CTCAE ver. 4.03. Sepsis in the study was defi ned as systemic infl ammatory reaction with microbiologically confi rmed bacteremia. Th e multivariate correction was performed with Hematopoietic Cell Transplantation-specifi c Comorbidity Index (HCT-CI) [14] and disease risk index (DRI) by Armand et al. [15].

Statistical Analysis

Comparison of groups was performed by Chi-square test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. Th e comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGVHD, cGVHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate analysis was done using proportional hazard regression. Fine and Grey regression was used for the multivariate analysis of cumulative incidences [16]. Factors used for multivariate correction had at least p=0.15 significance in the univariate analysis. Heterogeneities between the hazard ratios in the subgroup analysis were tested for significance using the Cochran’s Q test, with df degrees of freedom. Incidence and severity of complications was compared using Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

Engraftment and graft-versus-host disease

Incidence of primary graft failure was not diff erent between groups (1.1 vs 1.6%, p=0.42). Nonetheless, engraft ment in the PTCy group was slower when assessed by neutrophil count (19 vs 24 days, p<0.001) and platelet count (17 vs 23 days, p=0.005). Acute GVHD grade II-IV was significantly less frequent in the PTCy group (8% vs 27%, p=0.0021, multivariate HR 0.239, 95% CI 0.099-0.58). The superiority of PTCy was also observed for grade III-IV acute GVHD (4% vs 15%, p=0.0040, multivariate HR 0.192, 95% CI 0.055-0.666) (Fig. 1). Incidence of grade I acute GVHD was not different (18% vs 13%, p=0.39) in the PTCy and conventional prophylaxis groups, respectively.
Moderate and severe chronic GVHD was not different between PTCy and CNIs groups (26% vs 30%, p=0.938, multivariate HR 0.898, 95% CI 0.477-1.69). Incidence of mild chronic GVHD was also not diff erent (9% vs 10%, p=0.60). Mortality, relapses and survival outcomes NRM was lower in the PTCy group in the univariate analysis (8% vs 22%, p=0.0195), although there was no diff erence when corrected for other variables (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Relapse incidence was not diff erent in the univariate analysis (40% vs 49%, p=0.0896) in the PTCy and CNIs groups, respectively. However, in the multivariate analysis the use of PTCy was associated with lower incidence of relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). These NRM and relapse incidence borderline improvements translated in superior OS (62% vs 41%, p=0.0027, multivariate HR 0.489, 95% CI 0.261-0.917), EFS (52% vs 31%, p=0.0013, multivariate HR 0.571, 95% CI 0.334-0.976) and GVHD-relapse-free survival (30% vs 12%, p=0.0006, multivariate HR 0.493, 95% CI 0.309-0.786) (Fig. 1).
Figure_1_Univariate_and_multivariate_analyses_of_transplantation_outcomes.png

Unadjusted parameters represent results of univariate analysis; adjusted parameters represent results of multivariate analysis. In the multivariate analyses, co-variables  or acute GVHD were as follows: intensity of the conditioning; age and female donor for male recipient. Co-variable for chronic moderate and severe (m&s) GVHD was only previous acute GVHD; co-variables for NRM were intensity of the conditioning, salvage status, HCT-CI, occurrence of severe sepsis, female donor for male recipient, development of transplant-associated microangiopathy and year of transplant; co-variables for Relapse incidence were acute GVHD, chronic GVHD, intensity of the conditioning, salvage status, DRI, reactivation of cytomegalovirus, age and time to engraft ment; co-variables for overall, event-free and GVHDrelapse- free survival were intensity of the conditioning, DRI, HCT-CI, CD34+ cells in the graft , severe sepsis, age and year of transplant.
The subgroup analysis of EFS demonstrated that signifi cant benefi t of PTCy prophylaxis was observed for both RIC (HR 0.57, p=0.0175) and MAC (HR 0.38, p=0.0259), patients with high DRI (HR 0.584, p=0.0385), patients younger than 40 years old (HR 0.497, p=0.0054), patients with acute leukemia (HR=0.545, p=0.089), non-salvage group (HR 0.609, p=0.0493) and donor-recipient pairs other than female to male (HR 0.516, p=0.0077). For the other subgroups, no significant diff erences were noted between PTCy and CNIbased prophylaxis, at least in the current study population (p>0.05), as seen in Fig. 2.

Figure_2_Subgroup_analysis_of_event-free_survival.png

Hazard ratio (HR) heterogeneity was calculated using Cochran’s Q test. Th e size of the marker represents the number of patients in the each subgroup.

Complications of transplantation

There was no difference in liver toxicity (p=0.08), neurotoxicity (p=0.11), incidence of hemorrhagic cystitis (13% vs 14%, p=0.38), veno-occlusive disease (p=0.19), sepsis (p=0.06), severe sepsis (p=0.77), invasive mycosis (p=0.07), CMV reactivation (p=0.84) and “overall” transplant-assocciated microangiopathy (TAM) according to Cho et al criteria (p=0.13) [17]. However, there was reduced incidence of nephrotoxicity in the PTCy group (33% vs 43%, p=0.0079), with no grade 3-4 cases observed in the PTCy group. A reduced incidence of mucositis was revealed aft er PTCy (78% vs 88%, p=0.0059), but grade 3 and 4 mucositis was more frequent in this group (41% vs 34%, p=0.0163). Th ere was a borderline significant increase of sepsis incidence aft er PTCy (29% vs 17%, p=0.0566), but similar incidence of severe sepsis (6% vs 5%, p=0.77).

Discussion

Despite previous reports of feasibility and safety of single-agent PTCy prophylaxis [8, 9] this is the fi rst to our knowledge comparison of this regimen to conventional regimen consisting of CNI and second other agent, like MMF or methotrexate. It should be mentioned that, when compared to previous studies, the incidence of grade II-IV acute GVHD was lower in our cohort (8% vs 43-51%). In the published trials, this could be explained by inclusion of patients with both related and unrelated graft s and by use of myeloablative therapy (MAC) in all the patients. In our study we included only related donors and majority of patients received RIC, which are the known factors that reduce GVHD incidence [18]. In this population of patients receiving predominantly RIC transplantation from related donor, a single-agent PTCy was associated with lower acute, but not chronic GVHD incidence. All of the other outcomes in this cohort were generally comparable to the previous reports [8,9] indicating the reproducibility of the results with single-agent PTCy.

We have observed a moderate superiority of PTCy, both in terms of NRM and relapse incidence, which, however, was translated into a signifi cant benefi t in OS, EFS and GFRS. The mechanisms underlying the improvement of results might include the reduced GVHD-related mortality, lower immunosuppression burden, preservation of certain T-cell antigen-specifi c subpopulations and faster development of graft -versus-leukemia (GVL) eff ect [19, 20]. Interestingly, 30% GRFS in the PTCy group indicate that one-third of the patients are cured without any further need for immunosuppression. However, the results of the study should be interpreted with caution because of its retrospective nature, inhomogeneous patient population, and diff erences in the time of transplant between the groups. Th e question whether single-agent PTCy is better than conventional prophylaxis should be addressed in a prospective clinical trial. The ongoing BMT CTN 1301 trial is addressing this issue, and the study completion is expected in 2021 [21].

The subgroup analysis revealed that the patients that benefit from PTCy are mostly young acute leukemia patients with high DRI. Th is could be explained by larger benefi t of GVL in this population of patients [22]. Absence of diff erences in the other patient populations might be due to a small sample size in these subgroups, since all non-signifi cant diff erences were observed in the smaller proportions of patients than did significant ones.

The analysis of clinical complications has shown a generally comparable safety profi le between PTCy-based and CNIbased prophylaxis. A reduced nephrotoxicity is anticipated, since calcineurin inhibitors are well-known agents causing acute kidney damage [23]. Our group had also reported the reduced TAM incidence in unrelated graft s with PTCy [24], but the diff erences were not statistically signifi cant in this patient cohort despite lower percentage (1% vs 5%). Larger studies are required to demonstrate that reduced acute GVHD incidence and absence of CNIs as well-known risk factors of TAM might diminish its occurence [25]. The alarming trend of higher sepsis incidence aft er PTCy might be a consequence of slower engraftment and longer neutropenia duration, but also, since PTCy group consisted of more recent transplantations, this might be due to improved sepsis diagnostics over time. Th e latter explanation might be more probable, because the incidence of bacteremia recently reported by other groups varies from 24 to 48% [26].

Conclusion

Despite the drawbacks of a single-center retrospective nature, our study in matched related bone marrow recipients has shown a reduced incidence of acute, but not chronic GVHD with single-agent PTCy compared to conventional GVHD prophylaxis. Moreover, the use of PTCy was associated with improved overall and event-free survival. Th ese fi ndings should be confi rmed in multicenter prospective randomized trials.

Financial Disclosure Statement

The authors have nothing to disclaim.

Acknowledgements and conflict of interests

The authors declare no confl ict of interest. We thank our nursing stuff and our patients for making this study possible.

References

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10. Kanakry CG, Bolaños-Meade J, Kasamon YL, Zahurak M, Durakovic N, Furlong T et al. Low immunosuppressive burden after HLA-matched related or unrelated
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11. Kanakry CG, Coff ey DG, Towlerton AM, Vulic A, Storer BE et al. Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight. 2016;1(5). pii: e86252. Epub 2016 Apr 21.
12. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Th omas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828.
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Introduction

Graft-versus-host disease (GVHD) prophylaxis based on calcineurin inhibitors (CNI), namely cyclosporin A and tacrolimus, was developed in 1980s by Donald Th omas group [1] and is still the standard of care in the majority of European centers [2]. Although tacrolimus and cyclosporin A have some diff erences in the effi cacy aft er unrelated hematopoietic stem cell transplantation (HSCT), there are no signifi cant differences between these two agents for matched related graft s in the majority of studies [3,4]. Th is type of prophylaxis results in grade II-IV acute GVHD and chronic GVHD in about 20-40% of patients undergoing HSCT from matched related donors (MRD) [5-7].
A recent study by Luznik et al. demonstrated that post-transplant cyclophosphamide (PTCy) could be used as single-agent GVHD prophylaxis for matched bone marrow graft s with relatively low incidence of acute and chronic GVHD [8]. Th is fi nding was subsequently confi rmed in a multicenter study [9]. Th e single-agent PTCy regimen is associated with low immunosuppression burden and relatively fast immunologic recovery, so it is anticipated to reduce the rate of infectious complications and potentiate graft -versus-leukemia (GVL) eff ect [10, 11]. However, no studies were published with direct comparison of the prophylaxis with CNIs and PTCy as the single agent. Th is retrospective study compares patients transplanted for malignant diseases with these two types of GVHD prophylaxis.

Patients and methods

Patients and transplantation procedures

183 patients transplanted in 2006-2016 at the First St.Petersburg State I. Pavlov Medical University were enrolled in the study. Only first allogeneic transplantations were included. All patients received 10/10 HLA-matched bone marrow graft from related donor. Th e Ethical Committee of Pavlov First St. Petersburg State Medical University approved the usage of PTCy as a single-agent for GVHD prophylaxis. All patients signed informed consent for the use of their medical data to research purposes. 78 subjects received PTCy, and 105 were administered either cyclosporine A or tacrolimus combined with a second immunosuppressive agent. 49% of patients had acute myeloid leukemia; 31%, acute lymphoblastic leukemia (ALL); 8%, chronic myeloid leukemia; 3%, myelodysplastic syndrome, and 8%, malignant lymphomas. 27% of patients underwent salvage transplantation, defi ned as acute leukemia without hematologic remission, chronic myeloid leukemia in blast crisis and lymphomas in less than partial remission status. Comparative clinical characteristics of the two groups are presented in Table 1. PTCy group comprised less ALL patients, less salvage patients and a significantly later year of transplant. Th e other characteristics were comparable. Median follow-up in the control group was 50 months (range 8 to 111); in the PTCy group, 24 months (range 5 to 41).

Table_1_Characteristics_of_patients_and_transplantation_conditions.png

Transplantation procedures

Myeloablative conditioning (MAC) was performed with oral busulfan at a dose of 16 mg/kg and cyclophosphamide (100-120 mg/kg). Reduced intensity conditioning (RIC) was performed with fl udarabine (180 mg/m2), and busulfan (8 mg/kg). Patients were assigned to RIC if they were 40 years or older, had HSCT-specifi c comorbidity index (HCTCI)≥ 2, grade >3 hepatic toxicity during induction therapy, or uncontrolled infection at the start of conditioning.
GVHD prophylaxis in the PTCy group consisted of single-agent cyclophosphamide (50 mg/kg) administered at days +3, +4. Mesna (50 mg/kg/day) was administered during the days of PTCy infusion. Glucocorticoid administration was prohibited from day -5 until day +5, except of cases with anaphylaxia and severe respiratory failure. In the groups with conventional prophylaxis, the patients received either tacrolimus with target concentrations of 5-15 ng/ml, or cyclosporine A, starting from the day -1, with target concentrations of 150-350 ng/ml. Th e second agent in the prophylaxis regimen was methotrexate administered as a short course (10-15 mg/m2) at days +1,+3,+6, or mycophenolate mofetil (MMF) 30 mg/kg from day -1 to day +30.
Supportive care included omeprasole 40 mg/day, acyclovir 600 mg/day, trimetoprim/sulfamethaxazole 960 mg/day, allopurinol and unfractionated heparin (100 IU/kg/day) starting day -7. In patients without previous history of invasive fungal infection, prophylaxis was done with fl uconazole (400 mg/day) starting on day 0, in patients with history or evidence of invasive aspergillosis, with voriconazole (400 mg/day) starting on day 0. Premedication before graft transfusion in the PTCy group was performed with metamesole 2 g and diphenhydramine 20 mg and steroids 1 mg/kg were added in the conventional prophylaxis group.

Clinical definitions

Time to disease relapse, acute GVHD (GVHD), moderate to severe chronic GVHD (cGVHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GVHD-relapse free survival (GRFS) were defi ned as the time from transplantation to the event. All these parameters were calculated for the two-year interval. Incidence of aGVHD was calculated at 125 days aft er HSCT, and the time frame for the other outcomes was three years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grade III-IV acute GVHD or systemic therapy-requiring chronic GVHD. Th e Consensus Conference criteria and NIH criteria were used for aGVHD and cGVHD grading, respectively [12, 13]. Primary graft failure was defined as a complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraft ment was calculated as a time period from HSCT to unsupported neutrophil count of >500/μl and white blood cell count >1000/μl for 3  onsecutive days. Toxicity was assessed with CTCAE ver. 4.03. Sepsis in the study was defi ned as systemic infl ammatory reaction with microbiologically confi rmed bacteremia. Th e multivariate correction was performed with Hematopoietic Cell Transplantation-specifi c Comorbidity Index (HCT-CI) [14] and disease risk index (DRI) by Armand et al. [15].

Statistical Analysis

Comparison of groups was performed by Chi-square test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. Th e comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGVHD, cGVHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate analysis was done using proportional hazard regression. Fine and Grey regression was used for the multivariate analysis of cumulative incidences [16]. Factors used for multivariate correction had at least p=0.15 significance in the univariate analysis. Heterogeneities between the hazard ratios in the subgroup analysis were tested for significance using the Cochran’s Q test, with df degrees of freedom. Incidence and severity of complications was compared using Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

Engraftment and graft-versus-host disease

Incidence of primary graft failure was not diff erent between groups (1.1 vs 1.6%, p=0.42). Nonetheless, engraft ment in the PTCy group was slower when assessed by neutrophil count (19 vs 24 days, p<0.001) and platelet count (17 vs 23 days, p=0.005). Acute GVHD grade II-IV was significantly less frequent in the PTCy group (8% vs 27%, p=0.0021, multivariate HR 0.239, 95% CI 0.099-0.58). The superiority of PTCy was also observed for grade III-IV acute GVHD (4% vs 15%, p=0.0040, multivariate HR 0.192, 95% CI 0.055-0.666) (Fig. 1). Incidence of grade I acute GVHD was not different (18% vs 13%, p=0.39) in the PTCy and conventional prophylaxis groups, respectively.
Moderate and severe chronic GVHD was not different between PTCy and CNIs groups (26% vs 30%, p=0.938, multivariate HR 0.898, 95% CI 0.477-1.69). Incidence of mild chronic GVHD was also not diff erent (9% vs 10%, p=0.60). Mortality, relapses and survival outcomes NRM was lower in the PTCy group in the univariate analysis (8% vs 22%, p=0.0195), although there was no diff erence when corrected for other variables (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Relapse incidence was not diff erent in the univariate analysis (40% vs 49%, p=0.0896) in the PTCy and CNIs groups, respectively. However, in the multivariate analysis the use of PTCy was associated with lower incidence of relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). These NRM and relapse incidence borderline improvements translated in superior OS (62% vs 41%, p=0.0027, multivariate HR 0.489, 95% CI 0.261-0.917), EFS (52% vs 31%, p=0.0013, multivariate HR 0.571, 95% CI 0.334-0.976) and GVHD-relapse-free survival (30% vs 12%, p=0.0006, multivariate HR 0.493, 95% CI 0.309-0.786) (Fig. 1).
Figure_1_Univariate_and_multivariate_analyses_of_transplantation_outcomes.png

Unadjusted parameters represent results of univariate analysis; adjusted parameters represent results of multivariate analysis. In the multivariate analyses, co-variables  or acute GVHD were as follows: intensity of the conditioning; age and female donor for male recipient. Co-variable for chronic moderate and severe (m&s) GVHD was only previous acute GVHD; co-variables for NRM were intensity of the conditioning, salvage status, HCT-CI, occurrence of severe sepsis, female donor for male recipient, development of transplant-associated microangiopathy and year of transplant; co-variables for Relapse incidence were acute GVHD, chronic GVHD, intensity of the conditioning, salvage status, DRI, reactivation of cytomegalovirus, age and time to engraft ment; co-variables for overall, event-free and GVHDrelapse- free survival were intensity of the conditioning, DRI, HCT-CI, CD34+ cells in the graft , severe sepsis, age and year of transplant.
The subgroup analysis of EFS demonstrated that signifi cant benefi t of PTCy prophylaxis was observed for both RIC (HR 0.57, p=0.0175) and MAC (HR 0.38, p=0.0259), patients with high DRI (HR 0.584, p=0.0385), patients younger than 40 years old (HR 0.497, p=0.0054), patients with acute leukemia (HR=0.545, p=0.089), non-salvage group (HR 0.609, p=0.0493) and donor-recipient pairs other than female to male (HR 0.516, p=0.0077). For the other subgroups, no significant diff erences were noted between PTCy and CNIbased prophylaxis, at least in the current study population (p>0.05), as seen in Fig. 2.

Figure_2_Subgroup_analysis_of_event-free_survival.png

Hazard ratio (HR) heterogeneity was calculated using Cochran’s Q test. Th e size of the marker represents the number of patients in the each subgroup.

Complications of transplantation

There was no difference in liver toxicity (p=0.08), neurotoxicity (p=0.11), incidence of hemorrhagic cystitis (13% vs 14%, p=0.38), veno-occlusive disease (p=0.19), sepsis (p=0.06), severe sepsis (p=0.77), invasive mycosis (p=0.07), CMV reactivation (p=0.84) and “overall” transplant-assocciated microangiopathy (TAM) according to Cho et al criteria (p=0.13) [17]. However, there was reduced incidence of nephrotoxicity in the PTCy group (33% vs 43%, p=0.0079), with no grade 3-4 cases observed in the PTCy group. A reduced incidence of mucositis was revealed aft er PTCy (78% vs 88%, p=0.0059), but grade 3 and 4 mucositis was more frequent in this group (41% vs 34%, p=0.0163). Th ere was a borderline significant increase of sepsis incidence aft er PTCy (29% vs 17%, p=0.0566), but similar incidence of severe sepsis (6% vs 5%, p=0.77).

Discussion

Despite previous reports of feasibility and safety of single-agent PTCy prophylaxis [8, 9] this is the fi rst to our knowledge comparison of this regimen to conventional regimen consisting of CNI and second other agent, like MMF or methotrexate. It should be mentioned that, when compared to previous studies, the incidence of grade II-IV acute GVHD was lower in our cohort (8% vs 43-51%). In the published trials, this could be explained by inclusion of patients with both related and unrelated graft s and by use of myeloablative therapy (MAC) in all the patients. In our study we included only related donors and majority of patients received RIC, which are the known factors that reduce GVHD incidence [18]. In this population of patients receiving predominantly RIC transplantation from related donor, a single-agent PTCy was associated with lower acute, but not chronic GVHD incidence. All of the other outcomes in this cohort were generally comparable to the previous reports [8,9] indicating the reproducibility of the results with single-agent PTCy.

We have observed a moderate superiority of PTCy, both in terms of NRM and relapse incidence, which, however, was translated into a signifi cant benefi t in OS, EFS and GFRS. The mechanisms underlying the improvement of results might include the reduced GVHD-related mortality, lower immunosuppression burden, preservation of certain T-cell antigen-specifi c subpopulations and faster development of graft -versus-leukemia (GVL) eff ect [19, 20]. Interestingly, 30% GRFS in the PTCy group indicate that one-third of the patients are cured without any further need for immunosuppression. However, the results of the study should be interpreted with caution because of its retrospective nature, inhomogeneous patient population, and diff erences in the time of transplant between the groups. Th e question whether single-agent PTCy is better than conventional prophylaxis should be addressed in a prospective clinical trial. The ongoing BMT CTN 1301 trial is addressing this issue, and the study completion is expected in 2021 [21].

The subgroup analysis revealed that the patients that benefit from PTCy are mostly young acute leukemia patients with high DRI. Th is could be explained by larger benefi t of GVL in this population of patients [22]. Absence of diff erences in the other patient populations might be due to a small sample size in these subgroups, since all non-signifi cant diff erences were observed in the smaller proportions of patients than did significant ones.

The analysis of clinical complications has shown a generally comparable safety profi le between PTCy-based and CNIbased prophylaxis. A reduced nephrotoxicity is anticipated, since calcineurin inhibitors are well-known agents causing acute kidney damage [23]. Our group had also reported the reduced TAM incidence in unrelated graft s with PTCy [24], but the diff erences were not statistically signifi cant in this patient cohort despite lower percentage (1% vs 5%). Larger studies are required to demonstrate that reduced acute GVHD incidence and absence of CNIs as well-known risk factors of TAM might diminish its occurence [25]. The alarming trend of higher sepsis incidence aft er PTCy might be a consequence of slower engraftment and longer neutropenia duration, but also, since PTCy group consisted of more recent transplantations, this might be due to improved sepsis diagnostics over time. Th e latter explanation might be more probable, because the incidence of bacteremia recently reported by other groups varies from 24 to 48% [26].

Conclusion

Despite the drawbacks of a single-center retrospective nature, our study in matched related bone marrow recipients has shown a reduced incidence of acute, but not chronic GVHD with single-agent PTCy compared to conventional GVHD prophylaxis. Moreover, the use of PTCy was associated with improved overall and event-free survival. Th ese fi ndings should be confi rmed in multicenter prospective randomized trials.

Financial Disclosure Statement

The authors have nothing to disclaim.

Acknowledgements and conflict of interests

The authors declare no confl ict of interest. We thank our nursing stuff and our patients for making this study possible.

References

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Моисеев<sup>1</sup>,<sup>2</sup>, Ольга В. Пирогова<sup>1</sup>, Елена В. Бабенко<sup>1</sup>, Елена И. Дарская<sup>1</sup>, Елена В. Морозова,<sup>1</sup>,<sup>2</sup>, Сергей Н. Бондаренко<sup>1</sup>, Борис В. Афанасьев<sup>1</sup>,<sup>2</sup>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(353) "Иван С. Моисеев1,2, Ольга В. Пирогова1, Елена В. Бабенко1, Елена И. Дарская1, Елена В. Морозова,1,2, Сергей Н. Бондаренко1, Борис В. Афанасьев1,2" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20022" ["VALUE"]=> array(2) { ["TEXT"]=> string(528) "<sup>1</sup>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой<br> <sup>2</sup>Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(498) "1НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой
2Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20023" ["VALUE"]=> array(2) { ["TEXT"]=> string(4071) "<p style="text-align: justify;"> В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4005) "

В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании.

Ключевые слова

Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20026" ["VALUE"]=> array(2) { ["TEXT"]=> string(350) "<sup>1</sup>R. M. Gorbacheva Memorial Institute of Children Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University<br> <sup>2</sup>Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(320) "1R. M. Gorbacheva Memorial Institute of Children Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University
2Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20027" ["VALUE"]=> array(2) { ["TEXT"]=> string(2134) "<p style="text-align: justify;"> A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2068) "

A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials.

Keywords

Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis.

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Moiseev<sup>1</sup>,<sup>2</sup>, Olga V. Pirogova<sup>1</sup>, Elena V. Babenko<sup>1</sup>, Tatyana L. Gindina<sup>1</sup>, Elena I. Darskaya<sup>1</sup>, Elena V. Morozova<sup>1</sup>,<sup>2</sup>, Sergey N. Bondarenko<sup>1</sup>, Boris V. Afanasyev<sup>1</sup>,<sup>2</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(290) "Ivan S. Moiseev1,2, Olga V. Pirogova1, Elena V. Babenko1, Tatyana L. Gindina1, Elena I. Darskaya1, Elena V. Morozova1,2, Sergey N. Bondarenko1, Boris V. Afanasyev1,2
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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20027" ["VALUE"]=> array(2) { ["TEXT"]=> string(2134) "<p style="text-align: justify;"> A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2068) "

A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials.

Keywords

Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2068) "

A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials.

Keywords

Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis.

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2Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(320) "1R. M. Gorbacheva Memorial Institute of Children Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University
2Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20021" ["VALUE"]=> array(2) { ["TEXT"]=> string(473) "Иван С. Моисеев<sup>1</sup>,<sup>2</sup>, Ольга В. Пирогова<sup>1</sup>, Елена В. Бабенко<sup>1</sup>, Елена И. Дарская<sup>1</sup>, Елена В. Морозова,<sup>1</sup>,<sup>2</sup>, Сергей Н. Бондаренко<sup>1</sup>, Борис В. Афанасьев<sup>1</sup>,<sup>2</sup>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(353) "Иван С. Моисеев1,2, Ольга В. Пирогова1, Елена В. Бабенко1, Елена И. Дарская1, Елена В. Морозова,1,2, Сергей Н. Бондаренко1, Борис В. Афанасьев1,2" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(353) "Иван С. Моисеев1,2, Ольга В. Пирогова1, Елена В. Бабенко1, Елена И. Дарская1, Елена В. Морозова,1,2, Сергей Н. Бондаренко1, Борис В. Афанасьев1,2" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20023" ["VALUE"]=> array(2) { ["TEXT"]=> string(4071) "<p style="text-align: justify;"> В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4005) "

В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании.

Ключевые слова

Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика.

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В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании.

Ключевые слова

Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика.

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Introduction

Primary immunodefi ciency (PID) is a relatively rare medical condition that oft en mimics infectious, autoimmune or malignant diseases. Common variable immunodefi ciency is the most common PID in children aft er 4 years of age and adults. Inherited CVID is revealed in only 20% of patients, showing autosomal recessive or autosomal dominant inheritance, while the rest of cases seem to occur sporadically [1]. In 2014, diagnostic criteria for CVID were revised by European Society of Immune Defi ciencies (ESID), and its major features were established (Table 1). Th ose signs include increased susceptibility to infections, autoimmune manifestations, unexplained polyclonal lymphoproliferation, marked decrease of IgG and IgA with or without low IgM levels, poor antibody response to vaccines (and/or absent isohemagglutinins), low switched memory B cells. Secondary hypogammaglobulinemia should be excluded. Variable manifestations reflect a possibly diff erent genetic background of the disease. At the present time, however, any specifi c mutations can be detected only in 30% of CVID cases, even with such a comprehensive method as whole exome sequencing [2].
Incidence of CVID is ca. 1 case per 30.000 European population. Clinical manifestation of the disease may be at any age, with a fi rst peak at 5 to 10 years and second, between 20 and 30 years. [3]. Common variable immunodefi ciency is oft en diagnosed in children, being associated with high mortality in this group. [4]. Diagnostic criteria have been established, aiming to suspect PID in children including frequent infections of ears, sinuses and lungs, recurrent abscesses, persistent rash aft er fi rst year of age, ineffi ciency of long-lasting treatment with antibiotics, inability to gain weight and growth, as well as family history of PID. Despite awareness of health care providers, a delay of several years is observed between first symptoms and diagnosis of PID [5]. This fact demonstrates that CVID is a diagnostic challenge, since it is often not considered. During diagnostic search, a wide spectrum of disorders may be considered at diff erential diagnosis. Detection of antibody defi ciency is an important clue to suggest a CVID diagnosis. In general, CVID may be regarded as a diagnosis of exclusion. Autoimmune complications are, generally, common in PID and may manifest as initial symptoms in some cases. Only 25% of CVID patients present with common infections as the only symptom. In most cases, the CVID symptoms are associated with immune dysregulation [6]. Benign generalized hypertrophy of lymphoid tissues is more common in CVID than lymphoma [7]. Lungs are aff ected by infections and uncontrollable infl ammation in up to 30%, and early development of bronchiectasis is often a key to CVID diagnosis [8].
Table_1_Revised_ESID_2014_diagnostic_criteria_for_CVID.png
The main approaches to CVID management are IVIG replacement therapy, adequate infectious control and, in severe cases, immunosuppressive treatment. Th e only option to cure CVID is allogeneic hematopoietic stem cell transplantation, but its administration is rather limited in this clinical setting due to high toxicity. In case of severe and refractory hemolytic anemia, splenectomy may be a treatment option. Th erefore, existence of life-saving management strategies, together with timely diagnosis increases chances for treatment success and underlines the necessity of awareness among medical staff [9].
In this report, we present a clinical case of a child with CVID which manifested with multiple autoimmune problems and progressive lung disease.

Case description

A 10-year-old female patient (PKD) with severe pancytopenia, giant splenomegaly, generalized lymphadenopathy, multiple lesions in lungs and febrile neutropenia was admitted to clinic R.Gorbacheva Memorial Institute with preliminary diagnosis of unverifi ed hemoblastosis in March 2016. The initial diagnosis was suspected based on above mentioned characteristic clinical symptoms and laboratory data (Table 2-5). Analysis demonstrated moderate anemia, leukopenia and thrombocytopenia, slightly elevated transaminases and triglycerides, decreased fibrinogen and immunoglobulins. At the moment the most probable diagnosis consistent with laboratory fi ndings was hematological disorder. Hypogammaglobulinemia at that time was explained as a consequence of lymphopenia and wasn’t attributed to primary immunodeficiency. No cases of PID were reported in the family history. The child didn’t previously suff er from recurrent or unusual or seasonal infections. At the age of 6 years, the patient had an episode of autoimmune hemolytic anemia which responded to Prednisolone treatment. Severe hemolytic anemia was the only registered autoimmune disorder phenomenon that never relapsed.
Diagnostic workup allowed to exclude bone marrow involvement. Bone marrow aspirate and trephine biopsy showed no signs of clonal proliferation or aplasia. Cytogenetic analysis of bone marrow demonstrated normal karyotype. Molecular-biologic analyses of genes associated with hemoblastosis (t8;21, inv16, t15;17, t9;22, FLT3, NPM1, WT1, EVI-1, MLL, t4;11, del (1) SIL/TAL, t1;19, t9;22, t12;21) were negative. Lymphoproliferative disorder was suspected as a possible primary diagnosis due to generalized lymphadenopathy and splenomegaly.
Table_2_Blood_counts_in_the_patient.png
Table_3_Biochemical_analysis_of_blood.png
Table_4_Blood_Level_of_Immunoglobulins.png
Table_5_Immunophenotyping_of_lymphocytes.png
Giant splenomegaly with hypersplenism that resulted in life-threatening severe pancytopenia were indications for splenectomy with dissection of enlarged regional lymph nodes. It appeared to be a therapeutic and diagnostic option. Splenectomy performed at 5th May 2016 was followed by recovery of peripheral blood counts, but hypogammaglobulinemia still persisted despite normal lymphocyte counts (See Fig. 1 for dynamics of immunoglobulins and lymphocytes). Aft er splenectomy, total number of lymphocytes raised above 1000 cells per mcL, and all major lymphocyte subpopulations raised to normal ranges (number of CD4+ > 300 cells per mcL; number of CD8+ cells > 250 per mcL, number of CD19+ cells > 170 per mcL, and number of CD56+ cells > 70 cells per mcL).
Histological and immunohistochemical analysis of removed spleen and lymph nodes demonstrated non-specifi c reactive changes that were not associated with any malignant disease (revised by 2 independent pathologists: Prof. V. V. Baykov and Prof. U. A. Krivolapov). Presence of enterovirus and Herpes simplex type 1/2 virus was shown in spleen and lymph nodes by PCR assays and confi rmed by immunohistochemistry. Blood samples were negative for viral, bacterial and fungal infections.
CT scanning prior to splenectomy revealed generalized lymphadenopathy of mediastinal and abdominal lymph nodes (Fig. 2A), and multiple lesions in lungs (Fig. 2B). Repeated microbiological cultures of bronchoalveolar lavage still were negative for bacterial, viral and fungal pathogens. Since the patient has recently travelled to Egypt, visceral leishmaniosis was also suspected, due to fever, hepatosplenomegaly and pancytopenia evolving after the trip. However, hypogammaglobulinemia (instead of hypergammaglobulinemia typical to leishmaniosis), negative serological and PCR results, as well as absence of leishmania species in bone marrow aspirate allowed to rule out this diagnosis.
Figure_1_Time_course_of_lymphocyte_counts_x103_per__956_L__and_IgG_levels_g_L.png
Figure_2_Computer_tomography_scans_of_mediastinal_structures_2A_and_lungs_2B.png
A, mediastinal lymphadenopathy with enlarged lymph nodes marked with black arrows.
B, multiple lesions in lungs in a patient with CVID. Numerous chaotic lesions (maximal size of 12х10 mm) are registered in lungs, with indefi nite margins and peribronchial wall thickening.

The diagnostic search also included Gaucher disease. Analysis of glucocerebrosidase activity in blood was performed at the Research Centre for Medical Genetics (Russian Academy of Sciences, Moscow). The enzyme activity was within reference ranges, without a decrease typical to this genetic disorder.
The patient remained diagnostically unclear. There was no defi nitive evidence of malignancy, thus three non-malignant disorders were considered in differential diagnosis at the moment. They included: hemophagocytic lymphohistiocytosis (HLH), autoimmune lymphoproliferative syndrome (ALPS), and a primary immunodefi ciency (PID). All these diseases share joint clinical signs and pathogenic mechanisms, being attributed to a common class of primary immunodefi ciency syndromes [10].
HLH is a real problem for health care providers, in terms of diagnostic and therapeutic issues. Our patient had four criteria consistent with HLH: fever, splenomegaly, cytopenia and hypertriglyceridemia with hypofi brinogenemia (Tables 2 and 3). Hemophagocytosis in bone marrow or spleen, hyperferritinemia and HLH-specifi c mutations were absent (PRF1, STXBP2, STX1, UNC13D), NK-cell activity in peripheral blood was normal. To establish diagnosis, according to Revised Diagnostic Guidelines for HLH, at least five of diagnostic criteria should be fulfilled, or HLH mutations should be present [11]. Hence, HLH was dismissed because only 4 criteria were present in the patient.
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by malfunction in apoptosis of lymphocytes that leads to excessive lymphoproliferation. Presence of lymphadenopathy and splenomegaly, hemolytic anemia in previous history are characteristic to ALPS, but low level of double-negative CD3+/CD8-/CD4-/TCRαβ+ mature lymphocytes in peripheral blood was not consistent with this diagnosis. Mutations in FAS gene were not found upon whole genome sequencing (University of Dusseldorf, see data in Appendix). Absence of double-negative T lymphocytes and mutations in FAS gene made the diagnosis of ALPS very unlikely.
Due to severe persistent hypogammaglobinemia in the patient, a work-up for CVID was done. Absolute count of switched memory B-cells was checked (0.48%), and it proved to be decreased (reference range 1-40%) that is consistent with diagnosis of CVID (Table 5).
The whole exome sequencing of the patient leukocytes has been performed at University of Dusseldorf using the primary Immunodefi ciency gene panel. The screening did not reveal any candidate genes considered related to primary immunodeficiency, autoimmune lymphoproliferative disorder, HLH or inherited lung disorders (Table 6).

Discussion

According to the established clinical criteria (Table 1), a CVID diagnosis was confi rmed, based on persisting hypogammaglobulinemia, decreased count of switched memory B-cells (CD27+IgM-IgG-), autoimmune complications (hemolytic anemia) and non-malignant lymphoproliferative syndrome. Lung involvement shown in the child may occur in 30% of patients with CVID, being an unfavorable prognostic sign. Sarcoid-like granuloma, organizing pneumonia, lymphocytic interstitial pneumonitis and nonspecifi c interstitial pneumonia are the most common types of histological fi ndings in aff ected lungs of CVID patients [13]. Hence, the CVID diagnosis is based on constellation of several non-specifi c criteria, while excluding other, less probable, clinical conditions.
The patient is now receiving regular infusions of intravenous immunoglobulins and level of immunoglobulin G is maintained at normal values. However, pulmonary complications of CVID still persist and slowly diminish with time. Lung biopsy has been performed, demonstrating granulomatous pneumonitis without any signs of malignancy. Immunosuppression with Rituximab was initiated due to progressing autoimmune problems and respiratory failure. The granulomatous pneumonitis is currently the only one and leading autoimmune disorder in the patient.
Table_6_Genetic_background_of_CVID_ALPS_and_HLH_12.png
Prognosis for the presented patient is uncertain due to progressive lung involvement. Further treatment options may consist of glucocorticosteroids, cyclosporine A, sirolimus, cyclophosphamide, hydroxychloroquine, azathioprine, methotrexate, etanercept, infl iximab and other immunosuppressive agents. If further respiratory deterioration will occur despite immunosuppressive treatment and IVIG, allogeneic hematopoietic stem cell transplantation and lung transplantation may be considerable options in this patient.

Conclusion

The present case report describes a 10-year old girl with major internationally approved criteria of common variable immunodefi ciency (CVID), and specifi c lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion, the attending doctor should suspect PID in clinical settings in cases of hypogammaglobulinaemia, non-specified lymphoproliferation, autoimmune features and absence of malignant disorder.

Acknowledgements

Th e authors are much appreciated to Dr. Ute Fischer from the University of Düsseldorf (Germany) who performed whole exome sequencing in this patient, and to thank Dr. Polina Stepensky from Hadassah Medical Center, Jerusalem (Israel) for valuable advices on this diagnostic procedure for the patient.

Conflicts of interest

No conflict interests are declared.

References

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6. Aleinikova OV, Fedorova AS, Sharapova SO. Should allogeneic hematopoietic stem cell transplantation be a treatment option for patients with Nijmegen breakage syndrome? Belarusian experience. Cell Th er Transplant. 2015; 4(1-2):31-36.
7. Gompels MM, Hodges E, Lock RJ, Angus B, White H, Larkin A, Chapel HM, Spicett GP, Misbah SA, Smith JL. Lymphoproliferative disease in antibody defi ciency: a multi- centre study, Associated Study Group. Clin Exp Immunol. 2003; 134(2): 314–320.
8. Busse PJ, Farzan S, Cunningham-Rundles C. Pulmonary complications of common variable immunodefi ciency. Ann Allergy Asthma Immunol. 2007;98(1):1-8; quiz 8-11, 43.
9. Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J. Intravenous immunoglobulins in immunodefi ciencies: more than mere replacement therapy. Clin Exp Immunol. 2011;164 Suppl 2:2-5.
10. Al-Herz W, Bousfi ha A, Casanova J-L, Chatila T, Conley M E, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM., Sullivan K, Tang MLK. Primary immunodefi ciency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodefi ciency. Front Immunol. 2014; 5:162.
11. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediat Blood Cancer. 2007;48(2):124-131.
12. Ochs D. Hans et al. Primary Immunodefi ciency diseases. A Molecular and Genetic Approach (3rd Edition). 2014. Publisher: Oxford University Press.
13. Prasse A, Kayser G, Warnatz K. Common variable immunodeficiency-associated granulomatous and interstitiallung disease. Curr Opin Pulm Med. 2013;19(5):503-509.

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Introduction

Primary immunodefi ciency (PID) is a relatively rare medical condition that oft en mimics infectious, autoimmune or malignant diseases. Common variable immunodefi ciency is the most common PID in children aft er 4 years of age and adults. Inherited CVID is revealed in only 20% of patients, showing autosomal recessive or autosomal dominant inheritance, while the rest of cases seem to occur sporadically [1]. In 2014, diagnostic criteria for CVID were revised by European Society of Immune Defi ciencies (ESID), and its major features were established (Table 1). Th ose signs include increased susceptibility to infections, autoimmune manifestations, unexplained polyclonal lymphoproliferation, marked decrease of IgG and IgA with or without low IgM levels, poor antibody response to vaccines (and/or absent isohemagglutinins), low switched memory B cells. Secondary hypogammaglobulinemia should be excluded. Variable manifestations reflect a possibly diff erent genetic background of the disease. At the present time, however, any specifi c mutations can be detected only in 30% of CVID cases, even with such a comprehensive method as whole exome sequencing [2].
Incidence of CVID is ca. 1 case per 30.000 European population. Clinical manifestation of the disease may be at any age, with a fi rst peak at 5 to 10 years and second, between 20 and 30 years. [3]. Common variable immunodefi ciency is oft en diagnosed in children, being associated with high mortality in this group. [4]. Diagnostic criteria have been established, aiming to suspect PID in children including frequent infections of ears, sinuses and lungs, recurrent abscesses, persistent rash aft er fi rst year of age, ineffi ciency of long-lasting treatment with antibiotics, inability to gain weight and growth, as well as family history of PID. Despite awareness of health care providers, a delay of several years is observed between first symptoms and diagnosis of PID [5]. This fact demonstrates that CVID is a diagnostic challenge, since it is often not considered. During diagnostic search, a wide spectrum of disorders may be considered at diff erential diagnosis. Detection of antibody defi ciency is an important clue to suggest a CVID diagnosis. In general, CVID may be regarded as a diagnosis of exclusion. Autoimmune complications are, generally, common in PID and may manifest as initial symptoms in some cases. Only 25% of CVID patients present with common infections as the only symptom. In most cases, the CVID symptoms are associated with immune dysregulation [6]. Benign generalized hypertrophy of lymphoid tissues is more common in CVID than lymphoma [7]. Lungs are aff ected by infections and uncontrollable infl ammation in up to 30%, and early development of bronchiectasis is often a key to CVID diagnosis [8].
Table_1_Revised_ESID_2014_diagnostic_criteria_for_CVID.png
The main approaches to CVID management are IVIG replacement therapy, adequate infectious control and, in severe cases, immunosuppressive treatment. Th e only option to cure CVID is allogeneic hematopoietic stem cell transplantation, but its administration is rather limited in this clinical setting due to high toxicity. In case of severe and refractory hemolytic anemia, splenectomy may be a treatment option. Th erefore, existence of life-saving management strategies, together with timely diagnosis increases chances for treatment success and underlines the necessity of awareness among medical staff [9].
In this report, we present a clinical case of a child with CVID which manifested with multiple autoimmune problems and progressive lung disease.

Case description

A 10-year-old female patient (PKD) with severe pancytopenia, giant splenomegaly, generalized lymphadenopathy, multiple lesions in lungs and febrile neutropenia was admitted to clinic R.Gorbacheva Memorial Institute with preliminary diagnosis of unverifi ed hemoblastosis in March 2016. The initial diagnosis was suspected based on above mentioned characteristic clinical symptoms and laboratory data (Table 2-5). Analysis demonstrated moderate anemia, leukopenia and thrombocytopenia, slightly elevated transaminases and triglycerides, decreased fibrinogen and immunoglobulins. At the moment the most probable diagnosis consistent with laboratory fi ndings was hematological disorder. Hypogammaglobulinemia at that time was explained as a consequence of lymphopenia and wasn’t attributed to primary immunodeficiency. No cases of PID were reported in the family history. The child didn’t previously suff er from recurrent or unusual or seasonal infections. At the age of 6 years, the patient had an episode of autoimmune hemolytic anemia which responded to Prednisolone treatment. Severe hemolytic anemia was the only registered autoimmune disorder phenomenon that never relapsed.
Diagnostic workup allowed to exclude bone marrow involvement. Bone marrow aspirate and trephine biopsy showed no signs of clonal proliferation or aplasia. Cytogenetic analysis of bone marrow demonstrated normal karyotype. Molecular-biologic analyses of genes associated with hemoblastosis (t8;21, inv16, t15;17, t9;22, FLT3, NPM1, WT1, EVI-1, MLL, t4;11, del (1) SIL/TAL, t1;19, t9;22, t12;21) were negative. Lymphoproliferative disorder was suspected as a possible primary diagnosis due to generalized lymphadenopathy and splenomegaly.
Table_2_Blood_counts_in_the_patient.png
Table_3_Biochemical_analysis_of_blood.png
Table_4_Blood_Level_of_Immunoglobulins.png
Table_5_Immunophenotyping_of_lymphocytes.png
Giant splenomegaly with hypersplenism that resulted in life-threatening severe pancytopenia were indications for splenectomy with dissection of enlarged regional lymph nodes. It appeared to be a therapeutic and diagnostic option. Splenectomy performed at 5th May 2016 was followed by recovery of peripheral blood counts, but hypogammaglobulinemia still persisted despite normal lymphocyte counts (See Fig. 1 for dynamics of immunoglobulins and lymphocytes). Aft er splenectomy, total number of lymphocytes raised above 1000 cells per mcL, and all major lymphocyte subpopulations raised to normal ranges (number of CD4+ > 300 cells per mcL; number of CD8+ cells > 250 per mcL, number of CD19+ cells > 170 per mcL, and number of CD56+ cells > 70 cells per mcL).
Histological and immunohistochemical analysis of removed spleen and lymph nodes demonstrated non-specifi c reactive changes that were not associated with any malignant disease (revised by 2 independent pathologists: Prof. V. V. Baykov and Prof. U. A. Krivolapov). Presence of enterovirus and Herpes simplex type 1/2 virus was shown in spleen and lymph nodes by PCR assays and confi rmed by immunohistochemistry. Blood samples were negative for viral, bacterial and fungal infections.
CT scanning prior to splenectomy revealed generalized lymphadenopathy of mediastinal and abdominal lymph nodes (Fig. 2A), and multiple lesions in lungs (Fig. 2B). Repeated microbiological cultures of bronchoalveolar lavage still were negative for bacterial, viral and fungal pathogens. Since the patient has recently travelled to Egypt, visceral leishmaniosis was also suspected, due to fever, hepatosplenomegaly and pancytopenia evolving after the trip. However, hypogammaglobulinemia (instead of hypergammaglobulinemia typical to leishmaniosis), negative serological and PCR results, as well as absence of leishmania species in bone marrow aspirate allowed to rule out this diagnosis.
Figure_1_Time_course_of_lymphocyte_counts_x103_per__956_L__and_IgG_levels_g_L.png
Figure_2_Computer_tomography_scans_of_mediastinal_structures_2A_and_lungs_2B.png
A, mediastinal lymphadenopathy with enlarged lymph nodes marked with black arrows.
B, multiple lesions in lungs in a patient with CVID. Numerous chaotic lesions (maximal size of 12х10 mm) are registered in lungs, with indefi nite margins and peribronchial wall thickening.

The diagnostic search also included Gaucher disease. Analysis of glucocerebrosidase activity in blood was performed at the Research Centre for Medical Genetics (Russian Academy of Sciences, Moscow). The enzyme activity was within reference ranges, without a decrease typical to this genetic disorder.
The patient remained diagnostically unclear. There was no defi nitive evidence of malignancy, thus three non-malignant disorders were considered in differential diagnosis at the moment. They included: hemophagocytic lymphohistiocytosis (HLH), autoimmune lymphoproliferative syndrome (ALPS), and a primary immunodefi ciency (PID). All these diseases share joint clinical signs and pathogenic mechanisms, being attributed to a common class of primary immunodefi ciency syndromes [10].
HLH is a real problem for health care providers, in terms of diagnostic and therapeutic issues. Our patient had four criteria consistent with HLH: fever, splenomegaly, cytopenia and hypertriglyceridemia with hypofi brinogenemia (Tables 2 and 3). Hemophagocytosis in bone marrow or spleen, hyperferritinemia and HLH-specifi c mutations were absent (PRF1, STXBP2, STX1, UNC13D), NK-cell activity in peripheral blood was normal. To establish diagnosis, according to Revised Diagnostic Guidelines for HLH, at least five of diagnostic criteria should be fulfilled, or HLH mutations should be present [11]. Hence, HLH was dismissed because only 4 criteria were present in the patient.
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by malfunction in apoptosis of lymphocytes that leads to excessive lymphoproliferation. Presence of lymphadenopathy and splenomegaly, hemolytic anemia in previous history are characteristic to ALPS, but low level of double-negative CD3+/CD8-/CD4-/TCRαβ+ mature lymphocytes in peripheral blood was not consistent with this diagnosis. Mutations in FAS gene were not found upon whole genome sequencing (University of Dusseldorf, see data in Appendix). Absence of double-negative T lymphocytes and mutations in FAS gene made the diagnosis of ALPS very unlikely.
Due to severe persistent hypogammaglobinemia in the patient, a work-up for CVID was done. Absolute count of switched memory B-cells was checked (0.48%), and it proved to be decreased (reference range 1-40%) that is consistent with diagnosis of CVID (Table 5).
The whole exome sequencing of the patient leukocytes has been performed at University of Dusseldorf using the primary Immunodefi ciency gene panel. The screening did not reveal any candidate genes considered related to primary immunodeficiency, autoimmune lymphoproliferative disorder, HLH or inherited lung disorders (Table 6).

Discussion

According to the established clinical criteria (Table 1), a CVID diagnosis was confi rmed, based on persisting hypogammaglobulinemia, decreased count of switched memory B-cells (CD27+IgM-IgG-), autoimmune complications (hemolytic anemia) and non-malignant lymphoproliferative syndrome. Lung involvement shown in the child may occur in 30% of patients with CVID, being an unfavorable prognostic sign. Sarcoid-like granuloma, organizing pneumonia, lymphocytic interstitial pneumonitis and nonspecifi c interstitial pneumonia are the most common types of histological fi ndings in aff ected lungs of CVID patients [13]. Hence, the CVID diagnosis is based on constellation of several non-specifi c criteria, while excluding other, less probable, clinical conditions.
The patient is now receiving regular infusions of intravenous immunoglobulins and level of immunoglobulin G is maintained at normal values. However, pulmonary complications of CVID still persist and slowly diminish with time. Lung biopsy has been performed, demonstrating granulomatous pneumonitis without any signs of malignancy. Immunosuppression with Rituximab was initiated due to progressing autoimmune problems and respiratory failure. The granulomatous pneumonitis is currently the only one and leading autoimmune disorder in the patient.
Table_6_Genetic_background_of_CVID_ALPS_and_HLH_12.png
Prognosis for the presented patient is uncertain due to progressive lung involvement. Further treatment options may consist of glucocorticosteroids, cyclosporine A, sirolimus, cyclophosphamide, hydroxychloroquine, azathioprine, methotrexate, etanercept, infl iximab and other immunosuppressive agents. If further respiratory deterioration will occur despite immunosuppressive treatment and IVIG, allogeneic hematopoietic stem cell transplantation and lung transplantation may be considerable options in this patient.

Conclusion

The present case report describes a 10-year old girl with major internationally approved criteria of common variable immunodefi ciency (CVID), and specifi c lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion, the attending doctor should suspect PID in clinical settings in cases of hypogammaglobulinaemia, non-specified lymphoproliferation, autoimmune features and absence of malignant disorder.

Acknowledgements

Th e authors are much appreciated to Dr. Ute Fischer from the University of Düsseldorf (Germany) who performed whole exome sequencing in this patient, and to thank Dr. Polina Stepensky from Hadassah Medical Center, Jerusalem (Israel) for valuable advices on this diagnostic procedure for the patient.

Conflicts of interest

No conflict interests are declared.

References

1. Vořechovský I, Cullen M, Carrington M, Hammarström L, Webster ADB. Fine mapping of IGAD1 in IgA defi ciency and common variable immunodefi ciency: identification and characterization of haplotypes shared by aff ected members of 101 multiple-case families. J Immunology. 2000; 164:4408–4416.
2. Maff ucci P, Filion C A, Boisson B, Itan Y, Shang L, Casanova J L, Cunningham-Rundles C. Front Immunol. 2016; (7):220.
3. Glocher E, Ehl S, Grimbacher B. Common variable immunodeficiency in children. Current opinion in pediatrics. 2007; 19:685-692.
4. Vukic EJ, Cunningham-Rundles C. Common variable immunodefi ciency in children: clinical and immunological features of patients diagnosed before the age of 13. J Allergy Clin Immunol. 2004: 113(2), S39.
5. Salzer U, Warnatz K, Hartmut PH. Common variable immunodeficiency – an update. Arthritis Research & Th erapy.2012:14:223.
6. Aleinikova OV, Fedorova AS, Sharapova SO. Should allogeneic hematopoietic stem cell transplantation be a treatment option for patients with Nijmegen breakage syndrome? Belarusian experience. Cell Th er Transplant. 2015; 4(1-2):31-36.
7. Gompels MM, Hodges E, Lock RJ, Angus B, White H, Larkin A, Chapel HM, Spicett GP, Misbah SA, Smith JL. Lymphoproliferative disease in antibody defi ciency: a multi- centre study, Associated Study Group. Clin Exp Immunol. 2003; 134(2): 314–320.
8. Busse PJ, Farzan S, Cunningham-Rundles C. Pulmonary complications of common variable immunodefi ciency. Ann Allergy Asthma Immunol. 2007;98(1):1-8; quiz 8-11, 43.
9. Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J. Intravenous immunoglobulins in immunodefi ciencies: more than mere replacement therapy. Clin Exp Immunol. 2011;164 Suppl 2:2-5.
10. Al-Herz W, Bousfi ha A, Casanova J-L, Chatila T, Conley M E, Cunningham-Rundles C, Etzioni A, Franco JL, Gaspar HB, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Picard C, Puck JM., Sullivan K, Tang MLK. Primary immunodefi ciency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodefi ciency. Front Immunol. 2014; 5:162.
11. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediat Blood Cancer. 2007;48(2):124-131.
12. Ochs D. Hans et al. Primary Immunodefi ciency diseases. A Molecular and Genetic Approach (3rd Edition). 2014. Publisher: Oxford University Press.
13. Prasse A, Kayser G, Warnatz K. Common variable immunodeficiency-associated granulomatous and interstitiallung disease. Curr Opin Pulm Med. 2013;19(5):503-509.

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Козлов, Татьяна А. Быкова, Анастасия С. Боровкова, Мария Ю. Аверьянова, Варвара Н. Овечкина, Елена В. Морозова, Людмила С. Зубаровская, Николай Н. Мамаев, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(327) "Андрей В. Козлов, Татьяна А. Быкова, Анастасия С. Боровкова, Мария Ю. Аверьянова, Варвара Н. Овечкина, Елена В. Морозова, Людмила С. Зубаровская, Николай Н. Мамаев, Борис В. Афанасьев
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20037" ["VALUE"]=> array(2) { ["TEXT"]=> string(445) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(445) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20038" ["VALUE"]=> array(2) { ["TEXT"]=> string(2948) "<p style="text-align: justify;"> Пациенты с синдромами первичного иммунодефицита встречаются относительно редко и им часто ставится ошибочный диагноз в связи с неспецифическими клиническими симптомами, напоминающими другие, более частые заболевания. Частота общей вариабельной иммунной недостаточности (ОВИН): 1 случай на 30.000 жителей Европы. Обычно имеется задержка в несколько лет между началом заболевания и диагнозом. Общая вариабельная иммунная недостаточность является наиболее частым первичным иммунодефицитом в возрасте старше 4 лет. Основным симптомом для установления диагноза является гипогаммаглобулинемия.<br> Целью данной статьи является показать существующие тенденции в диагностике ОВИН. Представленный клинический случай описывает 10-летнюю девочку, позитивную по четырем международным клиническим критериям ОВИН и с наличием специфического поражения легких. При этом были исключены злокачественные заболевания. Генетическое исследование методом глубинного генного секвенирования (NGS) не выявило какой-либо генной мутации, которая могла бы быть ответственной за ОВИН или родственные синдромы (ALPS, HLH). Таким образом, ОВИН остается диагнозом исключения. У нашего пациента, несмотря на заместительную терапию внутривенным иммуноглобулином, легочная функция продолжала ухудшаться, что привело к необходимости приступить к иммуносупрессивной терапии. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Первичный иммунодефицит, общая вариабельная<br> иммунная недостаточность, диагностические крите-<br> рии, аутоиммунные осложнения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2864) "

Пациенты с синдромами первичного иммунодефицита встречаются относительно редко и им часто ставится ошибочный диагноз в связи с неспецифическими клиническими симптомами, напоминающими другие, более частые заболевания. Частота общей вариабельной иммунной недостаточности (ОВИН): 1 случай на 30.000 жителей Европы. Обычно имеется задержка в несколько лет между началом заболевания и диагнозом. Общая вариабельная иммунная недостаточность является наиболее частым первичным иммунодефицитом в возрасте старше 4 лет. Основным симптомом для установления диагноза является гипогаммаглобулинемия.
Целью данной статьи является показать существующие тенденции в диагностике ОВИН. Представленный клинический случай описывает 10-летнюю девочку, позитивную по четырем международным клиническим критериям ОВИН и с наличием специфического поражения легких. При этом были исключены злокачественные заболевания. Генетическое исследование методом глубинного генного секвенирования (NGS) не выявило какой-либо генной мутации, которая могла бы быть ответственной за ОВИН или родственные синдромы (ALPS, HLH). Таким образом, ОВИН остается диагнозом исключения. У нашего пациента, несмотря на заместительную терапию внутривенным иммуноглобулином, легочная функция продолжала ухудшаться, что привело к необходимости приступить к иммуносупрессивной терапии.

Ключевые слова

Первичный иммунодефицит, общая вариабельная
иммунная недостаточность, диагностические крите-
рии, аутоиммунные осложнения.

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Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(186) "Andrey V. Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20033" ["VALUE"]=> array(2) { ["TEXT"]=> string(232) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, Chair of Hematology, Transfusiology and Transplantation, First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(232) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, Chair of Hematology, Transfusiology and Transplantation, First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20034" ["VALUE"]=> array(2) { ["TEXT"]=> string(1512) "<p style="text-align: justify;"> Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.<br> The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1440) "

Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.
The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment.

Keywords

Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications.

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Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(186) "Andrey V. Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(186) "Andrey V. Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20034" ["VALUE"]=> array(2) { ["TEXT"]=> string(1512) "<p style="text-align: justify;"> Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.<br> The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1440) "

Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.
The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment.

Keywords

Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications.

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Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.
The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment.

Keywords

Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications.

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Козлов, Татьяна А. Быкова, Анастасия С. Боровкова, Мария Ю. Аверьянова, Варвара Н. Овечкина, Елена В. Морозова, Людмила С. Зубаровская, Николай Н. Мамаев, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(327) "Андрей В. Козлов, Татьяна А. Быкова, Анастасия С. Боровкова, Мария Ю. Аверьянова, Варвара Н. Овечкина, Елена В. Морозова, Людмила С. Зубаровская, Николай Н. Мамаев, Борис В. Афанасьев
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Пациенты с синдромами первичного иммунодефицита встречаются относительно редко и им часто ставится ошибочный диагноз в связи с неспецифическими клиническими симптомами, напоминающими другие, более частые заболевания. Частота общей вариабельной иммунной недостаточности (ОВИН): 1 случай на 30.000 жителей Европы. Обычно имеется задержка в несколько лет между началом заболевания и диагнозом. Общая вариабельная иммунная недостаточность является наиболее частым первичным иммунодефицитом в возрасте старше 4 лет. Основным симптомом для установления диагноза является гипогаммаглобулинемия.
Целью данной статьи является показать существующие тенденции в диагностике ОВИН. Представленный клинический случай описывает 10-летнюю девочку, позитивную по четырем международным клиническим критериям ОВИН и с наличием специфического поражения легких. При этом были исключены злокачественные заболевания. Генетическое исследование методом глубинного генного секвенирования (NGS) не выявило какой-либо генной мутации, которая могла бы быть ответственной за ОВИН или родственные синдромы (ALPS, HLH). Таким образом, ОВИН остается диагнозом исключения. У нашего пациента, несмотря на заместительную терапию внутривенным иммуноглобулином, легочная функция продолжала ухудшаться, что привело к необходимости приступить к иммуносупрессивной терапии.

Ключевые слова

Первичный иммунодефицит, общая вариабельная
иммунная недостаточность, диагностические крите-
рии, аутоиммунные осложнения.

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Пациенты с синдромами первичного иммунодефицита встречаются относительно редко и им часто ставится ошибочный диагноз в связи с неспецифическими клиническими симптомами, напоминающими другие, более частые заболевания. Частота общей вариабельной иммунной недостаточности (ОВИН): 1 случай на 30.000 жителей Европы. Обычно имеется задержка в несколько лет между началом заболевания и диагнозом. Общая вариабельная иммунная недостаточность является наиболее частым первичным иммунодефицитом в возрасте старше 4 лет. Основным симптомом для установления диагноза является гипогаммаглобулинемия.
Целью данной статьи является показать существующие тенденции в диагностике ОВИН. Представленный клинический случай описывает 10-летнюю девочку, позитивную по четырем международным клиническим критериям ОВИН и с наличием специфического поражения легких. При этом были исключены злокачественные заболевания. Генетическое исследование методом глубинного генного секвенирования (NGS) не выявило какой-либо генной мутации, которая могла бы быть ответственной за ОВИН или родственные синдромы (ALPS, HLH). Таким образом, ОВИН остается диагнозом исключения. У нашего пациента, несмотря на заместительную терапию внутривенным иммуноглобулином, легочная функция продолжала ухудшаться, что привело к необходимости приступить к иммуносупрессивной терапии.

Ключевые слова

Первичный иммунодефицит, общая вариабельная
иммунная недостаточность, диагностические крите-
рии, аутоиммунные осложнения.

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Introduction

According to a classical determination, vascular endothelium represents a monolayer of fl at cells by mesenchymal origin that are lining the inner lumen of blood and lymph vessels, as well as heart chambers. For a long time, vascular endothelium was regarded only as a protective layer separating blood from inner vascular envelopes. By the end of XX century, aft er awarding a Nobel Prize (1998) in Physiology and Medicine to R. Furchgott, L.S. Ignorro, F. Murad “for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system”, a broader concept emerged which covers diff erent humoral mechanisms of cardiovascular system regulation under normal and pathological conditions. This approach aimed to elucidate a role of endothelium in pathogenesis of arterial hypertension and other cardiovascular disorders. Hence, vascular endothelium could be viewed as an active secretory organ which is the biggest structure in a human body. Large total vascular area and penetration to all organs provides extended infl uence of endothelium upon either tissue structure. Five specialized types of endotheliocytes could be discerned by morphofunctional criteria including fenestrated, sinusoid-like, ethmoid cells, and endothelium of high postcapillary venules [1-3]. Along with common gene activation mechanisms, a distinct endothelial phenotype is acquired due to local microenvironment and interactions with adjacent cells, also being influenced by intravascular hemodynamic factors.

Endothelial functions and secretory factors

The following functions of endothelial cells are widely known, i.e., vasomotor, hemostatic, adhesive, angiogenic eff ects. These actions are determined by levels of appropriate active protein factors produced by endothelium. Sometimes, these factors exert reciprocal eff ects upon the vascular wall [3]. E.g., vasomotor function of endothelium is determined by a vasoconstrictor complex, i.e., endothelin-1 (ET-1), thromboxane A2, 20-HETE (20-hydroxyeicosotetraenic acid), angiotensin II, being in balance with vasodilators (nitrogen monoxide, NO; prostacycline (PGI2); endothelial hyperpolarizing factor (EDHF), natriuretic peptides(BNP, C-type NP), adrenomedullin).
A set of compounds determines thromboresistance (NO, PGI2, PGE2, thrombomodulin (TM), tussue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA), urokinase, plasminogen and urokinase inhibitors,antithrombin III, protein C receptors, protein S, annexin A5), thus counteracting some thrombogenicity factors of the vascular wall (von Willebrand factor (vWF), tissue factor (TF), plasminogen activator inhibitors (PAI-1 and PAI-2).
Adherence function of endothelium is controlled by adhesive molecules from the immunoglobulin superfamily (ICAM-1 (Intercellular adhesion molecule, CD54a), ICAM-2 (CD102), РЕCAM-1 (Рlatelet/endothelial cell adhesion molecule, CD31), VCAM-1 (Vascular cellular adhesion molecule, CD106)), like as selectins (E-selectin, P-selectin).
Angiogenic function of endothelium depends on production of vascular endothelial growth factor (VEGF), fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1), transforming growth factor (TGF-β) [3].
Some common functions are inherent to endothelial cells of either location. Th eir activity and shift ed balance are connected, e.g., with hemodynamic fl uctuations, as well as with damaging eff ects of mechanical, ischemic, or toxic factors. Moreover, concentration of a biologically active substance may suffi ciently modify biological eff ect. I.e., at lower synthesis rates (<1 mcM), direct NO eff ects are generally observed, which support cardiovascular functioning. At higher concentrations (>1 mcM), indirect eff ects predominate which are determined by free-radical properties of NO products, e.g., its ability to produce peroxynitrites [4]. At the present time, bidirectional eff ects of these substances are known, with regard of their mutually additive, synergistic or inhibitory eff ects [5].
Along with well-known substances like nitric oxide (NO), prostacyclin (PGI2), endothelin-1 (ET-1), neuregulin-1 (NRG-1), the endothelial cells lining blood capillaries secrete many factors in adaptable fashion. Some factors were discovered recently, e.g., Dickkopf-3 (DKK3), periostin, thrombospondin-1 (TSP-1), TSP-4, follistatin (FST) and follistatin- like factors (Fstl1, Fstl3), apelin, connective tissue growth factor (CTGF), MicroRNA-146a factor [2-4]. Further in-depth studies have revealed their multiple isoforms which exhibit diff erent properties. Combined eff ects of the mentioned biologically active substances upon specialized cells of distinct organs will be diff erent, depending on functional characteristics of the given tissue. Intercellular interactions between endothelium and specialized somatic cells show tissue specifi city, e.g., endothelium-cardiomyocyte interactions in cardiac tissues.
With aging and signs of age-dependent coronary pathology, endothelium is more scarcely regenerated, and becomes dysfunctional [6]. As a result, its ability to release vasoactive molecules such as acetylcholine (ACh), prostacyclin (PGI2), endothelium-derived hyperpolarizing factor (EDHF), and nitric oxide (NO) is reduced and the cellular response to these molecules is also impaired, also due to age-related higher production of reactive oxygen and nitrogen species, endothelin and angiotensin.

Systemic and local endothelial ysfunction

Sax et al. (1987) have shown that altered endothelial functions of skin microvessels in patients with microvascular coronary arterial disease (CAD) correlate with appropriate changes in myocardium [7]. This finding has allowed a view on endothelial dysfunction (ED) as a systemic pathological process, and served as a basis for development of non-invasive techniques for the vascular ED evaluation in available peripheral vessels.
Heart as an active muscular organ which reacts quite rapidly to the changes of its local blood supply. Regulation of muscular contraction, neuromuscular conduction system, myocardial metabolism and regeneration suffi ciently depend on both neuro-endocrine eff ects and interactions between local cell populations. E.g., specifi c interactions between endothelium and cardiomyocytes exist within heart. These eff ects are determined by the balance of endothelium-secreted cytokines which may be shift ed due to alterations of endothelium and cardiomyocytes. Th is imbalance may manifest as disturbed myocardial contraction, dilatation of cardiac chambers, altered heart rate, clinically presenting as a heart failure.
Different production rates and lifetime are demonstrated for biologically active substances produced by endothelium. The lifetime for products synthesized by the coronary endothelium is very short (<1 sec), thus being limited by neighbouring cells, e.g., cardiomyocytes, and does not extend to entire cardiovascular system. Therefore, it is reasonable to specify a local endothelial function connected with endothelial-cardiomyocyte interactions.

Local attraction and recruitment of injected bone marrow cells: role of endothelium

Several experimental studies concerned fi nal residence of marrow mononuclears injected either systemically or locally (Table 1). Comparative studies have shown much higher MNC capture when injected intracoronarily than via peripheral veins [8,9]. Intramyocardial injections resulted in even higher cell capture in injured area [10]. Measurable rates of MNC homing in the heart were approximately 6-7% [9, 11].Table_1_Local_capture_of_bone_marrow_mononuclear_cell_MNC_in_experimental_myocardial_infarction_in_pigs.png
Potential mechanisms of leukocyte attraction from blood fl ow to the vascular endothelium are discussed by Rao et al. [12]. The authors regard local recruitment of some leukocyte subpopulations to the tissues through endothelial-dependent mechanisms. These complex events are associated with endothelial secretion of various prothrombotic molecules, i.e., platelet-derived growth factor, von Willebrand factor, prostacyclin, NO, endothelin-1, expression of adhesion molecules (selectins, ICAM etc.). Short-distance leukocyte attraction is promoted by chemokines (MCP-1, MIP, RANTES etc.). Th e recruited lymphocytes and monocytes in turn, are also induced for secretion of proinfl ammatory factors and emigrate via endothelial layer, thus promoting tissue remodeling and neovasculogenesis. Hence, “molecular conversations” of endothelium with recruited leukocytes may play a key role in triggering the infl ammatory response including tissue pathology following myocardial infarction.
A number of diff erentiation options is presented for the bone marrow mononuclear cells. Cellular composition of such MNC preparations is quite heterogenous, including T and B cells, monocytes, a small fraction of blood precursors etc. Th ere are few studies concerning their in vivo fate. E.g., Fatkhudinov et al. [13] have injected autologous labeled bone marrow MNCs into the right and left coronary arteries in rats at day 30 aft er infarction. The labelled cells were then detected only in the damaged zone of the myocardium. However, these cells were not found in vascular walls. Interestingly, the transplanted cells were surrounded by thick collagen fi bers with time, thus presuming their fibroblastic differentiation. In their later study, this group has shown that the injected mononuclear cells migrated to the cicatrix zone where they diff erentiated into fi broblasts and myofi broblasts [14]. Meanwhile, there was no evidence of their in vivo differentiation to cardiomyocytes, endothelial cells, or smooth muscle cells of vascular media. However, stimulation of angiogenesis and reparation of the myocardium was observed after BM MNC treatment, thus uggesting a positive effect for repair of heart function.

Clinical evidence

Cellular therapy of heart by means of autologous bone marrow has been worldwide in frames of clinical trials since 2002. Aft er 15 years of its usage, its safety and positive eff ect are shown by most workers worldwide. Primary pre-clinical studies [15], and initial clinical experience in Düsseldorf (Germany) performed and summarized by Strauer et al.[16], and in Rostock by Stamm et al. [17] used autologous bone marrow cells (ABMC) for treatment of coronary artery disease (CAD). Trials with CAD patients have revealed a positive functional response to the cellular therapy. Over the last 15 years, since introduction of this treatment modality, some distinct positive results are shown in randomized clinical studies. Th is treatment still did not become a standard for CAD patients, despite several meta- analyses have shown some benefits of the cellular therapy [18-20].
Over 2003-2017, a research team at the First St. Petersburg I. Pavlov Medical University (FSPMU) performed several studies dedicated to usage of autologous bone marrow hematopoietic cells (ABMC) for treatment of CAD patients and dilated cardiomyopathy. A total of 250 patients have received ABMC by 2017. Th e results of our studies were presented in several publications [21, 22, 23, 25].
At the present time, upon additional analysis and further controlled studies, we conclude that the most positive effects of the cellular therapy could be explained by neoangiogenesis which could be observed following an eff ective cellular therapy. Most workers agree that a paracrine mechanism for the cytokine action is predominant under these conditions [24]. However, intercellular relations are known to be mediated by the cytokine eff ects. Th erefore, a term of paracrine mechanism needs to be specified.
We attempted to ascribe some eff ects of the cellular therapy not only to angiogenesis, but also to possible correction of coronary endothelium using our own experience, as well as some facts from present publications.
During two years (2003-2004), after preclinical studies, we performed a pilot study in 12 patients which confi rmed safety and reproducibility of ABMC intramyocardial injections (during aorto-coronary bypass surgery), or intracoronary infusion (during coronarography) to patients within first hours aft er ex vivo bone marrow separation. We have noted a positive effect of additional AMBC usage in both groups. However, we were unable to discern a favorable action of cellular therapy from positive eff ects of revasculatization.
From 2005 to 2011, we performed a controlled study of hydroxyethyl starch (HES)-separated AMBC upon intracoronary injections applied in patients with marked coronary lesions who were not fi t for coronary bypass surgery, or coronary angioplastics and stenting [21]. Th is study included 97 CAD patients. These persons received ABMC via coronary vessels, without any special revascularization procedures. Control group consisted of 37 patients who did not receive ABMC injections, being only subjected to adequate conventional medical therapy. The patients received intracoronary injections of ABMC obtained by multiple sternal and iliac punctures and enriched by gradient centrifugation (900 g for 15 min at 1-st stage, and 700 g for 15 min at 2-nd stage) by means of HES solution. Mean total number of isolated nucleated cells was 6.8±3.5x108; mononuclear cell yield was 9±7.85x108; average CD34-positive cell number was 1.6±0.85x106. Total cell viability was about 95-98%. Clinical eff ect of ABMC injections in the study group was expressed in terms of decreased CAD symptoms by 1 functional class (68% of total), by 2 functional classes (12%); 20% patients did not feel any changes. Such eff ect was evident at 6 to 9 months aft er single AMBC injections. We have observed a distinct gradual improvement of myocardial perfusion within the fi rst year, as shown by means of positron emission tomography (PET) with isotopic ammonium, and increased myocardial metabolism according to PET studies with fl uorodeoxyglucose (FDG). E.g., improved perfusion and myocardial metabolism were revealed as soon as 3 months later, however, more expressed positive changes are detected 6 and 12 months aft er single ABMC injection (Fig. 1). It should be noted that the detected increase of myocardial perfusion and improved cardiac metabolism represent two parallel, and, probably, interacting processes in heart aft er cellular therapy by local infusions of non-modifi ed ABMC. Of note, this improvement of myocardial perfusion and enhanced local metabolism are two parallel, and, probably, interconnected processes in heart aft er cellular therapy with intracoronary injection of non-modifi ed ABMC to left ventricular myocardium.
Figure_1_Metabolic_pattern_evaluated_by_positron_emission_tomography_PET_of_myocardium_dynamics_of_fluordeoxyglucose_FDG.png
At initial PET scans (A), a marked decrease in glucose metabolism is observed in the area of recent myocardial infarction (anteroseptal segment, arrow). After stem cell transplantation, a subsequent improvement is noted in the area of interest (B, 3 months); significant improvement (C, 6 months), and normalization of 18F-FDG capture (D, 12 months), thus being indicative for successive normalization of metabolic processes in the given area of left ventricle.


These protective events were accompanied by increased myocardial contractibility, according to Echo-CG data, thus being ascribed to improved collateral blood fl ow. The revealed increase of collateral circulation could explain alleviation of coronary disorder and increased myocardial perfusion, as shown by SPECT and PET studies. Meanwhile, CAD functional class did not change in control group. This effect retained forca. 3 years, followed by decreased antianginal effect at 4-5 years. Coronary angiography performed at these late terms showed stabililization of coronary arteries, without any significant progression of atherosclerotic lesions. It should be noted that impaired coronary circulation developed in presence of retained collateral blood flow.
Worth of note, we did not observe any cases of heart teratomas, pathological local ossifi cations, unfavorable immune reactions, or other adverse eff ects connected with ABMC injections over years of this study.
Consequent SPECT studies of myocardial perfusion in 19 patients have confi rmed a decreased perfusion defi ciency, as compared to initial levels, at the terms of up to 3 years after ABMC injections, thus being indicative for improvement of myocardial function. Th e decreased hypoperfusion area was patient-specific, and the year-by-year changes varied from 0.79±9.7% to 5.44±8.7% of hypoperfused area (<60% of reference levels).
Four years later, the average perfusion deficiency resumed to grow against initial level, i.e., myocardial blood supply changed to inferior values (Fig. 2). These findings prompted us to perform repeated ABMC injections four years later. Coronary angiography was performed before repeated ABMC injections. One should note that consecutive coronarography, as a rule, did not reveal any significant repair of initially aff ected coronaries. Meanwhile, the denovo developed collaterals continued their functioning aft er primary ABMC injection. Four patients were subjected to repeated intracoronary ABMC injection, without any other revascularization procedures. Distinct improvement of myocardial perfusion, according to SPECT data, and better clinical condition (decreased CAD functional class) were noted in all four patients, who underwent repeated intracoronary ABMC injections. 6 to 12 months later, a second wave of improved myocardial perfusion was observed, according to consequent SPECT examinations with technetryl labeling [25].

Figure_2_Time_changes_of_median_values_of_myocardial_perfusion_deficiency_60__assessed_by_SPECT_performed_with_Technetril.png
Such transient improvement of myocardial blood flow at 3-6-12 months after primary ABMC infusion followed by decreased heart blood supply at later terms (despite functioning collaterals), and repeated increase of blood supply at 3-6-12 months aft er repeated ABMC injections suggest some accessory bioactive factors responsible for the positive circulatory changes, probably, due to functional correction of coronary endothelial cells in severe CAD patients.

Dilated cardiomyopathy

Improvement of myocardial contractile ability was obtained also in a group of patients with dilated cardiomyopathy (DCMP), i.e., primary myocardial aff ection without coronary changes [22, 23]. All these patients (n=20) were devoid of coronary atherosclerotic lesions, thus confi rming a DCMP diagnosis. Th e patients had cardiac insuffi ciency of NIHA functional class 3-4, with initial ejection fraction of 17 to 41%. In all those cases, ABMC were injected during coronary angiography, as intracoronary infusions of freshly isolated autologous marrow cells.
A positive clinical eff ect of this procedure was registered in 18 cases (90% of total), as refl ected by decreased apnoe caused by physical loadings, decreased left ventricle end-systolic diameter, and increased left ventricle ejection fraction (LVEF). Notably, these positive eff ects allowed to decrease intensity of diuretic therapy (by tapering Furosemide dose, and switching to Torasemide). Assessment of metabolism by PET examination with fl uorodeoxyglucose (FDG) has shown that the cellular therapy, lead to improved capture of the radiopharmaceutical in the segments with initially decreased metabolic level. Moderate increase of FDG capture was also noted in segments with virtually normal metabolism. One could suggest a direct eff ect of the cellular therapy upon cardiomyocytes. A distinct answer to this question is impossible, because myocardial microcirculation is affected in DCMP as well. Following cellular therapy, improved blood supply in DCMP was shown in the same segments as those with increased metabolism. The positive metabolic changes detected by PET were also found in DCMP patients within next 3-6 months aft er cellular therapy and were traceable over 2 years [23].
Altered myocardial blood supply in severe DCMP patients is associated with increased intramyocardial tension, and, accordingly, with disturbed blood supply at the microcirculatory level. One cannot exclude endothelial dysfunction of coronary microcirculation, and altered production of nitrogen monoxide and other substances negatively infl uencing myocardial contraction and coronary blood fl ow. Causal relations between the two processes (perfusion dynamics and intramyocardial tension) are hardly to discriminate at the present time.
Second ABMC injections in DCMP patients were performed in two cases 4-6 years aft er the fi rst treatment, showing repeated improvement of clinical state (fi rst of all, decreased apnoe) as reported by the both patients 6 to 9 months after cell therapy. Of note, repeated positive changes of left ventricle end-diastolic diameter, and accordingly, LVEF, are shown in these cases. These facts also suggest a functional mechanism of ABMC eff ects upon myocardium and endothelium. The issue of primary effect of ABMC injections upon coronary endothelium, with subsequent myocardial recovery, still remains open.
Thus, a repeated injection of ABMC 4-5 years later allows to achieve the second wave of clinical improvement. If such second injection is performed earlier, at 6-8 months aft er primary treatment (termed double infusion) the procedure may lead to suffi ciently improved well-being, which is accompanied by marked positive changes of left ventricle end-systolic and -diastolic diameters, and more signifi cant LVEF increase, than following a single injection. We have performed such double ABMC injection in only two patients. However, these cases are characterized by more suffi cient cardiotropic effects than single ABMC infusions. A successful experience with repeated injections of BM MNCs was also published by a group of workers from Frankfurt [24]. The authors used intracoronary injections of autologous bone marrow-derived mononuclear cells (BM-MNCs). The data from their local registry included 297 post-infarction heart failure patients. The results of this study have shown that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P=0.03). Likewise, mortality is signifi cantly lower at 2-year follow-up compared with the mortality estimated by the use of the  Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P=0.02). The repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. The authors propose a design of the multicentre randomized, controlled, open-label REPEAT trial in patients with chronic post-infarction heart failure.

Discussion

At the present time, exact mechanism of cellular therapy is not known. Some distinct positive clinical results are detected over 15 years of its implementation in cardiology. These successful data are presented in randomized clinical studies. Meta-analyses of 2012 and 2015 showed a distinct value when applying cellular therapy for CAD and DCMP treatment.
Development of collateral vascular network due to neoangiogenesis was demonstrated in majority of works concerning mechanism of stem cell action upon heart tissues in CAD. Some workers consider formation of new vascular collaterals to be the main effect of hematopoietic stem cell treatment. A mechanism and consequences of bone marrow cell recruiting following a coronary arterial occlusion are suggested by Schaper [26]. In brief, the shear stressed endothelium leads, in particular, to high NO production and VEGF secretion by endothelial cells followed by MCP-1 release. Th ese compounds cause attraction and homing of T cells and monocytes at the collateral vessels. Th e blood-derived mononuclear cells and degrade extracellular matrix (ECM) and produce vascular growth factors (VEGF), thus causing tissue remodeling and arteriogenesis mainly of the smooth muscle layer. Blood fl ow is partially restored which is indeed observed in clinical.
According to many authors, a cytokine or paracrine effect is understood to be an immediate mechanism of the cellular therapy, i.e., the transplanted cells are solely cytokine suppliers, including growth factors which provide augmented natural regeneration [19, 20]. One may propose that the injected stem cells represent a kind of reservoirs containing growth factors that promote regeneration even when these cells are subsequently dying. This hypothesis is quite possible, especially if stem cell isolation was accompanied by their damage, growth factor leakage and subsequent death. In such cases, a real eff ect of the cellular therapy should not exceed 3-6 months, and we cannot consider a solely cytokine effect. However, a long-term duration of a positive effect from cellular therapy with autologous freshly isolated bone marrow cells is as long as 3-4 years in most cases, thus suggesting a stem cell-mediated regeneration of some heart cell populations [25].
Cardiomyocytogenesis as an important mechanism of heart regeneration, was shown by several works, and by present time, some data are accumulated in favor of cardiomyocyte regeneration [27]. The more sufficient arguments for cellular component of heart regeneration were reported by Anversa et al. [28], i.e., upon female-to-male heart transplantation, large numbers of male cells were revealed in female heart graft, thus suggesting a cellular regeneration mechanism in this setting. A mean number of male (Y chromosome-positive) cardiomyocytes was 18%, compared to 20% among smooth muscle cells of arterioles, and 14% of capillary endotheliocytes, as based on examination of eight female heart transplants in male recipients at different terms (4 to 552 days) posttransplant. This result suggests an intensive pprobably via blood circulation) transfer of male cells (possibly, hematopoietic stem cells and endothelium precursors) to the female heart graft . Hence, one may note that a sufficient renewal occurs not only among cardiomyocytes, but also for smooth muscle cells of arterioles and heart capillary endothelium [28]. One may presume these cells to regenerate in native heart tissues in other diseases in absence of heart transplantation, thus supposing similar regeneration mechanisms. Additional information on cellular but not only cytokine-mediated effects of injected stem cells was presented by a group of workers from Frankfurt [29] who performed experiments in mice containing a suicide gene introduced to their myocardial cells subjected to death, after their incorporation to myocardial syncytium, vascular endothelium and vascular wall. In this model of acute myocardial infarction, injection of bone marrow cells committed to endothelial differentiation lead to signifi cant improvement of the myocardial contractibility. Provoked death of cells induced for endothelial diff erentiation lead to decreased cardiac output. Interestingly, provoked death of cells committed for myocardial diff erentiation did not exert such an effect. Moreover, elimination of endothelial cells with NO synthase expression caused a decreased density of capillaries and arteriolae [29].
These data point to a suffi cient infl uence of endothelium upon functional ability of myocardium. Endothelium layer regulates transendothelial transport, including stem cell transfer, due to increased production of adhesion molecules on the surface of endothelial cells. The cells of diff erent phenotypes exhibited diff erent ability for transendothelial migration in an in vitro model with bone marrow-derived endothelial cell line [30]. BMEC-1 cells support transmigration of hematopoietic progenitors and more mature hematopoietic cells, thus representing predominantly committed progenitor cells. One may suggest that recovery of endothelial function is accompanied by correction of transendothelial transport. The resulting interactions between endothelium and myocardium may play a sufficient role in heart tissue regeneration.
The first experimental study which demonstrated an effect of injected marrow precursors upon endothelial dysfunction was presented by the workers from Oklahoma University [31]. In murine experiment, they have shown that treatment with bone marrow endothelial precursors is followed by a decreased thickness of lipid plaque layers. This effect could be used in future for atherosclerosis therapy. In addition, the authors noted that the injected endothelial precursors promote NO production by endothelial cells of appropriate vessels, thus augmenting the endothelium-dependent vascular relaxation. The authors did not conclude on probable necessity of bone marrow cells for endothelial recovery, in order to correct altered endothelial function. However, the results of this study suggest such an option.
Interactions between endotheliocytes of coronary bed and cardiomyocytes are rather complex, multifaceted, and are mediated not only by nitrogen monoxide, but also by numerous substances produced by endothelial cells that, in turn, influence cardiomyocyte populations, for either increasing, or inhibiting their function [5]. Th erefore, functional correction of coronary endothelium could be quite important for treatment of myocardial heart insuffi ciency. By the present time, some new factors were studied, in order to treat chronic heart insuffi ciency, in particular, neuregulin. However, one should bear in mind that activation at certain regeneration stages may lead to evolvement of unfavorable consequences including neoplasia [32, 33]. Apparently, detailed studies of interactions between endotheliocytes and cardiomyocytes will take much time, like as search and clinical implementation of single synthesized biologically active substances. Today, however, basing on current results of cellular therapy performed in 250 patients over 15 years, one may presume that a local infusion of freshly isolated ABMC could exert favorable eff ects upon coronary blood fl ow and diminish clinical signs of heart insufficiency. Correction of endothelial dysfunction may be a sufficient component of this mechanism [25].

Conclusion

On the basis of current knowledge and data about endothelium and its effects upon functional state of myocardium and entire heart, one may conclude that endocardial and coronary bed endothelium cannot only be a protective barrier between blood fl ow and cardiomyocytes. Endothelium seems to be a complex and well-balanced secretory system which control functional cellular activity, metabolism, survival and regeneration of cardiomyocytes, due to interactions between diff erent cell populations, by secreting short-range biological substances.
Local endothelial dysfunction plays a suffi cient role in pathogenesis of such heart diseases as CAD and DCMP. Therefore, its correction, e.g., by intracoronary injection of freshly isolated ABMCs, may be an important therapeutic component for future treatment of these diseases. Our hypothesis on important role of endothelium in MNC recruitment to the damaged site seems to be supported by experimental and clinical evidence, but still needs additional studies to be confirmed.

Acknowledgments

The authors are much appreciated to Professor Boris V. Afanasyev, Director, R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I.Pavlov Medical University and to the Institute staff for a long-term cooperation when performing clinical studies.

Conflict of interest

No conflict of interest is reported.

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Introduction

According to a classical determination, vascular endothelium represents a monolayer of fl at cells by mesenchymal origin that are lining the inner lumen of blood and lymph vessels, as well as heart chambers. For a long time, vascular endothelium was regarded only as a protective layer separating blood from inner vascular envelopes. By the end of XX century, aft er awarding a Nobel Prize (1998) in Physiology and Medicine to R. Furchgott, L.S. Ignorro, F. Murad “for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system”, a broader concept emerged which covers diff erent humoral mechanisms of cardiovascular system regulation under normal and pathological conditions. This approach aimed to elucidate a role of endothelium in pathogenesis of arterial hypertension and other cardiovascular disorders. Hence, vascular endothelium could be viewed as an active secretory organ which is the biggest structure in a human body. Large total vascular area and penetration to all organs provides extended infl uence of endothelium upon either tissue structure. Five specialized types of endotheliocytes could be discerned by morphofunctional criteria including fenestrated, sinusoid-like, ethmoid cells, and endothelium of high postcapillary venules [1-3]. Along with common gene activation mechanisms, a distinct endothelial phenotype is acquired due to local microenvironment and interactions with adjacent cells, also being influenced by intravascular hemodynamic factors.

Endothelial functions and secretory factors

The following functions of endothelial cells are widely known, i.e., vasomotor, hemostatic, adhesive, angiogenic eff ects. These actions are determined by levels of appropriate active protein factors produced by endothelium. Sometimes, these factors exert reciprocal eff ects upon the vascular wall [3]. E.g., vasomotor function of endothelium is determined by a vasoconstrictor complex, i.e., endothelin-1 (ET-1), thromboxane A2, 20-HETE (20-hydroxyeicosotetraenic acid), angiotensin II, being in balance with vasodilators (nitrogen monoxide, NO; prostacycline (PGI2); endothelial hyperpolarizing factor (EDHF), natriuretic peptides(BNP, C-type NP), adrenomedullin).
A set of compounds determines thromboresistance (NO, PGI2, PGE2, thrombomodulin (TM), tussue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA), urokinase, plasminogen and urokinase inhibitors,antithrombin III, protein C receptors, protein S, annexin A5), thus counteracting some thrombogenicity factors of the vascular wall (von Willebrand factor (vWF), tissue factor (TF), plasminogen activator inhibitors (PAI-1 and PAI-2).
Adherence function of endothelium is controlled by adhesive molecules from the immunoglobulin superfamily (ICAM-1 (Intercellular adhesion molecule, CD54a), ICAM-2 (CD102), РЕCAM-1 (Рlatelet/endothelial cell adhesion molecule, CD31), VCAM-1 (Vascular cellular adhesion molecule, CD106)), like as selectins (E-selectin, P-selectin).
Angiogenic function of endothelium depends on production of vascular endothelial growth factor (VEGF), fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1), transforming growth factor (TGF-β) [3].
Some common functions are inherent to endothelial cells of either location. Th eir activity and shift ed balance are connected, e.g., with hemodynamic fl uctuations, as well as with damaging eff ects of mechanical, ischemic, or toxic factors. Moreover, concentration of a biologically active substance may suffi ciently modify biological eff ect. I.e., at lower synthesis rates (<1 mcM), direct NO eff ects are generally observed, which support cardiovascular functioning. At higher concentrations (>1 mcM), indirect eff ects predominate which are determined by free-radical properties of NO products, e.g., its ability to produce peroxynitrites [4]. At the present time, bidirectional eff ects of these substances are known, with regard of their mutually additive, synergistic or inhibitory eff ects [5].
Along with well-known substances like nitric oxide (NO), prostacyclin (PGI2), endothelin-1 (ET-1), neuregulin-1 (NRG-1), the endothelial cells lining blood capillaries secrete many factors in adaptable fashion. Some factors were discovered recently, e.g., Dickkopf-3 (DKK3), periostin, thrombospondin-1 (TSP-1), TSP-4, follistatin (FST) and follistatin- like factors (Fstl1, Fstl3), apelin, connective tissue growth factor (CTGF), MicroRNA-146a factor [2-4]. Further in-depth studies have revealed their multiple isoforms which exhibit diff erent properties. Combined eff ects of the mentioned biologically active substances upon specialized cells of distinct organs will be diff erent, depending on functional characteristics of the given tissue. Intercellular interactions between endothelium and specialized somatic cells show tissue specifi city, e.g., endothelium-cardiomyocyte interactions in cardiac tissues.
With aging and signs of age-dependent coronary pathology, endothelium is more scarcely regenerated, and becomes dysfunctional [6]. As a result, its ability to release vasoactive molecules such as acetylcholine (ACh), prostacyclin (PGI2), endothelium-derived hyperpolarizing factor (EDHF), and nitric oxide (NO) is reduced and the cellular response to these molecules is also impaired, also due to age-related higher production of reactive oxygen and nitrogen species, endothelin and angiotensin.

Systemic and local endothelial ysfunction

Sax et al. (1987) have shown that altered endothelial functions of skin microvessels in patients with microvascular coronary arterial disease (CAD) correlate with appropriate changes in myocardium [7]. This finding has allowed a view on endothelial dysfunction (ED) as a systemic pathological process, and served as a basis for development of non-invasive techniques for the vascular ED evaluation in available peripheral vessels.
Heart as an active muscular organ which reacts quite rapidly to the changes of its local blood supply. Regulation of muscular contraction, neuromuscular conduction system, myocardial metabolism and regeneration suffi ciently depend on both neuro-endocrine eff ects and interactions between local cell populations. E.g., specifi c interactions between endothelium and cardiomyocytes exist within heart. These eff ects are determined by the balance of endothelium-secreted cytokines which may be shift ed due to alterations of endothelium and cardiomyocytes. Th is imbalance may manifest as disturbed myocardial contraction, dilatation of cardiac chambers, altered heart rate, clinically presenting as a heart failure.
Different production rates and lifetime are demonstrated for biologically active substances produced by endothelium. The lifetime for products synthesized by the coronary endothelium is very short (<1 sec), thus being limited by neighbouring cells, e.g., cardiomyocytes, and does not extend to entire cardiovascular system. Therefore, it is reasonable to specify a local endothelial function connected with endothelial-cardiomyocyte interactions.

Local attraction and recruitment of injected bone marrow cells: role of endothelium

Several experimental studies concerned fi nal residence of marrow mononuclears injected either systemically or locally (Table 1). Comparative studies have shown much higher MNC capture when injected intracoronarily than via peripheral veins [8,9]. Intramyocardial injections resulted in even higher cell capture in injured area [10]. Measurable rates of MNC homing in the heart were approximately 6-7% [9, 11].Table_1_Local_capture_of_bone_marrow_mononuclear_cell_MNC_in_experimental_myocardial_infarction_in_pigs.png
Potential mechanisms of leukocyte attraction from blood fl ow to the vascular endothelium are discussed by Rao et al. [12]. The authors regard local recruitment of some leukocyte subpopulations to the tissues through endothelial-dependent mechanisms. These complex events are associated with endothelial secretion of various prothrombotic molecules, i.e., platelet-derived growth factor, von Willebrand factor, prostacyclin, NO, endothelin-1, expression of adhesion molecules (selectins, ICAM etc.). Short-distance leukocyte attraction is promoted by chemokines (MCP-1, MIP, RANTES etc.). Th e recruited lymphocytes and monocytes in turn, are also induced for secretion of proinfl ammatory factors and emigrate via endothelial layer, thus promoting tissue remodeling and neovasculogenesis. Hence, “molecular conversations” of endothelium with recruited leukocytes may play a key role in triggering the infl ammatory response including tissue pathology following myocardial infarction.
A number of diff erentiation options is presented for the bone marrow mononuclear cells. Cellular composition of such MNC preparations is quite heterogenous, including T and B cells, monocytes, a small fraction of blood precursors etc. Th ere are few studies concerning their in vivo fate. E.g., Fatkhudinov et al. [13] have injected autologous labeled bone marrow MNCs into the right and left coronary arteries in rats at day 30 aft er infarction. The labelled cells were then detected only in the damaged zone of the myocardium. However, these cells were not found in vascular walls. Interestingly, the transplanted cells were surrounded by thick collagen fi bers with time, thus presuming their fibroblastic differentiation. In their later study, this group has shown that the injected mononuclear cells migrated to the cicatrix zone where they diff erentiated into fi broblasts and myofi broblasts [14]. Meanwhile, there was no evidence of their in vivo differentiation to cardiomyocytes, endothelial cells, or smooth muscle cells of vascular media. However, stimulation of angiogenesis and reparation of the myocardium was observed after BM MNC treatment, thus uggesting a positive effect for repair of heart function.

Clinical evidence

Cellular therapy of heart by means of autologous bone marrow has been worldwide in frames of clinical trials since 2002. Aft er 15 years of its usage, its safety and positive eff ect are shown by most workers worldwide. Primary pre-clinical studies [15], and initial clinical experience in Düsseldorf (Germany) performed and summarized by Strauer et al.[16], and in Rostock by Stamm et al. [17] used autologous bone marrow cells (ABMC) for treatment of coronary artery disease (CAD). Trials with CAD patients have revealed a positive functional response to the cellular therapy. Over the last 15 years, since introduction of this treatment modality, some distinct positive results are shown in randomized clinical studies. Th is treatment still did not become a standard for CAD patients, despite several meta- analyses have shown some benefits of the cellular therapy [18-20].
Over 2003-2017, a research team at the First St. Petersburg I. Pavlov Medical University (FSPMU) performed several studies dedicated to usage of autologous bone marrow hematopoietic cells (ABMC) for treatment of CAD patients and dilated cardiomyopathy. A total of 250 patients have received ABMC by 2017. Th e results of our studies were presented in several publications [21, 22, 23, 25].
At the present time, upon additional analysis and further controlled studies, we conclude that the most positive effects of the cellular therapy could be explained by neoangiogenesis which could be observed following an eff ective cellular therapy. Most workers agree that a paracrine mechanism for the cytokine action is predominant under these conditions [24]. However, intercellular relations are known to be mediated by the cytokine eff ects. Th erefore, a term of paracrine mechanism needs to be specified.
We attempted to ascribe some eff ects of the cellular therapy not only to angiogenesis, but also to possible correction of coronary endothelium using our own experience, as well as some facts from present publications.
During two years (2003-2004), after preclinical studies, we performed a pilot study in 12 patients which confi rmed safety and reproducibility of ABMC intramyocardial injections (during aorto-coronary bypass surgery), or intracoronary infusion (during coronarography) to patients within first hours aft er ex vivo bone marrow separation. We have noted a positive effect of additional AMBC usage in both groups. However, we were unable to discern a favorable action of cellular therapy from positive eff ects of revasculatization.
From 2005 to 2011, we performed a controlled study of hydroxyethyl starch (HES)-separated AMBC upon intracoronary injections applied in patients with marked coronary lesions who were not fi t for coronary bypass surgery, or coronary angioplastics and stenting [21]. Th is study included 97 CAD patients. These persons received ABMC via coronary vessels, without any special revascularization procedures. Control group consisted of 37 patients who did not receive ABMC injections, being only subjected to adequate conventional medical therapy. The patients received intracoronary injections of ABMC obtained by multiple sternal and iliac punctures and enriched by gradient centrifugation (900 g for 15 min at 1-st stage, and 700 g for 15 min at 2-nd stage) by means of HES solution. Mean total number of isolated nucleated cells was 6.8±3.5x108; mononuclear cell yield was 9±7.85x108; average CD34-positive cell number was 1.6±0.85x106. Total cell viability was about 95-98%. Clinical eff ect of ABMC injections in the study group was expressed in terms of decreased CAD symptoms by 1 functional class (68% of total), by 2 functional classes (12%); 20% patients did not feel any changes. Such eff ect was evident at 6 to 9 months aft er single AMBC injections. We have observed a distinct gradual improvement of myocardial perfusion within the fi rst year, as shown by means of positron emission tomography (PET) with isotopic ammonium, and increased myocardial metabolism according to PET studies with fl uorodeoxyglucose (FDG). E.g., improved perfusion and myocardial metabolism were revealed as soon as 3 months later, however, more expressed positive changes are detected 6 and 12 months aft er single ABMC injection (Fig. 1). It should be noted that the detected increase of myocardial perfusion and improved cardiac metabolism represent two parallel, and, probably, interacting processes in heart aft er cellular therapy by local infusions of non-modifi ed ABMC. Of note, this improvement of myocardial perfusion and enhanced local metabolism are two parallel, and, probably, interconnected processes in heart aft er cellular therapy with intracoronary injection of non-modifi ed ABMC to left ventricular myocardium.
Figure_1_Metabolic_pattern_evaluated_by_positron_emission_tomography_PET_of_myocardium_dynamics_of_fluordeoxyglucose_FDG.png
At initial PET scans (A), a marked decrease in glucose metabolism is observed in the area of recent myocardial infarction (anteroseptal segment, arrow). After stem cell transplantation, a subsequent improvement is noted in the area of interest (B, 3 months); significant improvement (C, 6 months), and normalization of 18F-FDG capture (D, 12 months), thus being indicative for successive normalization of metabolic processes in the given area of left ventricle.


These protective events were accompanied by increased myocardial contractibility, according to Echo-CG data, thus being ascribed to improved collateral blood fl ow. The revealed increase of collateral circulation could explain alleviation of coronary disorder and increased myocardial perfusion, as shown by SPECT and PET studies. Meanwhile, CAD functional class did not change in control group. This effect retained forca. 3 years, followed by decreased antianginal effect at 4-5 years. Coronary angiography performed at these late terms showed stabililization of coronary arteries, without any significant progression of atherosclerotic lesions. It should be noted that impaired coronary circulation developed in presence of retained collateral blood flow.
Worth of note, we did not observe any cases of heart teratomas, pathological local ossifi cations, unfavorable immune reactions, or other adverse eff ects connected with ABMC injections over years of this study.
Consequent SPECT studies of myocardial perfusion in 19 patients have confi rmed a decreased perfusion defi ciency, as compared to initial levels, at the terms of up to 3 years after ABMC injections, thus being indicative for improvement of myocardial function. Th e decreased hypoperfusion area was patient-specific, and the year-by-year changes varied from 0.79±9.7% to 5.44±8.7% of hypoperfused area (<60% of reference levels).
Four years later, the average perfusion deficiency resumed to grow against initial level, i.e., myocardial blood supply changed to inferior values (Fig. 2). These findings prompted us to perform repeated ABMC injections four years later. Coronary angiography was performed before repeated ABMC injections. One should note that consecutive coronarography, as a rule, did not reveal any significant repair of initially aff ected coronaries. Meanwhile, the denovo developed collaterals continued their functioning aft er primary ABMC injection. Four patients were subjected to repeated intracoronary ABMC injection, without any other revascularization procedures. Distinct improvement of myocardial perfusion, according to SPECT data, and better clinical condition (decreased CAD functional class) were noted in all four patients, who underwent repeated intracoronary ABMC injections. 6 to 12 months later, a second wave of improved myocardial perfusion was observed, according to consequent SPECT examinations with technetryl labeling [25].

Figure_2_Time_changes_of_median_values_of_myocardial_perfusion_deficiency_60__assessed_by_SPECT_performed_with_Technetril.png
Such transient improvement of myocardial blood flow at 3-6-12 months after primary ABMC infusion followed by decreased heart blood supply at later terms (despite functioning collaterals), and repeated increase of blood supply at 3-6-12 months aft er repeated ABMC injections suggest some accessory bioactive factors responsible for the positive circulatory changes, probably, due to functional correction of coronary endothelial cells in severe CAD patients.

Dilated cardiomyopathy

Improvement of myocardial contractile ability was obtained also in a group of patients with dilated cardiomyopathy (DCMP), i.e., primary myocardial aff ection without coronary changes [22, 23]. All these patients (n=20) were devoid of coronary atherosclerotic lesions, thus confi rming a DCMP diagnosis. Th e patients had cardiac insuffi ciency of NIHA functional class 3-4, with initial ejection fraction of 17 to 41%. In all those cases, ABMC were injected during coronary angiography, as intracoronary infusions of freshly isolated autologous marrow cells.
A positive clinical eff ect of this procedure was registered in 18 cases (90% of total), as refl ected by decreased apnoe caused by physical loadings, decreased left ventricle end-systolic diameter, and increased left ventricle ejection fraction (LVEF). Notably, these positive eff ects allowed to decrease intensity of diuretic therapy (by tapering Furosemide dose, and switching to Torasemide). Assessment of metabolism by PET examination with fl uorodeoxyglucose (FDG) has shown that the cellular therapy, lead to improved capture of the radiopharmaceutical in the segments with initially decreased metabolic level. Moderate increase of FDG capture was also noted in segments with virtually normal metabolism. One could suggest a direct eff ect of the cellular therapy upon cardiomyocytes. A distinct answer to this question is impossible, because myocardial microcirculation is affected in DCMP as well. Following cellular therapy, improved blood supply in DCMP was shown in the same segments as those with increased metabolism. The positive metabolic changes detected by PET were also found in DCMP patients within next 3-6 months aft er cellular therapy and were traceable over 2 years [23].
Altered myocardial blood supply in severe DCMP patients is associated with increased intramyocardial tension, and, accordingly, with disturbed blood supply at the microcirculatory level. One cannot exclude endothelial dysfunction of coronary microcirculation, and altered production of nitrogen monoxide and other substances negatively infl uencing myocardial contraction and coronary blood fl ow. Causal relations between the two processes (perfusion dynamics and intramyocardial tension) are hardly to discriminate at the present time.
Second ABMC injections in DCMP patients were performed in two cases 4-6 years aft er the fi rst treatment, showing repeated improvement of clinical state (fi rst of all, decreased apnoe) as reported by the both patients 6 to 9 months after cell therapy. Of note, repeated positive changes of left ventricle end-diastolic diameter, and accordingly, LVEF, are shown in these cases. These facts also suggest a functional mechanism of ABMC eff ects upon myocardium and endothelium. The issue of primary effect of ABMC injections upon coronary endothelium, with subsequent myocardial recovery, still remains open.
Thus, a repeated injection of ABMC 4-5 years later allows to achieve the second wave of clinical improvement. If such second injection is performed earlier, at 6-8 months aft er primary treatment (termed double infusion) the procedure may lead to suffi ciently improved well-being, which is accompanied by marked positive changes of left ventricle end-systolic and -diastolic diameters, and more signifi cant LVEF increase, than following a single injection. We have performed such double ABMC injection in only two patients. However, these cases are characterized by more suffi cient cardiotropic effects than single ABMC infusions. A successful experience with repeated injections of BM MNCs was also published by a group of workers from Frankfurt [24]. The authors used intracoronary injections of autologous bone marrow-derived mononuclear cells (BM-MNCs). The data from their local registry included 297 post-infarction heart failure patients. The results of this study have shown that repeated intracoronary application of autologous bone marrow-derived cells is associated with a significant better 2-year survival compared with a single BM-MNC application (2-year survival 93.6 vs. 84.0%, P=0.03). Likewise, mortality is signifi cantly lower at 2-year follow-up compared with the mortality estimated by the use of the  Seattle Heart Failure Model (SHFM) in patients receiving repeated BM-MNC application (observed mortality 6.4%, predicted mortality 16.2%, P=0.02). The repeated intracoronary administration of BM-MNC appears to be associated with improved clinical outcome compared with single treatment at 2 years. The authors propose a design of the multicentre randomized, controlled, open-label REPEAT trial in patients with chronic post-infarction heart failure.

Discussion

At the present time, exact mechanism of cellular therapy is not known. Some distinct positive clinical results are detected over 15 years of its implementation in cardiology. These successful data are presented in randomized clinical studies. Meta-analyses of 2012 and 2015 showed a distinct value when applying cellular therapy for CAD and DCMP treatment.
Development of collateral vascular network due to neoangiogenesis was demonstrated in majority of works concerning mechanism of stem cell action upon heart tissues in CAD. Some workers consider formation of new vascular collaterals to be the main effect of hematopoietic stem cell treatment. A mechanism and consequences of bone marrow cell recruiting following a coronary arterial occlusion are suggested by Schaper [26]. In brief, the shear stressed endothelium leads, in particular, to high NO production and VEGF secretion by endothelial cells followed by MCP-1 release. Th ese compounds cause attraction and homing of T cells and monocytes at the collateral vessels. Th e blood-derived mononuclear cells and degrade extracellular matrix (ECM) and produce vascular growth factors (VEGF), thus causing tissue remodeling and arteriogenesis mainly of the smooth muscle layer. Blood fl ow is partially restored which is indeed observed in clinical.
According to many authors, a cytokine or paracrine effect is understood to be an immediate mechanism of the cellular therapy, i.e., the transplanted cells are solely cytokine suppliers, including growth factors which provide augmented natural regeneration [19, 20]. One may propose that the injected stem cells represent a kind of reservoirs containing growth factors that promote regeneration even when these cells are subsequently dying. This hypothesis is quite possible, especially if stem cell isolation was accompanied by their damage, growth factor leakage and subsequent death. In such cases, a real eff ect of the cellular therapy should not exceed 3-6 months, and we cannot consider a solely cytokine effect. However, a long-term duration of a positive effect from cellular therapy with autologous freshly isolated bone marrow cells is as long as 3-4 years in most cases, thus suggesting a stem cell-mediated regeneration of some heart cell populations [25].
Cardiomyocytogenesis as an important mechanism of heart regeneration, was shown by several works, and by present time, some data are accumulated in favor of cardiomyocyte regeneration [27]. The more sufficient arguments for cellular component of heart regeneration were reported by Anversa et al. [28], i.e., upon female-to-male heart transplantation, large numbers of male cells were revealed in female heart graft, thus suggesting a cellular regeneration mechanism in this setting. A mean number of male (Y chromosome-positive) cardiomyocytes was 18%, compared to 20% among smooth muscle cells of arterioles, and 14% of capillary endotheliocytes, as based on examination of eight female heart transplants in male recipients at different terms (4 to 552 days) posttransplant. This result suggests an intensive pprobably via blood circulation) transfer of male cells (possibly, hematopoietic stem cells and endothelium precursors) to the female heart graft . Hence, one may note that a sufficient renewal occurs not only among cardiomyocytes, but also for smooth muscle cells of arterioles and heart capillary endothelium [28]. One may presume these cells to regenerate in native heart tissues in other diseases in absence of heart transplantation, thus supposing similar regeneration mechanisms. Additional information on cellular but not only cytokine-mediated effects of injected stem cells was presented by a group of workers from Frankfurt [29] who performed experiments in mice containing a suicide gene introduced to their myocardial cells subjected to death, after their incorporation to myocardial syncytium, vascular endothelium and vascular wall. In this model of acute myocardial infarction, injection of bone marrow cells committed to endothelial differentiation lead to signifi cant improvement of the myocardial contractibility. Provoked death of cells induced for endothelial diff erentiation lead to decreased cardiac output. Interestingly, provoked death of cells committed for myocardial diff erentiation did not exert such an effect. Moreover, elimination of endothelial cells with NO synthase expression caused a decreased density of capillaries and arteriolae [29].
These data point to a suffi cient infl uence of endothelium upon functional ability of myocardium. Endothelium layer regulates transendothelial transport, including stem cell transfer, due to increased production of adhesion molecules on the surface of endothelial cells. The cells of diff erent phenotypes exhibited diff erent ability for transendothelial migration in an in vitro model with bone marrow-derived endothelial cell line [30]. BMEC-1 cells support transmigration of hematopoietic progenitors and more mature hematopoietic cells, thus representing predominantly committed progenitor cells. One may suggest that recovery of endothelial function is accompanied by correction of transendothelial transport. The resulting interactions between endothelium and myocardium may play a sufficient role in heart tissue regeneration.
The first experimental study which demonstrated an effect of injected marrow precursors upon endothelial dysfunction was presented by the workers from Oklahoma University [31]. In murine experiment, they have shown that treatment with bone marrow endothelial precursors is followed by a decreased thickness of lipid plaque layers. This effect could be used in future for atherosclerosis therapy. In addition, the authors noted that the injected endothelial precursors promote NO production by endothelial cells of appropriate vessels, thus augmenting the endothelium-dependent vascular relaxation. The authors did not conclude on probable necessity of bone marrow cells for endothelial recovery, in order to correct altered endothelial function. However, the results of this study suggest such an option.
Interactions between endotheliocytes of coronary bed and cardiomyocytes are rather complex, multifaceted, and are mediated not only by nitrogen monoxide, but also by numerous substances produced by endothelial cells that, in turn, influence cardiomyocyte populations, for either increasing, or inhibiting their function [5]. Th erefore, functional correction of coronary endothelium could be quite important for treatment of myocardial heart insuffi ciency. By the present time, some new factors were studied, in order to treat chronic heart insuffi ciency, in particular, neuregulin. However, one should bear in mind that activation at certain regeneration stages may lead to evolvement of unfavorable consequences including neoplasia [32, 33]. Apparently, detailed studies of interactions between endotheliocytes and cardiomyocytes will take much time, like as search and clinical implementation of single synthesized biologically active substances. Today, however, basing on current results of cellular therapy performed in 250 patients over 15 years, one may presume that a local infusion of freshly isolated ABMC could exert favorable eff ects upon coronary blood fl ow and diminish clinical signs of heart insufficiency. Correction of endothelial dysfunction may be a sufficient component of this mechanism [25].

Conclusion

On the basis of current knowledge and data about endothelium and its effects upon functional state of myocardium and entire heart, one may conclude that endocardial and coronary bed endothelium cannot only be a protective barrier between blood fl ow and cardiomyocytes. Endothelium seems to be a complex and well-balanced secretory system which control functional cellular activity, metabolism, survival and regeneration of cardiomyocytes, due to interactions between diff erent cell populations, by secreting short-range biological substances.
Local endothelial dysfunction plays a suffi cient role in pathogenesis of such heart diseases as CAD and DCMP. Therefore, its correction, e.g., by intracoronary injection of freshly isolated ABMCs, may be an important therapeutic component for future treatment of these diseases. Our hypothesis on important role of endothelium in MNC recruitment to the damaged site seems to be supported by experimental and clinical evidence, but still needs additional studies to be confirmed.

Acknowledgments

The authors are much appreciated to Professor Boris V. Afanasyev, Director, R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I.Pavlov Medical University and to the Institute staff for a long-term cooperation when performing clinical studies.

Conflict of interest

No conflict of interest is reported.

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Эндотелий представляет собой клеточный слой, выстилающий кровеносные сосуды любого человеческого органа или ткани. В течение десятилетий, защитные и барьерные функции считались основными свойствами сосудистого эндотелия. На протяжении последних 20 лет, однако, эндотелий стал рассматриваться как активный эндокринный орган в связи с секрецией множества энзимов, метаболических и ростовых факторов, может оказывать существенные регуляторные воздействия на ткани сердца и кровеносных сосудов, тем самым играя важную роль в патогенезе определенных сердечно-сосудистых заболеваний. Накопление данных об изменении взаимодействий между эндотелием сосудов сердца и миокардом позволяет нам предположить дополнительную местную функцию коронарного эндотелия, т.е. предполагаемую продукцию биологически активных веществ клетками эндотелия и их эффекты на метаболизм, функционирование, выживание и регенерацию кардиомиоцитов. Данная статья предлагает обсуждение и анализ конкретных исследований, касающихся клеточной терапии при заболеваниях сердца у человека. Эти данные говорят в пользу гипотезы о дополнительной роли эндотелия в функционировании сердца и предлагают потенциальную возможность коррекции эндотелиальной дисфункции посредством клеточной терапии.

Ключевые слова

Сердце, заболевание коронарных артерий, эндотелиальная дисфункция, клеточная терапия, дилатационная кардиомиопатия.

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Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(79) "First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20047" ["VALUE"]=> array(2) { ["TEXT"]=> string(1462) "<p style="text-align: justify;"> Endothelium is a cellular layer lining blood vessels in either a human organ or tissue. For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1396) "

Endothelium is a cellular layer lining blood vessels in either a human organ or tissue. For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy.

Keywords

Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy.

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For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1396) "

Endothelium is a cellular layer lining blood vessels in either a human organ or tissue. For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy.

Keywords

Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy.

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Endothelium is a cellular layer lining blood vessels in either a human organ or tissue. For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy.

Keywords

Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy.

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Эндотелий представляет собой клеточный слой, выстилающий кровеносные сосуды любого человеческого органа или ткани. В течение десятилетий, защитные и барьерные функции считались основными свойствами сосудистого эндотелия. На протяжении последних 20 лет, однако, эндотелий стал рассматриваться как активный эндокринный орган в связи с секрецией множества энзимов, метаболических и ростовых факторов, может оказывать существенные регуляторные воздействия на ткани сердца и кровеносных сосудов, тем самым играя важную роль в патогенезе определенных сердечно-сосудистых заболеваний. Накопление данных об изменении взаимодействий между эндотелием сосудов сердца и миокардом позволяет нам предположить дополнительную местную функцию коронарного эндотелия, т.е. предполагаемую продукцию биологически активных веществ клетками эндотелия и их эффекты на метаболизм, функционирование, выживание и регенерацию кардиомиоцитов. Данная статья предлагает обсуждение и анализ конкретных исследований, касающихся клеточной терапии при заболеваниях сердца у человека. Эти данные говорят в пользу гипотезы о дополнительной роли эндотелия в функционировании сердца и предлагают потенциальную возможность коррекции эндотелиальной дисфункции посредством клеточной терапии.

Ключевые слова

Сердце, заболевание коронарных артерий, эндотелиальная дисфункция, клеточная терапия, дилатационная кардиомиопатия.

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Эндотелий представляет собой клеточный слой, выстилающий кровеносные сосуды любого человеческого органа или ткани. В течение десятилетий, защитные и барьерные функции считались основными свойствами сосудистого эндотелия. На протяжении последних 20 лет, однако, эндотелий стал рассматриваться как активный эндокринный орган в связи с секрецией множества энзимов, метаболических и ростовых факторов, может оказывать существенные регуляторные воздействия на ткани сердца и кровеносных сосудов, тем самым играя важную роль в патогенезе определенных сердечно-сосудистых заболеваний. Накопление данных об изменении взаимодействий между эндотелием сосудов сердца и миокардом позволяет нам предположить дополнительную местную функцию коронарного эндотелия, т.е. предполагаемую продукцию биологически активных веществ клетками эндотелия и их эффекты на метаболизм, функционирование, выживание и регенерацию кардиомиоцитов. Данная статья предлагает обсуждение и анализ конкретных исследований, касающихся клеточной терапии при заболеваниях сердца у человека. Эти данные говорят в пользу гипотезы о дополнительной роли эндотелия в функционировании сердца и предлагают потенциальную возможность коррекции эндотелиальной дисфункции посредством клеточной терапии.

Ключевые слова

Сердце, заболевание коронарных артерий, эндотелиальная дисфункция, клеточная терапия, дилатационная кардиомиопатия.

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Introduction

Treatment of classical Hodgkin’s disease (HD) is one of the successful stories in hematology. Since the introduction of ABVD regimen in 1970s, the results of treatment are constantly improving [1]. Even only aft er ABVD regimen administered for advanced disease stages the overall survival in large patient cohorts is 78%, however freedom from disease is only 66% [2], indicating the need for high-dose chemotherapy for approximately 35% of patients. Th is led to development of more intensive protocols, like BECOPP [3], and subsequently BEACOPPescalated and BEACOPP14 [4] that produced failure-free-survival (FFS) of 85-89% in advanced HD. Nonetheless these intensifi ed approaches were associated with signifi cant incidence of secondary malignancies [5,6] as well as both male and female infertility [7]. This is the reason why several developed countries like the US, ABVD remains the standard of care for all disease stages [8].
The efforts to overcome the limitation of BEACOPP regimens were done aft er introduction of positron-emission tomography (PET) into clinical practice. It was demonstrated that PET status after two courses of chemotherapy strongly predict the outcome of treatment [9]. This finding was the foundation of several escalation studies [10,11] where absence of complete response led to switching therapy from ABVD to BEACOPPesc. Also several de-escalation studies were lunched, where complete response based on PET triggered change of therapy from BEACOPPesc to ABVD [12]. These two approaches were used as the basis for protocol development by Russian North West Oncology and Hematology Group (RNWOHG).
In Russian Federation around 3200 cases of HD are documented annually, which translates into 2.2 cases per 100000 people per year. Th e mortality from HD is 28,3% [13], which is significantly higher than reported in the foreign registry studies. Th ere might be several reasons for that: large distances between towns, poor excess to high-technology care, like second-line chemotherapy, autologous and allogeneic stem cell transplantation (auto and allo SCT), poor capabilities for supportive care in some of the oncology and hematology departments. In this study we wanted to solve several of these issues: coordinate the transfer of patients for the second line and to develop low toxicity protocol with relative high FFS aft er the fi rst line therapy.

Rationale and study design

The study upon diagnosis separates the patients into two groups: favorable prognosis and unfavorable prognosis. The definition of favorable is diff erent from the one of the German Hodgkin Study Group (GHSG). In this study presence stage IIB, large mediastinal mass, ESR more than 50 mm/h and IPS [2] more than 2 places a patient into unfavorable group, while stages I-IIA without these factors are considered favorable. Th e reason for that is the planned omission of radiotherapy in the PET(-) patients and truncation of therapy to 4 ABVD cycles in the group with partial response after two cycles. Th us we wanted to exclude the majority of patients who will fail this tapered therapy in the favorable arm (Fig. 1).
The treatment in the favorable arm includes two cycles of ABVD. Aft er that the therapy is selected based on the PET status. Patients with PET(-) CR go into follow up. This decision is based on the two studies: HD10 trial and NCIC CTG– ECOG HD.6 trial [14,15]. Th e fi rst study demonstrates that 2xABVD are equivalent two 4xABVD with subsequent radiation therapy and the second that radiation therapy could be omitted aft er 4xABVD. Th ese were not PET-guided studies. We believe that strict selection of good prognosis patients and verifi cation of PET(-) status before end of therapy will produce the same results as in these two studies. Patients achieving PET(+) partial response undergo subsequent 2xABVD courses and radiation therapy, which the standard approach for the low risk responding well to the chemotherapy, used for example in HD10 study [14]. Patients that will have less then partial response aft er 2xABVD are switched to 4xBEACOPPesc or 4xBEACOPP14 according investigator choice. The efficacy of this approach was tested in the study by Johnson et al. and Italian RATHL trial [10,16]. In these two trials the FFS was more than 70% in all risk and stage groups, thus in the favorable group the FFS is expected to be more than 80%. Th e omission of radiotherapy aft er 4xBEACOPPesc is based on GHSG HD12 trial, where there was no difference in FFS between radiotherapy and stop therapy groups [17]. In conclusion, based on the current data available the suggested approach should produce around 80-85% FFS in the favorable group.
The decision to leave BEACOPPesc or BEACOPP14 to an investigator choice is based on many consultations with participating centers. Several of them, which treat HD in inpatient setting were not willing to participate if there will be no option for BEACOPPesc, the other which predominantly treat HD in the outpatient setting were not willing to participate, if there will no option of BEACOPP14, because it is much better tolerated and could be reproduced in the outpatient facilities. In HD14 trial it was demonstrated that these two approaches are equivalent in terms of FFS [4].
Thus in the unfavorable group the therapy is started from 2xBEACOPPesc or 2xBEACOPP14 according investigator choice. In PET(-) patients the de-escalation to ABVD/AVD cycles is planned. Th is is based on HD12 study, where without PET guidance switch to 4xABVD from 4xBEACOPPesc was not compromising the results, on study by Aviqdor et al. [18], and on the randomized study by Johnson et al. where in PET (-) patients there was no diff erence between ABVD and AVD. Th is is the only randomization present in the study. The expected effi cacy of this approach is 85% FFS [10]. Patients who are PET(+) aft er two cycles continue BEACOPPesc/BEACOPP14 therapy up to 6 cycles. It is demonstrated in HD18 trial that the FFS is not compromised in PET(+) patients when they continued up to 8 BEACOPPesc courses [19]. In our study the therapy is limited two six cycles. This is based on the decision of opinion leaders from the participating centers. Radiation therapy is omitted aft er BEACOPPesc on the same basis as in the favorable arm of the study [17]. In conclusion, the unfavorable arm 1-st line is also expected to produce 80-85% FFS.
In the second line therapy four types of treatment is chosen by the investigator: DHAP, ICE, IGEV and brentuximab+ bendamustine (BB). There are no restrictions in the choice of therapy since there are no large prospective randomized trials addressing this issue [20]. For patients with primary IPS ≥4 and primary refractory disease the BB second line is recommended because the effi cacy of standard approach with autoSCT results only in 9% FFS in this group of patients, while BB protocol seems to induce higher proportion of complete responses [21-23]. The third line includes only BB re-induction and mandatory alloSCT from related, unrelated or haploidentical donor, whoever is available.

Figure_1_Study_design_for_HIV-negative_patients.png

Statistical considerations and expected results

The study is completed with observation program which will include patients treated with conventional approaches in the participating centers. Thus it is planned to compare the results of this RNWOHG-HD1 with standard care in Russian Federation. The expected overall survival in the protocol is at least 85% and the estimated enrollment is 900 patients. Thus the study is expected to demonstrate the improvement in survival with 100% power and alpha=0.01.

HIV-infected patients

The RNWOHG-HD1 program has the sub-study for HIV-infected patients. Since BEACOPPesc is poorly tolerated in this population of patients and results in 7% mortality [24], all treatment in the fi rst line is based on ABVD courses with subsequent de-escalation to randomized ABVD/AVD cycles as in the general protocol (Figure 2). Th e 2nd and 3rd line therapies are identical to the general protocol. The protocol encourages the attending physicians to control the continuation of HAART therapy throughout the whole treatment process.

Figure_2_Study_protocol_for_HIV-infected_patients.png

Conclusion

In conclusion, the study is expected to improve the treatment practices in one region of Russian Federation. It is also expected to answer the questions of possible truncation of therapy based on prognostic factors and interim PET-assessed response.

Acknowledgements

Th e study is supported by the unrestricted grant from Takeda Inc. and is managed by Aston Health, Moscow. Special thanks to Daria Pridatchina, Dmitrii Kosov and Sofi a Demura for the help in the development of the study and its electronic platform.

Financial Disclosure Statement

The authors have nothing to disclaim. Multicenter prospective escalation-de-escalation PET-guided clinical study in classical type Hodgkin disease in the Noth-Earst of Russian Federation (RNWOHG-HD1): rational and design.

References

1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.
2. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506-1514.
3. Diehl V, Sieber M, Rüff er U, Lathan B, Hasenclever D, Pfreundschuh M et al. BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin’s disease. Th e German Hodgkin’s Lymphoma Study Group. Ann Oncol. 1997;8(2):143-148.
4. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.
5. Sasse S, Klimm B, Görgen H, Fuchs M, Heyden-Honerkamp A, Lohri A et al. Comparing long-term toxicity and effi cacy of combined modality treatment including  extended-or involved-fi eld radiotherapy in early-stage Hodgkin’s lymphoma. Ann Oncol. 2012;23(11):2953-2959.
6. Dörff el W, Riepenhausenl M, Lüders H, Brämswig J, Schellong G. Secondary Malignancies Following Treatment for Hodgkin’s Lymphoma in Childhood and Adolescence. Dtsch Arztebl Int. 2015;112(18):320-327.
7. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.
8. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014;9(3):222-226.
9. Gallamini A, Patti C, Viviani S, Rossi A, Fiore F, Di Raimondo F et al. Early chemotherapy intensifi cation with BEACOPP in advanced-stage Hodgkin lymphoma patients with an interim-PET positive aft er two ABVD courses. Br J Haematol. 2011;152(5):551-560.
10. Johnson P, Federico M, Kirkwood A et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016; 374(25):2419-2429.
11. Press OW, Li H, Schöder H et al. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fl uorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
12. Eichenauer DA, Engert A. Advances in the treatment of Hodgkin lymphoma. Int J Hematol 2012; 96:535–543.
13. Kaprina AD, Starinskii VV, Petrova GP. Malignant neoplasms in Russia in 2015 (Morbidity and Mortality). Мoscow. P.Gertcen MNIOI, 2017. ISBN 978-5-85502-227-8 (In Russian).
14. Engert A, Plütschow A, Eich HT, Lohri A, Dörken B, Borchmann P et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.
15. Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012 366(5):399-408.
16. Lugano conference presentation, Switzerland, June 17-20, 2015 (abstr 008).
17. Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s lymphoma: fi nal analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.
18. Avigdor A, Bulvik S, Levi I, Dann EJ, Shemtov N, Perez-Avraham G et al. Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an eff ective regimen for advanced high-risk Hodgkin’s lymphoma. Ann Oncol. 2010;21(1):126-132.
19. Borchmann P, Haverkamp H, Lohri A, Mey U, Kreissl S, Greil R et al. Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin’s lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol. 2017;18(4):454-463.
20. Engert A, Horning SJ. Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics. 2011, Springer-Verlag, Berlin.
21. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory Hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.
22. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
23. Moskowitz CH, Nimer SD, Glassman JR et al. Th e International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant. 1999;23(6):561-567.
24. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.

" ["~DETAIL_TEXT"]=> string(15584) "

Introduction

Treatment of classical Hodgkin’s disease (HD) is one of the successful stories in hematology. Since the introduction of ABVD regimen in 1970s, the results of treatment are constantly improving [1]. Even only aft er ABVD regimen administered for advanced disease stages the overall survival in large patient cohorts is 78%, however freedom from disease is only 66% [2], indicating the need for high-dose chemotherapy for approximately 35% of patients. Th is led to development of more intensive protocols, like BECOPP [3], and subsequently BEACOPPescalated and BEACOPP14 [4] that produced failure-free-survival (FFS) of 85-89% in advanced HD. Nonetheless these intensifi ed approaches were associated with signifi cant incidence of secondary malignancies [5,6] as well as both male and female infertility [7]. This is the reason why several developed countries like the US, ABVD remains the standard of care for all disease stages [8].
The efforts to overcome the limitation of BEACOPP regimens were done aft er introduction of positron-emission tomography (PET) into clinical practice. It was demonstrated that PET status after two courses of chemotherapy strongly predict the outcome of treatment [9]. This finding was the foundation of several escalation studies [10,11] where absence of complete response led to switching therapy from ABVD to BEACOPPesc. Also several de-escalation studies were lunched, where complete response based on PET triggered change of therapy from BEACOPPesc to ABVD [12]. These two approaches were used as the basis for protocol development by Russian North West Oncology and Hematology Group (RNWOHG).
In Russian Federation around 3200 cases of HD are documented annually, which translates into 2.2 cases per 100000 people per year. Th e mortality from HD is 28,3% [13], which is significantly higher than reported in the foreign registry studies. Th ere might be several reasons for that: large distances between towns, poor excess to high-technology care, like second-line chemotherapy, autologous and allogeneic stem cell transplantation (auto and allo SCT), poor capabilities for supportive care in some of the oncology and hematology departments. In this study we wanted to solve several of these issues: coordinate the transfer of patients for the second line and to develop low toxicity protocol with relative high FFS aft er the fi rst line therapy.

Rationale and study design

The study upon diagnosis separates the patients into two groups: favorable prognosis and unfavorable prognosis. The definition of favorable is diff erent from the one of the German Hodgkin Study Group (GHSG). In this study presence stage IIB, large mediastinal mass, ESR more than 50 mm/h and IPS [2] more than 2 places a patient into unfavorable group, while stages I-IIA without these factors are considered favorable. Th e reason for that is the planned omission of radiotherapy in the PET(-) patients and truncation of therapy to 4 ABVD cycles in the group with partial response after two cycles. Th us we wanted to exclude the majority of patients who will fail this tapered therapy in the favorable arm (Fig. 1).
The treatment in the favorable arm includes two cycles of ABVD. Aft er that the therapy is selected based on the PET status. Patients with PET(-) CR go into follow up. This decision is based on the two studies: HD10 trial and NCIC CTG– ECOG HD.6 trial [14,15]. Th e fi rst study demonstrates that 2xABVD are equivalent two 4xABVD with subsequent radiation therapy and the second that radiation therapy could be omitted aft er 4xABVD. Th ese were not PET-guided studies. We believe that strict selection of good prognosis patients and verifi cation of PET(-) status before end of therapy will produce the same results as in these two studies. Patients achieving PET(+) partial response undergo subsequent 2xABVD courses and radiation therapy, which the standard approach for the low risk responding well to the chemotherapy, used for example in HD10 study [14]. Patients that will have less then partial response aft er 2xABVD are switched to 4xBEACOPPesc or 4xBEACOPP14 according investigator choice. The efficacy of this approach was tested in the study by Johnson et al. and Italian RATHL trial [10,16]. In these two trials the FFS was more than 70% in all risk and stage groups, thus in the favorable group the FFS is expected to be more than 80%. Th e omission of radiotherapy aft er 4xBEACOPPesc is based on GHSG HD12 trial, where there was no difference in FFS between radiotherapy and stop therapy groups [17]. In conclusion, based on the current data available the suggested approach should produce around 80-85% FFS in the favorable group.
The decision to leave BEACOPPesc or BEACOPP14 to an investigator choice is based on many consultations with participating centers. Several of them, which treat HD in inpatient setting were not willing to participate if there will be no option for BEACOPPesc, the other which predominantly treat HD in the outpatient setting were not willing to participate, if there will no option of BEACOPP14, because it is much better tolerated and could be reproduced in the outpatient facilities. In HD14 trial it was demonstrated that these two approaches are equivalent in terms of FFS [4].
Thus in the unfavorable group the therapy is started from 2xBEACOPPesc or 2xBEACOPP14 according investigator choice. In PET(-) patients the de-escalation to ABVD/AVD cycles is planned. Th is is based on HD12 study, where without PET guidance switch to 4xABVD from 4xBEACOPPesc was not compromising the results, on study by Aviqdor et al. [18], and on the randomized study by Johnson et al. where in PET (-) patients there was no diff erence between ABVD and AVD. Th is is the only randomization present in the study. The expected effi cacy of this approach is 85% FFS [10]. Patients who are PET(+) aft er two cycles continue BEACOPPesc/BEACOPP14 therapy up to 6 cycles. It is demonstrated in HD18 trial that the FFS is not compromised in PET(+) patients when they continued up to 8 BEACOPPesc courses [19]. In our study the therapy is limited two six cycles. This is based on the decision of opinion leaders from the participating centers. Radiation therapy is omitted aft er BEACOPPesc on the same basis as in the favorable arm of the study [17]. In conclusion, the unfavorable arm 1-st line is also expected to produce 80-85% FFS.
In the second line therapy four types of treatment is chosen by the investigator: DHAP, ICE, IGEV and brentuximab+ bendamustine (BB). There are no restrictions in the choice of therapy since there are no large prospective randomized trials addressing this issue [20]. For patients with primary IPS ≥4 and primary refractory disease the BB second line is recommended because the effi cacy of standard approach with autoSCT results only in 9% FFS in this group of patients, while BB protocol seems to induce higher proportion of complete responses [21-23]. The third line includes only BB re-induction and mandatory alloSCT from related, unrelated or haploidentical donor, whoever is available.

Figure_1_Study_design_for_HIV-negative_patients.png

Statistical considerations and expected results

The study is completed with observation program which will include patients treated with conventional approaches in the participating centers. Thus it is planned to compare the results of this RNWOHG-HD1 with standard care in Russian Federation. The expected overall survival in the protocol is at least 85% and the estimated enrollment is 900 patients. Thus the study is expected to demonstrate the improvement in survival with 100% power and alpha=0.01.

HIV-infected patients

The RNWOHG-HD1 program has the sub-study for HIV-infected patients. Since BEACOPPesc is poorly tolerated in this population of patients and results in 7% mortality [24], all treatment in the fi rst line is based on ABVD courses with subsequent de-escalation to randomized ABVD/AVD cycles as in the general protocol (Figure 2). Th e 2nd and 3rd line therapies are identical to the general protocol. The protocol encourages the attending physicians to control the continuation of HAART therapy throughout the whole treatment process.

Figure_2_Study_protocol_for_HIV-infected_patients.png

Conclusion

In conclusion, the study is expected to improve the treatment practices in one region of Russian Federation. It is also expected to answer the questions of possible truncation of therapy based on prognostic factors and interim PET-assessed response.

Acknowledgements

Th e study is supported by the unrestricted grant from Takeda Inc. and is managed by Aston Health, Moscow. Special thanks to Daria Pridatchina, Dmitrii Kosov and Sofi a Demura for the help in the development of the study and its electronic platform.

Financial Disclosure Statement

The authors have nothing to disclaim. Multicenter prospective escalation-de-escalation PET-guided clinical study in classical type Hodgkin disease in the Noth-Earst of Russian Federation (RNWOHG-HD1): rational and design.

References

1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.
2. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506-1514.
3. Diehl V, Sieber M, Rüff er U, Lathan B, Hasenclever D, Pfreundschuh M et al. BEACOPP: an intensified chemotherapy regimen in advanced Hodgkin’s disease. Th e German Hodgkin’s Lymphoma Study Group. Ann Oncol. 1997;8(2):143-148.
4. Engert A, Haverkamp H, Kobe C, Markova J, Renner C, Ho A et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.
5. Sasse S, Klimm B, Görgen H, Fuchs M, Heyden-Honerkamp A, Lohri A et al. Comparing long-term toxicity and effi cacy of combined modality treatment including  extended-or involved-fi eld radiotherapy in early-stage Hodgkin’s lymphoma. Ann Oncol. 2012;23(11):2953-2959.
6. Dörff el W, Riepenhausenl M, Lüders H, Brämswig J, Schellong G. Secondary Malignancies Following Treatment for Hodgkin’s Lymphoma in Childhood and Adolescence. Dtsch Arztebl Int. 2015;112(18):320-327.
7. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.
8. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014;9(3):222-226.
9. Gallamini A, Patti C, Viviani S, Rossi A, Fiore F, Di Raimondo F et al. Early chemotherapy intensifi cation with BEACOPP in advanced-stage Hodgkin lymphoma patients with an interim-PET positive aft er two ABVD courses. Br J Haematol. 2011;152(5):551-560.
10. Johnson P, Federico M, Kirkwood A et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016; 374(25):2419-2429.
11. Press OW, Li H, Schöder H et al. US Intergroup trial of response-adapted therapy for stage III to IV Hodgkin lymphoma using early interim fl uorodeoxyglucose-positron emission tomography imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
12. Eichenauer DA, Engert A. Advances in the treatment of Hodgkin lymphoma. Int J Hematol 2012; 96:535–543.
13. Kaprina AD, Starinskii VV, Petrova GP. Malignant neoplasms in Russia in 2015 (Morbidity and Mortality). Мoscow. P.Gertcen MNIOI, 2017. ISBN 978-5-85502-227-8 (In Russian).
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Беляев2
Главные научные кураторы: Борис В. Афанасьев1,Сергей М. Алексеев2, Иван С. Моисеев1
Наблюдательный совет: Алексей М. Беляев2, Андрей Ю. Зарицкий4, Николай В. Ильин3, Наталья Б. Михайлова1, Надежда В. Медведева5, Георгий М. Манихас6, Сергей В. Волошин7, Владимир М. Моисеенко8, Татьяна В. Шнейдер9
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2ФБГУ Национальный медицинский исследовательский центр онкологии имени Н. Н. Петрова, Санкт-Петербург, Россия
3Российский научный центр радиологии и хирургических технологий имени академика А. М. Гранова, Санкт-Петербург, Россия
4Институт гематологии ФГБУ «НМИЦ им. В. А. Алмазова», Санкт-Петербург, Россия
5Городская клиническая больница № 31, Санкт-Петербург, Россия
6Городской клинический онкологический диспансер, Санкт-Петербург, Россия
7Российский НИИ гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия
8Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический), Санкт-Петербург, Россия
9Ленинградская областная клиническая больница, Санкт-Петербург, Россия
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В настоящий момент на территории Российской Федерации (РФ) отсутствует стандарт лечения лимфомы Ходжкина (ЛХ). Летальность от ЛХ в РФ составляет 28,3%, что свидетельствует о необходимости улучшения качества оказания медицинской помощи. В данной статье приведено описание и обоснование проспективного кооперативного исследования RNWOHG-HD1, инициированного в Северо-Западном регионе РФ. Обсуждаются ключевые моменты протокола, включая эскалацию терапии с ABVD до BEACOPPesc в случае ПЭТ-позитивности после двух циклов в группе благоприятного прогноза, и деэскалация с BEACOPPesc до AVD/ABVD в варианте рандомизации в случае достижения ПЭТ-негативного статуса в группе неблагоприятного прогноза. Протокол также подразумевает координацию медицинской помощи с целью получения пациентами доступа к второй и третьей линиям терапии, включая брентуксимаб, а также доступ к аутологичной и аллогенной трансплантации гемопоэтических стволовых клеток.

Ключевые слова

Лимфома Ходжкина, многоцентровое исследование, позитронно-эмиссионная томография (ПЭТ), RNWOHG-HD1.

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Nadejda V. Medvedeva5, Georgii M. Manikhas6, Sergey V. Voloshin7, Vladimir M. Moiseenko8, Tatyana V. Shneider9" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20056" ["VALUE"]=> array(2) { ["TEXT"]=> string(1138) "<sup>1</sup>R. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation<br> <sup>2</sup>Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation<br> <sup>3</sup>Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia <sup>4</sup>Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia<br> <sup>5</sup>St. Petersburg City Hospital №31, St. Petersburg, Russian Federation<br> <sup>6</sup>St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation<br> <sup>7</sup>Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia<br> <sup>8</sup>St. Petersburg Oncological Center, St. Petersburg, Russia<br> <sup>9</sup>Leningrad District Clinical Hospital, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(988) "1R. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation
2Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation
3Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia 4Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia
5St. Petersburg City Hospital №31, St. Petersburg, Russian Federation
6St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation
7Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
8St. Petersburg Oncological Center, St. Petersburg, Russia
9Leningrad District Clinical Hospital, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20057" ["VALUE"]=> array(2) { ["TEXT"]=> string(1098) "<p style="text-align: justify;"> Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1032) "

Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation.

Keywords

Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1.

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Afanasyev<sup>1</sup>, Ivan S. Moiseev<sup>1</sup>, Sergey M. Alekseev<sup>2</sup>, Natalia B. Mikhailova<sup>1</sup>, Elena V. Kondakova<sup>1</sup>, Nikolai V. Ilyin<sup>3</sup>, Alexey M. Belyaеv<sup>2</sup> Chief scientifi c advisors: Boris V. Afanasyev<sup>1</sup>, Sergey M. Alekseev<sup>2</sup>, Ivan S. Moiseev<sup>1</sup> Supervisory board: Alexey M. Belyaеv<sup>2</sup>, Andrey Yu. Zaritskey<sup>4</sup>, Nikolai V. Ilyin<sup>3</sup>, Natalia B. Mikhailova<sup>1</sup>,<br> Nadejda V. Medvedeva<sup>5</sup>, Georgii M. Manikhas<sup>6</sup>, Sergey V. Voloshin<sup>7</sup>, Vladimir M. Moiseenko<sup>8</sup>, Tatyana V. Shneider<sup>9</sup>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(679) "Study authors: Boris V. Afanasyev1, Ivan S. Moiseev1, Sergey M. Alekseev2, Natalia B. Mikhailova1, Elena V. Kondakova1, Nikolai V. Ilyin3, Alexey M. Belyaеv2 Chief scientifi c advisors: Boris V. Afanasyev1, Sergey M. Alekseev2, Ivan S. Moiseev1 Supervisory board: Alexey M. Belyaеv2, Andrey Yu. Zaritskey4, Nikolai V. Ilyin3, Natalia B. Mikhailova1,
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Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation.

Keywords

Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1.

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Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation.

Keywords

Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1.

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Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation<br> <sup>2</sup>Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation<br> <sup>3</sup>Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia <sup>4</sup>Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia<br> <sup>5</sup>St. Petersburg City Hospital №31, St. Petersburg, Russian Federation<br> <sup>6</sup>St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation<br> <sup>7</sup>Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia<br> <sup>8</sup>St. Petersburg Oncological Center, St. Petersburg, Russia<br> <sup>9</sup>Leningrad District Clinical Hospital, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(988) "1R. 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2Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation
3Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia 4Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia
5St. Petersburg City Hospital №31, St. Petersburg, Russian Federation
6St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation
7Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
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3Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia 4Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia
5St. Petersburg City Hospital №31, St. Petersburg, Russian Federation
6St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation
7Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
8St. Petersburg Oncological Center, St. Petersburg, Russia
9Leningrad District Clinical Hospital, St. Petersburg, Russia" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20051" ["VALUE"]=> array(2) { ["TEXT"]=> string(1287) "Авторы протокола: Борис В. Афанасьев<sup>1</sup>, Иван С. Моисеев<sup>1</sup>, Сергей М. Алексеев<sup>2</sup>, Наталья Б. Михайлова<sup>1</sup>, Елена В. Кондакова<sup>1</sup>, Николай В. Ильин<sup>3</sup>, Алексей М. Беляев<sup>2</sup><br> Главные научные кураторы: Борис В. Афанасьев<sup>1</sup>,Сергей М. Алексеев<sup>2</sup>, Иван С. Моисеев<sup>1</sup><br> Наблюдательный совет: Алексей М. Беляев<sup>2</sup>, Андрей Ю. Зарицкий<sup>4</sup>, Николай В. Ильин<sup>3</sup>, Наталья Б. Михайлова<sup>1</sup>, Надежда В. Медведева<sup>5</sup>, Георгий М. Манихас<sup></sup><sup>6</sup>, Сергей В. Волошин<sup>7</sup>, Владимир М. Моисеенко<sup>8</sup>, Татьяна В. Шнейдер<sup>9</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1029) "Авторы протокола: Борис В. Афанасьев1, Иван С. Моисеев1, Сергей М. Алексеев2, Наталья Б. Михайлова1, Елена В. Кондакова1, Николай В. Ильин3, Алексей М. Беляев2
Главные научные кураторы: Борис В. Афанасьев1,Сергей М. Алексеев2, Иван С. Моисеев1
Наблюдательный совет: Алексей М. Беляев2, Андрей Ю. Зарицкий4, Николай В. Ильин3, Наталья Б. Михайлова1, Надежда В. Медведева5, Георгий М. Манихас6, Сергей В. Волошин7, Владимир М. Моисеенко8, Татьяна В. Шнейдер9
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1029) "Авторы протокола: Борис В. Афанасьев1, Иван С. Моисеев1, Сергей М. Алексеев2, Наталья Б. Михайлова1, Елена В. Кондакова1, Николай В. Ильин3, Алексей М. Беляев2
Главные научные кураторы: Борис В. Афанасьев1,Сергей М. Алексеев2, Иван С. Моисеев1
Наблюдательный совет: Алексей М. Беляев2, Андрей Ю. Зарицкий4, Николай В. Ильин3, Наталья Б. Михайлова1, Надежда В. Медведева5, Георгий М. Манихас6, Сергей В. Волошин7, Владимир М. Моисеенко8, Татьяна В. Шнейдер9
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20053" ["VALUE"]=> array(2) { ["TEXT"]=> string(2092) "<p style="text-align: justify;"> В настоящий момент на территории Российской Федерации (РФ) отсутствует стандарт лечения лимфомы Ходжкина (ЛХ). Летальность от ЛХ в РФ составляет 28,3%, что свидетельствует о необходимости улучшения качества оказания медицинской помощи. В данной статье приведено описание и обоснование проспективного кооперативного исследования RNWOHG-HD1, инициированного в Северо-Западном регионе РФ. Обсуждаются ключевые моменты протокола, включая эскалацию терапии с ABVD до BEACOPPesc в случае ПЭТ-позитивности после двух циклов в группе благоприятного прогноза, и деэскалация с BEACOPPesc до AVD/ABVD в варианте рандомизации в случае достижения ПЭТ-негативного статуса в группе неблагоприятного прогноза. Протокол также подразумевает координацию медицинской помощи с целью получения пациентами доступа к второй и третьей линиям терапии, включая брентуксимаб, а также доступ к аутологичной и аллогенной трансплантации гемопоэтических стволовых клеток. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Лимфома Ходжкина, многоцентровое исследование, позитронно-эмиссионная томография (ПЭТ), RNWOHG-HD1. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2026) "

В настоящий момент на территории Российской Федерации (РФ) отсутствует стандарт лечения лимфомы Ходжкина (ЛХ). Летальность от ЛХ в РФ составляет 28,3%, что свидетельствует о необходимости улучшения качества оказания медицинской помощи. В данной статье приведено описание и обоснование проспективного кооперативного исследования RNWOHG-HD1, инициированного в Северо-Западном регионе РФ. Обсуждаются ключевые моменты протокола, включая эскалацию терапии с ABVD до BEACOPPesc в случае ПЭТ-позитивности после двух циклов в группе благоприятного прогноза, и деэскалация с BEACOPPesc до AVD/ABVD в варианте рандомизации в случае достижения ПЭТ-негативного статуса в группе неблагоприятного прогноза. Протокол также подразумевает координацию медицинской помощи с целью получения пациентами доступа к второй и третьей линиям терапии, включая брентуксимаб, а также доступ к аутологичной и аллогенной трансплантации гемопоэтических стволовых клеток.

Ключевые слова

Лимфома Ходжкина, многоцентровое исследование, позитронно-эмиссионная томография (ПЭТ), RNWOHG-HD1.

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В настоящий момент на территории Российской Федерации (РФ) отсутствует стандарт лечения лимфомы Ходжкина (ЛХ). Летальность от ЛХ в РФ составляет 28,3%, что свидетельствует о необходимости улучшения качества оказания медицинской помощи. В данной статье приведено описание и обоснование проспективного кооперативного исследования RNWOHG-HD1, инициированного в Северо-Западном регионе РФ. Обсуждаются ключевые моменты протокола, включая эскалацию терапии с ABVD до BEACOPPesc в случае ПЭТ-позитивности после двух циклов в группе благоприятного прогноза, и деэскалация с BEACOPPesc до AVD/ABVD в варианте рандомизации в случае достижения ПЭТ-негативного статуса в группе неблагоприятного прогноза. Протокол также подразумевает координацию медицинской помощи с целью получения пациентами доступа к второй и третьей линиям терапии, включая брентуксимаб, а также доступ к аутологичной и аллогенной трансплантации гемопоэтических стволовых клеток.

Ключевые слова

Лимфома Ходжкина, многоцентровое исследование, позитронно-эмиссионная томография (ПЭТ), RNWOHG-HD1.

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2ФБГУ Национальный медицинский исследовательский центр онкологии имени Н. Н. Петрова, Санкт-Петербург, Россия
3Российский научный центр радиологии и хирургических технологий имени академика А. М. Гранова, Санкт-Петербург, Россия
4Институт гематологии ФГБУ «НМИЦ им. В. А. Алмазова», Санкт-Петербург, Россия
5Городская клиническая больница № 31, Санкт-Петербург, Россия
6Городской клинический онкологический диспансер, Санкт-Петербург, Россия
7Российский НИИ гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия
8Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический), Санкт-Петербург, Россия
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2ФБГУ Национальный медицинский исследовательский центр онкологии имени Н. Н. Петрова, Санкт-Петербург, Россия
3Российский научный центр радиологии и хирургических технологий имени академика А. М. Гранова, Санкт-Петербург, Россия
4Институт гематологии ФГБУ «НМИЦ им. В. А. Алмазова», Санкт-Петербург, Россия
5Городская клиническая больница № 31, Санкт-Петербург, Россия
6Городской клинический онкологический диспансер, Санкт-Петербург, Россия
7Российский НИИ гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия
8Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический), Санкт-Петербург, Россия
9Ленинградская областная клиническая больница, Санкт-Петербург, Россия
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string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20073" ["VALUE"]=> array(2) { ["TEXT"]=> string(7460) "<h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3> <p style="text-align: justify;"> «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета. </p> <h3 style="text-align: justify;">Главные научные кураторы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Моисеев Иван Сергеевич</b><br> Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н. </p> <h3 style="text-align: justify;">Наблюдательный совет программы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Беляев Алексей Михайлович</b><br> Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br> <b>Зарицкий Андрей Юрьевич</b><br> Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Ильин Николай Васильевич</b><br> Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br> <b>Михайлова Наталья Борисовна</b><br> Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br> <b>Медведева Надежда Вадимовна</b><br> Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br> <b>Манихас Георгий Моисеевич</b><br> Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br> <b>Волошин Сергей Владимирович</b><br> Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br> <b>Моисеенко Владимир Михайлович</b><br> Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br> <b>Шнейдер Татьяна Владимировна</b><br> Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7004) "

Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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string(41168) "<h2></h2> <h2 style="text-align: justify;">14. МЕТОДОЛОГИЯ СБОРА ДАННЫХ</h2> <p style="text-align: justify;"> Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.<br> E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).<br> Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования. </p> <h2 style="text-align: justify;">15. РАЗМЕР ВЫБОРКИ</h2> <p style="text-align: justify;"> Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек. </p> <h2 style="text-align: justify;">16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА</h2> <p style="text-align: justify;"> Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. </p> <h3 style="text-align: justify;">Статистические методы</h3> <p style="text-align: justify;"> Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.<br> Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу. </p> <h3 style="text-align: justify;">Статистическая обработка полученных результатов:</h3> <p style="text-align: justify;"> В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. </p> <h3 style="text-align: justify;">Определение конечных точек исследования:</h3> <p style="text-align: justify;"> Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.<br> Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.<br> Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах<sup>20</sup>.<br> Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.<br> Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага&gt; 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville &gt;3)20.<br> Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей. </p> <h3 style="text-align: justify;">Рандомизация</h3> <p style="text-align: justify;"> В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.<br> С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR&gt; 1.1. </p> <h2 style="text-align: justify;">17. ЭТИЧЕСКИЕ АСПЕКТЫ</h2> <p style="text-align: justify;"> Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.<br> Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.<br> Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.<br> В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования. </p> <h2 style="text-align: justify;">18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ</h2> <p style="text-align: justify;"> Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.<br> Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF. </p> <h2 style="text-align: justify;">19. МОНИТОРИНГ</h2> <p style="text-align: justify;"> Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией. </p> <h2 style="text-align: justify;">20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ</h2> <p style="text-align: justify;"> Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии. </p> <h2 style="text-align: justify;">21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:</h2> <p style="text-align: justify;"> Схематичная форма регистрируемых параметров представлена в приложении 5.<br> Первичная регистрация в электронной системе:<br> 1. Фамилия/Имя/Отчество<br> 2. Пол<br> 3. Дата рождения _____ Возраст (калькулятор)<br> 4. Регион<br> 5. Телефон для связи<br> 6. Социальный статус (работающий, неработающий, учащийся, пенсионер)<br> 7. Дата внесения регистрационной информации<br> Первичное стадирование:<br> 1. Дата постановки диагноза<br> 2. Длительность заболевания на момент включения па циента в программу<br> 3. Гистологический вариант заболевания<br> 4. Дата биопсии, по которой был поставлен гистологи-<br> ческий диагноз<br> 5. Проводилось ли ИГХ диагностика:<br> 6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)<br> 7. Стадия по классификации Ann Arbor<br> 8. Вовлеченные зоны по данным ПЭТ-КТ<br> 9. Максимальные размеры опухоли для 6 очагов (либо<br> меньше, если вовлечены менее 6)<br> 10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).<br> 12. СОЭ<br> 13. ЛДГ<br> 14. АЛТ<br> 15. АСТ<br> 16. Креатинин<br> 17. Билирубин<br> 18. Гемоглобин<br> 19. Альбумин<br> 20. Абсолютное число лейкоцитов<br> 21. Абсолютное число нейтрофилов<br> 22. Абсолютное число лимфоцитов<br> 23. Тромбоциты<br> 24. Вариант терапии первой линии<br> 25. Запланированное число курсов (не для RNWOHGHD1)<br> 26. Дата начала 1-ого цикла химиотерапии<br> 27. Препараты 1ого цикла химиотерапии: длительность<br> и дозы<br> <img width="752" alt="Tvblitsa_0.png" src="/upload/medialibrary/b1e/tvblitsa_0.png" height="513" title="Tvblitsa_0.png"><br> Рестадирование после двух циклов химиотерапии:<br> 1. Дата начала 2-ого цикла химиотерапии<br> 2. Препараты 2-ого цикла химиотерапии: длительность и дозы<br> 3. Ответ по оценке лечащего врача<br> 4. Максимальный уровень метаболической активности по Deauville<br> 5. Вовлеченные зоны по данным ПЭТ-КТ<br> 6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 8. Токсичность, если была, по NCI CTCAE 4.03<br> 9. Инфекционные осложнения, если были<br> 10. Потребность в Г-КСФ<br> 11. Количество переливаний эритроцитов<br> 12. Другая сопроводительная терапия<br> Рестадирование после четырех циклов химиотерапии (где применимо):<br> 1. Дата начала курсов химиотерапии<br> 2. Препараты химиотерапии<br> 3. Ответ по оценке лечащего врача<br> 4. Максимальный уровень метаболической активности по Deauville<br> 5. Вовлеченные зоны по данным КТ<br> 6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. Токсичность, если была, по NCI CTCAE 4.03<br> 8. Инфекционные осложнения, если были<br> 9. Потребность в Г-КСФ<br> 10. Количество переливаний эритроцитов<br> 11. Другая сопроводительная терапия<br> 12. Рестадирование после шести циклов химиотерапии (где применимо):<br> 13. Дата начала курсов химиотерапии<br> 14. Ответ по оценке лечащего врача<br> 15. Максимальный уровень метаболической активности по Deauville<br> 16. Вовлеченные зоны по данным ПЭТ-КТ<br> 17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)<br> 18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 19. Токсичность, если была, по NCI CTCAE 4.03<br> 20. Инфекционные осложнения, если были<br> 21. Потребность в Г-КСФ<br> 22. Количество переливаний эритроцитов<br> 23. Другая сопроводительная терапия<br> Рестадирование после лучевой терапии (где применимо):<br> 1. Дата начала лучевой терапии<br> 2. Режим лучевой терапии<br> 3. Доза лучевой терапии<br> 4. Ответ по оценке лечащего врача<br> 5. Максимальный уровень метаболической активности по Deauville<br> 6. Вовлеченные зоны по данным КТ<br> 7. Максимальные размеры опухоли для 6 очагов (либо<br> меньше, если вовлечены менее 6)<br> 8. Токсичность, если была, по NCI CTCAE 4.03<br> Наблюдение каждые 6 месяцев после окончания лечения:<br> 1. Дата контакта<br> 2. Жив/умер/потеряна связь<br> 3. Статус заболевания<br> 4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03<br> 5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)<br> Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):<br> 1. Дата фиксации рецидива<br> 2. Длительность от момента первичной диагностики заболевания<br> 3. Стадия по классификации Ann Arbor<br> 4. Вовлеченные зоны по данным ПЭТ-КТ<br> 5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)<br> 6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. СОЭ<br> 8. ЛДГ<br> 9. АЛТ<br> 10. АСТ<br> 11. Креатинин<br> 12. Билирубин<br> 13. Гемоглобин<br> 14. Альбумин<br> 15. Абсолютное число лейкоцитов<br> 16. Абсолютное число нейтрофилов<br> 17. Абсолютное число лимфоцитов<br> 18. Тромбоциты<br> 19. Дата начала химиотерапии второй линии<br> 20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)<br> Статус после 2-ой линии химиотерапии (где применимо):<br> 1. Дата рестадирования<br> 2. Ответ по оценке лечащего врача<br> 3. Максимальный уровень метаболической активности по Deauville<br> 4. Вовлеченные зоны по данным ПЭТ-КТ<br> 5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)<br> 7. Токсичность, если была, по NCI CTCAE 4.03<br> 8. Инфекционные осложнения, если были<br> 9. Потребность в Г-КСФ<br> 10. Количество переливаний эритроцитов<br> 11. Другая сопроводительная терапия<br> 12. Направлен на аутоТКМ: да/нет<br> 13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия<br> Статус после аутоТКМ (где применимо):<br> 1. Дата ТКМ<br> 2. Дата рестадирования<br> 3. Режим кондиционирования<br> 4. Количество CD34+ в трансплантате<br> 5. Ответ по оценке лечащего врача<br> 6. Максимальный уровень метаболической активности по Deauville<br> 7. Вовлеченные зоны по данным ПЭТ-КТ<br> 8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)<br> 10. Токсичность, если была, по NCI CTCAE 4.03<br> 11. Инфекционные осложнения, если были<br> 12. Поддерживающая терапия брентуксимабом – да/нет<br> Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):<br> 1. Стадия по классификации Ann Arbor<br> 2. Вовлеченные зоны по данным ПЭТ-КТ<br> 3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)<br> 5. СОЭ<br> 6. ЛДГ<br> 7. Гемоглобин<br> 8. Альбумин<br> 9. Абсолютное число лейкоцитов<br> 10. Абсолютное число нейтрофилов<br> 11. Абсолютное число лимфоцитов<br> 12. Тромбоциты<br> 13. Дата начала терапии третьей линии<br> 14. Вариант терапии третьей линии: брентуксимаб или другой<br> 15. Направлен на аллоТКМ да/нет<br> 16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая<br> 6. ЛДГ<br> 7. Гемоглобин<br> 8. Альбумин<br> 9. Абсолютное число лейкоцитов<br> 10. Абсолютное число нейтрофилов<br> 11. Абсолютное число лимфоцитов<br> 12. Тромбоциты<br> 13. Дата начала терапии третьей линии<br> 14. Вариант терапии третьей линии: брентуксимаб или другой<br> 15. Направлен на аллоТКМ да/нет<br> 16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая<br> Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.<br> Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:<br> – массивная (bulky) медиастинальная опухоль &gt;10 см<br> – экстранодальное поражение, в том числе по контакту<br> – скорость оседания эритроцитов (СОЭ) &gt;50 мм/ч<br> – вовлечение трех и более групп лимфоузлов. </p> <h2 style="text-align: justify;">Первая линия</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):</h3> <p style="text-align: justify;"> • Проводится 2 курса ABVD.<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР проводится наблюдение.<br> • При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.<br> • При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.<br> • При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.<br> • При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):</h3> <p style="text-align: justify;"> • Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.<br> • При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.<br> • При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии.<br> • При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(39198) "

14. МЕТОДОЛОГИЯ СБОРА ДАННЫХ

Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.
E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).
Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

15. РАЗМЕР ВЫБОРКИ

Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек.

16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Статистические методы

Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.
Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу.

Статистическая обработка полученных результатов:

В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Определение конечных точек исследования:

Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.
Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.
Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах20.
Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.
Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага> 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville >3)20.
Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей.

Рандомизация

В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.
С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR> 1.1.

17. ЭТИЧЕСКИЕ АСПЕКТЫ

Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.
Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.
Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.
В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования.

18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ

Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.
Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF.

19. МОНИТОРИНГ

Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией.

20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ

Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:

Схематичная форма регистрируемых параметров представлена в приложении 5.
Первичная регистрация в электронной системе:
1. Фамилия/Имя/Отчество
2. Пол
3. Дата рождения _____ Возраст (калькулятор)
4. Регион
5. Телефон для связи
6. Социальный статус (работающий, неработающий, учащийся, пенсионер)
7. Дата внесения регистрационной информации
Первичное стадирование:
1. Дата постановки диагноза
2. Длительность заболевания на момент включения па циента в программу
3. Гистологический вариант заболевания
4. Дата биопсии, по которой был поставлен гистологи-
ческий диагноз
5. Проводилось ли ИГХ диагностика:
6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)
7. Стадия по классификации Ann Arbor
8. Вовлеченные зоны по данным ПЭТ-КТ
9. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).
12. СОЭ
13. ЛДГ
14. АЛТ
15. АСТ
16. Креатинин
17. Билирубин
18. Гемоглобин
19. Альбумин
20. Абсолютное число лейкоцитов
21. Абсолютное число нейтрофилов
22. Абсолютное число лимфоцитов
23. Тромбоциты
24. Вариант терапии первой линии
25. Запланированное число курсов (не для RNWOHGHD1)
26. Дата начала 1-ого цикла химиотерапии
27. Препараты 1ого цикла химиотерапии: длительность
и дозы
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Рестадирование после двух циклов химиотерапии:
1. Дата начала 2-ого цикла химиотерапии
2. Препараты 2-ого цикла химиотерапии: длительность и дозы
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным ПЭТ-КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
9. Инфекционные осложнения, если были
10. Потребность в Г-КСФ
11. Количество переливаний эритроцитов
12. Другая сопроводительная терапия
Рестадирование после четырех циклов химиотерапии (где применимо):
1. Дата начала курсов химиотерапии
2. Препараты химиотерапии
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Рестадирование после шести циклов химиотерапии (где применимо):
13. Дата начала курсов химиотерапии
14. Ответ по оценке лечащего врача
15. Максимальный уровень метаболической активности по Deauville
16. Вовлеченные зоны по данным ПЭТ-КТ
17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
19. Токсичность, если была, по NCI CTCAE 4.03
20. Инфекционные осложнения, если были
21. Потребность в Г-КСФ
22. Количество переливаний эритроцитов
23. Другая сопроводительная терапия
Рестадирование после лучевой терапии (где применимо):
1. Дата начала лучевой терапии
2. Режим лучевой терапии
3. Доза лучевой терапии
4. Ответ по оценке лечащего врача
5. Максимальный уровень метаболической активности по Deauville
6. Вовлеченные зоны по данным КТ
7. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
Наблюдение каждые 6 месяцев после окончания лечения:
1. Дата контакта
2. Жив/умер/потеряна связь
3. Статус заболевания
4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03
5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)
Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):
1. Дата фиксации рецидива
2. Длительность от момента первичной диагностики заболевания
3. Стадия по классификации Ann Arbor
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
7. СОЭ
8. ЛДГ
9. АЛТ
10. АСТ
11. Креатинин
12. Билирубин
13. Гемоглобин
14. Альбумин
15. Абсолютное число лейкоцитов
16. Абсолютное число нейтрофилов
17. Абсолютное число лимфоцитов
18. Тромбоциты
19. Дата начала химиотерапии второй линии
20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)
Статус после 2-ой линии химиотерапии (где применимо):
1. Дата рестадирования
2. Ответ по оценке лечащего врача
3. Максимальный уровень метаболической активности по Deauville
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Направлен на аутоТКМ: да/нет
13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия
Статус после аутоТКМ (где применимо):
1. Дата ТКМ
2. Дата рестадирования
3. Режим кондиционирования
4. Количество CD34+ в трансплантате
5. Ответ по оценке лечащего врача
6. Максимальный уровень метаболической активности по Deauville
7. Вовлеченные зоны по данным ПЭТ-КТ
8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
10. Токсичность, если была, по NCI CTCAE 4.03
11. Инфекционные осложнения, если были
12. Поддерживающая терапия брентуксимабом – да/нет
Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):
1. Стадия по классификации Ann Arbor
2. Вовлеченные зоны по данным ПЭТ-КТ
3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
5. СОЭ
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.
Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:
– массивная (bulky) медиастинальная опухоль >10 см
– экстранодальное поражение, в том числе по контакту
– скорость оседания эритроцитов (СОЭ) >50 мм/ч
– вовлечение трех и более групп лимфоузлов.

Первая линия

Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):

• Проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится наблюдение.
• При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.
• При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.

Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):

• Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.
• При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии.

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«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета. </p> <h3 style="text-align: justify;">Главные научные кураторы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Моисеев Иван Сергеевич</b><br> Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н. </p> <h3 style="text-align: justify;">Наблюдательный совет программы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Беляев Алексей Михайлович</b><br> Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br> <b>Зарицкий Андрей Юрьевич</b><br> Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Ильин Николай Васильевич</b><br> Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br> <b>Михайлова Наталья Борисовна</b><br> Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br> <b>Медведева Надежда Вадимовна</b><br> Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br> <b>Манихас Георгий Моисеевич</b><br> Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br> <b>Волошин Сергей Владимирович</b><br> Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br> <b>Моисеенко Владимир Михайлович</b><br> Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br> <b>Шнейдер Татьяна Владимировна</b><br> Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7004) "

Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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МЕТОДОЛОГИЯ СБОРА ДАННЫХ</h2> <p style="text-align: justify;"> Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.<br> E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).<br> Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования. </p> <h2 style="text-align: justify;">15. РАЗМЕР ВЫБОРКИ</h2> <p style="text-align: justify;"> Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек. </p> <h2 style="text-align: justify;">16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА</h2> <p style="text-align: justify;"> Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. </p> <h3 style="text-align: justify;">Статистические методы</h3> <p style="text-align: justify;"> Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.<br> Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу. </p> <h3 style="text-align: justify;">Статистическая обработка полученных результатов:</h3> <p style="text-align: justify;"> В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. </p> <h3 style="text-align: justify;">Определение конечных точек исследования:</h3> <p style="text-align: justify;"> Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.<br> Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.<br> Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах<sup>20</sup>.<br> Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.<br> Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага&gt; 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville &gt;3)20.<br> Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей. </p> <h3 style="text-align: justify;">Рандомизация</h3> <p style="text-align: justify;"> В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.<br> С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR&gt; 1.1. </p> <h2 style="text-align: justify;">17. ЭТИЧЕСКИЕ АСПЕКТЫ</h2> <p style="text-align: justify;"> Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.<br> Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.<br> Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.<br> В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования. </p> <h2 style="text-align: justify;">18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ</h2> <p style="text-align: justify;"> Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.<br> Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF. </p> <h2 style="text-align: justify;">19. МОНИТОРИНГ</h2> <p style="text-align: justify;"> Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией. </p> <h2 style="text-align: justify;">20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ</h2> <p style="text-align: justify;"> Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии. </p> <h2 style="text-align: justify;">21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:</h2> <p style="text-align: justify;"> Схематичная форма регистрируемых параметров представлена в приложении 5.<br> Первичная регистрация в электронной системе:<br> 1. Фамилия/Имя/Отчество<br> 2. Пол<br> 3. Дата рождения _____ Возраст (калькулятор)<br> 4. Регион<br> 5. Телефон для связи<br> 6. Социальный статус (работающий, неработающий, учащийся, пенсионер)<br> 7. Дата внесения регистрационной информации<br> Первичное стадирование:<br> 1. Дата постановки диагноза<br> 2. Длительность заболевания на момент включения па циента в программу<br> 3. Гистологический вариант заболевания<br> 4. Дата биопсии, по которой был поставлен гистологи-<br> ческий диагноз<br> 5. Проводилось ли ИГХ диагностика:<br> 6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)<br> 7. Стадия по классификации Ann Arbor<br> 8. Вовлеченные зоны по данным ПЭТ-КТ<br> 9. Максимальные размеры опухоли для 6 очагов (либо<br> меньше, если вовлечены менее 6)<br> 10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).<br> 12. СОЭ<br> 13. ЛДГ<br> 14. АЛТ<br> 15. АСТ<br> 16. Креатинин<br> 17. Билирубин<br> 18. Гемоглобин<br> 19. Альбумин<br> 20. Абсолютное число лейкоцитов<br> 21. Абсолютное число нейтрофилов<br> 22. Абсолютное число лимфоцитов<br> 23. Тромбоциты<br> 24. Вариант терапии первой линии<br> 25. Запланированное число курсов (не для RNWOHGHD1)<br> 26. Дата начала 1-ого цикла химиотерапии<br> 27. Препараты 1ого цикла химиотерапии: длительность<br> и дозы<br> <img width="752" alt="Tvblitsa_0.png" src="/upload/medialibrary/b1e/tvblitsa_0.png" height="513" title="Tvblitsa_0.png"><br> Рестадирование после двух циклов химиотерапии:<br> 1. Дата начала 2-ого цикла химиотерапии<br> 2. Препараты 2-ого цикла химиотерапии: длительность и дозы<br> 3. Ответ по оценке лечащего врача<br> 4. Максимальный уровень метаболической активности по Deauville<br> 5. Вовлеченные зоны по данным ПЭТ-КТ<br> 6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 8. Токсичность, если была, по NCI CTCAE 4.03<br> 9. Инфекционные осложнения, если были<br> 10. Потребность в Г-КСФ<br> 11. Количество переливаний эритроцитов<br> 12. Другая сопроводительная терапия<br> Рестадирование после четырех циклов химиотерапии (где применимо):<br> 1. Дата начала курсов химиотерапии<br> 2. Препараты химиотерапии<br> 3. Ответ по оценке лечащего врача<br> 4. Максимальный уровень метаболической активности по Deauville<br> 5. Вовлеченные зоны по данным КТ<br> 6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. Токсичность, если была, по NCI CTCAE 4.03<br> 8. Инфекционные осложнения, если были<br> 9. Потребность в Г-КСФ<br> 10. Количество переливаний эритроцитов<br> 11. Другая сопроводительная терапия<br> 12. Рестадирование после шести циклов химиотерапии (где применимо):<br> 13. Дата начала курсов химиотерапии<br> 14. Ответ по оценке лечащего врача<br> 15. Максимальный уровень метаболической активности по Deauville<br> 16. Вовлеченные зоны по данным ПЭТ-КТ<br> 17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)<br> 18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 19. Токсичность, если была, по NCI CTCAE 4.03<br> 20. Инфекционные осложнения, если были<br> 21. Потребность в Г-КСФ<br> 22. Количество переливаний эритроцитов<br> 23. Другая сопроводительная терапия<br> Рестадирование после лучевой терапии (где применимо):<br> 1. Дата начала лучевой терапии<br> 2. Режим лучевой терапии<br> 3. Доза лучевой терапии<br> 4. Ответ по оценке лечащего врача<br> 5. Максимальный уровень метаболической активности по Deauville<br> 6. Вовлеченные зоны по данным КТ<br> 7. Максимальные размеры опухоли для 6 очагов (либо<br> меньше, если вовлечены менее 6)<br> 8. Токсичность, если была, по NCI CTCAE 4.03<br> Наблюдение каждые 6 месяцев после окончания лечения:<br> 1. Дата контакта<br> 2. Жив/умер/потеряна связь<br> 3. Статус заболевания<br> 4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03<br> 5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)<br> Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):<br> 1. Дата фиксации рецидива<br> 2. Длительность от момента первичной диагностики заболевания<br> 3. Стадия по классификации Ann Arbor<br> 4. Вовлеченные зоны по данным ПЭТ-КТ<br> 5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)<br> 6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. СОЭ<br> 8. ЛДГ<br> 9. АЛТ<br> 10. АСТ<br> 11. Креатинин<br> 12. Билирубин<br> 13. Гемоглобин<br> 14. Альбумин<br> 15. Абсолютное число лейкоцитов<br> 16. Абсолютное число нейтрофилов<br> 17. Абсолютное число лимфоцитов<br> 18. Тромбоциты<br> 19. Дата начала химиотерапии второй линии<br> 20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)<br> Статус после 2-ой линии химиотерапии (где применимо):<br> 1. Дата рестадирования<br> 2. Ответ по оценке лечащего врача<br> 3. Максимальный уровень метаболической активности по Deauville<br> 4. Вовлеченные зоны по данным ПЭТ-КТ<br> 5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)<br> 7. Токсичность, если была, по NCI CTCAE 4.03<br> 8. Инфекционные осложнения, если были<br> 9. Потребность в Г-КСФ<br> 10. Количество переливаний эритроцитов<br> 11. Другая сопроводительная терапия<br> 12. Направлен на аутоТКМ: да/нет<br> 13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия<br> Статус после аутоТКМ (где применимо):<br> 1. Дата ТКМ<br> 2. Дата рестадирования<br> 3. Режим кондиционирования<br> 4. Количество CD34+ в трансплантате<br> 5. Ответ по оценке лечащего врача<br> 6. Максимальный уровень метаболической активности по Deauville<br> 7. Вовлеченные зоны по данным ПЭТ-КТ<br> 8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)<br> 10. Токсичность, если была, по NCI CTCAE 4.03<br> 11. Инфекционные осложнения, если были<br> 12. Поддерживающая терапия брентуксимабом – да/нет<br> Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):<br> 1. Стадия по классификации Ann Arbor<br> 2. Вовлеченные зоны по данным ПЭТ-КТ<br> 3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)<br> 5. СОЭ<br> 6. ЛДГ<br> 7. Гемоглобин<br> 8. Альбумин<br> 9. Абсолютное число лейкоцитов<br> 10. Абсолютное число нейтрофилов<br> 11. Абсолютное число лимфоцитов<br> 12. Тромбоциты<br> 13. Дата начала терапии третьей линии<br> 14. Вариант терапии третьей линии: брентуксимаб или другой<br> 15. Направлен на аллоТКМ да/нет<br> 16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая<br> 6. ЛДГ<br> 7. Гемоглобин<br> 8. Альбумин<br> 9. Абсолютное число лейкоцитов<br> 10. Абсолютное число нейтрофилов<br> 11. Абсолютное число лимфоцитов<br> 12. Тромбоциты<br> 13. Дата начала терапии третьей линии<br> 14. Вариант терапии третьей линии: брентуксимаб или другой<br> 15. Направлен на аллоТКМ да/нет<br> 16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая<br> Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.<br> Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:<br> – массивная (bulky) медиастинальная опухоль &gt;10 см<br> – экстранодальное поражение, в том числе по контакту<br> – скорость оседания эритроцитов (СОЭ) &gt;50 мм/ч<br> – вовлечение трех и более групп лимфоузлов. </p> <h2 style="text-align: justify;">Первая линия</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):</h3> <p style="text-align: justify;"> • Проводится 2 курса ABVD.<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР проводится наблюдение.<br> • При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.<br> • При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.<br> • При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.<br> • При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):</h3> <p style="text-align: justify;"> • Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.<br> • При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.<br> • При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии.<br> • При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(39198) "

14. МЕТОДОЛОГИЯ СБОРА ДАННЫХ

Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.
E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).
Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

15. РАЗМЕР ВЫБОРКИ

Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек.

16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Статистические методы

Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.
Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу.

Статистическая обработка полученных результатов:

В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Определение конечных точек исследования:

Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.
Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.
Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах20.
Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.
Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага> 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville >3)20.
Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей.

Рандомизация

В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.
С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR> 1.1.

17. ЭТИЧЕСКИЕ АСПЕКТЫ

Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.
Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.
Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.
В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования.

18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ

Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.
Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF.

19. МОНИТОРИНГ

Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией.

20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ

Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:

Схематичная форма регистрируемых параметров представлена в приложении 5.
Первичная регистрация в электронной системе:
1. Фамилия/Имя/Отчество
2. Пол
3. Дата рождения _____ Возраст (калькулятор)
4. Регион
5. Телефон для связи
6. Социальный статус (работающий, неработающий, учащийся, пенсионер)
7. Дата внесения регистрационной информации
Первичное стадирование:
1. Дата постановки диагноза
2. Длительность заболевания на момент включения па циента в программу
3. Гистологический вариант заболевания
4. Дата биопсии, по которой был поставлен гистологи-
ческий диагноз
5. Проводилось ли ИГХ диагностика:
6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)
7. Стадия по классификации Ann Arbor
8. Вовлеченные зоны по данным ПЭТ-КТ
9. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).
12. СОЭ
13. ЛДГ
14. АЛТ
15. АСТ
16. Креатинин
17. Билирубин
18. Гемоглобин
19. Альбумин
20. Абсолютное число лейкоцитов
21. Абсолютное число нейтрофилов
22. Абсолютное число лимфоцитов
23. Тромбоциты
24. Вариант терапии первой линии
25. Запланированное число курсов (не для RNWOHGHD1)
26. Дата начала 1-ого цикла химиотерапии
27. Препараты 1ого цикла химиотерапии: длительность
и дозы
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Рестадирование после двух циклов химиотерапии:
1. Дата начала 2-ого цикла химиотерапии
2. Препараты 2-ого цикла химиотерапии: длительность и дозы
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным ПЭТ-КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
9. Инфекционные осложнения, если были
10. Потребность в Г-КСФ
11. Количество переливаний эритроцитов
12. Другая сопроводительная терапия
Рестадирование после четырех циклов химиотерапии (где применимо):
1. Дата начала курсов химиотерапии
2. Препараты химиотерапии
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Рестадирование после шести циклов химиотерапии (где применимо):
13. Дата начала курсов химиотерапии
14. Ответ по оценке лечащего врача
15. Максимальный уровень метаболической активности по Deauville
16. Вовлеченные зоны по данным ПЭТ-КТ
17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
19. Токсичность, если была, по NCI CTCAE 4.03
20. Инфекционные осложнения, если были
21. Потребность в Г-КСФ
22. Количество переливаний эритроцитов
23. Другая сопроводительная терапия
Рестадирование после лучевой терапии (где применимо):
1. Дата начала лучевой терапии
2. Режим лучевой терапии
3. Доза лучевой терапии
4. Ответ по оценке лечащего врача
5. Максимальный уровень метаболической активности по Deauville
6. Вовлеченные зоны по данным КТ
7. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
Наблюдение каждые 6 месяцев после окончания лечения:
1. Дата контакта
2. Жив/умер/потеряна связь
3. Статус заболевания
4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03
5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)
Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):
1. Дата фиксации рецидива
2. Длительность от момента первичной диагностики заболевания
3. Стадия по классификации Ann Arbor
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
7. СОЭ
8. ЛДГ
9. АЛТ
10. АСТ
11. Креатинин
12. Билирубин
13. Гемоглобин
14. Альбумин
15. Абсолютное число лейкоцитов
16. Абсолютное число нейтрофилов
17. Абсолютное число лимфоцитов
18. Тромбоциты
19. Дата начала химиотерапии второй линии
20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)
Статус после 2-ой линии химиотерапии (где применимо):
1. Дата рестадирования
2. Ответ по оценке лечащего врача
3. Максимальный уровень метаболической активности по Deauville
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Направлен на аутоТКМ: да/нет
13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия
Статус после аутоТКМ (где применимо):
1. Дата ТКМ
2. Дата рестадирования
3. Режим кондиционирования
4. Количество CD34+ в трансплантате
5. Ответ по оценке лечащего врача
6. Максимальный уровень метаболической активности по Deauville
7. Вовлеченные зоны по данным ПЭТ-КТ
8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
10. Токсичность, если была, по NCI CTCAE 4.03
11. Инфекционные осложнения, если были
12. Поддерживающая терапия брентуксимабом – да/нет
Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):
1. Стадия по классификации Ann Arbor
2. Вовлеченные зоны по данным ПЭТ-КТ
3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
5. СОЭ
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.
Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:
– массивная (bulky) медиастинальная опухоль >10 см
– экстранодальное поражение, в том числе по контакту
– скорость оседания эритроцитов (СОЭ) >50 мм/ч
– вовлечение трех и более групп лимфоузлов.

Первая линия

Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):

• Проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится наблюдение.
• При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.
• При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.

Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):

• Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.
• При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии.

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14. МЕТОДОЛОГИЯ СБОРА ДАННЫХ

Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.
E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).
Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

15. РАЗМЕР ВЫБОРКИ

Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек.

16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Статистические методы

Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.
Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу.

Статистическая обработка полученных результатов:

В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Определение конечных точек исследования:

Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.
Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.
Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах20.
Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.
Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага> 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville >3)20.
Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей.

Рандомизация

В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.
С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR> 1.1.

17. ЭТИЧЕСКИЕ АСПЕКТЫ

Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.
Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.
Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.
В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования.

18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ

Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.
Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF.

19. МОНИТОРИНГ

Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией.

20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ

Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:

Схематичная форма регистрируемых параметров представлена в приложении 5.
Первичная регистрация в электронной системе:
1. Фамилия/Имя/Отчество
2. Пол
3. Дата рождения _____ Возраст (калькулятор)
4. Регион
5. Телефон для связи
6. Социальный статус (работающий, неработающий, учащийся, пенсионер)
7. Дата внесения регистрационной информации
Первичное стадирование:
1. Дата постановки диагноза
2. Длительность заболевания на момент включения па циента в программу
3. Гистологический вариант заболевания
4. Дата биопсии, по которой был поставлен гистологи-
ческий диагноз
5. Проводилось ли ИГХ диагностика:
6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)
7. Стадия по классификации Ann Arbor
8. Вовлеченные зоны по данным ПЭТ-КТ
9. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).
12. СОЭ
13. ЛДГ
14. АЛТ
15. АСТ
16. Креатинин
17. Билирубин
18. Гемоглобин
19. Альбумин
20. Абсолютное число лейкоцитов
21. Абсолютное число нейтрофилов
22. Абсолютное число лимфоцитов
23. Тромбоциты
24. Вариант терапии первой линии
25. Запланированное число курсов (не для RNWOHGHD1)
26. Дата начала 1-ого цикла химиотерапии
27. Препараты 1ого цикла химиотерапии: длительность
и дозы
Tvblitsa_0.png
Рестадирование после двух циклов химиотерапии:
1. Дата начала 2-ого цикла химиотерапии
2. Препараты 2-ого цикла химиотерапии: длительность и дозы
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным ПЭТ-КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
9. Инфекционные осложнения, если были
10. Потребность в Г-КСФ
11. Количество переливаний эритроцитов
12. Другая сопроводительная терапия
Рестадирование после четырех циклов химиотерапии (где применимо):
1. Дата начала курсов химиотерапии
2. Препараты химиотерапии
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Рестадирование после шести циклов химиотерапии (где применимо):
13. Дата начала курсов химиотерапии
14. Ответ по оценке лечащего врача
15. Максимальный уровень метаболической активности по Deauville
16. Вовлеченные зоны по данным ПЭТ-КТ
17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
19. Токсичность, если была, по NCI CTCAE 4.03
20. Инфекционные осложнения, если были
21. Потребность в Г-КСФ
22. Количество переливаний эритроцитов
23. Другая сопроводительная терапия
Рестадирование после лучевой терапии (где применимо):
1. Дата начала лучевой терапии
2. Режим лучевой терапии
3. Доза лучевой терапии
4. Ответ по оценке лечащего врача
5. Максимальный уровень метаболической активности по Deauville
6. Вовлеченные зоны по данным КТ
7. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
Наблюдение каждые 6 месяцев после окончания лечения:
1. Дата контакта
2. Жив/умер/потеряна связь
3. Статус заболевания
4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03
5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)
Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):
1. Дата фиксации рецидива
2. Длительность от момента первичной диагностики заболевания
3. Стадия по классификации Ann Arbor
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
7. СОЭ
8. ЛДГ
9. АЛТ
10. АСТ
11. Креатинин
12. Билирубин
13. Гемоглобин
14. Альбумин
15. Абсолютное число лейкоцитов
16. Абсолютное число нейтрофилов
17. Абсолютное число лимфоцитов
18. Тромбоциты
19. Дата начала химиотерапии второй линии
20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)
Статус после 2-ой линии химиотерапии (где применимо):
1. Дата рестадирования
2. Ответ по оценке лечащего врача
3. Максимальный уровень метаболической активности по Deauville
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Направлен на аутоТКМ: да/нет
13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия
Статус после аутоТКМ (где применимо):
1. Дата ТКМ
2. Дата рестадирования
3. Режим кондиционирования
4. Количество CD34+ в трансплантате
5. Ответ по оценке лечащего врача
6. Максимальный уровень метаболической активности по Deauville
7. Вовлеченные зоны по данным ПЭТ-КТ
8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
10. Токсичность, если была, по NCI CTCAE 4.03
11. Инфекционные осложнения, если были
12. Поддерживающая терапия брентуксимабом – да/нет
Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):
1. Стадия по классификации Ann Arbor
2. Вовлеченные зоны по данным ПЭТ-КТ
3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
5. СОЭ
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.
Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:
– массивная (bulky) медиастинальная опухоль >10 см
– экстранодальное поражение, в том числе по контакту
– скорость оседания эритроцитов (СОЭ) >50 мм/ч
– вовлечение трех и более групп лимфоузлов.

Первая линия

Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):

• Проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится наблюдение.
• При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.
• При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.

Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):

• Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.
• При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20061" ["VALUE"]=> array(2) { ["TEXT"]=> string(7460) "<h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3> <p style="text-align: justify;"> «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета. </p> <h3 style="text-align: justify;">Главные научные кураторы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Моисеев Иван Сергеевич</b><br> Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н. </p> <h3 style="text-align: justify;">Наблюдательный совет программы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Беляев Алексей Михайлович</b><br> Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br> <b>Зарицкий Андрей Юрьевич</b><br> Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Ильин Николай Васильевич</b><br> Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br> <b>Михайлова Наталья Борисовна</b><br> Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br> <b>Медведева Надежда Вадимовна</b><br> Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br> <b>Манихас Георгий Моисеевич</b><br> Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br> <b>Волошин Сергей Владимирович</b><br> Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br> <b>Моисеенко Владимир Михайлович</b><br> Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br> <b>Шнейдер Татьяна Владимировна</b><br> Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7004) "

Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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логотипы.png

ПРОТОКОЛ № RNWOHG-HD1 ВЕРСИЯ 1.01 ОТ 18.09.2017

ЗАЯВЛЕНИЕ О КОНФИДЕНЦИАЛЬНОСТИ. Этот документ является конфиденциальным и может быть предоставлен для пересмотра только исследователям, потенциальным исследователям, консультантам, персоналу исследования и независимым этическим комитетам или локальным этическим комитетам. Содержимое этого документа не может быть раскрыто третьим лицам без письменного разрешения организации или отдельных лиц, за исключением случаев, когда необходимо получить информированное согласие от потенциальных участников исследования.
Санкт-Петербург 2017

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"FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20065" ["VALUE"]=> array(2) { ["TEXT"]=> string(66692) "<h2></h2> <h2 style="text-align: justify;"><sup></sup>Список сокращений</h2> <p style="text-align: justify;"> аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток<br> АЛТ – аланинаминотрансфераза<br> АСТ – аспартамаминотрансфераза<br> аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток<br> БДУ – без дополнительных уточнений<br> ВБП – выживаемость без прогрессирования<br> ДО – длительность ответа<br> ИГХ – иммуногистохимия<br> КТ – компьютерная томография<br> ЛХ – лимфома Ходжкина<br> ОВ – общая выживаемость<br> ПЭТ – позитронной эмиссионной томографии<br> ПР – полная ремиссия<br> СОЭ – скорость оседания эритроцитов<br> ЧО – частичный ответ<br> eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)<br> SUV – standard uptake value – стандартизированный показатель накопления<br> Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы<br> Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции. </p> <h2 style="text-align: justify;">СОДЕРЖАНИЕ ПРОТОКОЛА</h2> <p style="text-align: justify;"> 1. Главные научные кураторы программы и наблюдательный совет 83<br> 2. Список сокращений 84<br> 3. Краткое содержание протокола программы 85<br> 4. Актуальность программы 86<br> 5. Задачи программы 86<br> 6. Цель программы 87<br> 7. Первичные конечные точки 87<br> 8. Вторичные конечные точки 87<br> 9. Дизайн программы 87<br> 10. Популяция пациентов, критерии включения и исключения 87<br> 11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89<br> 12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90<br> 13. Лечение в проспективной группе пациентов наблюдательной программы 91<br> 14. Методология сбора данных 91<br> 15. Размер выборки 92<br> 16. План статистического анализа 92<br> 17. Этические аспекты 93<br> 18. Конфиденциальность персональных данных 93<br> 19. Мониторинг 93<br> 20. Ожидаемые результаты 93<br> 21. Блоки данных, обязательные для регистрации в e-CRF 93<br> 22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96<br> 23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99<br> 24. Список литературы 102 </p> <h2 style="text-align: justify;">3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Название программы</h3> <p style="text-align: justify;"> Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ. </p> <h3 style="text-align: justify;">Актуальность</h3> <p style="text-align: justify;"> Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ. </p> <h3 style="text-align: justify;">Задача программы</h3> <p style="text-align: justify;"> Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации. </p> <h3 style="text-align: justify;">Цель программы</h3> <p style="text-align: justify;"> Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения. </p> <h3 style="text-align: justify;">Дизайн программы</h3> <p style="text-align: justify;"> Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов. </p> <h3 style="text-align: justify;">Длительность программы</h3> <p style="text-align: justify;"> Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода. </p> <h3 style="text-align: justify;">Популяция пациентов</h3> <p style="text-align: justify;"> В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца. </p> <h3 style="text-align: justify;">Критерии включения пациентов в программу</h3> <p style="text-align: justify;"> • Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;<br> • Возраст не моложе 16 лет на момент начала лечения;<br> • Начало лечения лимфомы Ходжкина не ранее 1.01.2017;<br> • Наличие подписанного информированного согласия на обработку персональных и медицинских данных.<br> Критерии исключения пациентов из программы<br> • Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.<br> • Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.<br> • Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.<br> • Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.<br> • Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:<br> – фракция выброса левого желудочка &lt; 50%;<br> – инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> – сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> – признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца. </p> <h3 style="text-align: justify;">Методология сбора данных</h3> <p style="text-align: justify;"> Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования. </p> <h3 style="text-align: justify;">Медико-статистический анализ данных</h3> <p style="text-align: justify;"> Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. </p> <h3 style="text-align: justify;">Ожидаемый результат</h3> <p style="text-align: justify;"> Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии. </p> <h2 style="text-align: justify;">ПРОТОКОЛ</h2> <p style="text-align: justify;"> <b>Многоцентровая кооперативная проспектив</b><b>но-ретроспективная наблюдательная программа по оценке методов диагностики и лечения </b><b>лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.</b> </p> <h2 style="text-align: justify;">4. АКТУАЛЬНОСТЬ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.<br> Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ. </p> <h2 style="text-align: justify;">5. ЗАДАЧИ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.<br> Подзадачи наблюдательной программы:<br> • Организация рабочей научной группы по ЛХ;<br> • Кумуляция данных о пациентах с ЛХ;<br> • Направление и координация потока пациентов;<br> • Увеличение доступа пациентов к высокотехнологическому лечению;<br> • Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;<br> • Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ. </p> <h2 style="text-align: justify;">6. ЦЕЛЬ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения. </p> <h2 style="text-align: justify;">7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ</h2> <p style="text-align: justify;"> Оценить выживаемость пациентов с ЛХ:<br> • без прогрессирования;<br> • с прогрессированием;<br> • общую выживаемость. </p> <h2 style="text-align: justify;">8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ</h2> <p style="text-align: justify;"> 1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;<br> 2. общая выживаемость (ОВ);<br> 3. частота полных ремиссий (ПР);<br> 4. частота рецидивов и прогрессирования заболевания;<br> 5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;<br> 6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;<br> 7. частота потребности во второй линии терапии;<br> 8. частота объективного ответа при использовании разных вариантов второй линии терапии;<br> 9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);<br> 10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;<br> 11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;<br> 12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;<br> 13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;<br> 14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;<br> 15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);<br> 16. оценка использование ресурсов здравоохранения;<br> 17. оценка фертильности на основании частоты удачных беременностей. </p> <h2 style="text-align: justify;">9. ДИЗАЙН ПРОГРАММЫ</h2> <p style="text-align: justify;"> Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты<br> пациентов.<br> Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.<br> В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.<br> В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.<br> Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.<br> Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально. </p> <h2 style="text-align: justify;">10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ</h2> <p style="text-align: justify;"> Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.<br> Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных. </p> <h3 style="text-align: justify;">Критерии включения пациентов в наблюдательную программу:</h3> <p style="text-align: justify;"> • Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;<br> • Возраст не моложе 16 лет на момент начала лечения;<br> • Начало лечения лимфомы Ходжкина не ранее 1.01.2017;<br> • Наличие подписанного информированного согласия на обработку персональных и медицинских данных. </p> <h3 style="text-align: justify;">Критерии исключения пациентов из наблюдательной программы:</h3> <p style="text-align: justify;"> • Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;<br> • Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;<br> • Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;<br> • Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;<br> • Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:<br> – фракция выброса левого желудочка &lt;50%;<br> – инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> – сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> – признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.<br> Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:<br> 1. Пациенты мужского или женского пола в возрасте 18 лет или старше.<br> 2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.<br> 3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).<br> 4. Общее состояние по шкале ECOG ≤ 3 баллов.<br> 5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.<br> 6. Пациентки, которые должны:<br> • находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ<br> • пройти процедуру хирургической стерилизации, ИЛИ<br> • если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или<br> • дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)<br> Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:<br> • дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ<br> • дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)<br> 7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.<br> 8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:<br> • абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;<br> • абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;<br> • общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;<br> • уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;<br> • уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту. </p> <h3 style="text-align: justify;">Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:</h3> <p style="text-align: justify;"> 1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.<br> 2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.<br> 3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.<br> 4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.<br> 5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.<br> 6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:<br> • фракция выброса левого желудочка &lt;50%;<br> • инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> • сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> • признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца. </p> <h2 style="text-align: justify;">11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ</h2> <p style="text-align: justify;"> В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.<br> Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.<br> Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.<br> Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.<br> В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.<br> Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов. </p> <h3 style="text-align: justify;">Лечение и стадирование с применением ПЭТстратегии</h3> <p style="text-align: justify;"> Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях<sup>12</sup>, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD<sup>13</sup>, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc<sup>14</sup>. </p> <h2 style="text-align: justify;">12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1</h2> <p style="text-align: justify;"> Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания<sup>1</sup>. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом<sup>2</sup>. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения<sup>3</sup>. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом<sup>4</sup>. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей<sup>3</sup>,<sup>5</sup>,<sup>6</sup>. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными<sup>7</sup>. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов<sup>10</sup>, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить<sup>11</sup>.<br> Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.<br> Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP14<sup>7,13</sup>, выбор варианта терапии остается на усмотрение учреждений здравоохранения.<br> Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям<sup>1</sup><sup>5</sup>,<sup>16</sup>. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).<br> Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом<sup>17-19</sup>. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом<sup>21,22</sup>. </p> <h2 style="text-align: justify;">13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ</h2> <p style="text-align: justify;"> При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(64288) "

Список сокращений

аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток
АЛТ – аланинаминотрансфераза
АСТ – аспартамаминотрансфераза
аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток
БДУ – без дополнительных уточнений
ВБП – выживаемость без прогрессирования
ДО – длительность ответа
ИГХ – иммуногистохимия
КТ – компьютерная томография
ЛХ – лимфома Ходжкина
ОВ – общая выживаемость
ПЭТ – позитронной эмиссионной томографии
ПР – полная ремиссия
СОЭ – скорость оседания эритроцитов
ЧО – частичный ответ
eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)
SUV – standard uptake value – стандартизированный показатель накопления
Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы
Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции.

СОДЕРЖАНИЕ ПРОТОКОЛА

1. Главные научные кураторы программы и наблюдательный совет 83
2. Список сокращений 84
3. Краткое содержание протокола программы 85
4. Актуальность программы 86
5. Задачи программы 86
6. Цель программы 87
7. Первичные конечные точки 87
8. Вторичные конечные точки 87
9. Дизайн программы 87
10. Популяция пациентов, критерии включения и исключения 87
11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89
12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90
13. Лечение в проспективной группе пациентов наблюдательной программы 91
14. Методология сбора данных 91
15. Размер выборки 92
16. План статистического анализа 92
17. Этические аспекты 93
18. Конфиденциальность персональных данных 93
19. Мониторинг 93
20. Ожидаемые результаты 93
21. Блоки данных, обязательные для регистрации в e-CRF 93
22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96
23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99
24. Список литературы 102

3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ

Название программы

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

Актуальность

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

Задача программы

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.

Цель программы

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

Дизайн программы

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов.

Длительность программы

Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.

Популяция пациентов

В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.

Критерии включения пациентов в программу

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.
Критерии исключения пациентов из программы
• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка < 50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

Методология сбора данных

Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

Медико-статистический анализ данных

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года.

Ожидаемый результат

Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

ПРОТОКОЛ

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

4. АКТУАЛЬНОСТЬ ПРОГРАММЫ

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.
Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

5. ЗАДАЧИ ПРОГРАММЫ

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.
Подзадачи наблюдательной программы:
• Организация рабочей научной группы по ЛХ;
• Кумуляция данных о пациентах с ЛХ;
• Направление и координация потока пациентов;
• Увеличение доступа пациентов к высокотехнологическому лечению;
• Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;
• Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ.

6. ЦЕЛЬ ПРОГРАММЫ

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

Оценить выживаемость пациентов с ЛХ:
• без прогрессирования;
• с прогрессированием;
• общую выживаемость.

8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;
2. общая выживаемость (ОВ);
3. частота полных ремиссий (ПР);
4. частота рецидивов и прогрессирования заболевания;
5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;
6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;
7. частота потребности во второй линии терапии;
8. частота объективного ответа при использовании разных вариантов второй линии терапии;
9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);
10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;
11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;
12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;
13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;
14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;
15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);
16. оценка использование ресурсов здравоохранения;
17. оценка фертильности на основании частоты удачных беременностей.

9. ДИЗАЙН ПРОГРАММЫ

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты
пациентов.
Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.
В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.
В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.
Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.
Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально.

10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ

Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.
Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных.

Критерии включения пациентов в наблюдательную программу:

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.

Критерии исключения пациентов из наблюдательной программы:

• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка <50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.
Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:
1. Пациенты мужского или женского пола в возрасте 18 лет или старше.
2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.
3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).
4. Общее состояние по шкале ECOG ≤ 3 баллов.
5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.
6. Пациентки, которые должны:
• находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ
• пройти процедуру хирургической стерилизации, ИЛИ
• если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)
Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:
• дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)
7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.
8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:
• абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;
• абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;
• общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;
• уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;
• уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту.

Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:

1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.
2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.
3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.
4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:
• фракция выброса левого желудочка <50%;
• инфаркт миокарда в течение 6 месяцев до включения в протокол;
• сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
• признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ

В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.
Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.
Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.
Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.
В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.
Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов.

Лечение и стадирование с применением ПЭТстратегии

Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.

12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1

Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания1. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом2. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения3. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом4. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей3,5,6. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными7. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов10, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить11.
Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.
Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP147,13, выбор варианта терапии остается на усмотрение учреждений здравоохранения.
Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям15,16. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).
Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом17-19. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом21,22.

13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ

При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года.

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title="логотипы.png"> </p> <h2 style="text-align: justify;">ПРОТОКОЛ № RNWOHG-HD1 ВЕРСИЯ 1.01 ОТ 18.09.2017</h2> <p style="text-align: justify;"> ЗАЯВЛЕНИЕ О КОНФИДЕНЦИАЛЬНОСТИ. Этот документ является конфиденциальным и может быть предоставлен для пересмотра только исследователям, потенциальным исследователям, консультантам, персоналу исследования и независимым этическим комитетам или локальным этическим комитетам. Содержимое этого документа не может быть раскрыто третьим лицам без письменного разрешения организации или отдельных лиц, за исключением случаев, когда необходимо получить информированное согласие от потенциальных участников исследования.<br> Санкт-Петербург 2017 </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1321) "

логотипы.png

ПРОТОКОЛ № RNWOHG-HD1 ВЕРСИЯ 1.01 ОТ 18.09.2017

ЗАЯВЛЕНИЕ О КОНФИДЕНЦИАЛЬНОСТИ. Этот документ является конфиденциальным и может быть предоставлен для пересмотра только исследователям, потенциальным исследователям, консультантам, персоналу исследования и независимым этическим комитетам или локальным этическим комитетам. Содержимое этого документа не может быть раскрыто третьим лицам без письменного разрешения организации или отдельных лиц, за исключением случаев, когда необходимо получить информированное согласие от потенциальных участников исследования.
Санкт-Петербург 2017

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логотипы.png

ПРОТОКОЛ № RNWOHG-HD1 ВЕРСИЯ 1.01 ОТ 18.09.2017

ЗАЯВЛЕНИЕ О КОНФИДЕНЦИАЛЬНОСТИ. Этот документ является конфиденциальным и может быть предоставлен для пересмотра только исследователям, потенциальным исследователям, консультантам, персоналу исследования и независимым этическим комитетам или локальным этическим комитетам. Содержимое этого документа не может быть раскрыто третьим лицам без письменного разрешения организации или отдельных лиц, за исключением случаев, когда необходимо получить информированное согласие от потенциальных участников исследования.
Санкт-Петербург 2017

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20061" ["VALUE"]=> array(2) { ["TEXT"]=> string(7460) "<h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3> <p style="text-align: justify;"> «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета. </p> <h3 style="text-align: justify;">Главные научные кураторы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Моисеев Иван Сергеевич</b><br> Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н. </p> <h3 style="text-align: justify;">Наблюдательный совет программы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Беляев Алексей Михайлович</b><br> Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br> <b>Зарицкий Андрей Юрьевич</b><br> Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Ильин Николай Васильевич</b><br> Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br> <b>Михайлова Наталья Борисовна</b><br> Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br> <b>Медведева Надежда Вадимовна</b><br> Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br> <b>Манихас Георгий Моисеевич</b><br> Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br> <b>Волошин Сергей Владимирович</b><br> Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br> <b>Моисеенко Владимир Михайлович</b><br> Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br> <b>Шнейдер Татьяна Владимировна</b><br> Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7004) "

Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20065" ["VALUE"]=> array(2) { ["TEXT"]=> string(66692) "<h2></h2> <h2 style="text-align: justify;"><sup></sup>Список сокращений</h2> <p style="text-align: justify;"> аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток<br> АЛТ – аланинаминотрансфераза<br> АСТ – аспартамаминотрансфераза<br> аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток<br> БДУ – без дополнительных уточнений<br> ВБП – выживаемость без прогрессирования<br> ДО – длительность ответа<br> ИГХ – иммуногистохимия<br> КТ – компьютерная томография<br> ЛХ – лимфома Ходжкина<br> ОВ – общая выживаемость<br> ПЭТ – позитронной эмиссионной томографии<br> ПР – полная ремиссия<br> СОЭ – скорость оседания эритроцитов<br> ЧО – частичный ответ<br> eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)<br> SUV – standard uptake value – стандартизированный показатель накопления<br> Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы<br> Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции. </p> <h2 style="text-align: justify;">СОДЕРЖАНИЕ ПРОТОКОЛА</h2> <p style="text-align: justify;"> 1. Главные научные кураторы программы и наблюдательный совет 83<br> 2. Список сокращений 84<br> 3. Краткое содержание протокола программы 85<br> 4. Актуальность программы 86<br> 5. Задачи программы 86<br> 6. Цель программы 87<br> 7. Первичные конечные точки 87<br> 8. Вторичные конечные точки 87<br> 9. Дизайн программы 87<br> 10. Популяция пациентов, критерии включения и исключения 87<br> 11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89<br> 12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90<br> 13. Лечение в проспективной группе пациентов наблюдательной программы 91<br> 14. Методология сбора данных 91<br> 15. Размер выборки 92<br> 16. План статистического анализа 92<br> 17. Этические аспекты 93<br> 18. Конфиденциальность персональных данных 93<br> 19. Мониторинг 93<br> 20. Ожидаемые результаты 93<br> 21. Блоки данных, обязательные для регистрации в e-CRF 93<br> 22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96<br> 23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99<br> 24. Список литературы 102 </p> <h2 style="text-align: justify;">3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Название программы</h3> <p style="text-align: justify;"> Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ. </p> <h3 style="text-align: justify;">Актуальность</h3> <p style="text-align: justify;"> Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ. </p> <h3 style="text-align: justify;">Задача программы</h3> <p style="text-align: justify;"> Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации. </p> <h3 style="text-align: justify;">Цель программы</h3> <p style="text-align: justify;"> Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения. </p> <h3 style="text-align: justify;">Дизайн программы</h3> <p style="text-align: justify;"> Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов. </p> <h3 style="text-align: justify;">Длительность программы</h3> <p style="text-align: justify;"> Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода. </p> <h3 style="text-align: justify;">Популяция пациентов</h3> <p style="text-align: justify;"> В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца. </p> <h3 style="text-align: justify;">Критерии включения пациентов в программу</h3> <p style="text-align: justify;"> • Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;<br> • Возраст не моложе 16 лет на момент начала лечения;<br> • Начало лечения лимфомы Ходжкина не ранее 1.01.2017;<br> • Наличие подписанного информированного согласия на обработку персональных и медицинских данных.<br> Критерии исключения пациентов из программы<br> • Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.<br> • Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.<br> • Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.<br> • Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.<br> • Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:<br> – фракция выброса левого желудочка &lt; 50%;<br> – инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> – сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> – признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца. </p> <h3 style="text-align: justify;">Методология сбора данных</h3> <p style="text-align: justify;"> Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования. </p> <h3 style="text-align: justify;">Медико-статистический анализ данных</h3> <p style="text-align: justify;"> Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. </p> <h3 style="text-align: justify;">Ожидаемый результат</h3> <p style="text-align: justify;"> Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии. </p> <h2 style="text-align: justify;">ПРОТОКОЛ</h2> <p style="text-align: justify;"> <b>Многоцентровая кооперативная проспектив</b><b>но-ретроспективная наблюдательная программа по оценке методов диагностики и лечения </b><b>лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.</b> </p> <h2 style="text-align: justify;">4. АКТУАЛЬНОСТЬ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.<br> Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ. </p> <h2 style="text-align: justify;">5. ЗАДАЧИ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.<br> Подзадачи наблюдательной программы:<br> • Организация рабочей научной группы по ЛХ;<br> • Кумуляция данных о пациентах с ЛХ;<br> • Направление и координация потока пациентов;<br> • Увеличение доступа пациентов к высокотехнологическому лечению;<br> • Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;<br> • Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ. </p> <h2 style="text-align: justify;">6. ЦЕЛЬ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения. </p> <h2 style="text-align: justify;">7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ</h2> <p style="text-align: justify;"> Оценить выживаемость пациентов с ЛХ:<br> • без прогрессирования;<br> • с прогрессированием;<br> • общую выживаемость. </p> <h2 style="text-align: justify;">8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ</h2> <p style="text-align: justify;"> 1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;<br> 2. общая выживаемость (ОВ);<br> 3. частота полных ремиссий (ПР);<br> 4. частота рецидивов и прогрессирования заболевания;<br> 5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;<br> 6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;<br> 7. частота потребности во второй линии терапии;<br> 8. частота объективного ответа при использовании разных вариантов второй линии терапии;<br> 9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);<br> 10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;<br> 11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;<br> 12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;<br> 13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;<br> 14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;<br> 15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);<br> 16. оценка использование ресурсов здравоохранения;<br> 17. оценка фертильности на основании частоты удачных беременностей. </p> <h2 style="text-align: justify;">9. ДИЗАЙН ПРОГРАММЫ</h2> <p style="text-align: justify;"> Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты<br> пациентов.<br> Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.<br> В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.<br> В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.<br> Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.<br> Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально. </p> <h2 style="text-align: justify;">10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ</h2> <p style="text-align: justify;"> Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.<br> Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных. </p> <h3 style="text-align: justify;">Критерии включения пациентов в наблюдательную программу:</h3> <p style="text-align: justify;"> • Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;<br> • Возраст не моложе 16 лет на момент начала лечения;<br> • Начало лечения лимфомы Ходжкина не ранее 1.01.2017;<br> • Наличие подписанного информированного согласия на обработку персональных и медицинских данных. </p> <h3 style="text-align: justify;">Критерии исключения пациентов из наблюдательной программы:</h3> <p style="text-align: justify;"> • Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;<br> • Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;<br> • Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;<br> • Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;<br> • Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:<br> – фракция выброса левого желудочка &lt;50%;<br> – инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> – сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> – признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.<br> Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:<br> 1. Пациенты мужского или женского пола в возрасте 18 лет или старше.<br> 2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.<br> 3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).<br> 4. Общее состояние по шкале ECOG ≤ 3 баллов.<br> 5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.<br> 6. Пациентки, которые должны:<br> • находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ<br> • пройти процедуру хирургической стерилизации, ИЛИ<br> • если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или<br> • дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)<br> Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:<br> • дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ<br> • дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)<br> 7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.<br> 8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:<br> • абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;<br> • абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;<br> • общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;<br> • уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;<br> • уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту. </p> <h3 style="text-align: justify;">Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:</h3> <p style="text-align: justify;"> 1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.<br> 2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.<br> 3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.<br> 4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.<br> 5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.<br> 6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:<br> • фракция выброса левого желудочка &lt;50%;<br> • инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> • сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> • признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца. </p> <h2 style="text-align: justify;">11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ</h2> <p style="text-align: justify;"> В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.<br> Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.<br> Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.<br> Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.<br> В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.<br> Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов. </p> <h3 style="text-align: justify;">Лечение и стадирование с применением ПЭТстратегии</h3> <p style="text-align: justify;"> Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях<sup>12</sup>, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD<sup>13</sup>, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc<sup>14</sup>. </p> <h2 style="text-align: justify;">12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1</h2> <p style="text-align: justify;"> Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания<sup>1</sup>. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом<sup>2</sup>. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения<sup>3</sup>. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом<sup>4</sup>. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей<sup>3</sup>,<sup>5</sup>,<sup>6</sup>. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными<sup>7</sup>. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов<sup>10</sup>, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить<sup>11</sup>.<br> Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.<br> Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP14<sup>7,13</sup>, выбор варианта терапии остается на усмотрение учреждений здравоохранения.<br> Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям<sup>1</sup><sup>5</sup>,<sup>16</sup>. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).<br> Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом<sup>17-19</sup>. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом<sup>21,22</sup>. </p> <h2 style="text-align: justify;">13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ</h2> <p style="text-align: justify;"> При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(64288) "

Список сокращений

аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток
АЛТ – аланинаминотрансфераза
АСТ – аспартамаминотрансфераза
аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток
БДУ – без дополнительных уточнений
ВБП – выживаемость без прогрессирования
ДО – длительность ответа
ИГХ – иммуногистохимия
КТ – компьютерная томография
ЛХ – лимфома Ходжкина
ОВ – общая выживаемость
ПЭТ – позитронной эмиссионной томографии
ПР – полная ремиссия
СОЭ – скорость оседания эритроцитов
ЧО – частичный ответ
eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)
SUV – standard uptake value – стандартизированный показатель накопления
Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы
Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции.

СОДЕРЖАНИЕ ПРОТОКОЛА

1. Главные научные кураторы программы и наблюдательный совет 83
2. Список сокращений 84
3. Краткое содержание протокола программы 85
4. Актуальность программы 86
5. Задачи программы 86
6. Цель программы 87
7. Первичные конечные точки 87
8. Вторичные конечные точки 87
9. Дизайн программы 87
10. Популяция пациентов, критерии включения и исключения 87
11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89
12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90
13. Лечение в проспективной группе пациентов наблюдательной программы 91
14. Методология сбора данных 91
15. Размер выборки 92
16. План статистического анализа 92
17. Этические аспекты 93
18. Конфиденциальность персональных данных 93
19. Мониторинг 93
20. Ожидаемые результаты 93
21. Блоки данных, обязательные для регистрации в e-CRF 93
22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96
23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99
24. Список литературы 102

3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ

Название программы

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

Актуальность

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

Задача программы

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.

Цель программы

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

Дизайн программы

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов.

Длительность программы

Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.

Популяция пациентов

В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.

Критерии включения пациентов в программу

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.
Критерии исключения пациентов из программы
• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка < 50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

Методология сбора данных

Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

Медико-статистический анализ данных

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года.

Ожидаемый результат

Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

ПРОТОКОЛ

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

4. АКТУАЛЬНОСТЬ ПРОГРАММЫ

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.
Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

5. ЗАДАЧИ ПРОГРАММЫ

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.
Подзадачи наблюдательной программы:
• Организация рабочей научной группы по ЛХ;
• Кумуляция данных о пациентах с ЛХ;
• Направление и координация потока пациентов;
• Увеличение доступа пациентов к высокотехнологическому лечению;
• Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;
• Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ.

6. ЦЕЛЬ ПРОГРАММЫ

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

Оценить выживаемость пациентов с ЛХ:
• без прогрессирования;
• с прогрессированием;
• общую выживаемость.

8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;
2. общая выживаемость (ОВ);
3. частота полных ремиссий (ПР);
4. частота рецидивов и прогрессирования заболевания;
5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;
6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;
7. частота потребности во второй линии терапии;
8. частота объективного ответа при использовании разных вариантов второй линии терапии;
9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);
10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;
11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;
12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;
13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;
14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;
15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);
16. оценка использование ресурсов здравоохранения;
17. оценка фертильности на основании частоты удачных беременностей.

9. ДИЗАЙН ПРОГРАММЫ

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты
пациентов.
Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.
В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.
В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.
Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.
Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально.

10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ

Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.
Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных.

Критерии включения пациентов в наблюдательную программу:

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.

Критерии исключения пациентов из наблюдательной программы:

• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка <50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.
Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:
1. Пациенты мужского или женского пола в возрасте 18 лет или старше.
2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.
3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).
4. Общее состояние по шкале ECOG ≤ 3 баллов.
5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.
6. Пациентки, которые должны:
• находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ
• пройти процедуру хирургической стерилизации, ИЛИ
• если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)
Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:
• дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)
7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.
8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:
• абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;
• абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;
• общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;
• уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;
• уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту.

Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:

1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.
2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.
3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.
4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:
• фракция выброса левого желудочка <50%;
• инфаркт миокарда в течение 6 месяцев до включения в протокол;
• сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
• признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ

В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.
Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.
Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.
Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.
В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.
Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов.

Лечение и стадирование с применением ПЭТстратегии

Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.

12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1

Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания1. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом2. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения3. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом4. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей3,5,6. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными7. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов10, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить11.
Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.
Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP147,13, выбор варианта терапии остается на усмотрение учреждений здравоохранения.
Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям15,16. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).
Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом17-19. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом21,22.

13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ

При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года.

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Список сокращений

аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток
АЛТ – аланинаминотрансфераза
АСТ – аспартамаминотрансфераза
аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток
БДУ – без дополнительных уточнений
ВБП – выживаемость без прогрессирования
ДО – длительность ответа
ИГХ – иммуногистохимия
КТ – компьютерная томография
ЛХ – лимфома Ходжкина
ОВ – общая выживаемость
ПЭТ – позитронной эмиссионной томографии
ПР – полная ремиссия
СОЭ – скорость оседания эритроцитов
ЧО – частичный ответ
eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)
SUV – standard uptake value – стандартизированный показатель накопления
Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы
Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции.

СОДЕРЖАНИЕ ПРОТОКОЛА

1. Главные научные кураторы программы и наблюдательный совет 83
2. Список сокращений 84
3. Краткое содержание протокола программы 85
4. Актуальность программы 86
5. Задачи программы 86
6. Цель программы 87
7. Первичные конечные точки 87
8. Вторичные конечные точки 87
9. Дизайн программы 87
10. Популяция пациентов, критерии включения и исключения 87
11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89
12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90
13. Лечение в проспективной группе пациентов наблюдательной программы 91
14. Методология сбора данных 91
15. Размер выборки 92
16. План статистического анализа 92
17. Этические аспекты 93
18. Конфиденциальность персональных данных 93
19. Мониторинг 93
20. Ожидаемые результаты 93
21. Блоки данных, обязательные для регистрации в e-CRF 93
22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96
23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99
24. Список литературы 102

3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ

Название программы

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

Актуальность

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

Задача программы

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.

Цель программы

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

Дизайн программы

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов.

Длительность программы

Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.

Популяция пациентов

В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.

Критерии включения пациентов в программу

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.
Критерии исключения пациентов из программы
• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка < 50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

Методология сбора данных

Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

Медико-статистический анализ данных

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года.

Ожидаемый результат

Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

ПРОТОКОЛ

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

4. АКТУАЛЬНОСТЬ ПРОГРАММЫ

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.
Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

5. ЗАДАЧИ ПРОГРАММЫ

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.
Подзадачи наблюдательной программы:
• Организация рабочей научной группы по ЛХ;
• Кумуляция данных о пациентах с ЛХ;
• Направление и координация потока пациентов;
• Увеличение доступа пациентов к высокотехнологическому лечению;
• Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;
• Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ.

6. ЦЕЛЬ ПРОГРАММЫ

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

Оценить выживаемость пациентов с ЛХ:
• без прогрессирования;
• с прогрессированием;
• общую выживаемость.

8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;
2. общая выживаемость (ОВ);
3. частота полных ремиссий (ПР);
4. частота рецидивов и прогрессирования заболевания;
5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;
6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;
7. частота потребности во второй линии терапии;
8. частота объективного ответа при использовании разных вариантов второй линии терапии;
9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);
10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;
11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;
12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;
13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;
14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;
15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);
16. оценка использование ресурсов здравоохранения;
17. оценка фертильности на основании частоты удачных беременностей.

9. ДИЗАЙН ПРОГРАММЫ

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты
пациентов.
Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.
В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.
В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.
Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.
Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально.

10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ

Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.
Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных.

Критерии включения пациентов в наблюдательную программу:

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.

Критерии исключения пациентов из наблюдательной программы:

• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка <50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.
Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:
1. Пациенты мужского или женского пола в возрасте 18 лет или старше.
2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.
3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).
4. Общее состояние по шкале ECOG ≤ 3 баллов.
5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.
6. Пациентки, которые должны:
• находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ
• пройти процедуру хирургической стерилизации, ИЛИ
• если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)
Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:
• дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)
7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.
8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:
• абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;
• абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;
• общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;
• уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;
• уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту.

Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:

1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.
2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.
3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.
4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:
• фракция выброса левого желудочка <50%;
• инфаркт миокарда в течение 6 месяцев до включения в протокол;
• сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
• признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ

В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.
Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.
Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.
Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.
В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.
Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов.

Лечение и стадирование с применением ПЭТстратегии

Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.

12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1

Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания1. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом2. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения3. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом4. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей3,5,6. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными7. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов10, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить11.
Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.
Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP147,13, выбор варианта терапии остается на усмотрение учреждений здравоохранения.
Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям15,16. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).
Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом17-19. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом21,22.

13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ

При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20074" ["VALUE"]=> array(2) { ["TEXT"]=> string(7460) "<h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3> <p style="text-align: justify;"> «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета. </p> <h3 style="text-align: justify;">Главные научные кураторы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Моисеев Иван Сергеевич</b><br> Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н. </p> <h3 style="text-align: justify;">Наблюдательный совет программы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Беляев Алексей Михайлович</b><br> Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br> <b>Зарицкий Андрей Юрьевич</b><br> Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Ильин Николай Васильевич</b><br> Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br> <b>Михайлова Наталья Борисовна</b><br> Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br> <b>Медведева Надежда Вадимовна</b><br> Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br> <b>Манихас Георгий Моисеевич</b><br> Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br> <b>Волошин Сергей Владимирович</b><br> Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br> <b>Моисеенко Владимир Михайлович</b><br> Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br> <b>Шнейдер Татьяна Владимировна</b><br> Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7004) "

Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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string(43638) "<h2></h2> <h2 style="text-align: justify;">Вторая линия химиотерапии:</h2> <p style="text-align: justify;"> • Курсы химиотерапии ICE, IGEV, DHAP, бендамустин + брентуксимаб 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:<br> – IPS 1-3;<br> – Химиочувствительная опухоль (по крайней мере, ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:<br> – IPS 4;<br> – Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.<br> • При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Аутологичная трансплантация</h3> <p style="text-align: justify;"> Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра. </p> <h3 style="text-align: justify;">Поддержка брентуксимабом после аутологичной ТГСК</h3> <p style="text-align: justify;"> Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):<br> – рецидив позднее 1 года от диагноза;<br> – нет экстранодального поражения в рецидиве;<br> – полный ответ после 2-ой линии химиотерапии;<br> – нет bulky опухоли в рецидиве.<br> Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):<br> – рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;<br> – есть экстранодальное поражение в рецидиве;<br> – менее, чем полный ответ после 2-ой линии химиотерапии;<br> – есть bulky опухоль в рецидиве. </p> <h2 style="text-align: justify;">Третья линия химиотерапии:</h2> <p style="text-align: justify;"> • Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.<br> • При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.<br> <img width="982" alt="Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png" src="/upload/medialibrary/29d/vetka_protokola_dlya_vich_assotsiirovannoy_limfomy_khodzhkina_risunok_2_risunok_2_lechenie_patsientov_s_vich_infektsiey.png" height="1010" title="Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png"><br> Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.<br> • Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.<br> • При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.<br> • При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.<br> • При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии.<br> • При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии. </p> <h2 style="text-align: justify;">Вторая линия химиотерапии:</h2> <p style="text-align: justify;"> • Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:<br> – IPS 1-3;<br> – Химиочувствительная опухоль (по крайней мере,<br> ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:<br> – IPS 4;<br> – Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.<br> • При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Аутологичная трансплантация</h3> <p style="text-align: justify;"> Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра. </p> <h3 style="text-align: justify;">Поддержка брентуксимабом после аутологичной ТГСК:</h3> <p style="text-align: justify;"> Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):<br> – рецидив позднее 1 года от диагноза;<br> – нет экстранодального поражения в рецидиве;<br> – полный ответ после 2-ой линии химиотерапии;<br> – нет bulky опухоли в рецидиве.<br> Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):<br> – рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;<br> – есть экстранодальное поражение в рецидиве;<br> – менее, чем полный ответ после 2-ой линии химиотерапии;<br> – есть bulky опухоль в рецидиве. </p> <h2 style="text-align: justify;">Третья линия химиотерапии:</h2> <p style="text-align: justify;"> • Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.<br> • При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК. </p> <h2 style="text-align: justify;">23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Схемы химиотерапии.</h3> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Курс полихимиотерапии ABVD:</h3> <p style="text-align: justify;"> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;<br> • V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла. </p> <h3 style="text-align: justify;">Курс полихимиотерапии AVD:</h3> <p style="text-align: justify;"> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP-14:</h3> <p style="text-align: justify;"> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;<br> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;<br> • P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP escalated:</h3> <p style="text-align: justify;"> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;<br> • E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;<br> • A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;<br> • P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP-14 с дакарбазином:</h3> <p style="text-align: justify;"> • Используется только при отсутсвии доступа к прокарбазину;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;<br> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;<br> • P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP escalated с дакарбазином:</h3> <p style="text-align: justify;"> • Используется только при отсутсвии доступа к прокарбазину;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;<br> • E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;<br> • A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;<br> • P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии DHAP:</h3> <p style="text-align: justify;"> • D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;<br> • HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;<br> • P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;<br> Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови. </p> <h3 style="text-align: justify;">Курс полихимиотерапии ICE:</h3> <p style="text-align: justify;"> • I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;<br> • С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;<br> Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови. </p> <h3 style="text-align: justify;">Курс полихимиотерапии IGEV:</h3> <p style="text-align: justify;"> • I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;<br> • GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;<br> • V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;<br> • преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Брентуксимаб:</h3> <p style="text-align: justify;"> • доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Брентуксимаб+бендамустин:</h3> <p style="text-align: justify;"> • брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;<br> • бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Редукция доз химиопрепаратов при почечной недостаточности:</h3> <p style="text-align: justify;"> Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.<br> • блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина &lt;10 мл/мин – 50% дозы;<br> • доксорубицин: коррекция дозы не проводится;<br> • винбластин/винкристин: коррекция дозы не проводится;<br> • дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина &lt;30 мл/мин – 70% дозы;<br> • прокарбазин: клиренс креатинина &lt;50 мл/мин – 50% дозы;<br> • циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;<br> • этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина &lt;15 мл/мин – 50% дозы;<br> • цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина &lt;45 мл/мин – выбор альтернативной схемы;<br> • карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина &lt;20 мл/мин - выбор альтернативной схемы;<br> • цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина &lt;45мл/мин – выбор альтернативной схемы;<br> • ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина &lt;45мл/мин – выбор альтернативной схемы;<br> • гемцитабин: клиренс креатинина &lt;30 мл/мин – нет редукции или 75% дозы;<br> • винорельбин: коррекция дозы не проводится;<br> • бендамутин: коррекция дозы не проводится. </p> <h3 style="text-align: justify;">Сопроводительная терапия:</h3> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">ABVD/AVD:</h3> <p style="text-align: justify;"> • Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;<br> • Ондасетрон 8 мг в дни введения химиопрепаратов;<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;<br> • Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;<br> • Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам. </p> <h3 style="text-align: justify;">BEACOPP14/BEACOPPesc:</h3> <p style="text-align: justify;"> • Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">DHAP:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации<br> • Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">ICE:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации<br> • уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">IGEV:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;<br> • Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.<br> Брентуксимаб+бендамустин:<br> • Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;<br> • Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">Условия коррекции сроков начала следующего курса:</h3> <p style="text-align: justify;"> Начало следующего курса может быть отложено в случае:<br> • Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);<br> • Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);<br> • Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок &gt;70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;<br> • Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома. </p> <h2 style="text-align: justify;">24. СПИСОК ЛИТЕРАТУРЫ</h2> <p style="text-align: justify;"> 1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.<br> 2. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014 Sep;9(3):222-226.<br> 3. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395.<br> 4. Eich HT, Diehl V, Görgen H et al. Intensified chemotherapy and dose-reduced involved-fi eld radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: fi nal analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-4206.<br> 5. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.<br> 6. Merli F, Luminari S, Gobbi PG et al. Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi. J Clin Oncol. 2016;34(11):1175-1181.<br> 7. Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.<br> 8. Borchmann P, Haverkamp H, Diehl V et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.<br> 9. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.<br> 10. Engert A, Plütschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.<br> 11. Meyer RM, Gospodarowicz MK, Connors JM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012; 366(5):399-408.<br> 12. Eichenauer DA, Engert A. 2012; Advances in the treatment of Hodgkin lymphoma. Int J Hematol 96:535–543.<br> 13. Johnson P, Federico M, Kirkwood A et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med. 2016;374(25):2419-2429.<br> 14. Engert A. ABVD or BEACOPP for Advanced Hodgkin Lymphoma. J Clin Oncol. 2016;34(11):1167-1169<br> 15. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.<br> 16. Press OW, Li H, Schöder H et al. US Intergroup Trial of Response-Adapted Th erapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.<br> 17. Andreas Engert,Sandra J. Horning. 2011; Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics. Springer-Verlag, Berlin.<br> 18. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.<br> 19. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.<br> 20. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant. 1999;23(6):561-567.<br> 21. Satwani P, Ahn KW, Carreras J et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015;50(11):1416-1423.<br> 22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.<br> 23. Cheson BD, Pfi stner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-586.<br> 24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(41176) "

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP, бендамустин + брентуксимаб 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере, ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.
Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png
Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.
• Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.
• При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.
• При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.
• При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии.

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере,
ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК:

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.

23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов

Схемы химиотерапии.

Курс полихимиотерапии ABVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии AVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии BEACOPP-14:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP-14 с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии DHAP:

• D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;
• HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;
• P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии ICE:

• I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;
• С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии IGEV:

• I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла.

Брентуксимаб:

• доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла.

Брентуксимаб+бендамустин:

• брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла.

Редукция доз химиопрепаратов при почечной недостаточности:

Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.
• блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина <10 мл/мин – 50% дозы;
• доксорубицин: коррекция дозы не проводится;
• винбластин/винкристин: коррекция дозы не проводится;
• дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина <30 мл/мин – 70% дозы;
• прокарбазин: клиренс креатинина <50 мл/мин – 50% дозы;
• циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;
• этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина <15 мл/мин – 50% дозы;
• цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина <45 мл/мин – выбор альтернативной схемы;
• карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина <20 мл/мин - выбор альтернативной схемы;
• цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• гемцитабин: клиренс креатинина <30 мл/мин – нет редукции или 75% дозы;
• винорельбин: коррекция дозы не проводится;
• бендамутин: коррекция дозы не проводится.

Сопроводительная терапия:

ABVD/AVD:

• Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;
• Ондасетрон 8 мг в дни введения химиопрепаратов;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;
• Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;
• Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам.

BEACOPP14/BEACOPPesc:

• Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

DHAP:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

ICE:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

IGEV:

• Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;
• Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.
Брентуксимаб+бендамустин:
• Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;
• Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

Условия коррекции сроков начала следующего курса:

Начало следующего курса может быть отложено в случае:
• Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок >70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;
• Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома.

24. СПИСОК ЛИТЕРАТУРЫ

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8. Borchmann P, Haverkamp H, Diehl V et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.
9. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.
10. Engert A, Plütschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.
11. Meyer RM, Gospodarowicz MK, Connors JM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012; 366(5):399-408.
12. Eichenauer DA, Engert A. 2012; Advances in the treatment of Hodgkin lymphoma. Int J Hematol 96:535–543.
13. Johnson P, Federico M, Kirkwood A et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med. 2016;374(25):2419-2429.
14. Engert A. ABVD or BEACOPP for Advanced Hodgkin Lymphoma. J Clin Oncol. 2016;34(11):1167-1169
15. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.
16. Press OW, Li H, Schöder H et al. US Intergroup Trial of Response-Adapted Th erapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
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18. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.
19. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
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22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
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24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf.

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«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета. </p> <h3 style="text-align: justify;">Главные научные кураторы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Моисеев Иван Сергеевич</b><br> Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н. </p> <h3 style="text-align: justify;">Наблюдательный совет программы:</h3> <p style="text-align: justify;"> <b>Афанасьев Борис Владимирович</b><br> Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br> <b>Беляев Алексей Михайлович</b><br> Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br> <b>Зарицкий Андрей Юрьевич</b><br> Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br> <b>Алексеев Сергей Михайлович</b><br> Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br> <b>Ильин Николай Васильевич</b><br> Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br> <b>Михайлова Наталья Борисовна</b><br> Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br> <b>Медведева Надежда Вадимовна</b><br> Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br> <b>Манихас Георгий Моисеевич</b><br> Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br> <b>Волошин Сергей Владимирович</b><br> Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br> <b>Моисеенко Владимир Михайлович</b><br> Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br> <b>Шнейдер Татьяна Владимировна</b><br> Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7004) "

Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра. </p> <h3 style="text-align: justify;">Поддержка брентуксимабом после аутологичной ТГСК</h3> <p style="text-align: justify;"> Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):<br> – рецидив позднее 1 года от диагноза;<br> – нет экстранодального поражения в рецидиве;<br> – полный ответ после 2-ой линии химиотерапии;<br> – нет bulky опухоли в рецидиве.<br> Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):<br> – рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;<br> – есть экстранодальное поражение в рецидиве;<br> – менее, чем полный ответ после 2-ой линии химиотерапии;<br> – есть bulky опухоль в рецидиве. </p> <h2 style="text-align: justify;">Третья линия химиотерапии:</h2> <p style="text-align: justify;"> • Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.<br> • При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.<br> <img width="982" alt="Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png" src="/upload/medialibrary/29d/vetka_protokola_dlya_vich_assotsiirovannoy_limfomy_khodzhkina_risunok_2_risunok_2_lechenie_patsientov_s_vich_infektsiey.png" height="1010" title="Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png"><br> Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.<br> • Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.<br> • При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.<br> • При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.<br> • При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии.<br> • При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии. </p> <h2 style="text-align: justify;">Вторая линия химиотерапии:</h2> <p style="text-align: justify;"> • Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:<br> – IPS 1-3;<br> – Химиочувствительная опухоль (по крайней мере,<br> ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:<br> – IPS 4;<br> – Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.<br> • При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Аутологичная трансплантация</h3> <p style="text-align: justify;"> Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра. </p> <h3 style="text-align: justify;">Поддержка брентуксимабом после аутологичной ТГСК:</h3> <p style="text-align: justify;"> Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):<br> – рецидив позднее 1 года от диагноза;<br> – нет экстранодального поражения в рецидиве;<br> – полный ответ после 2-ой линии химиотерапии;<br> – нет bulky опухоли в рецидиве.<br> Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):<br> – рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;<br> – есть экстранодальное поражение в рецидиве;<br> – менее, чем полный ответ после 2-ой линии химиотерапии;<br> – есть bulky опухоль в рецидиве. </p> <h2 style="text-align: justify;">Третья линия химиотерапии:</h2> <p style="text-align: justify;"> • Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.<br> • При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК. </p> <h2 style="text-align: justify;">23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Схемы химиотерапии.</h3> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Курс полихимиотерапии ABVD:</h3> <p style="text-align: justify;"> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;<br> • V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла. </p> <h3 style="text-align: justify;">Курс полихимиотерапии AVD:</h3> <p style="text-align: justify;"> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP-14:</h3> <p style="text-align: justify;"> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;<br> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;<br> • P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP escalated:</h3> <p style="text-align: justify;"> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;<br> • E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;<br> • A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;<br> • P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP-14 с дакарбазином:</h3> <p style="text-align: justify;"> • Используется только при отсутсвии доступа к прокарбазину;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;<br> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;<br> • P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP escalated с дакарбазином:</h3> <p style="text-align: justify;"> • Используется только при отсутсвии доступа к прокарбазину;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;<br> • E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;<br> • A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;<br> • P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии DHAP:</h3> <p style="text-align: justify;"> • D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;<br> • HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;<br> • P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;<br> Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови. </p> <h3 style="text-align: justify;">Курс полихимиотерапии ICE:</h3> <p style="text-align: justify;"> • I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;<br> • С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;<br> Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови. </p> <h3 style="text-align: justify;">Курс полихимиотерапии IGEV:</h3> <p style="text-align: justify;"> • I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;<br> • GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;<br> • V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;<br> • преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Брентуксимаб:</h3> <p style="text-align: justify;"> • доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Брентуксимаб+бендамустин:</h3> <p style="text-align: justify;"> • брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;<br> • бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Редукция доз химиопрепаратов при почечной недостаточности:</h3> <p style="text-align: justify;"> Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.<br> • блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина &lt;10 мл/мин – 50% дозы;<br> • доксорубицин: коррекция дозы не проводится;<br> • винбластин/винкристин: коррекция дозы не проводится;<br> • дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина &lt;30 мл/мин – 70% дозы;<br> • прокарбазин: клиренс креатинина &lt;50 мл/мин – 50% дозы;<br> • циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;<br> • этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина &lt;15 мл/мин – 50% дозы;<br> • цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина &lt;45 мл/мин – выбор альтернативной схемы;<br> • карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина &lt;20 мл/мин - выбор альтернативной схемы;<br> • цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина &lt;45мл/мин – выбор альтернативной схемы;<br> • ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина &lt;45мл/мин – выбор альтернативной схемы;<br> • гемцитабин: клиренс креатинина &lt;30 мл/мин – нет редукции или 75% дозы;<br> • винорельбин: коррекция дозы не проводится;<br> • бендамутин: коррекция дозы не проводится. </p> <h3 style="text-align: justify;">Сопроводительная терапия:</h3> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">ABVD/AVD:</h3> <p style="text-align: justify;"> • Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;<br> • Ондасетрон 8 мг в дни введения химиопрепаратов;<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;<br> • Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;<br> • Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам. </p> <h3 style="text-align: justify;">BEACOPP14/BEACOPPesc:</h3> <p style="text-align: justify;"> • Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">DHAP:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации<br> • Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">ICE:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации<br> • уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">IGEV:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;<br> • Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.<br> Брентуксимаб+бендамустин:<br> • Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;<br> • Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">Условия коррекции сроков начала следующего курса:</h3> <p style="text-align: justify;"> Начало следующего курса может быть отложено в случае:<br> • Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);<br> • Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);<br> • Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок &gt;70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;<br> • Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома. </p> <h2 style="text-align: justify;">24. СПИСОК ЛИТЕРАТУРЫ</h2> <p style="text-align: justify;"> 1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.<br> 2. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014 Sep;9(3):222-226.<br> 3. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395.<br> 4. Eich HT, Diehl V, Görgen H et al. Intensified chemotherapy and dose-reduced involved-fi eld radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: fi nal analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-4206.<br> 5. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.<br> 6. Merli F, Luminari S, Gobbi PG et al. Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi. J Clin Oncol. 2016;34(11):1175-1181.<br> 7. Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.<br> 8. Borchmann P, Haverkamp H, Diehl V et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.<br> 9. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.<br> 10. Engert A, Plütschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.<br> 11. Meyer RM, Gospodarowicz MK, Connors JM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012; 366(5):399-408.<br> 12. Eichenauer DA, Engert A. 2012; Advances in the treatment of Hodgkin lymphoma. Int J Hematol 96:535–543.<br> 13. Johnson P, Federico M, Kirkwood A et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med. 2016;374(25):2419-2429.<br> 14. Engert A. ABVD or BEACOPP for Advanced Hodgkin Lymphoma. J Clin Oncol. 2016;34(11):1167-1169<br> 15. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.<br> 16. Press OW, Li H, Schöder H et al. US Intergroup Trial of Response-Adapted Th erapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.<br> 17. Andreas Engert,Sandra J. Horning. 2011; Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics. Springer-Verlag, Berlin.<br> 18. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.<br> 19. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.<br> 20. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant. 1999;23(6):561-567.<br> 21. Satwani P, Ahn KW, Carreras J et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015;50(11):1416-1423.<br> 22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.<br> 23. Cheson BD, Pfi stner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-586.<br> 24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(41176) "

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP, бендамустин + брентуксимаб 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере, ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.
Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png
Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.
• Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.
• При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.
• При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.
• При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии.

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере,
ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК:

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.

23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов

Схемы химиотерапии.

Курс полихимиотерапии ABVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии AVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии BEACOPP-14:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP-14 с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии DHAP:

• D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;
• HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;
• P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии ICE:

• I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;
• С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии IGEV:

• I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла.

Брентуксимаб:

• доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла.

Брентуксимаб+бендамустин:

• брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла.

Редукция доз химиопрепаратов при почечной недостаточности:

Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.
• блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина <10 мл/мин – 50% дозы;
• доксорубицин: коррекция дозы не проводится;
• винбластин/винкристин: коррекция дозы не проводится;
• дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина <30 мл/мин – 70% дозы;
• прокарбазин: клиренс креатинина <50 мл/мин – 50% дозы;
• циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;
• этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина <15 мл/мин – 50% дозы;
• цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина <45 мл/мин – выбор альтернативной схемы;
• карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина <20 мл/мин - выбор альтернативной схемы;
• цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• гемцитабин: клиренс креатинина <30 мл/мин – нет редукции или 75% дозы;
• винорельбин: коррекция дозы не проводится;
• бендамутин: коррекция дозы не проводится.

Сопроводительная терапия:

ABVD/AVD:

• Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;
• Ондасетрон 8 мг в дни введения химиопрепаратов;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;
• Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;
• Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам.

BEACOPP14/BEACOPPesc:

• Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

DHAP:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

ICE:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

IGEV:

• Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;
• Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.
Брентуксимаб+бендамустин:
• Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;
• Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

Условия коррекции сроков начала следующего курса:

Начало следующего курса может быть отложено в случае:
• Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок >70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;
• Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома.

24. СПИСОК ЛИТЕРАТУРЫ

1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.
2. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014 Sep;9(3):222-226.
3. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395.
4. Eich HT, Diehl V, Görgen H et al. Intensified chemotherapy and dose-reduced involved-fi eld radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: fi nal analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-4206.
5. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.
6. Merli F, Luminari S, Gobbi PG et al. Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi. J Clin Oncol. 2016;34(11):1175-1181.
7. Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.
8. Borchmann P, Haverkamp H, Diehl V et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.
9. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.
10. Engert A, Plütschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.
11. Meyer RM, Gospodarowicz MK, Connors JM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012; 366(5):399-408.
12. Eichenauer DA, Engert A. 2012; Advances in the treatment of Hodgkin lymphoma. Int J Hematol 96:535–543.
13. Johnson P, Federico M, Kirkwood A et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med. 2016;374(25):2419-2429.
14. Engert A. ABVD or BEACOPP for Advanced Hodgkin Lymphoma. J Clin Oncol. 2016;34(11):1167-1169
15. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.
16. Press OW, Li H, Schöder H et al. US Intergroup Trial of Response-Adapted Th erapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
17. Andreas Engert,Sandra J. Horning. 2011; Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics. Springer-Verlag, Berlin.
18. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.
19. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
20. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant. 1999;23(6):561-567.
21. Satwani P, Ahn KW, Carreras J et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015;50(11):1416-1423.
22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
23. Cheson BD, Pfi stner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-586.
24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf.

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Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP, бендамустин + брентуксимаб 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере, ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.
Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png
Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.
• Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.
• При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.
• При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.
• При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии.

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере,
ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК:

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.

23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов

Схемы химиотерапии.

Курс полихимиотерапии ABVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии AVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии BEACOPP-14:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP-14 с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии DHAP:

• D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;
• HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;
• P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии ICE:

• I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;
• С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии IGEV:

• I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла.

Брентуксимаб:

• доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла.

Брентуксимаб+бендамустин:

• брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла.

Редукция доз химиопрепаратов при почечной недостаточности:

Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.
• блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина <10 мл/мин – 50% дозы;
• доксорубицин: коррекция дозы не проводится;
• винбластин/винкристин: коррекция дозы не проводится;
• дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина <30 мл/мин – 70% дозы;
• прокарбазин: клиренс креатинина <50 мл/мин – 50% дозы;
• циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;
• этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина <15 мл/мин – 50% дозы;
• цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина <45 мл/мин – выбор альтернативной схемы;
• карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина <20 мл/мин - выбор альтернативной схемы;
• цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• гемцитабин: клиренс креатинина <30 мл/мин – нет редукции или 75% дозы;
• винорельбин: коррекция дозы не проводится;
• бендамутин: коррекция дозы не проводится.

Сопроводительная терапия:

ABVD/AVD:

• Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;
• Ондасетрон 8 мг в дни введения химиопрепаратов;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;
• Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;
• Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам.

BEACOPP14/BEACOPPesc:

• Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

DHAP:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

ICE:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

IGEV:

• Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;
• Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.
Брентуксимаб+бендамустин:
• Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;
• Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

Условия коррекции сроков начала следующего курса:

Начало следующего курса может быть отложено в случае:
• Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок >70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;
• Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома.

24. СПИСОК ЛИТЕРАТУРЫ

1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.
2. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014 Sep;9(3):222-226.
3. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395.
4. Eich HT, Diehl V, Görgen H et al. Intensified chemotherapy and dose-reduced involved-fi eld radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: fi nal analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-4206.
5. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.
6. Merli F, Luminari S, Gobbi PG et al. Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi. J Clin Oncol. 2016;34(11):1175-1181.
7. Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.
8. Borchmann P, Haverkamp H, Diehl V et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.
9. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.
10. Engert A, Plütschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.
11. Meyer RM, Gospodarowicz MK, Connors JM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012; 366(5):399-408.
12. Eichenauer DA, Engert A. 2012; Advances in the treatment of Hodgkin lymphoma. Int J Hematol 96:535–543.
13. Johnson P, Federico M, Kirkwood A et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med. 2016;374(25):2419-2429.
14. Engert A. ABVD or BEACOPP for Advanced Hodgkin Lymphoma. J Clin Oncol. 2016;34(11):1167-1169
15. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.
16. Press OW, Li H, Schöder H et al. US Intergroup Trial of Response-Adapted Th erapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.
17. Andreas Engert,Sandra J. Horning. 2011; Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics. Springer-Verlag, Berlin.
18. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.
19. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
20. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant. 1999;23(6):561-567.
21. Satwani P, Ahn KW, Carreras J et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015;50(11):1416-1423.
22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
23. Cheson BD, Pfi stner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-586.
24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf.

" } } } }
Volume 6, Number 4
12/27/2017 10:03:02 pm
Volume 6, Number 4
Editor-in-Chief
Afanasyev B. V. (St. Petersburg, Russia)
Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A.R. (Hamburg, Germany)
Deputy Editor
Fehse B. (Hamburg, Germany)
Managing Editor
Chukhlovin A. B. (St. Petersburg, Russia)
Editorial Board
Aleynikova O. V. (Minsk, Belarus)
Borset M. (Trondheim, Norway)
Chechetkin A. V. (St. Petersburg, Russia)
Fibbe W. (Leiden, Netherlands)
Galibin O. V. (St. Petersburg, Russia)
Hölzer D. (Frankfurt a.M., Germany)
Klimko N. N. (St. Petersburg, Russia)
Kolb H.-J. (München, Germany)
Kröger N. (Hamburg, Germany)
Kulagin A. D. (St. Petersburg, Russia)
Lange C. (Hamburg, Germany)
Mamaev N. N. (St. Petersburg, Russia)
Mikhailova N. B. (St. Petersburg, Russia)
Moiseev I. S. (St. Petersburg, Russia)
Nagler A. (Tel-Aviv, Israel)
Nemkov A. S. (St. Petersburg, Russia)
Paramonov I. V. (Kirov, Russia)
Roumiantsev A. G. (Moscow, Russia)
In this Issue

Current issue begins with a review article by Prof. Rüdiger Hehlmann dedicated to modern strategies of chronic myeloid leukemia treatment (CML) and the role of HSCT, which suffi ciently changed upon introduction of tyrosine kinase inhibitors. His considerations are mostly based on the results of the big CML Study IV, concerning imatinib dosage, or combined therapy with imatinib and cytarabine or interferon α in newly diagnosed patients in chronic phase. The issues of stopping imatinib therapy are discussed.

In his article, Prof. Axel R.Zander considers indications for HSCT in a clinically heterogenous group of chronic myeloproliferative diseases. Distinct molecular defects discovered over last decades are now subjected to specifi c targeted therapy which provides long-term remission states in most patients with chronic myeloid leukemia, primary myelofibrosis, however, using allogeneic HSCT in advanced and high-risk cases.

Some controversies occurring during selection of acute myeloblastic leukemia patients for alo-HSCT are critically evaluated by Prof. Robert P. Gale. To his opinion, the previously used and newer statistic approaches are not accurate enough to predictably discriminate high-risk patients, even if based on the known risk factors of the patients and individual tumor biology.

Dr. Marina O. Popova et al., describe their clinical experience with HIV-infected lymphoma patients treated by autologous HSCT, survival and relapse rate at 12 months aft er transplantation. The matched case-control study was performed at a single institution, (CIC725 EBMT center) designed to prospectively evaluate the safety and efficiency of ASCT for the patients with HIV-related lymphoma.

Another original article is presented by Dr. Ivan S. Moiseev and co-authors, being dedicated to intensively studied cyclophosphamide (Cy) treatment for the graft -versus-host disease. Its comparison with calcineurin inhibitor-based prophylaxis shows distinct benefi t of Cy therapy with respect to the main clinical HSCT outcomes and results.

A clinical case of common variable immunodefi ciency (CVID) and the main approaches to its diagnostics are described in a report by Dr. Andrey V. Kozlov et al. A number of immunological and genetic tests were performed, including new-generation sequencing provided several recognized clinical criteria for the CVID diagnostics.

The items discussed in the article by Prof. Alexander S. Nemkov and Yi Zhang concern probable role of endothelial dysfunction in cardiac disease and potential long-term favorable effects of intracoronary administration of the bone marrow mononuclear cells.

T is CTT issue also contains a synopsis of Regional clinical protocol for Hodgkin’s disease treatment using PET-assisted control and novel targeted drugs (Boris V. Afanasyev et al.). This protocol is endorsed by the leading clinical specialists from St. Petersburg.

For Russian readers, the full text of the multicenter observational program for the North-Western Russia is published in Russian language as well.

Editorial article

Editorial article
Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation
Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal
Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal

Comment

Review articles

Clinical studies

Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of a single center (CIC725) matched case-control study
Marina O. Popova, Yulia A. Rogacheva, Anastasia V. Nekrasova, Ivan V. Tsygankov, Ali Basahel, Kirill V. Lepik, Olga V. Pirogova, Elena I. Darskaya, Lilia V. Stelmakh, Yurii R. Zalyalov, Ivan S. Moiseev, Sergey N. Bondarenko, Natalia B. Mikhailova, Boris V. Afanasyev
Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation
Ivan S. Moiseev1,2, Olga V. Pirogova1, Elena V. Babenko1, Tatyana L. Gindina1, Elena I. Darskaya1, Elena V. Morozova1,2, Sergey N. Bondarenko1, Boris V. Afanasyev1,2

Case report

Common variable immunodeficiency in a child. A case report
Andrey V. Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev

Experimental studies

Clinical trials

Multicenter prospective escalation-deescalation PET-guided clinical study in classical type Hodgkin disease in the North-West of Russian Federation (RNWOHG-HD1): rationale and design
Study authors: Boris V. Afanasyev1, Ivan S. Moiseev1, Sergey M. Alekseev2, Natalia B. Mikhailova1, Elena V. Kondakova1, Nikolai V. Ilyin3, Alexey M. Belyaеv2 Chief scientifi c advisors: Boris V. Afanasyev1, Sergey M. Alekseev2, Ivan S. Moiseev1 Supervisory board: Alexey M. Belyaеv2, Andrey Yu. Zaritskey4, Nikolai V. Ilyin3, Natalia B. Mikhailova1,
Nadejda V. Medvedeva5, Georgii M. Manikhas6, Sergey V. Voloshin7, Vladimir M. Moiseenko8, Tatyana V. Shneider9

Clinical protocol

Editorial article

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 Профессор Аксель Р. Цандер, Со-редактор журнала СТТ (Германия)<br>
 Профессор Герард Вагемакер, Со-редактор журнала СТТ (Нидерланды)<br>
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Профессор Аксель Р. Цандер, Со-редактор журнала СТТ (Германия)
Профессор Герард Вагемакер, Со-редактор журнала СТТ (Нидерланды)
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Уважаемые авторы и рецензенты журнала СТТ!
Прежде всего, мы бы хотели выразить нашу глубокую благодарность за ваш труд по подготовке и отправке статей в наш журнал, а также за рецензирование рукописей, что обеспечило важную поддержку журналу СТТ за прошедшие годы. Кроме того, редакторы журнала выражают надежду на то, что это сотрудничество будет со временем усиливаться, расширяя участие российских и зарубежных специалистов, публикующих свои данные в СТТ.
Публикация в этом журнале дает хорошую возможность для российских и иностранных специалистов публиковать исследования на английском языке, цитируемые в базе данных Scopus. Журнал обеспечивает быстрое и адекватное рецензирование, языковое редактирование и резюме на русском языке, расширяющие аудиторию читателей.
Журнал ориентирован, прежде всего, на преклинические и клинические аспекты клеточной терапии и трансплантации. Несмотря на множество таргетных препаратов, внедренных в клинику за последние годы, например модуляторов PD-1, ингибиторов киназ, моноклональных антител, новые подходы к генной терапии, изменившие горизонты терапии в онкогематологии, роль аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК) не снижается, а быстро растет, поскольку для многих пациентов эта процедура становится пригодной из-за улучшения статуса заболевания после таргетной терапии, и при этом у большего числа больных можно достичь долгосрочного контроля заболевания благодаря специфической профилактике или циторедуктивной стратегии после трансплантации.
Таким образом, журнал охотно принимает статьи, касающиеся различных способов улучшения исхода ТГСК,включая до- и посттрансплантационную терапию, режимы кондиционирования и профилактику реакции «трансплантат против хозяина».
Другой задачей журнала является описание преклинических исследований, поскольку ТГСК сейчас становится основой для генной терапии, стратегий доставки препаратов и иммунотерапии. Мы охотно примем результаты исследований на моделях in vitro, где оценивается эффективность генного редактирования, иммунологические аспекты противораковой терапии и новые подходы к доставке противоопухолевых препаратов.
Итак, мы желаем вам многих успехов в ваших исследованиях, более тесного сотрудничества с российскими коллегами и журналом СТТ, который готов публиковать новые и оригинальные результаты в области клинической и экспериментальной клеточной терапии.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 19960 [VALUE] => 10.18620/ctt-1866-8836-2017-6-4-10-12 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.18620/ctt-1866-8836-2017-6-4-10-12 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19961 [VALUE] => Array ( [TEXT] => Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation<br> Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal<br> Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation
Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal
Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19962 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Dear CTT authors and reviewers,<br> First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.<br> Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.<br> The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.<br> Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.<br> Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Dear CTT authors and reviewers,
First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.
Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.
The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.
Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.
Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy.

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Editorial article

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Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Th erapy and Transplantation
Professor Axel R. Zander (Germany), Co-Editor-in Chief, CTT Journal
Professor Gerard Wagemaker (Netherlands), Co-Editor-in Chief, CTT Journal

Dear CTT authors and reviewers,
First of all, we would like to express our deep gratitude for your work on preparing and submitting your papers to our Journal as well as for reviewing the submissions, thus providing an important support to the CTT Journal over last years. Moreover, the Editors express a hope that this co-operation will be more advanced with time, expanding the membership of specialists publishing their data in CTT, both from Russia and abroad.
Publication in this journal is a great opportunity for the Russian as well as international specialists to publish Scopuscited research in English. The Journal provides fast and adequate peer reviewing, language editing and summaries in Russian to broaden the readers’ audience.
The Journal focuses on both preclinical and clinical aspects of cellular therapy and transplantation. In spite of numerous targeted drugs implemented over last years, e.g., PD-1 modulators, novel kinase inhibitors, monoclonal antibodies, gene therapy approaches, which have now changed the therapeutic landscape in hematology/oncology, the role of allogeneic hematopoietic stem cell transplantation (HSCT) is not diminishing, but rapidly growing, because more patients become eligible due to improvement of the disease status after targeted therapy, and more patients have long-term disease control due to disease-specifi c prophylaxis or pre-emptive strategies aft er transplantation. Thus the Journal welcomes articles addressing various aspects of improving the outcome after HSCT, including pre- and post-transplant therapy, conditionin regimens, and graft -versus-host-disease prophylaxis.
Another focus of the journal is on preclinical studies, because HSCT is now becoming the backbone of gene therapy, drug delivery strategies and immunotherapy. We welcome the researchers with their results on in vitro models that evaluate the efficacy of gene editing, immunological aspects of cancer therapy and novel approaches to antineoplastic drug delivery.
Hence, we wish much success in your studies, being in more close cooperation with Russian colleagues and the CTT Journal, which is ready to publish novel and original results in clinical and experimental cellular therapy.

Comment

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В статье обсуждается многообразие факторов, влияющих на отбор пациентов с острым миелобластным лейкозом (ОМЛ) для трансплантации гемопоэтических клеток. Чтобы уточнить расчеты вероятности рецидива в 1-й ремиссии ОМЛ, оцениваются соответствующие прогностические и предиктивные переменные величины, например, применяется построение и анализ кривых ROC с точностью, выражаемой в виде конкордантности или С-статистики. Вопрос состоит в том, за счет чего возникает остающаяся необъяснимой изменчивость результатов. У нее есть 3 источника: (1) неизвестные, но потенциально выявляемые (скрытые) переменные; (2) ошибка измерений; и (3) случайность. Поэтому мы не можем сейчас с достаточной точностью предсказать, у кого из больных разовьется рецидив.
Например, результаты тестирования минимальной остаточной болезни ассоциированы примерно с 30% ложно-позитивных и ложно-негативных ответов. Также невозможно заключить о том, есть ли выгода от проведения трансплантации до рецидива, или же ждать развития рецидива, а потом выполнять трансплантацию по необходимости. Некоторые из этих посылок нужно доказать в рандомизированных клинических исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, острый миелобластный лейкоз, риск рецидива, выбор лечения, статистика, ROC-анализ.

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Keywords

Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis. [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Description / Summary [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [NAME_EN] => Array ( [ID] => 40 [TIMESTAMP_X] => 2015-09-03 10:49:47 [IBLOCK_ID] => 2 [NAME] => Name [ACTIVE] => Y [SORT] => 500 [CODE] => NAME_EN [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 40 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => Y [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 19967 [VALUE] => Transplants for аcute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Transplants for аcute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us [~DESCRIPTION] => [~NAME] => Name [~DEFAULT_VALUE] => ) [FULL_TEXT_RU] => Array ( [ID] => 42 [TIMESTAMP_X] => 2015-09-07 20:29:18 [IBLOCK_ID] => 2 [NAME] => Полный текст [ACTIVE] => Y [SORT] => 500 [CODE] => FULL_TEXT_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 42 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Полный текст [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [PDF_RU] => Array ( [ID] => 43 [TIMESTAMP_X] => 2015-09-09 16:05:20 [IBLOCK_ID] => 2 [NAME] => PDF RUS [ACTIVE] => Y [SORT] => 500 [CODE] => PDF_RU [DEFAULT_VALUE] => [PROPERTY_TYPE] => F [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 43 [FILE_TYPE] => doc, txt, rtf, pdf [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 19974 [VALUE] => 1063 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 1063 [~DESCRIPTION] => [~NAME] => PDF RUS [~DEFAULT_VALUE] => ) [PDF_EN] => Array ( [ID] => 44 [TIMESTAMP_X] => 2015-09-09 16:05:20 [IBLOCK_ID] => 2 [NAME] => PDF ENG [ACTIVE] => Y [SORT] => 500 [CODE] => PDF_EN [DEFAULT_VALUE] => [PROPERTY_TYPE] => F [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 44 [FILE_TYPE] => doc, txt, rtf, pdf [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 19975 [VALUE] => 1064 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 1064 [~DESCRIPTION] => [~NAME] => PDF ENG [~DEFAULT_VALUE] => ) [NAME_LONG] => Array ( [ID] => 45 [TIMESTAMP_X] => 2023-04-13 00:55:00 [IBLOCK_ID] => 2 [NAME] => Название (для очень длинных заголовков) [ACTIVE] => Y [SORT] => 500 [CODE] => NAME_LONG [DEFAULT_VALUE] => Array ( [TYPE] => HTML [TEXT] => ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 45 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 80 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Название (для очень длинных заголовков) [~DEFAULT_VALUE] => Array ( [TYPE] => HTML [TEXT] => ) ) )
Transplants for аcute myeloid leukaemia in 1st remission: statisticians, magicians and the rest of us

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Robert P. Gale MD, PhD DSc(hc), FACP, FRSM

Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK SW7 2AZ
The article concerns multiple factors infl uencing selection of patients with acute myeloid leukemia (AML) for hematopoietic stem cell transplantation. A number of prognostic and predictive variables may determine better probability of AML relapse, i.e., ROC analysis, thus allowing more accurate evaluation expressed in terms of concordance, or C-statistics. Th e fi nal results are, however, subject to unexplainable variance.

Keywords

Hematopoietic stem cell transplantation, acute myeloid leukemia, relapse risk, treatment options, statistics, ROC analysis.

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[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20000 [VALUE] => Array ( [TEXT] => <sup>1</sup>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский<br> государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup>Университетский госпиталь Тампере, Финляндия [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => 1НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский
государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
2Университетский госпиталь Тампере, Финляндия [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20001 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.<br> В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Ранний и тяжелый иммунодефицит развивается после циторедуктивной терапии злокачественных новообразований, особенно после кондиционирующей терапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Восстановление иммунного ответа после трансплантации происходит медленно, особенно в субпопуляциях лимфоцитов. В более поздние сроки иммуносупрессивные препараты способствуют поддержанию состояния иммунного дефицита. Поэтому после ТГСК отмечается активация различных эндогенных инфекций. В большинстве случаев инфекционные осложнения здесь вызываются оппортунистическими микроорганизмами (бактериями, грибами или вирусами), которые в норме заселяют кожные покровы, слизистые и др.). После трансплантации, их пролиферация и миграция может возникать в зонах, которые в норме не вовлечены в инфекционный процесс (сосудистый кровоток, бронхоальвеолярные зоны, мочевые пути, дермальные структуры кожи, лимфоузлы и др.). Таким образом, ранняя посттрансплантационная активация латентных патогенов может определяться в периферической крови, спинно-мозговой жидкости, бронхоальвеолярных смывах, ротовой жидкости, моче и других биологических материалах, которые в норме защищены иммунными факторами. Число видов инфекционных агентов у данного пациента также коррелирует c более высокой смертностью трансплантационных больных.
В связи с этим, диагностика обычно применяемых маркеров иммунодефицита после интенсивной циторедуктивной терапии может быть дополнена выявлением оппортунистических инфекций в тех биоматериалах, которые обычно не инфицированы ими (периферическая кровь, ротовая жидкость, моча) а также на пораженных слизистых (мокрота, бронхиальные смывы, спинномозговая жидкость). Разработаны несколько валидированных диагностических панелей, основанные, главным образом, на мультиплексной ПЦР для того, чтобы выявить и определить число маркерных микроорганизмов (вирусов, грибов и бактерий) у пациента. Их можно применять для более точной оценки глубины иммунного дефицита.

Ключевые слова

Циторедуктивная терапия, иммунодефицит, бактерии, вирусы, активация, экспансия, множественные инфекции, маркерные микроорганизмы.

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2Tampere University Hospital, Tampere, Finland [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20005 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.<br> Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms. </p> <h2 style="text-align: justify;"></h2> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.
Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade.

Keywords

Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms.

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Opportunistic microflora at unusual sites: marker pathogens in severe posttransplant immune deficiency

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Alexey B. Chukhlovin1, Olga S. Pankratova2

1R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, Th e First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
2Tampere University Hospital, Tampere, Finland

Early severe immune suppression occurs aft er cytoreductive cancer treatment, especially, following conditioning therapy and hematopoietic stem cell transplantation (HSCT). Posttransplant recovery of immune response proceeds slowly, in particular, for the lymphocyte subsets. At later terms, immunosuppressive drugs promote the immune defi ciency state. Therefore, HSCT is associated with activation of diff erent endogenous infections. In most instances, the infectious complications are caused by opportunistic microorganisms (bacteria, fungi and viruses) which normally inhabit skin, mucosae etc. Th eir post-treatment proliferation and migration may occur to normally non-involved body areas (blood flow, bronchoalveolar areas, urinary pathways, skin dermal layers, lymph nodes, etc.). Hence, the early posttransplant activation of latent pathogens may be detected in peripheral blood, cerebrospinal fluid, ronchoalveolar lavage, saliva, urine and other samples being normally protected by immune system. The number of infectious species found in the same patient also correlates with higher posttransplant mortality.
Therefore, diagnostics of common immune defi ciency markers aft er intensive cytoreductive chemotherapy could be combined with a search for opportunistic infections at the normally non-infected sites (peripheral blood, saliva, urine) as well as aff ected mucosal surfaces (sputum, bronchial secretions, cerebrospinal fl uid). Several validated diagnostic panels (mostly multiplex PCR) were developed, in order to detect and assess number of infectious markers (viral, fungal and bacterial) in the patient. Th ey could be applied for more specific evaluation of immune defi ciency grade.

Keywords

Cytoreductive therapy, immune defi ciency, bacteria, viruses, activation, expansion, multiple infections, marker microorganisms.

Review articles

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Значительная часть аллогенных трансплантаций гемопоэтических стволовых клеток (алло-ТГСК) сейчас проводится по поводу миелодиспластического синдрома или миелопролиферативных заболеваний, тогда как хронический миелоидный лейкоз (ХМЛ) лечат, в основном, ингибиторами тирозинкиназ (ИТК). В некоторых особых ситуациях, есть следующие причины для алло-ТГСК при ХМЛ: токсичность препаратов ИТК, резистентность к обычной лекарственной терапии и прогрессия болезни (фаза акселерации или бластный криз). Однако повышения выживаемости без прогрессии можно добиться в продвинутой фазе ХМЛ после гаплоидентичной ТГСК, по сравнению с пересадкой от HLA-совместимого родственного или неродственного донора.
При планировании терапии первичного миелофиброза (ПМФ) следует учитывать различия в клиническом течении заболевания, применяя, например, Лилльскую систему оценок, которая дает прогностические критерии, а также молекулярно-генетические маркеры, в особенности, гиперэкспрессию гена JAK2, что дает основания к применению рук солитиниба. Алло-ТГСК может излечивать больных с ПМФ при трансформации его в лейкоз. В случаях рецидива, вторая алло-ТГСК или инфузия лимфоцитов донора может привести к удлинению продолжительности жизни пациентов.
Результаты терапии больных с хроническим миеломоноцитарным лейкозом, леченных алло-ТГСК, зависят от оценок их клинического риска до пересадки. Пациенты, трансплантированные в полной ремиссии, имеют большую длительность общей и безрецидивной выживаемости. Раннее выполнение трансплантации коррелирует с более высокими цифрами выживаемости пациентов. В случаях атипичного ХМЛ следует проводить раннюю трансплантацию. Алло-ТГСК является методом выбора при обширном системном мастоцитозе. Она проводится в случаях, ассоциированных с вовлечением других клеток, кроме мастоцитов, при агрессивном системном мастоцитозе и при мастоцитарной форме лейкоза.

Ключевые слова

Миелопролиферативные заболевания, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназ, хронический миелоидный лейкоз, первичный миелофиброз, хронический миеломоноцитарный лейкоз, системный мастоцитоз.

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Zander [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Axel R. Zander [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19992 [VALUE] => Array ( [TEXT] => Huntsman Cancer Institute, University of Utah, USA [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Huntsman Cancer Institute, University of Utah, USA [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 19997 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> A sufficient part of allo-HSCT is now performed for myelodysplastic syndromes and myeloproliferative neoplasms (MPN), whereas chronic myeloid leukemia is mostly treated by tyrosine kinase inhibitors (TKI). In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.<br> When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.<br> Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis. </p> <h2 style="text-align: justify;"></h2> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

A sufficient part of allo-HSCT is now performed for myelodysplastic syndromes and myeloproliferative neoplasms (MPN), whereas chronic myeloid leukemia is mostly treated by tyrosine kinase inhibitors (TKI). In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.
When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.
Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia.

Keywords

Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis.

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Stem cell transplantation for myeloproliferative diseases in the era of molecular therapy

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Axel R. Zander

Huntsman Cancer Institute, University of Utah, USA

A sufficient part of allo-HSCT is now performed for myelodysplastic syndromes and myeloproliferative neoplasms (MPN), whereas chronic myeloid leukemia is mostly treated by tyrosine kinase inhibitors (TKI). In some special situations, the reasons for allo-SCT in CML are as follows: TKI toxicity; resistance to common drug therapy, and advanced disease (accelerated phase or blast crisis). However, an improvement in progression-free survival may be obtained in advanced CML aft er haploidentical allo-HSCT versus graft ing from HLA-matched related/unrelated donors.
When planning therapy of primary myelofi brosis, one should take into account variable clinical course of the disease using, e.g., Lille scoring system which provides some prognostic criteria, molecular genetic markers, especially, overexpression of JAK2 gene thus allowing usage of ruxolitinib. Allo-SCT can cure myelofi brosis patients transformed to leukemia. In cases of relapse, a 2nd allo-HSCT or donor lymphocyte infusion may result into prolonged survival of the patients.
Results in chronic myelomonocytic leukemia patients treated with allo-HSCT depend on the pre-transplant risk scores. Patients transplanted in CR had signifi cantly longer relapse-free survival and signifi cantly longer overall survival. Early transplants were associated with higher survival rates. In cases of atypical CML, early allogeneic transplant should be performed. Allo-SCT is a method of choice in advanced systemic mastocytosis. It is performed in cases associated with non-mast cell involvement; in aggressive systemic mastocytosis, and in mast cell leukemia.

Keywords

Myeloproliferative disorders, allogeneic hematopoietic stem cell transplantation, tyrosine kinase inhibitors, chronic myeloid leukemia, primary myelofi brosis, chronic myelomyelocytic leukemia, systemic mastocytosis.

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	 Стратегия лечения хронического миелолейкоза (ХМЛ) сильно изменилась после внедрения иматиниба – ингибитора тирозинкиназы (ИТК). Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.<br>
	 В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
	 Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость.
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Стратегия лечения хронического миелолейкоза (ХМЛ) сильно изменилась после внедрения иматиниба – ингибитора тирозинкиназы (ИТК). Эти препараты стали часто применяться для первой линии лечения при ХМЛ вместо аллогенной трансплантации гемопоэтических стволовых клеток (ТГСК). При выборе ИТК в качестве терапии первой линии учитывают следующие факторы: оценка риска для больного по принятой шкале, цитогенетические маркеры со значимыми дополнительными хромосомными аномалиями (ДХА) при постановке диагноза, а также ДХА высокого риска в процессе развития ХМЛ, сопутствующие заболевания, расходы на лечение. В случаях отсутствия ответа на иматиниб, рассматриваются возможности 2-й линии терапии, с учетом показателей клинического ответа на лечение, соблюдения режима лечения, мутаций, ведущих к лекарственной устойчивости, клональной эволюции лейкоза, непереносимости данного лечения, типа лечебного учреждения.
В программе CML IV, рандомизированном исследовании, направленном на оптимизацию дозы иматиниба и эффектов сочетанной терапии иматиниба с цитарабином или интерфероном α, участвовали 1551 свежевыявленных пациентов в хронической фазе ХМЛ. Основным результатом было отсутствие какого-либо преимущества любого из применявшихся методов лечения. Иматиниб в дозе 400 мг обеспечивает близкую к норме ожидаемую продолжительность жизни у больных с ХМЛ в хронической фазе. Выживаемость пациентов независима от времениответа. Клинические исходы ХМЛ теперь определяются скорее факторами заболевания и особенностями пациентов, например – сопутствующими заболеваниями и курением, а также подходом конкретных медицинских центров, нежели выбором тактики первичного лечения. Сравнение долгосрочной выживаемости после ТГСК или лечения иматинибом показало, что больные из группы низкого риска имели сходную выживаемость при обоих вариантах лечения. Попытки улучшения терапии, например, с применением ТГСК должны быть сосредоточены на группах рефрактерных пациентов, а также на показателях выживаемости, не связанных с ХМЛ. После прогрессии в бластный криз ТГСК не обеспечивает существенного преимущества в выживаемости, хотя специальное исследование показало, что наиболее долгоживущие пациенты (72%) были леченными посредством ТГСК. 70% – 80% частота 10-летней глубокой молекулярной ремиссии указывает на то, что большинство больных, леченых иматинибом, являются кандидатами на прекращение терапии.

Ключевые слова

Хронический миелоидный лейкоз, ингибиторы тирозинкиназы, иматиниб, стратегия лечения, трансплантация гемопоэтических клеток, выживаемость.

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TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.<br> CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

With introduction of the tyrosine kinase inhibitor (TKI) imatinib, the treatment strategy of CML has profoundly changed. TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.
CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation.

Keywords

Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival.

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Long-term survival with CML with imatinib or transplantation as first-line treatment: Comparison of outcomes from CML Studies IIIA and IV

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Rüdiger Hehlmann

Mannheim Medical Faculty, Heidelberg University

With introduction of the tyrosine kinase inhibitor (TKI) imatinib, the treatment strategy of CML has profoundly changed. TKIs became the fi rst-line treatment of choice for CML competing with allogeneic hematopoietic stem cell transplantation (HCT). Variables to be considered in choosing TKIs for fi rst-line therapy are as follows: conventional risk score; cytogenetic fi ndings with majorroute additional chromosomal aberrations (ACA) at diagnosis, and high-risk ACA in the course of CML; comorbidities; treatment costs. In cases of refractoriness to imatinib, the 2nd line treatment options are: clinical response milestones; adherence to therapy; resistance mutations; clonal evolution; therapy intolerance; drug safety; health care setting.
CML Study IV, a randomized treatment study concerning imatinib dose optimization and combined therapy with imatinib and cytarabine or interferon α included 1551 newly diagnosed patients in chronic phase. The key outcome was no superiority of survival of any treatment option. Imatinib 400 mg provides close to normal life expectancy in chronic-phase CML patients. Survival is independent of time to response. Outcome of CML is currently more determined by disease and patients’ factors, e.g., comorbidities and smoking, and by center eff ects than by initial treatment selection. A comparison of long-term survival aft er HCT or imatinib treatment showed that low risk patients had similar survival with both options. Attempts at improving treatment should focus on subgroups of refractory disease e.g. by HCT, and on non-CML determinants of survival. After progression to blast crisis, HCT did not provide a signifi cant survival advantage, although a special study showed that most long-term survivors (72%) were patients who received a transplant. The 10-year deep molecular remission rates of 70%-80% indicate that the majority of imatinib-treated patients are candidates for treatment discontinuation.

Keywords

Chronic myeloid leukemia, tyrosine kinase inhibitors, imatinib, treatment strategy, hematopoietic stem cell transplantation, survival.

Clinical studies

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                    [TEXT] => Марина O. Попова, Юлия A. Рогачева, Анастасия В. Некрасова, Иван В. Циганков, Али Базахел, Кирилл В. Лепик, Ольга В. Пирогова, Елена И. Дарская, Лилия В. Стельмах, Юрий Р. Залялов, Иван С. Моисеев, Сергей Н. Бондаренко, Наталья Б. Михайлова, Борис В. Афанасьев<br>
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[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20012 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль». </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Пациенты, инфицированные вирусом иммунодефицита человека (ВИЧ) находятся в группе повышенного риска развития неходжскинских лимфом и лимфомы Ходжкина. При внедрении высокоактивной антиретровирусной терапии (ВААРТ) продемонстрировано, что аутологичная трансплантация стволовых клеток (ауто-ТГСК) является приемлемым, безопасный и эффективным методом лечения пациентов с лимфомами на фоне ВИЧ. Однако количество сравнительных исследований влияния статуса ВИЧ на результаты ауто-ТГСК ограничено. Мы представляем исследование, целью которого является оценить безопасность и эффективность высокодозной химиотерапии с ауто-ТГСК у пациентов с лимфомами на фоне ВИЧ. С января 2016 года выполнены ауто-ТГСК семи пациентам с ВИЧ-ассоциированными лимфомами. Для проведения сравнительного анализа, в исследование включены 28 пациентов с лимфомами без ВИЧ инфекции, которым выполнена ауто-ТГСК в тот же период времени (группа контроля, в соотношении 1:4). Проводилась сравнительная оценка общей 1-годичной выживаемости, восстановления кроветворения, токсичности, выживаемости без прогрессирования и кумулятивной частоты рецидивов/прогрессирования в течение одного года после ауто-ТГСК. Общая выживаемость в течение одного года после ауто-ТГСК у пациентов с ВИЧ-ассоциированными лимфомами составила 100%, выживаемость без прогрессирования – 85,7%, частота рецидивов – 14,3% и не отличалась от группы сравнения. При анализе токсичности и скорости восстановления кроветворения значимых различий в группах сравнения не обнаружено. Предварительные данные подтверждают, что ВИЧ статус не влияет на результаты ауто-ТГСК для лечения лимфом, и поэтому наличие ВИЧ-инфекции само по себе, не должно влиять на принятие решения о проведении высокодозной химиотерапии с аутологичной трансплантацией гемопоэтических стволовых клеток.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ВИЧ, ВИЧ-ассоциированные лимфомы, высокодозная химиотерапия, неходжкинские лимфомы, лимфома Ходжкина, сравнительное исследование «случай-контроль».

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[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20015 [VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantation, Th e St. Petersburg First State Medical I. Pavlov University (CIC725) [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantation, Th e St. Petersburg First State Medical I. Pavlov University (CIC725) [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20016 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials.

Keywords

Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study.

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Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of a single center (CIC725) matched case-control study

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Marina O. Popova, Yulia A. Rogacheva, Anastasia V. Nekrasova, Ivan V. Tsygankov, Ali Basahel, Kirill V. Lepik, Olga V. Pirogova, Elena I. Darskaya, Lilia V. Stelmakh, Yurii R. Zalyalov, Ivan S. Moiseev, Sergey N. Bondarenko, Natalia B. Mikhailova, Boris V. Afanasyev

R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantation, Th e St. Petersburg First State Medical I. Pavlov University (CIC725)

Human immunodefi ciency virus (HIV) infection is associated with an increased incidence of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Throughout the HAART era, autologous stem cell transplantation (ASCT) has been reported as a feasible, safe, and useful approach to either rescue or consolidate HIV-related lymphoma patients. However, the number of published comparative studies according to the HIV status is limited. Th e aim of the study was to estimate the early safety and effi cacy of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in HIV-related lymphoma. Since the Jan 2016 seven patients with HIV-related lymphoma who have undergone ASCT were included in the prospective singe centre study (study group – HIV group, n=7). T e data of the non-HIV-infected patients with lymphoma who have undergone ASCT at the same period of time (control group, n=28) were collected to compare the efficacy and safety of the procedure (ratio 1:4). Median follow up time was 12 (1-20) months in study group and 8 (1-20) months in control group. The primary endpoint was overall survival (OS) at 12 months after ASCT. Secondary end points were hematopoietic recovery and organ toxicity, progression free survival (PFS) and relapse rate at 12 months aft er ASCT. Here we report the early results of a single institution (EBMT center CIC725) matched case-control study. Th is was an observation trial designed to prospectively evaluate the safety and eff ectiveness of ASCT for patients with HIV-related lymphoma. One-year overall survival in patients with HIV-related lymphoma was 100%, the probability of PFS – 85,7%, relapse rate – 14,3% and did not diff er from the control group. There were not found statistical signifi cant diff erences between two groups in hematopoietic recovery and toxicity rate. Preliminary data provide further evidence that HIV status does not affect the outcome of ASCT for lymphoma, and therefore HIV status alone should no longer exclude these patients from transplant clinical trials.

Keywords

Autologous hematopoietic cell transplantation, HIV, HIV-related lymphoma, high-dose chemotherapy, non-Hodgkin lymphoma, Hodgkin lymphoma, matched case-control study.

Clinical studies

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 <sup>2</sup>Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия
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                    [TEXT] => 1НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой
2Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20023 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

В настоящий момент опубликован ряд исследований, показавших эффективность профилактики реакции «трансплантат против хозяина» (РТПХ) с использованием пост-трансплантационного циклофосфана в качестве единственного препарата (моноПТЦф) при HLA-совместимых трансплантациях костного мозга (ТКМ). Тем не менее, до сих пор не было опубликовано прямых сравнений эффективности моноПТЦф и классической профилактики с использованием ингибиторов кальциневрина (ИКН). В данном исследовании проведено сравнение результатов ТКМ у 78 пациентов, получавших профилактику РТПХ с использованием моноПТЦф, и 105 пациентов исторического контроля, получавших профилактику такролимусом/циклоспорином А и микофенолатом мофетилом/метотрексатом. Исследуемые группы были сравнимы по клиническим характеристикам, однако в группе с ИКН было больше пациентов группы «спасения» и больший процент пациентов с острым лимфобластным лейкозом. ПТЦф достоверно лучше предотвращал развитие острой РТПХ II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) и III-IV степени (HR 0.192, 95% CI 0.055-0.666, p=0.009), а также снижал вероятность рецидива (HR 0.519, 95% CI 0.297-0.893, p=0.023). Частота хронической РТПХ (HR 0.898, 95% CI 0.477-1.69, p=0.74) и трансплантационной летальности (HR 0.384, 95% CI 0.089-1.437, p=0.1768) достоверно не различались между группами. В группе пациентов с моноПТЦф наблюдалась достоверно более высокая общая выживаемость (HR 0.489, 95% CI 0.261-0.917, p=0.03), бессобытийная выживаемость (HR 0.571, 95% CI 0.334-0.976, p=0.04) и выживаемость без рецидива и РТПХ (HR 0.493, 95% CI 0.309-0.786, p=0.003). Токсичность ТКМ была сравнима в двух группах, за исключения меньшей нефротоксичности (33% против 43%, p=0.008) и частоты пост-трансплантационной микроангиопатии (3% против 11%, p=0.04) режима с ПТЦф, и большей частотой мукозитов 3-4 степени при данном режиме (41% против 34%, p=0.02). Несмотря на недостатки ретроспективного и одноцентрового подхода, в данном исследовании было показано преимущество режима профилактики РТПХ на основе моноПТЦф. Полученные результаты должны быть подтверждены в проспективном рандомизированном исследовании.

Ключевые слова

Трансплантация костного мозга, реакция «трансплантат против хозяина», пост-трансплантационный циклофосфан, профилактика.

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[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20026 [VALUE] => Array ( [TEXT] => <sup>1</sup>R. M. Gorbacheva Memorial Institute of Children Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University<br> <sup>2</sup>Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => 1R. M. Gorbacheva Memorial Institute of Children Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University
2Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20027 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials.

Keywords

Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis.

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Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation

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Ivan S. Moiseev1,2, Olga V. Pirogova1, Elena V. Babenko1, Tatyana L. Gindina1, Elena I. Darskaya1, Elena V. Morozova1,2, Sergey N. Bondarenko1, Boris V. Afanasyev1,2

1R. M. Gorbacheva Memorial Institute of Children Hematology, Oncology and Transplantation, Pavlov First Saint Petersburg State Medical University
2Chair of Hematology, Transfusiology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation

A number of studies were published demonstrating efficacy of single-agent graft-versus-host disease prophylaxis (GVHD) with post-transplantation cyclophosphamide (saPTCy) in matched related bone marrow transplantations (BMT), however no comparisons were published so far between saPTCy and conventional GVHD prophylaxis based on calcineurin inhibitors (CNIs). In this study, 78 patients graft ed with bone marrow from matched related donor (MRD) with saPTCy GVHD prophylaxis were compared to 105 historical control patients also receiving bone marrow from MRD, but with tacrolimus/cyclosporine A and mycophenolate mofetil/methotrexate prophylaxis. Groups were comparable in pre-transplant characteristics of patients, except higher prevalence of salvage patients and acute lymphoblastic leukemia in CNIs cohort. PTCy was superior to CNIs in prevention of grade II-IV (HR 0.239, 95% CI 0.099-0.58, p=0.002) and grade III-IV acute GVHD (HR 0.192, 95% CI 0.055-0.666, p=0.009), relapse (HR 0.519, 95% CI 0.297-0.893, p=0.023). No difference was observed for moderate and severe chronic GVHD (HR 0.898, 95% CI 0.477-1.69, p=0.74) and non-relapse mortality (HR 0.384, 95% CI 0.089-1.437, p=0.1768). Patients after saPTCy had improved overall survival (HR 0.489, 95% CI 0.261-0.917, p=0.03), event-free-survival (HR 0.571, 95% CI 0.334-0.976, p=0.04) and GVHD-relapse-free survival (HR 0.493, 95% CI 0.309-0.786, p=0.003). Th e toxicity of BMT was generally comparable, except lower incidence of nephrotoxicity (33% vs 43%, p=0.008) aft er PTCy, but with higher incidence of grade 3-4 mucositis in this group (41% vs 34%, p=0.02). Despite limitations of single-center retrospective design, this study demonstrated superiority of saPTCy vs CNI-based prophylaxis, but these results should be confirmed in prospective randomized trials.

Keywords

Bone marrow transplantation, graft-versus-host disease, post-transplantation cyclophosphamide, prophylaxis.

Case report

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Пациенты с синдромами первичного иммунодефицита встречаются относительно редко и им часто ставится ошибочный диагноз в связи с неспецифическими клиническими симптомами, напоминающими другие, более частые заболевания. Частота общей вариабельной иммунной недостаточности (ОВИН): 1 случай на 30.000 жителей Европы. Обычно имеется задержка в несколько лет между началом заболевания и диагнозом. Общая вариабельная иммунная недостаточность является наиболее частым первичным иммунодефицитом в возрасте старше 4 лет. Основным симптомом для установления диагноза является гипогаммаглобулинемия.
Целью данной статьи является показать существующие тенденции в диагностике ОВИН. Представленный клинический случай описывает 10-летнюю девочку, позитивную по четырем международным клиническим критериям ОВИН и с наличием специфического поражения легких. При этом были исключены злокачественные заболевания. Генетическое исследование методом глубинного генного секвенирования (NGS) не выявило какой-либо генной мутации, которая могла бы быть ответственной за ОВИН или родственные синдромы (ALPS, HLH). Таким образом, ОВИН остается диагнозом исключения. У нашего пациента, несмотря на заместительную терапию внутривенным иммуноглобулином, легочная функция продолжала ухудшаться, что привело к необходимости приступить к иммуносупрессивной терапии.

Ключевые слова

Первичный иммунодефицит, общая вариабельная
иммунная недостаточность, диагностические крите-
рии, аутоиммунные осложнения.

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Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Andrey V. Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20033 [VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, Chair of Hematology, Transfusiology and Transplantation, First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, Chair of Hematology, Transfusiology and Transplantation, First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20034 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.<br> The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.
The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment.

Keywords

Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications.

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Common variable immunodeficiency in a child. A case report

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Andrey V. Kozlov, Tatiana A. Bykova, Anastasia S. Borovkova, Maria Yu. Averjanova, Varvara N. Ovechkina, Elena V. Morozova, Ludmila S. Zubarovskaya, Nikolay N. Mamaev, Boris V. Afanasyev

R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, Chair of Hematology, Transfusiology and Transplantation, First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

Primary immunodefi ciency syndromes are relatively rare medical conditions that are oft en misdiagnosed because of unspecifi c clinical presentation that mimics other more common diseases. Incidence of combined common variable immunodefi ciency (CVID) is ca. 1 case per 30.000 European population. Usually, a delay of several years is observed between onset and diagnosis. CVID is the most frequent primary immunodefi ciency aft er 4 years of life. The key symptom to establish the disorder is hypogammaglobulinemia.
The aim of this article is to demonstrate current trends in diagnostics of common variable immunodefi ciency (CVID). The present case report describes a 10-year old girl with four major internationally approved criteria of common variable immunodefi ciency (CVID), and specific lung involvement. Malignant conditions were excluded. NGS genetic study did not detect any gene mutation which could be responsible for CVID or related syndromes (ALPS, HLH). Hence, the CVID remains a diagnosis of exclusion. Despite replacement with intravenous immunoglobulins, the lung function in our patient continued to deteriorate that necessitated initiation of immunosuppressive treatment.

Keywords

Primary immunodefi ciency, common variable immunodeficiency, diagnostic criteria, autoimmune complications.

Experimental studies

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Эндотелий представляет собой клеточный слой, выстилающий кровеносные сосуды любого человеческого органа или ткани. В течение десятилетий, защитные и барьерные функции считались основными свойствами сосудистого эндотелия. На протяжении последних 20 лет, однако, эндотелий стал рассматриваться как активный эндокринный орган в связи с секрецией множества энзимов, метаболических и ростовых факторов, может оказывать существенные регуляторные воздействия на ткани сердца и кровеносных сосудов, тем самым играя важную роль в патогенезе определенных сердечно-сосудистых заболеваний. Накопление данных об изменении взаимодействий между эндотелием сосудов сердца и миокардом позволяет нам предположить дополнительную местную функцию коронарного эндотелия, т.е. предполагаемую продукцию биологически активных веществ клетками эндотелия и их эффекты на метаболизм, функционирование, выживание и регенерацию кардиомиоцитов. Данная статья предлагает обсуждение и анализ конкретных исследований, касающихся клеточной терапии при заболеваниях сердца у человека. Эти данные говорят в пользу гипотезы о дополнительной роли эндотелия в функционировании сердца и предлагают потенциальную возможность коррекции эндотелиальной дисфункции посредством клеточной терапии.

Ключевые слова

Сердце, заболевание коронарных артерий, эндотелиальная дисфункция, клеточная терапия, дилатационная кардиомиопатия.

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Endothelium is a cellular layer lining blood vessels in either a human organ or tissue. For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy.

Keywords

Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy.

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Does the local coronary endothelial dysfunction exist? Potential implications for cardiac cellular therapy

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Alexander S. Nemkov, Zhang Yi

First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia

Endothelium is a cellular layer lining blood vessels in either a human organ or tissue. For decades, protective and barrier functions were considered to be the main property of vascular endothelium. Over last 20 years, however, endothelium is also considered an active endocrine organ which, due to secretion of multiple enzymes, metabolic and growth factors, may exert suffi cient regulatory effects upon heart and blood vessels, thus playing an important role in pathogenesis of certain cardiovascular disorders. Accumulating data on changing interactions between heart vascular endothelium and myocardium allow us to suggest an additional local function for coronary endothelium, i.e., a proposed production of biologically active substances by endothelial cells, and their eff ects upon metabolism, functioning, survival and regeneration of cardiomyocytes. The discussion article presents analysis of distinct studies concerning cellular therapy in human heart diseases. These data are favoring a hypothesis about additional role of endothelium in cardiac function, and offer a potential ability to correct endothelial dysfunction by means of cellular therapy.

Keywords

Heart, coronary artery disease, endothelial dysfunction, cellular therapy, dilated cardiomyopathy.

Clinical trials

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Главные научные кураторы: Борис В. Афанасьев1,Сергей М. Алексеев2, Иван С. Моисеев1
Наблюдательный совет: Алексей М. Беляев2, Андрей Ю. Зарицкий4, Николай В. Ильин3, Наталья Б. Михайлова1, Надежда В. Медведева5, Георгий М. Манихас6, Сергей В. Волошин7, Владимир М. Моисеенко8, Татьяна В. Шнейдер9
[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20052 [VALUE] => Array ( [TEXT] => <sup>1</sup>НИИ детской онкологии, гематологии и трансплантологии, ГБОУ ВПО Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup>ФБГУ Национальный медицинский исследовательский центр онкологии имени Н. Н. Петрова, Санкт-Петербург, Россия<br> <sup>3</sup>Российский научный центр радиологии и хирургических технологий имени академика А. М. Гранова, Санкт-Петербург, Россия<br> <sup>4</sup>Институт гематологии ФГБУ «НМИЦ им. В. А. Алмазова», Санкт-Петербург, Россия<br> <sup>5</sup>Городская клиническая больница № 31, Санкт-Петербург, Россия<br> <sup>6</sup>Городской клинический онкологический диспансер, Санкт-Петербург, Россия<br> <sup>7</sup>Российский НИИ гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия<br> <sup>8</sup>Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический), Санкт-Петербург, Россия<br> <sup>9</sup>Ленинградская областная клиническая больница, Санкт-Петербург, Россия<br> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => 1НИИ детской онкологии, гематологии и трансплантологии, ГБОУ ВПО Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова, Санкт-Петербург, Россия
2ФБГУ Национальный медицинский исследовательский центр онкологии имени Н. Н. Петрова, Санкт-Петербург, Россия
3Российский научный центр радиологии и хирургических технологий имени академика А. М. Гранова, Санкт-Петербург, Россия
4Институт гематологии ФГБУ «НМИЦ им. В. А. Алмазова», Санкт-Петербург, Россия
5Городская клиническая больница № 31, Санкт-Петербург, Россия
6Городской клинический онкологический диспансер, Санкт-Петербург, Россия
7Российский НИИ гематологии и трансфузиологии ФМБА России, Санкт-Петербург, Россия
8Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический), Санкт-Петербург, Россия
9Ленинградская областная клиническая больница, Санкт-Петербург, Россия
[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20053 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> В настоящий момент на территории Российской Федерации (РФ) отсутствует стандарт лечения лимфомы Ходжкина (ЛХ). Летальность от ЛХ в РФ составляет 28,3%, что свидетельствует о необходимости улучшения качества оказания медицинской помощи. В данной статье приведено описание и обоснование проспективного кооперативного исследования RNWOHG-HD1, инициированного в Северо-Западном регионе РФ. Обсуждаются ключевые моменты протокола, включая эскалацию терапии с ABVD до BEACOPPesc в случае ПЭТ-позитивности после двух циклов в группе благоприятного прогноза, и деэскалация с BEACOPPesc до AVD/ABVD в варианте рандомизации в случае достижения ПЭТ-негативного статуса в группе неблагоприятного прогноза. Протокол также подразумевает координацию медицинской помощи с целью получения пациентами доступа к второй и третьей линиям терапии, включая брентуксимаб, а также доступ к аутологичной и аллогенной трансплантации гемопоэтических стволовых клеток. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Лимфома Ходжкина, многоцентровое исследование, позитронно-эмиссионная томография (ПЭТ), RNWOHG-HD1. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

В настоящий момент на территории Российской Федерации (РФ) отсутствует стандарт лечения лимфомы Ходжкина (ЛХ). Летальность от ЛХ в РФ составляет 28,3%, что свидетельствует о необходимости улучшения качества оказания медицинской помощи. В данной статье приведено описание и обоснование проспективного кооперативного исследования RNWOHG-HD1, инициированного в Северо-Западном регионе РФ. Обсуждаются ключевые моменты протокола, включая эскалацию терапии с ABVD до BEACOPPesc в случае ПЭТ-позитивности после двух циклов в группе благоприятного прогноза, и деэскалация с BEACOPPesc до AVD/ABVD в варианте рандомизации в случае достижения ПЭТ-негативного статуса в группе неблагоприятного прогноза. Протокол также подразумевает координацию медицинской помощи с целью получения пациентами доступа к второй и третьей линиям терапии, включая брентуксимаб, а также доступ к аутологичной и аллогенной трансплантации гемопоэтических стволовых клеток.

Ключевые слова

Лимфома Ходжкина, многоцентровое исследование, позитронно-эмиссионная томография (ПЭТ), RNWOHG-HD1.

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Nadejda V. Medvedeva5, Georgii M. Manikhas6, Sergey V. Voloshin7, Vladimir M. Moiseenko8, Tatyana V. Shneider9 [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20056 [VALUE] => Array ( [TEXT] => <sup>1</sup>R. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation<br> <sup>2</sup>Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation<br> <sup>3</sup>Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia <sup>4</sup>Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia<br> <sup>5</sup>St. Petersburg City Hospital №31, St. Petersburg, Russian Federation<br> <sup>6</sup>St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation<br> <sup>7</sup>Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia<br> <sup>8</sup>St. Petersburg Oncological Center, St. Petersburg, Russia<br> <sup>9</sup>Leningrad District Clinical Hospital, St. Petersburg, Russia [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => 1R. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation
2Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation
3Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia 4Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia
5St. Petersburg City Hospital №31, St. Petersburg, Russian Federation
6St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation
7Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
8St. Petersburg Oncological Center, St. Petersburg, Russia
9Leningrad District Clinical Hospital, St. Petersburg, Russia [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20057 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation.

Keywords

Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1.

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Multicenter prospective escalation-deescalation PET-guided clinical study in classical type Hodgkin disease in the North-West of Russian Federation (RNWOHG-HD1): rationale and design

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Study authors: Boris V. Afanasyev1, Ivan S. Moiseev1, Sergey M. Alekseev2, Natalia B. Mikhailova1, Elena V. Kondakova1, Nikolai V. Ilyin3, Alexey M. Belyaеv2 Chief scientifi c advisors: Boris V. Afanasyev1, Sergey M. Alekseev2, Ivan S. Moiseev1 Supervisory board: Alexey M. Belyaеv2, Andrey Yu. Zaritskey4, Nikolai V. Ilyin3, Natalia B. Mikhailova1,
Nadejda V. Medvedeva5, Georgii M. Manikhas6, Sergey V. Voloshin7, Vladimir M. Moiseenko8, Tatyana V. Shneider9

1R. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Pavlov First St. Petersburg State Medical University, St. Petersburg, Russian Federation
2Prof. N. N. Petrov Research Institute of Oncology, St. Petersburg, Russian Federation
3Central Research Institute of X-ray and Radiation Studies, Ministry of Health of the Russian Federation, St. Petersburg, Russia 4Oncohaematology Department, Almazov Federal Heart, Blood and Endocrinology Centre, St. Petersburg, Russia
5St. Petersburg City Hospital №31, St. Petersburg, Russian Federation
6St. Petersburg City Clinical Oncology Dispensary, St. Petersburg, Russian Federation
7Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia
8St. Petersburg Oncological Center, St. Petersburg, Russia
9Leningrad District Clinical Hospital, St. Petersburg, Russia

Currently there is no established standard of care for Hodgkin’s disease (HD) in Russian Federation (RF). The mortality from HD in RF is 28,3%, thus improvement of care is required. Here we describe the design and the rational for the fi rst cooperative prospective study in the Nort-West region of RF, RNWOHG-HD1. The key points of the protocol are discussed, including escalation from ABVD to BEACOPPesc in case of PET-positive disease aft er fi rst two cycles in the favorable prognosis group, and de-escalation to randomized ABVD/AVD in case of PET(-) status aft er fi rst two BEACOPPesc courses in the unfavorable prognosis group. The protocol also is planned to facilitate access to second and third line treatments, including brentuximab, as well as autologous and allogeneic stem cell transplantation.

Keywords

Hodgkin’s disease, multicenter study, positron emission tomography (PET), RNWOHG-HD1.

Clinical protocol

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                    [TEXT] => <h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3>
<p style="text-align: justify;">
	 «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.
</p>
<h3 style="text-align: justify;">Главные научные кураторы:</h3>
<p style="text-align: justify;">
 <b>Афанасьев Борис Владимирович</b><br>
	 Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br>
 <b>Алексеев Сергей Михайлович</b><br>
	 Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br>
 <b>Моисеев Иван Сергеевич</b><br>
	 Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.
</p>
<h3 style="text-align: justify;">Наблюдательный совет программы:</h3>
<p style="text-align: justify;">
 <b>Афанасьев Борис Владимирович</b><br>
	 Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br>
 <b>Беляев Алексей Михайлович</b><br>
	 Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br>
 <b>Зарицкий Андрей Юрьевич</b><br>
	 Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br>
 <b>Алексеев Сергей Михайлович</b><br>
	 Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br>
 <b>Ильин Николай Васильевич</b><br>
	 Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br>
 <b>Михайлова Наталья Борисовна</b><br>
	 Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br>
 <b>Медведева Надежда Вадимовна</b><br>
	 Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br>
 <b>Манихас Георгий Моисеевич</b><br>
	 Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br>
 <b>Волошин Сергей Владимирович</b><br>
	 Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br>
 <b>Моисеенко Владимир Михайлович</b><br>
	 Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br>
 <b>Шнейдер Татьяна Владимировна</b><br>
	 Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области
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Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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2015-09-03 10:49:47 [IBLOCK_ID] => 2 [NAME] => Name [ACTIVE] => Y [SORT] => 500 [CODE] => NAME_EN [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 40 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => Y [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 20069 [VALUE] => Multicenter cooperative prospectiveretrospective observational program for diagnostics and treatment of Hodgkin disease in the North-Western District of Russian Federation (RNWOHG-HD1 Protocol, the full-text version in Russian) 2nd part [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Multicenter cooperative prospectiveretrospective observational program for diagnostics and treatment of Hodgkin disease in the North-Western District of Russian Federation (RNWOHG-HD1 Protocol, the full-text version in Russian) 2nd part [~DESCRIPTION] => [~NAME] => Name [~DEFAULT_VALUE] => ) [FULL_TEXT_RU] => Array ( [ID] => 42 [TIMESTAMP_X] => 2015-09-07 20:29:18 [IBLOCK_ID] => 2 [NAME] => Полный текст [ACTIVE] => Y [SORT] => 500 [CODE] => FULL_TEXT_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 42 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20070 [VALUE] => Array ( [TEXT] => <h2></h2> <h2 style="text-align: justify;">14. МЕТОДОЛОГИЯ СБОРА ДАННЫХ</h2> <p style="text-align: justify;"> Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.<br> E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).<br> Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования. </p> <h2 style="text-align: justify;">15. РАЗМЕР ВЫБОРКИ</h2> <p style="text-align: justify;"> Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек. </p> <h2 style="text-align: justify;">16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА</h2> <p style="text-align: justify;"> Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. </p> <h3 style="text-align: justify;">Статистические методы</h3> <p style="text-align: justify;"> Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.<br> Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу. </p> <h3 style="text-align: justify;">Статистическая обработка полученных результатов:</h3> <p style="text-align: justify;"> В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. </p> <h3 style="text-align: justify;">Определение конечных точек исследования:</h3> <p style="text-align: justify;"> Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.<br> Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.<br> Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах<sup>20</sup>.<br> Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.<br> Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага&gt; 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville &gt;3)20.<br> Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей. </p> <h3 style="text-align: justify;">Рандомизация</h3> <p style="text-align: justify;"> В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.<br> С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR&gt; 1.1. </p> <h2 style="text-align: justify;">17. ЭТИЧЕСКИЕ АСПЕКТЫ</h2> <p style="text-align: justify;"> Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.<br> Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.<br> Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.<br> В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования. </p> <h2 style="text-align: justify;">18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ</h2> <p style="text-align: justify;"> Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.<br> Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF. </p> <h2 style="text-align: justify;">19. МОНИТОРИНГ</h2> <p style="text-align: justify;"> Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией. </p> <h2 style="text-align: justify;">20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ</h2> <p style="text-align: justify;"> Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии. </p> <h2 style="text-align: justify;">21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:</h2> <p style="text-align: justify;"> Схематичная форма регистрируемых параметров представлена в приложении 5.<br> Первичная регистрация в электронной системе:<br> 1. Фамилия/Имя/Отчество<br> 2. Пол<br> 3. Дата рождения _____ Возраст (калькулятор)<br> 4. Регион<br> 5. Телефон для связи<br> 6. Социальный статус (работающий, неработающий, учащийся, пенсионер)<br> 7. Дата внесения регистрационной информации<br> Первичное стадирование:<br> 1. Дата постановки диагноза<br> 2. Длительность заболевания на момент включения па циента в программу<br> 3. Гистологический вариант заболевания<br> 4. Дата биопсии, по которой был поставлен гистологи-<br> ческий диагноз<br> 5. Проводилось ли ИГХ диагностика:<br> 6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)<br> 7. Стадия по классификации Ann Arbor<br> 8. Вовлеченные зоны по данным ПЭТ-КТ<br> 9. Максимальные размеры опухоли для 6 очагов (либо<br> меньше, если вовлечены менее 6)<br> 10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).<br> 12. СОЭ<br> 13. ЛДГ<br> 14. АЛТ<br> 15. АСТ<br> 16. Креатинин<br> 17. Билирубин<br> 18. Гемоглобин<br> 19. Альбумин<br> 20. Абсолютное число лейкоцитов<br> 21. Абсолютное число нейтрофилов<br> 22. Абсолютное число лимфоцитов<br> 23. Тромбоциты<br> 24. Вариант терапии первой линии<br> 25. Запланированное число курсов (не для RNWOHGHD1)<br> 26. Дата начала 1-ого цикла химиотерапии<br> 27. Препараты 1ого цикла химиотерапии: длительность<br> и дозы<br> <img width="752" alt="Tvblitsa_0.png" src="/upload/medialibrary/b1e/tvblitsa_0.png" height="513" title="Tvblitsa_0.png"><br> Рестадирование после двух циклов химиотерапии:<br> 1. Дата начала 2-ого цикла химиотерапии<br> 2. Препараты 2-ого цикла химиотерапии: длительность и дозы<br> 3. Ответ по оценке лечащего врача<br> 4. Максимальный уровень метаболической активности по Deauville<br> 5. Вовлеченные зоны по данным ПЭТ-КТ<br> 6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 8. Токсичность, если была, по NCI CTCAE 4.03<br> 9. Инфекционные осложнения, если были<br> 10. Потребность в Г-КСФ<br> 11. Количество переливаний эритроцитов<br> 12. Другая сопроводительная терапия<br> Рестадирование после четырех циклов химиотерапии (где применимо):<br> 1. Дата начала курсов химиотерапии<br> 2. Препараты химиотерапии<br> 3. Ответ по оценке лечащего врача<br> 4. Максимальный уровень метаболической активности по Deauville<br> 5. Вовлеченные зоны по данным КТ<br> 6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. Токсичность, если была, по NCI CTCAE 4.03<br> 8. Инфекционные осложнения, если были<br> 9. Потребность в Г-КСФ<br> 10. Количество переливаний эритроцитов<br> 11. Другая сопроводительная терапия<br> 12. Рестадирование после шести циклов химиотерапии (где применимо):<br> 13. Дата начала курсов химиотерапии<br> 14. Ответ по оценке лечащего врача<br> 15. Максимальный уровень метаболической активности по Deauville<br> 16. Вовлеченные зоны по данным ПЭТ-КТ<br> 17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)<br> 18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 19. Токсичность, если была, по NCI CTCAE 4.03<br> 20. Инфекционные осложнения, если были<br> 21. Потребность в Г-КСФ<br> 22. Количество переливаний эритроцитов<br> 23. Другая сопроводительная терапия<br> Рестадирование после лучевой терапии (где применимо):<br> 1. Дата начала лучевой терапии<br> 2. Режим лучевой терапии<br> 3. Доза лучевой терапии<br> 4. Ответ по оценке лечащего врача<br> 5. Максимальный уровень метаболической активности по Deauville<br> 6. Вовлеченные зоны по данным КТ<br> 7. Максимальные размеры опухоли для 6 очагов (либо<br> меньше, если вовлечены менее 6)<br> 8. Токсичность, если была, по NCI CTCAE 4.03<br> Наблюдение каждые 6 месяцев после окончания лечения:<br> 1. Дата контакта<br> 2. Жив/умер/потеряна связь<br> 3. Статус заболевания<br> 4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03<br> 5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)<br> Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):<br> 1. Дата фиксации рецидива<br> 2. Длительность от момента первичной диагностики заболевания<br> 3. Стадия по классификации Ann Arbor<br> 4. Вовлеченные зоны по данным ПЭТ-КТ<br> 5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)<br> 6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)<br> 7. СОЭ<br> 8. ЛДГ<br> 9. АЛТ<br> 10. АСТ<br> 11. Креатинин<br> 12. Билирубин<br> 13. Гемоглобин<br> 14. Альбумин<br> 15. Абсолютное число лейкоцитов<br> 16. Абсолютное число нейтрофилов<br> 17. Абсолютное число лимфоцитов<br> 18. Тромбоциты<br> 19. Дата начала химиотерапии второй линии<br> 20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)<br> Статус после 2-ой линии химиотерапии (где применимо):<br> 1. Дата рестадирования<br> 2. Ответ по оценке лечащего врача<br> 3. Максимальный уровень метаболической активности по Deauville<br> 4. Вовлеченные зоны по данным ПЭТ-КТ<br> 5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)<br> 7. Токсичность, если была, по NCI CTCAE 4.03<br> 8. Инфекционные осложнения, если были<br> 9. Потребность в Г-КСФ<br> 10. Количество переливаний эритроцитов<br> 11. Другая сопроводительная терапия<br> 12. Направлен на аутоТКМ: да/нет<br> 13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия<br> Статус после аутоТКМ (где применимо):<br> 1. Дата ТКМ<br> 2. Дата рестадирования<br> 3. Режим кондиционирования<br> 4. Количество CD34+ в трансплантате<br> 5. Ответ по оценке лечащего врача<br> 6. Максимальный уровень метаболической активности по Deauville<br> 7. Вовлеченные зоны по данным ПЭТ-КТ<br> 8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)<br> 10. Токсичность, если была, по NCI CTCAE 4.03<br> 11. Инфекционные осложнения, если были<br> 12. Поддерживающая терапия брентуксимабом – да/нет<br> Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):<br> 1. Стадия по классификации Ann Arbor<br> 2. Вовлеченные зоны по данным ПЭТ-КТ<br> 3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)<br> 4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)<br> 5. СОЭ<br> 6. ЛДГ<br> 7. Гемоглобин<br> 8. Альбумин<br> 9. Абсолютное число лейкоцитов<br> 10. Абсолютное число нейтрофилов<br> 11. Абсолютное число лимфоцитов<br> 12. Тромбоциты<br> 13. Дата начала терапии третьей линии<br> 14. Вариант терапии третьей линии: брентуксимаб или другой<br> 15. Направлен на аллоТКМ да/нет<br> 16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая<br> 6. ЛДГ<br> 7. Гемоглобин<br> 8. Альбумин<br> 9. Абсолютное число лейкоцитов<br> 10. Абсолютное число нейтрофилов<br> 11. Абсолютное число лимфоцитов<br> 12. Тромбоциты<br> 13. Дата начала терапии третьей линии<br> 14. Вариант терапии третьей линии: брентуксимаб или другой<br> 15. Направлен на аллоТКМ да/нет<br> 16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая<br> Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.<br> Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:<br> – массивная (bulky) медиастинальная опухоль &gt;10 см<br> – экстранодальное поражение, в том числе по контакту<br> – скорость оседания эритроцитов (СОЭ) &gt;50 мм/ч<br> – вовлечение трех и более групп лимфоузлов. </p> <h2 style="text-align: justify;">Первая линия</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):</h3> <p style="text-align: justify;"> • Проводится 2 курса ABVD.<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР проводится наблюдение.<br> • При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.<br> • При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.<br> • При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.<br> • При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):</h3> <p style="text-align: justify;"> • Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.<br> • При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.<br> • При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии.<br> • При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

14. МЕТОДОЛОГИЯ СБОРА ДАННЫХ

Поскольку данный проект представляет собой наблюдательную программу, то обязательное оценивание пациентов или центров не требуется. Тем не менее сбор данных/отчетности будет проводиться на постоянной основе во избежание предвзятости в процессе сбора данных и анализа. Собранные данные будут загружаться всеми исследовательскими центрами в электронную систему с использованием утвержденной электронной индивидуальной регистрационной карты пациента (eCRF) и верифицироваться. Данные, необходимые с точки зрения основных целей исследования, а также демографические данные и клинические характеристики пациентов будут браться из eCRF, заполненных персоналом центров.
E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta»», правообладатель ЗАО «Астон Консалтинг»). Ее использование происходит через индивидуальный электронный удаленный on-line доступ: индивидуальный логин и пароль. Рекомендованный браузер для работы Microsoft Internet Explorer 10.0 (интернет настройка).
Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/ 15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

15. РАЗМЕР ВЫБОРКИ

Поскольку программа является наблюдательной и не предлагает доказательства никакой гипотезы, то расчет выборки не производился. Однако в программу планируется достаточное для поставленных задач число пациентов – 900 человек.

16. ПЛАН СТАТИСТИЧЕСКОГО АНАЛИЗА

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Статистические методы

Сравнение непараметрических величин между группами будет проводиться тестом Манна-Уитни. Сравнение числовых переменных между группами будет проводится двусторонним t-тестом. Сравнение показателей выживаемости без прогрессирования (ИБП) и общей выживаемости (ОВ) между группами лечения будет проводится с использованием log-ранг теста. Многофакторный анализ ВБП и ОВ будет проводиться на основании построения моделей  пропорционального риска. Для пациентов, которым проводится аутологичная и аллогенная ТСК трансплантационная летальность и рецидивы будут расцениваться как конкурирующие риски. Статистическая значимость для всех тестов устанавливается на уровне 0.05.
Расчет фармакоэкономики на одного пациента будет проводиться исходя из следующих параметров: стоимость химиопрепаратов и сопроводительных препаратов, стоимость дополнительных исследований, стоимость логистических и дополнительных расходов, стоимость лечения осложнений в соответствии со стандартами МЗ РФ, расходы на оплату нетрудоспособности, исходя из параметров средней заработной платы по региону и длительности лечения по протоколу.

Статистическая обработка полученных результатов:

В целом, сводные таблицы будут представлены по группам лечения с включением количества случаев, средних значений, стандартных отклонений, медиан, минимальных и максимальных значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события.

Определение конечных точек исследования:

Выживаемость без прогрессирования: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти, рецидива или прогрессии ЛХ.
Общая выживаемость: время от начала лечения в рамках 1-ой, 2-ой или 3-ей линии химиотерапии до смерти.
Полная ремиссия: ПЭТ- негативный статус (Deauville ≤3) даже при сохраняющихся резидуальных массах20.
Частичный ответ: Регресс ≥50% шести наиболее крупных опухолевых масс при отсутствии появления новых опухолевых очагов и одного или более ПЭТ- позитивного опухолевого очага20.
Прогрессия/рецидив: появление новых опухолевых очагов более 1.5 см, или увеличение на 50% суммы диаметров по крайней мере одного из опухолевых очагов, или увеличение на 50% в одном измерении ранее существовавшего очага> 1 см, или появление новых ПЭТ- позитивных опухолевых очагов (Deauville >3)20.
Пациенты будут исследоваться в течение как минимум четырех лет с момента начала терапии и будут постоянно наблюдаться в течении и после лечения один раз в три месяца до момента, когда ими будет отозвано согласие на участие или до момента смерти, или исчезновения из поля зрения исследователей.

Рандомизация

В группе пациентов, которые с самого начала лечения курировались с использованием ПЭТ будет проводится рандомизация. Рандомизация будет проводиться на момент достижения полной ПЭТ-негативной ремиссии после двух курсов терапии в группе высокого риска. В ходе рандомизации будет выполняться стратификация риска по IPS на основании U-критерия теста Манна-Уитни.
С учетом рандомизации 60% всех пациентов, включенных в программу, отношение риска худшего результата (inferiority) на 1, 2 и 3 года рассчитывается из числа 180, 360 и 540 пациентов, с ожидаемой частотой наступления события 15%, выбранной на основании литературных данных13. Сила анализа – 80%. Исходя из количества пациентов и силы исследования за худший результат (inferiority) принимается отношение рисков (HR) БРВ 11.0, 3.5 и 2.2 для промежуточного анализа на 1, 2 и 3 года исследования, соответственно. Результаты промежуточного анализа предоставляются наблюдательному совету для решения вопроса о целесообразности продолжения рандомизации. При оценке окончательных показателей 5-летней БРВ худший результат (inferiority) – HR> 1.1.

17. ЭТИЧЕСКИЕ АСПЕКТЫ

Данная программа была разработана и будет проводиться в соответствии с этическими принципами Хельсинской декларации, трехсторонним соглашением Международной Конференции по Гармонизации и российским ГОСТом по надлежащей клинической практике.
Пациенты, подходящие по критериям, могут быть включены в программу только после подписания формы информированного согласия, одобренной Независимым или Локальным Этическим Комитетом. Подписанное информированное согласие необходимо получить до применения процессов, описанных в настоящем протоколе. Процесс получения подписанного информированного согласия должен быть отражен в первичной исследовательской документации по каждому пациенту.
Персональные данные пациентов будут использоваться исключительно в целях наблюдательной программы. Любая информация, с помощью которой можно идентифицировать пациентов, не подлежит раскрытию. Идентификация пациентов в базе данных будет осуществляться на сновании присвоенных номеров.
В силу наблюдательного и неинтервенционного характера данного исследования протокол исследования, карта пациента, форма информированного согласия и информация, предоставляемая пациентам, не должны получать одобрения российского Министерства здравоохранения и социального развития, Совета по этике при Министерстве Здравоохранения и этических комитетов в местах проведения исследования.

18. КОНФИДЕНЦИАЛЬНОСТЬ ПЕРСОНАЛЬНЫХ ДАННЫХ

Конфиденциальность ПД находится под защитой действующего законодательства. ЗАО «Астон Консалтинг» является официально зарегистрированным оператором персональных данных (ссылка на документ), что дает возможность врачу-участнику программы при подписании информированного согласия не кодировать пациентов, вносить их персональные данные (а именно ФИО, дату рождения, возраст) в базу данных для обработки (информированное согласие – приложение 4). После введения ФИО пациента e-CRF генерирует код, под которым пациент будет виден другим участникам программы, не имеющим доступ к полной базе данных.
Персональные данные пациентов, принимающих участие в программе, будут сохраняться в тайне. Идентификация пациентов будет осуществляться при помощи уникальных номеров, присвоенных пациентам e-CRF.

19. МОНИТОРИНГ

Мониторинг во всех центрах, включающих пациентов в программу будет проводиться 2 раза в год. В случае выявления несоответствия первичной медицинской документации и eCRF, которые не повлияли на выбор схем лечения, eCRF приводится в соответствие с первичной документацией.

20. ОЖИДАЕМЫЕ РЕЗУЛЬТАТЫ

Ожидается улучшения качества оказания медицинской помощи пациентам с ЛХ в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

21. БЛОКИ ДАННЫХ, ОБЯЗАТЕЛЬНЫЕ ДЛЯ РЕГИСТРАЦИИ В E-CRF:

Схематичная форма регистрируемых параметров представлена в приложении 5.
Первичная регистрация в электронной системе:
1. Фамилия/Имя/Отчество
2. Пол
3. Дата рождения _____ Возраст (калькулятор)
4. Регион
5. Телефон для связи
6. Социальный статус (работающий, неработающий, учащийся, пенсионер)
7. Дата внесения регистрационной информации
Первичное стадирование:
1. Дата постановки диагноза
2. Длительность заболевания на момент включения па циента в программу
3. Гистологический вариант заболевания
4. Дата биопсии, по которой был поставлен гистологи-
ческий диагноз
5. Проводилось ли ИГХ диагностика:
6. Если проводилась ИГХ диагностика, необходимо отметить ИГХ Маркеры (нужное отметить)
7. Стадия по классификации Ann Arbor
8. Вовлеченные зоны по данным ПЭТ-КТ
9. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
10. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
11. ВИЧ-статус (в случае положительного – вирусная нагрузка, CD4+ в мкл).
12. СОЭ
13. ЛДГ
14. АЛТ
15. АСТ
16. Креатинин
17. Билирубин
18. Гемоглобин
19. Альбумин
20. Абсолютное число лейкоцитов
21. Абсолютное число нейтрофилов
22. Абсолютное число лимфоцитов
23. Тромбоциты
24. Вариант терапии первой линии
25. Запланированное число курсов (не для RNWOHGHD1)
26. Дата начала 1-ого цикла химиотерапии
27. Препараты 1ого цикла химиотерапии: длительность
и дозы
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Рестадирование после двух циклов химиотерапии:
1. Дата начала 2-ого цикла химиотерапии
2. Препараты 2-ого цикла химиотерапии: длительность и дозы
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным ПЭТ-КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
9. Инфекционные осложнения, если были
10. Потребность в Г-КСФ
11. Количество переливаний эритроцитов
12. Другая сопроводительная терапия
Рестадирование после четырех циклов химиотерапии (где применимо):
1. Дата начала курсов химиотерапии
2. Препараты химиотерапии
3. Ответ по оценке лечащего врача
4. Максимальный уровень метаболической активности по Deauville
5. Вовлеченные зоны по данным КТ
6. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 6)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Рестадирование после шести циклов химиотерапии (где применимо):
13. Дата начала курсов химиотерапии
14. Ответ по оценке лечащего врача
15. Максимальный уровень метаболической активности по Deauville
16. Вовлеченные зоны по данным ПЭТ-КТ
17. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
18. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
19. Токсичность, если была, по NCI CTCAE 4.03
20. Инфекционные осложнения, если были
21. Потребность в Г-КСФ
22. Количество переливаний эритроцитов
23. Другая сопроводительная терапия
Рестадирование после лучевой терапии (где применимо):
1. Дата начала лучевой терапии
2. Режим лучевой терапии
3. Доза лучевой терапии
4. Ответ по оценке лечащего врача
5. Максимальный уровень метаболической активности по Deauville
6. Вовлеченные зоны по данным КТ
7. Максимальные размеры опухоли для 6 очагов (либо
меньше, если вовлечены менее 6)
8. Токсичность, если была, по NCI CTCAE 4.03
Наблюдение каждые 6 месяцев после окончания лечения:
1. Дата контакта
2. Жив/умер/потеряна связь
3. Статус заболевания
4. Остаточные побочные явления, если есть, по NCI CTCAE 4.03
5. Для женщин факт наличия беременности (планировалась – не было, не планировалась – не было, была – аборт, в анамнезе – невынашивание, в анмнезе – роды)
Статус на момент рецидива/прогрессии после 1-ой линии (где применимо):
1. Дата фиксации рецидива
2. Длительность от момента первичной диагностики заболевания
3. Стадия по классификации Ann Arbor
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 очагов (либо меньше, если вовлечены менее 3)
6. Уровень метаболической активности по Deauville для 6 очагов (либо меньше, если вовлечены менее 6)
7. СОЭ
8. ЛДГ
9. АЛТ
10. АСТ
11. Креатинин
12. Билирубин
13. Гемоглобин
14. Альбумин
15. Абсолютное число лейкоцитов
16. Абсолютное число нейтрофилов
17. Абсолютное число лимфоцитов
18. Тромбоциты
19. Дата начала химиотерапии второй линии
20. Вариант химиотерапии второй линии: DHAP, IGEV, ICE, брентуксимаб, брентуксимаб + бендамустин, BEACOPP, DexaBeam, LABO, другая (вписать)
Статус после 2-ой линии химиотерапии (где применимо):
1. Дата рестадирования
2. Ответ по оценке лечащего врача
3. Максимальный уровень метаболической активности по Deauville
4. Вовлеченные зоны по данным ПЭТ-КТ
5. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
6. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 3)
7. Токсичность, если была, по NCI CTCAE 4.03
8. Инфекционные осложнения, если были
9. Потребность в Г-КСФ
10. Количество переливаний эритроцитов
11. Другая сопроводительная терапия
12. Направлен на аутоТКМ: да/нет
13. Причина, если не направлен на аутоТКМ: не кандидат (и причина), неудача сбора стволовых клеток, отзыв согласия
Статус после аутоТКМ (где применимо):
1. Дата ТКМ
2. Дата рестадирования
3. Режим кондиционирования
4. Количество CD34+ в трансплантате
5. Ответ по оценке лечащего врача
6. Максимальный уровень метаболической активности по Deauville
7. Вовлеченные зоны по данным ПЭТ-КТ
8. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
9. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
10. Токсичность, если была, по NCI CTCAE 4.03
11. Инфекционные осложнения, если были
12. Поддерживающая терапия брентуксимабом – да/нет
Статус на момент рецидива/прогрессии после 2-ой линии (где применимо):
1. Стадия по классификации Ann Arbor
2. Вовлеченные зоны по данным ПЭТ-КТ
3. Максимальные размеры опухоли для 6 зон (либо меньше, если вовлечены менее 6)
4. Уровень метаболической активности по Deauville для 6 зон (либо меньше, если вовлечены менее 6)
5. СОЭ
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
6. ЛДГ
7. Гемоглобин
8. Альбумин
9. Абсолютное число лейкоцитов
10. Абсолютное число нейтрофилов
11. Абсолютное число лимфоцитов
12. Тромбоциты
13. Дата начала терапии третьей линии
14. Вариант терапии третьей линии: брентуксимаб или другой
15. Направлен на аллоТКМ да/нет
16. Причины невыполнения аллоТКМ: нет донора/отзыв согласия/другая
Пациенты ретроспективной ветки наблюдательной программы RHWOHG-HD1, могут быть отнесены к группе интенсивного или неинтенсивного ведения.
Неблагоприятные факторы, требующие включения пациента к интенсивной ветке протокола лечения:
– массивная (bulky) медиастинальная опухоль >10 см
– экстранодальное поражение, в том числе по контакту
– скорость оседания эритроцитов (СОЭ) >50 мм/ч
– вовлечение трех и более групп лимфоузлов.

Первая линия

Неинтенсивная ветка протокола (стадия I-IIA и нет неблагоприятных факторов):

• Проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится наблюдение.
• При достижении ПЭТ(+) ЧО проводится радиотерапия 20 Gy и последующее наблюдение.
• При ПЭТ(+) статусе менее ЧО проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(-) ПР после 4 курсов BEACOPP-14 или BEACOPPesc проводится наблюдение.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.

Интенсивная ветка протокола (стадия IIB-IV или есть неблагоприятные факторы):

• Проводится 2 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения).
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР проводится рандомизация со стратификацией риска по международной прогностической системе (IPS) между 4 курсами ABVD и AVD. После 2-х курсов выполняется промежуточная КТ. При сохранении ремиссии проводится еще два курса, при наличии рецидива пациент переводится на 2-ую линию. После завершения терапии проводится ПЭТ-КТ, при сохранении ремиссии проводится наблюдение.
• При наличии ПЭТ(+) статуса, но без критериев прогрессии, проводится 4 курса BEACOPP-14 или BEACOPPesc (на усмотрение лечебного учреждения) с промежуточной КТ после 2-х курсов. При наличии прогрессии по данным промежуточной КТ, пациент переводится на вторую линию терапии, во все остальных случаях продолжается терапия BEACOPP-14 или BEACOPPesc.
• При ПЭТ(+) статусе, размере лимфоузлов менее 2.5 см и SUV<6 после 6 курсов BEACOPP-14 или BEACOPPesc проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе, пациент переводится на вторую линию терапии.

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Multicenter cooperative prospectiveretrospective observational program for diagnostics and treatment of Hodgkin disease in the North-Western District of Russian Federation (RNWOHG-HD1 Protocol, the full-text version in Russian) 2nd part

Download PDF version

Clinical protocol

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                    [TEXT] => <h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3>
<p style="text-align: justify;">
	 «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.
</p>
<h3 style="text-align: justify;">Главные научные кураторы:</h3>
<p style="text-align: justify;">
 <b>Афанасьев Борис Владимирович</b><br>
	 Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br>
 <b>Алексеев Сергей Михайлович</b><br>
	 Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br>
 <b>Моисеев Иван Сергеевич</b><br>
	 Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.
</p>
<h3 style="text-align: justify;">Наблюдательный совет программы:</h3>
<p style="text-align: justify;">
 <b>Афанасьев Борис Владимирович</b><br>
	 Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br>
 <b>Беляев Алексей Михайлович</b><br>
	 Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br>
 <b>Зарицкий Андрей Юрьевич</b><br>
	 Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br>
 <b>Алексеев Сергей Михайлович</b><br>
	 Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br>
 <b>Ильин Николай Васильевич</b><br>
	 Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br>
 <b>Михайлова Наталья Борисовна</b><br>
	 Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br>
 <b>Медведева Надежда Вадимовна</b><br>
	 Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br>
 <b>Манихас Георгий Моисеевич</b><br>
	 Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br>
 <b>Волошин Сергей Владимирович</b><br>
	 Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br>
 <b>Моисеенко Владимир Михайлович</b><br>
	 Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br>
 <b>Шнейдер Татьяна Владимировна</b><br>
	 Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области
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Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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логотипы.png

ПРОТОКОЛ № RNWOHG-HD1 ВЕРСИЯ 1.01 ОТ 18.09.2017

ЗАЯВЛЕНИЕ О КОНФИДЕНЦИАЛЬНОСТИ. Этот документ является конфиденциальным и может быть предоставлен для пересмотра только исследователям, потенциальным исследователям, консультантам, персоналу исследования и независимым этическим комитетам или локальным этическим комитетам. Содержимое этого документа не может быть раскрыто третьим лицам без письменного разрешения организации или отдельных лиц, за исключением случаев, когда необходимо получить информированное согласие от потенциальных участников исследования.
Санкт-Петербург 2017

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justify;"><sup></sup>Список сокращений</h2> <p style="text-align: justify;"> аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток<br> АЛТ – аланинаминотрансфераза<br> АСТ – аспартамаминотрансфераза<br> аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток<br> БДУ – без дополнительных уточнений<br> ВБП – выживаемость без прогрессирования<br> ДО – длительность ответа<br> ИГХ – иммуногистохимия<br> КТ – компьютерная томография<br> ЛХ – лимфома Ходжкина<br> ОВ – общая выживаемость<br> ПЭТ – позитронной эмиссионной томографии<br> ПР – полная ремиссия<br> СОЭ – скорость оседания эритроцитов<br> ЧО – частичный ответ<br> eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)<br> SUV – standard uptake value – стандартизированный показатель накопления<br> Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы<br> Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции. </p> <h2 style="text-align: justify;">СОДЕРЖАНИЕ ПРОТОКОЛА</h2> <p style="text-align: justify;"> 1. Главные научные кураторы программы и наблюдательный совет 83<br> 2. Список сокращений 84<br> 3. Краткое содержание протокола программы 85<br> 4. Актуальность программы 86<br> 5. Задачи программы 86<br> 6. Цель программы 87<br> 7. Первичные конечные точки 87<br> 8. Вторичные конечные точки 87<br> 9. Дизайн программы 87<br> 10. Популяция пациентов, критерии включения и исключения 87<br> 11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89<br> 12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90<br> 13. Лечение в проспективной группе пациентов наблюдательной программы 91<br> 14. Методология сбора данных 91<br> 15. Размер выборки 92<br> 16. План статистического анализа 92<br> 17. Этические аспекты 93<br> 18. Конфиденциальность персональных данных 93<br> 19. Мониторинг 93<br> 20. Ожидаемые результаты 93<br> 21. Блоки данных, обязательные для регистрации в e-CRF 93<br> 22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96<br> 23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99<br> 24. Список литературы 102 </p> <h2 style="text-align: justify;">3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Название программы</h3> <p style="text-align: justify;"> Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ. </p> <h3 style="text-align: justify;">Актуальность</h3> <p style="text-align: justify;"> Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ. </p> <h3 style="text-align: justify;">Задача программы</h3> <p style="text-align: justify;"> Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации. </p> <h3 style="text-align: justify;">Цель программы</h3> <p style="text-align: justify;"> Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения. </p> <h3 style="text-align: justify;">Дизайн программы</h3> <p style="text-align: justify;"> Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов. </p> <h3 style="text-align: justify;">Длительность программы</h3> <p style="text-align: justify;"> Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода. </p> <h3 style="text-align: justify;">Популяция пациентов</h3> <p style="text-align: justify;"> В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца. </p> <h3 style="text-align: justify;">Критерии включения пациентов в программу</h3> <p style="text-align: justify;"> • Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;<br> • Возраст не моложе 16 лет на момент начала лечения;<br> • Начало лечения лимфомы Ходжкина не ранее 1.01.2017;<br> • Наличие подписанного информированного согласия на обработку персональных и медицинских данных.<br> Критерии исключения пациентов из программы<br> • Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.<br> • Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.<br> • Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.<br> • Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.<br> • Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:<br> – фракция выброса левого желудочка &lt; 50%;<br> – инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> – сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> – признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца. </p> <h3 style="text-align: justify;">Методология сбора данных</h3> <p style="text-align: justify;"> Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования. </p> <h3 style="text-align: justify;">Медико-статистический анализ данных</h3> <p style="text-align: justify;"> Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. </p> <h3 style="text-align: justify;">Ожидаемый результат</h3> <p style="text-align: justify;"> Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии. </p> <h2 style="text-align: justify;">ПРОТОКОЛ</h2> <p style="text-align: justify;"> <b>Многоцентровая кооперативная проспектив</b><b>но-ретроспективная наблюдательная программа по оценке методов диагностики и лечения </b><b>лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.</b> </p> <h2 style="text-align: justify;">4. АКТУАЛЬНОСТЬ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.<br> Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ. </p> <h2 style="text-align: justify;">5. ЗАДАЧИ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.<br> Подзадачи наблюдательной программы:<br> • Организация рабочей научной группы по ЛХ;<br> • Кумуляция данных о пациентах с ЛХ;<br> • Направление и координация потока пациентов;<br> • Увеличение доступа пациентов к высокотехнологическому лечению;<br> • Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;<br> • Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ. </p> <h2 style="text-align: justify;">6. ЦЕЛЬ ПРОГРАММЫ</h2> <p style="text-align: justify;"> Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения. </p> <h2 style="text-align: justify;">7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ</h2> <p style="text-align: justify;"> Оценить выживаемость пациентов с ЛХ:<br> • без прогрессирования;<br> • с прогрессированием;<br> • общую выживаемость. </p> <h2 style="text-align: justify;">8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ</h2> <p style="text-align: justify;"> 1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;<br> 2. общая выживаемость (ОВ);<br> 3. частота полных ремиссий (ПР);<br> 4. частота рецидивов и прогрессирования заболевания;<br> 5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;<br> 6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;<br> 7. частота потребности во второй линии терапии;<br> 8. частота объективного ответа при использовании разных вариантов второй линии терапии;<br> 9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);<br> 10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;<br> 11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;<br> 12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;<br> 13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;<br> 14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;<br> 15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);<br> 16. оценка использование ресурсов здравоохранения;<br> 17. оценка фертильности на основании частоты удачных беременностей. </p> <h2 style="text-align: justify;">9. ДИЗАЙН ПРОГРАММЫ</h2> <p style="text-align: justify;"> Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты<br> пациентов.<br> Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.<br> В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.<br> В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.<br> Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.<br> Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально. </p> <h2 style="text-align: justify;">10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ</h2> <p style="text-align: justify;"> Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.<br> Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных. </p> <h3 style="text-align: justify;">Критерии включения пациентов в наблюдательную программу:</h3> <p style="text-align: justify;"> • Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;<br> • Возраст не моложе 16 лет на момент начала лечения;<br> • Начало лечения лимфомы Ходжкина не ранее 1.01.2017;<br> • Наличие подписанного информированного согласия на обработку персональных и медицинских данных. </p> <h3 style="text-align: justify;">Критерии исключения пациентов из наблюдательной программы:</h3> <p style="text-align: justify;"> • Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;<br> • Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;<br> • Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;<br> • Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;<br> • Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:<br> – фракция выброса левого желудочка &lt;50%;<br> – инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> – сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> – признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.<br> Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:<br> 1. Пациенты мужского или женского пола в возрасте 18 лет или старше.<br> 2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.<br> 3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).<br> 4. Общее состояние по шкале ECOG ≤ 3 баллов.<br> 5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.<br> 6. Пациентки, которые должны:<br> • находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ<br> • пройти процедуру хирургической стерилизации, ИЛИ<br> • если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или<br> • дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)<br> Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:<br> • дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ<br> • дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)<br> 7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.<br> 8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:<br> • абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;<br> • абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;<br> • общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;<br> • уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;<br> • уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту. </p> <h3 style="text-align: justify;">Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:</h3> <p style="text-align: justify;"> 1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.<br> 2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.<br> 3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.<br> 4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.<br> 5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.<br> 6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:<br> • фракция выброса левого желудочка &lt;50%;<br> • инфаркт миокарда в течение 6 месяцев до включения в протокол;<br> • сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);<br> • признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца. </p> <h2 style="text-align: justify;">11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ</h2> <p style="text-align: justify;"> В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.<br> Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.<br> Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.<br> Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.<br> В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.<br> Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов. </p> <h3 style="text-align: justify;">Лечение и стадирование с применением ПЭТстратегии</h3> <p style="text-align: justify;"> Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях<sup>12</sup>, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD<sup>13</sup>, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc<sup>14</sup>. </p> <h2 style="text-align: justify;">12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1</h2> <p style="text-align: justify;"> Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания<sup>1</sup>. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом<sup>2</sup>. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения<sup>3</sup>. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом<sup>4</sup>. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей<sup>3</sup>,<sup>5</sup>,<sup>6</sup>. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными<sup>7</sup>. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов<sup>10</sup>, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить<sup>11</sup>.<br> Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.<br> Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP14<sup>7,13</sup>, выбор варианта терапии остается на усмотрение учреждений здравоохранения.<br> Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям<sup>1</sup><sup>5</sup>,<sup>16</sup>. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).<br> Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом<sup>17-19</sup>. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом<sup>21,22</sup>. </p> <h2 style="text-align: justify;">13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ</h2> <p style="text-align: justify;"> При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Список сокращений

аллоТГСК – аллогенная трансплантация гемопоэтических стволовых клеток
АЛТ – аланинаминотрансфераза
АСТ – аспартамаминотрансфераза
аутоТГСК – аутологичная трансплантация гемопоэтических стволовых клеток
БДУ – без дополнительных уточнений
ВБП – выживаемость без прогрессирования
ДО – длительность ответа
ИГХ – иммуногистохимия
КТ – компьютерная томография
ЛХ – лимфома Ходжкина
ОВ – общая выживаемость
ПЭТ – позитронной эмиссионной томографии
ПР – полная ремиссия
СОЭ – скорость оседания эритроцитов
ЧО – частичный ответ
eCRF – electronic case report form (электронная индивидуальная регистрационная карта пациента)
SUV – standard uptake value – стандартизированный показатель накопления
Стратификация – процесс или результат разделения выборки на подгруппы (страты) в соответствии с определенными критериями, например, на возрастные, социально-экономические группы
Случайная выборка (Stratified random sample) подразумевает деление популяции на отдельные подгруппы в соответствии с важными характеристиками, например, такими, как возраст или социально-экономический статус, и проведение случайного отбора в каждой из подгрупп. Если из каждой подгруппы (страты) выбирается одинаковая доля, то в выборке будут представлены все страты в таком же соотношении, как в популяции.

СОДЕРЖАНИЕ ПРОТОКОЛА

1. Главные научные кураторы программы и наблюдательный совет 83
2. Список сокращений 84
3. Краткое содержание протокола программы 85
4. Актуальность программы 86
5. Задачи программы 86
6. Цель программы 87
7. Первичные конечные точки 87
8. Вторичные конечные точки 87
9. Дизайн программы 87
10. Популяция пациентов, критерии включения и исключения 87
11. Применяемая терапия в рутинной клинической практике в Российской Федерации 89
12. Обоснование проспективной части наблюдательной программы RNWOHG-HD1 90
13. Лечение в проспективной группе пациентов наблюдательной программы 91
14. Методология сбора данных 91
15. Размер выборки 92
16. План статистического анализа 92
17. Этические аспекты 93
18. Конфиденциальность персональных данных 93
19. Мониторинг 93
20. Ожидаемые результаты 93
21. Блоки данных, обязательные для регистрации в e-CRF 93
22. Приложение 1. Краткое описание схемы лечения в рамках ретроспективной ветки наблюдательной программы RNWOHG-HD1 96
23. Приложение 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов 99
24. Список литературы 102

3. КРАТКОЕ СОДЕРЖАНИЕ ПРОТОКОЛА ПРОГРАММЫ

Название программы

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

Актуальность

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

Задача программы

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.

Цель программы

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

Дизайн программы

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты пациентов.

Длительность программы

Планируемая длительность программы: на 7 лет с 2018 по 2024 годы. В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком. Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.

Популяция пациентов

В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.

Критерии включения пациентов в программу

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.
Критерии исключения пациентов из программы
• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием.
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения.
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка < 50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

Методология сбора данных

Ретроспективно-проспективный сбор данных будет осуществляться на постоянной основе с использованием e-CRF. E-CRF разработана на платформе Quinta (Свидетельство о государственной регистрации программы ЭВМ № 2016615129 «Универсальный программный комплекс для сбора, обработки и управления территориально распределенными клинико-эпидемиологическими данными в режиме удаленного доступа «Quinta», правообладатель ЗАО «Астон Консалтинг»). Для фиксации данных наблюдении пациентов в электронной карте предусмотрена следующая схема из 18 визитов в течении 4 лет с кратностью внесения информации раз в три месяца: Визит 0 – регистрационный визит, Визит 0’/15 – мониторинговые визиты, Визит 16 – закрывающий мониторинговый визит. Регистрационный визит происходит при обращении пациента в любой из включенных в программу центров, и состоит из сбора минимального набора информации: дата обращения, социально демографические данные, данные лабораторных анализов (в том числе патоморфорфологический диагноз), диагноз, назначенное лечение. при включении в программу пациентов, ранее лечившихся по поводу ЛХ, в регистрационную карту будут вноситься ретроспективные данные обследования и лечения и проспективные результаты. Каждый последующий мониторинговый визит собирает всю необходимую медицинскую информацию за прошедшие три месяца, в том числе статус пациента (жив или мертв, в ремиссии или с рецидивом и т.д.), что позволит оценить в последующем общую выживаемость, выживаемость без прогрессирования и другие вторичные точки исследования.

Медико-статистический анализ данных

Исследование носит описательный характер. Все собранные данные и переменные конечных точек будут суммированы с использованием методов описательной статистики и статистического моделирования. Сводные таблицы будут представлены по группам лечения с включением количества случаев (N), средних значений (М), стандартных отклонений (SD), медиан (Me), минимальных (min) и максимальных (max) значений для непрерывных переменных, а также количества и процентной доли в соответствии с категорией для категориальных данных. Будут представлены кривые выживаемости, полученные по методу Каплана-Майера, и 25-й, 50-й (медиана) и 75-й процентили наряду с анализом значимости при 2-стороннем уровне для 95% ДИ для данных времени до наступления события. Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года.

Ожидаемый результат

Ожидается улучшение качества оказания медицинской помощи пациентам с лимфомой Ходжкина в Северо-Западном Федеральном округе Российской Федерации, повышение безрецидивной выживаемости, снижение токсичности проводимой терапии и уменьшение долгосрочных эффектов лечения. Также ожидается снижение финансовой нагрузки на территориальные фонды социального страхования за счет уменьшения числа резистентных пациентов, требующих непрерывного длительного лечения и социальной поддержки. Ожидаемые научные результаты исследования: подтверждение возможности исключения этапа лучевой терапии у пациентов низкого риска с ПЭТ(-) статусом, отсутствие компрометации эффективности лечения при деэскалационной тактике при распространенных стадиях, возможность исключения блеомицина и снижения пульмотоксичности на этапах деэскалации терапии.

ПРОТОКОЛ

Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке методов диагностики и лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ.

4. АКТУАЛЬНОСТЬ ПРОГРАММЫ

Заболеваемость лимфомой Ходжкина (ЛХ) в России составляет 2,1 случая на 100 000 населения в год (3 164 впервые диагностированных больных). Летальность достигает 0,77 случаев на 100 000 населения в год. Заболевание возникает в любом возрасте, но преимущественно в интервале 16-35 лет и в этой возрастной группе преобладают женщины.
Применение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) позволило добиваться излечения у более 90% пациентов даже при продвинутых стадиях заболевания, но до настоящего времени главной задачей остается достижение максимального числа полных и стойких ремиссий уже на первой линии терапии, а основными проблемами лечения являются снижение токсичности, деэскалация проводимой терапии без потери эффективности, так же рассматривается вопрос о возможности снижения дозы лучевой терапии, своевременном выполнением ауто- или аллогенной трансплантации костного мозга. При обследовании больных важную, практически определяющую роль для установления диагноза и точного стадирования болезни, и, соответственно, определения тактики лечения, играет позитронно-эмиссионная томография (ПЭТ). Однако в Российской Федерации она не является распространенным методом диагностики, так как возможность ее выполнения имеется не во всех регионах. Поэтому в рутинной практике имеется разброс в выборе методов диагностики и тактики лечения. Отсутствие единых подходов к диагностике и лечению ЛХ в существующей клинической практики негативно отражается на прогнозе пациентов с ЛХ.

5. ЗАДАЧИ ПРОГРАММЫ

Стратегическая задача программы – стандартизация и улучшение подходов к лечению пациентов с ЛХ в Северо-Западном Федеральном округе Российской Федерации.
Подзадачи наблюдательной программы:
• Организация рабочей научной группы по ЛХ;
• Кумуляция данных о пациентах с ЛХ;
• Направление и координация потока пациентов;
• Увеличение доступа пациентов к высокотехнологическому лечению;
• Оценка возможности выполнения стандартизованного проспективного протокола лечения во все центрах-участниках;
• Исследование значимости позитронно-эмиссионной томографии в лечении ЛХ.

6. ЦЕЛЬ ПРОГРАММЫ

Основная цель – получение данных существующей клинической практики о методах диагностики и лечения ЛХ и сравнение с результатами предлагаемой проспективной схемы лечения на основании оценки выживаемости без прогрессирования и других показателей эффективности и безопасности лечения.

7. ПЕРВИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

Оценить выживаемость пациентов с ЛХ:
• без прогрессирования;
• с прогрессированием;
• общую выживаемость.

8. ВТОРИЧНЫЕ КОНЕЧНЫЕ ТОЧКИ

1. влияние методов обследования, верификации диагноза, роли ПЭТ и варианта лечения на свободу от неудач лечения;
2. общая выживаемость (ОВ);
3. частота полных ремиссий (ПР);
4. частота рецидивов и прогрессирования заболевания;
5. частота ПЭТ-негативного статуса после цикла 2 химиотерапии;
6. частота стабилизации или прогрессирования заболевания после цикла 4 химиотерапии по данным КТ;
7. частота потребности во второй линии терапии;
8. частота объективного ответа при использовании разных вариантов второй линии терапии;
9. частота и потребность выполнения аутологичной трансплантации гемопоэтических стволовых клеток (ауто ТКМ);
10. частота рецидивов и выживаемость без прогрессирования после второй линии терапии с ауто ТКМ;
11. выживаемость без прогрессирования у пациентов при назначении поддержки брентуксимабом после ауто ТКМ;
12. частота объективного ответа при применении 3-ей линии терапии с применением брентуксимаба;
13. частота рецидивов и выживаемость без прогрессирования после третьей линии терапии с или без алло ТКМ;
14. частота токсических осложнений на основании использования критериев СTCAE ver 4.03;
15. частота инфекционных осложнений (пневмония, сепсис, инфекция мягких тканей, инвазивный аспергиллез, инвазивный кандидоз, вирусные оппортунистические инфекции);
16. оценка использование ресурсов здравоохранения;
17. оценка фертильности на основании частоты удачных беременностей.

9. ДИЗАЙН ПРОГРАММЫ

Многоцентровая, кооперативная проспективно-ретроспективная наблюдательная программа с элементом проспективного протокола лечения. Исследование не предусматривает вмешательство в обычный лечебный процесс. Для достижения целей исследования будут анализироваться медицинские карты
пациентов.
Планируемая длительность программы: на 7 лет с 2018 по 2024 годы.
В программу планируется включить не менее 12 центров Северо-Западного Федерального округа РФ. Однако количество центров, принимающих участие в программе, не ограничено территориальным признаком.
В рамках программы планируется проанализировать результаты лечения 900 пациентов, в течение 3 лет планируется включение в программу по 300 пациентов в год. Пациенты будут наблюдаться в течение минимум четырех лет с момента включения в программу и будут постоянно наблюдаться во время и после лечения один раз в три месяца.
Планируемая дата закрытия базы данных 31 декабря 2024 года, если не будет принято решение о продолжении программы. Программа может быть остановлена в любой момент при отсутствии финансирования в течении указанного периода.
Промежуточный медико-статистический отчет по результатам наблюдений планируется готовить ежегодно. На основании ежегодной оценки результатов планируется принятие решения о необходимости внесения изменений в протокол или прекращение программы. Итоговый аналитический отчет планируется подготовить в феврале 2024 года. По НЯ отчеты будут готовиться ежеквартально.

10. ПОПУЛЯЦИЯ ПАЦИЕНТОВ, КРИТЕРИИ ВКЛЮЧЕНИЯ И ИСКЛЮЧЕНИЯ

Взрослые пациенты мужского или женского пола в возрасте от 18 лет и старше с ЛХ (С90) I-IV стадий заболевания с установленным диагнозом классической лимфомы Ходжкина, получающие или получавшие лечение в условиях существующей медицинской практики независимо от линии проведенной терапии. Кандидаты на участие в программе будут отбираться случайным образом, используя методы, исключающие смещение выборки в сторону преобладания каких-либо экономических, социальных, национальных или других групп населения.
Вся персональная информация об участниках исследования будет храниться с соблюдением законов РФ об охране персональных данных.

Критерии включения пациентов в наблюдательную программу:

• Наличие подтвержденного гистологического диагноза классической лимфомы Ходжкина и возможности стадирования в соответствии с классификацией Ann Arbor;
• Возраст не моложе 16 лет на момент начала лечения;
• Начало лечения лимфомы Ходжкина не ранее 1.01.2017;
• Наличие подписанного информированного согласия на обработку персональных и медицинских данных.

Критерии исключения пациентов из наблюдательной программы:

• Нодулярная лимфома Ходжкина с лимфоцитарным преобладанием;
• Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения;
• Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие;
• Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли;
• Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения лимфомы Ходжкина:
– фракция выброса левого желудочка <50%;
– инфаркт миокарда в течение 6 месяцев до включения в протокол;
– сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
– признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.
Критерии включения пациентов в проспективный протокол лечения RNWOHG-HD1 в рамках наблюдательной программы:
1. Пациенты мужского или женского пола в возрасте 18 лет или старше.
2. Пациенты с ЛХ, ранее не получавшие лечения по данному показанию, с рецидивом или прогрессией ЛХ после терапии первой линии, с первым рецидивом или прогрессией после аутоТГСК.
3. Пациенты должны иметь гистологически и иммуногистохимически подтвержденный диагноз классической ЛХ согласно действующей классификации Всемирной организации здравоохранения (нодулярный склероз, смешанная насыщенность клетками, лимфоцитарное преобладание, лимфоцитарное истощение, или же классическая лимфома Ходжкина БДУ (без дополнительных уточнений).
4. Общее состояние по шкале ECOG ≤ 3 баллов.
5. У пациентов должна присутствовать опухоль, поддающаяся двумерному измерению при регистрации рентгенографическим методом (предпочтительно спиральной КТ) в соответствии с пересмотренными критериями оценки ответа для злокачественных лимфом, изложенных в руководстве Международной рабочей группы (Cheson, 2007)23.
6. Пациентки, которые должны:
• находиться в периоде постменопаузы не менее 1 года до визита в рамках скрининга, ИЛИ
• пройти процедуру хирургической стерилизации, ИЛИ
• если они способны к деторождению, дать свое согласие на использование эффективного метода контрацепции в течение периода от подписания формы информированного согласия и вплоть до 6 месяцев после получения последней дозы химиопрепаратов или последней дозы облучения, или
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациентки. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы] и прерванный половой акт не являются приемлемыми методами контрацепции.)
Пациенты мужского пола, даже после хирургической стерилизации (т. е. после вазэктомии), которые должны:
• дать согласие на использование эффективного барьерного метода контрацепции в течение всего периода лечения в рамках исследования, а также в течение 6 месяцев после химиопрепаратов или последней дозы облучения, ИЛИ
• дать согласие на полное воздержание от половых контактов, если это согласуется с предпочтительным и обычным укладом жизни пациента. (Периодическое воздержание [например, календарь, установление факта овуляции, измерение температуры, постовуляционные методы для партнерш мужчин-участников исследования] и прерванный половой акт не являются приемлемыми методами контрацепции.)
7. Добровольно подписанное согласие должно быть получено до проведения любых связанных с исследованием процедур, не являющихся частью стандартного медицинского лечения, с пониманием того, что согласие может быть отозвано пациентом в любое время без ущерба для предоставляемой в будущем медицинской помощи.
8. Клинические лабораторные показатели, указанные ниже, полученные в течение 7 дней до начала лечения:
• абсолютное число нейтрофилов ≥ 1500 /мкл, за исключением известного поражения костного мозга при ЛХ;
• абсолютное число тромбоцитов ≥ 25 000/мкл, за исключением известного поражения костного мозга при ЛХ;
• общий билирубин должен составлять ≤ 1,5х от верхней границы нормы (ВГН), за исключением случаев, когда известно, что повышение уровня связано с синдромом Жильбера;
• уровни АЛТ и АСТ должны составлять ≤ 3х от верхнего предела диапазона нормальных значений; уровни АЛТ и АСТ могут быть до 5 раз выше ВГН, если их повышение может быть обоснованно приписано поражению печени при ЛХ;
• уровень креатинина в сыворотке должен составлять ≤ 200 мкмоль/л и/или расчетный клиренс креатинина должен составлять ≥ 10 мл/минуту.

Критерии исключения пациентов из проспективного протокола лечения RNWOHG-HD1 в рамках наблюдательной программы:

1. Лимфома Ходжкина нодулярного типа с лимфоцитарным преобладанием.
2. Пациентки, выделяющие молоко и кормящие грудью, или имеющие положительный результат анализа сыворотки на беременность в рамках периода скрининга или положительный результат анализа на беременность в день 1 перед началом лечения.
3. Любые серьезные соматические и психические заболевания, которые могут, по мнению исследователя, потенциально помешать завершению лечения согласно протоколу.
4. Любые серьезные соматические и психические заболевания, не позволяющие пациенту подписать информированное согласие.
5. Другое диагностированное злокачественное новообразование с наличием любых признаков активной или остаточной опухоли.
6. Любое из следующих сердечно-сосудистых заболеваний или состояний в течение 6 месяцев до начала лечения:
• фракция выброса левого желудочка <50%;
• инфаркт миокарда в течение 6 месяцев до включения в протокол;
• сердечная недостаточность класса III или IV по классификации Нью-Йоркской кардиологической ассоциации (NYHA);
• признаки текущих неконтролируемых сердечно-сосудистых состояний, включая сердечные аритмии, застойную сердечную недостаточность (ЗСН), стенокардию III-IV функционального класса или электрокардиографические признаки острой ишемии или аномалий проводящей системы сердца.

11. ПРИМЕНЯЕМАЯ ТЕРАПИЯ В РУТИННОЙ КЛИНИЧЕСКОЙ ПРАКТИКЕ В РОССИЙСКОЙ ФЕДЕРАЦИИ

В 2014 году были разработаны клинические рекомендации по обследованию и лечению лимфопролиферативных заболеваний, в том числе лимфомы Ходжкина24. В соответствии с ними стандартом лечения ЛХ для ранних стадий заболевания с благоприятным прогнозом являются 2-4 цикла ПХТ по схеме ABVD с последующей лучевой терапией на зоны исходного поражения в стандартном режиме. Предпочтение отдается 4 циклам ABVD, за исключением тех, кто после тщательно проведенного современного обследования имеет на более 2 зон поражения, отсутствует экстранодальное поражение, массивные конгломераты и ускоренное СОЭ. Вопрос о отмене ЛТ у некоторых больных остается открытым, т.к. до настоящего времени отсутствуют данные клинических исследований, доказывающие эту возможность.
Для ранних стадий с неблагоприятным прогнозом стандартным лечением являются 4-6 циклов ПХТ по схеме ABVD в сочетании с ЛТ СОД 30Гр. на зоны исходного поражения. В группе соматически сохранных больных моложе 50 лет существует возможность применения более интенсивного лечения, которое включает 2 цикла BEACOPP-эскалированный +2 цикла ABVD с последующей ЛТ СОД 30Гр. На зоны исходного поражения. При применении этой программы лечения отмечено увеличение 3-летней выживаемости, свободной от неудач лечения. В тоже время данные о поздней токсичности отсутствуют, поэтому эта программа должна обсуждаться с больными.
Стандартом лечения распространенных стадий является ХТ в сочетании с ЛТ на зоны больших опухолевых массивов, оставшихся после ХТ. Больным в возрасте до 60 лет без симптомов интоксикации и с МПИ 0-2 может быть рекомендовано лечение 6 циклами ABVD при достижении полной ремиссии после 4-х циклов или 8 циклов ABVD при достижении частичной ремиссии после 4-х циклов. В этой ситуации возможно проведение только 2 циклов (а не 4-х) –всего 6 циклов и в последующем ЛТ СОД 30Гр. а остаточные опухолевые массы размером более 2,5 см.
Больным в возрасте до 50 лет с МПИ 3-7 предпочтительнее лечение 6-8 циклами BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2,5 см СОД 30Гр. Подобная терапия приводит к улучшению выживаемости, свободной от неудач лечения, и общей выживаемости. Однако эта схема характеризуется большой токсичностью и требует дополнительного лечения.
В группе соматически сохранных больных в возрасте 50-60 лет без тяжелой сопутствующей патологии с МПИ 3-7 возможно проведение лечения по программе 6-8 циклов BEACOPP-14 с последующим облучением резидуальных опухолевых масс размером более 2.5 см СОД 30Гр.
Терапией выбора для всех больных старше 60 лет остается режим ABVD+ЛТ на резидуальную опухоль размером более 2.5 см СОД 30Гр. BEACOPP-14 является высокотоксичным режимом для большинства этих больных. Таким образом, в Российской Федерации большинство центров используют протоколы ABVD, BEACOPP-14 или BEACOPP эскалированный для различных стадий, групп риска и возрастных групп. Во второй линии терапии рекомендуется использование высокодозных схем DHAP, IGEV и др. Тем не менее, есть центры, рассматривающие возможность проведения BEACOPP во второй линии, если в первой был ABVD. Проспективно-ретроспективная часть программы оценит эффективность этих терапевтических подходов.

Лечение и стадирование с применением ПЭТстратегии

Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом в лечении является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при распространенных стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.

12. ОБОСНОВАНИЕ ПРОСПЕКТИНОЙ ЧАСТИ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ RNWOHG-HD1

Внедрение полихимиотерапии для лечения лимфомы Ходжкина (ЛХ) в 1970-х годах позволило добиваться излечения у более 70% пациентов даже при продвинутых стадиях заболевания1. С этого периода времени длительное время стандартом лечения оставалась схема ABVD в сочетании с радиотерапией. В ряде стран, таких как США, данная схема остается стандартом2. Тем не менее, дальнейшее улучшение результатов лечения ЛХ связано с обширной исследовательской работой German Hodgkin Study Group и внедрением вариантов протокола BEACOPP. В исследовании HD9 было показано, что при продвинутых стадиях ЛХ использование BEACOPP escalated (esc) позволяет излечивать до 87% пациентов, при этом BEACOPP стандартный показывает достоверно худшие результаты лечения3. Для ранних стадий нет преимуществ BEACOPP над ABVD, поэтому ABVD остается стандартом4. Тем не менее, использование такой агрессивной терапии, как BEACOPPesc приводит к повышению гематологической токсичности, нарушениям фертильности и некоторым увеличением частоты вторичных опухолей3,5,6. Поэтому целью дальнейших исследований стало снижение токсичности терапии в группе высокого риска. Одним из подходов – уменьшение интервала введения химиопрепаратов при снижении доз. Данный подход показывает сравнимую эффективность схем BEACOPP14 и BEACOPPesc и несколько меньшую токсичность BEACOPP14, поэтому данные схемы можно считать эквивалентными7. Другой подход к снижению токсичности – деэскалация терапии после двух циклов при достижении полной ремиссии. Было показано, что при переходе на BEACOPP8 standard и даже ABVD9 без снижения эффективности. Параллельно шли исследования возможности уменьшения дозы лучевой терапии. Было показано, что снижение дозы облучения до 20 Gy при ранних стадиях не приводило к повышению частоты рецидивов10, более того достижение ПЭТ (-) статуса при ранних стадиях ЛХ после ABVD, или при продвинутых стадиях после BEACOPP, позволяет радиотерапию не проводить11.
Крайне большую роль в современной терапии ЛХ, как уже упоминалось выше, играет ПЭТ-исследование, которое позволяет выделять группы риска, вовремя деэскалировать терапию со снижением токсичности у пациентов с благоприятным прогнозом и эскалировать у пациентов с неблагоприятным течением заболевания. Было показано, что ключевым моментом влечение является ПЭТ-ответ после двух курсов химиотерапии. Мониторинг ПЭТ в эти сроки позволяет завершить терапию двумя циклами ABVD при ранних стадиях12, при продвинутых стадиях выделить группу пациентов, у которых можно уменьшить токсичность за счет исключения блеомицина из ABVD13, и выделить неблагоприятную группу пациентов, которым требуется продолжение интенсивной терапии BEACOPP14 или BEACOPPesc14.
Таким образом, в основу данного протокола лечения ЛХ легка ПЭТ-адаптированная стратегия с разделением на группы риска. Пациента с ранними стадиями ЛХ при достижении ПЭТ(-) ремиссии не получают дальнейшего лечения, пациенты с ПЭТ (+) статусов в зависимости от степени ответа продолжают ABVD или переходят на терапию BEACOPPesc/BEACOPP14±радиотерапия 20 Gy. При неблагоприятных факторах прогноза и продвинутых стадиях планируется деэскалационная стратегия с переходом на AVD/ABVD после двух циклов BEACOPPesc/BEACOPP14. В ходе деэскалации планируется рандомизацию с целью подтверждения возможности исключения блеомицина в ходе дальнейшей терапии при ПЭТ(-)-статусе. Пациенты, остающиеся ПЭТ(+) после 2 курсов получают полную интенсивную терапию BEACOPPesc/BEACOPP14 до 6 циклов ± радиотерапия в дозе 20 Gy в зависимости от ответа. Учитывая многочисленные данные об эквивалентности BEACOPPesc и BEACOPP147,13, выбор варианта терапии остается на усмотрение учреждений здравоохранения.
Отдельной веткой протокола является лечение пациентов, инфицированных вирусом иммунодефицита человека (ВИЧ). В этой группе пациентов химиотерапия переносится существенно хуже, использование схем на основе BEACOPP приводит к значительной гематологической токсичности и инфекционным осложнениям15,16. Поэтому для данной группы планируется использовать только ABVD в первой линии, с попыткой исключения блеомицина в ходе проведения 3-6 циклов. Как и в основной группе планируется использование ПЭТ после 2-х курсов для сокращения терапии или раннего перехода на 2-ую линию (рис.2).
Данный протокол предусматривает также проведение 2-ой и третьей линии терапии. Выбор варианта второй линии остается на усмотрение учреждений здравоохранения, учитывая сравнимую эффективность схем терапии DHAP, ICE, IGEV, брентуксимаба и бендомустина с брентуксимабом17-19. Для пациентов с IPS 4 или первично химиорезистентной опухолью в рамках 2-ой линии рекомендовано проведение терапии брентуксимабом и бендомустином, учитывая, что в этой группе пациентов эффективность химиотерапии во второй линии значительно ниже и обычно не превышает 20%20. Проведение аутологичной и аллогенной ТГСК будет проводится в центрах Северо-Западного Федерального округа РФ в соответствии с внутренними протоколами. Для пациентов с факторами риска рецидива после аутологичной трансплантации, такими как рецидив ранее 1 года от момента лечения, bulky опухоль, экстрамедуллярные очаги и менее полной ремиссии после 2-ой линии, допустимо проведение поддержки брентуксимабом21,22.

13. ЛЕЧЕНИЕ В ПРОСПЕКТИВНОЙ ГРУППЕ НАБЛЮДАТЕЛЬНОЙ ПРОГРАММЫ

При невозможности выполнения ПЭТ-исследования в процессе лечения, используются схемы лечения на выбор центра, участника наблюдательной программы. В случае возможности выполнения ПЭТ-исследования (3 раза для терапии 1-ой линии, 2 раза для терапии второй линии, 2 раза для терапии 3-ей линии) в процессе лечения, участники наблюдательной программы заявляют о намерении лечить пациентов в соответствии со стандартизованным риск адаптированным ПЭТ-направленным протоколом лечения, далее именуемым RNWOHG-HD1. Схема лечения представлена в приложении 1 (рисунок 1). Схемы лечения, критерии переноса начала курсов и критерии редукции доз при почечной и печеночной недостаточности представлены в приложении 2. Требуется отметить, что проспективная часть программы RNWOHG-HD1 не использует незарегистрированные для лечения ЛХ препараты. Все курсы полихимиотерапии, входящие в данную программу, перечислены в национальных рекомендациях 2014 года. Особенностью протокола является только их последовательная комбинация на основании ПЭТ-направленных эскалационных и деэскалационная стратегий. Лечение ЛХ у пациентов с ВИЧ планируется по отдельному протоколу. Схема протокола представлена в приложении 1 (рисунок 2). В протоколе для ВИЧ-ассоциированной ЛХ также используются только курсы, перечисленные в национальных рекомендациях 2014 года.

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Multicenter cooperative prospectiveretrospective observational program for diagnostics and treatment of Hodgkin disease in the North-Western District of Russian Federation (RNWOHG-HD1 Protocol, the full-text version in Russian), 1st part

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Clinical protocol

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                    [TEXT] => <h3 style="text-align: justify;">Главные научные кураторы программы и наблюдательный совет:</h3>
<p style="text-align: justify;">
	 «Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.
</p>
<h3 style="text-align: justify;">Главные научные кураторы:</h3>
<p style="text-align: justify;">
 <b>Афанасьев Борис Владимирович</b><br>
	 Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br>
 <b>Алексеев Сергей Михайлович</b><br>
	 Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br>
 <b>Моисеев Иван Сергеевич</b><br>
	 Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.
</p>
<h3 style="text-align: justify;">Наблюдательный совет программы:</h3>
<p style="text-align: justify;">
 <b>Афанасьев Борис Владимирович</b><br>
	 Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор<br>
 <b>Беляев Алексей Михайлович</b><br>
	 Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор<br>
 <b>Зарицкий Андрей Юрьевич</b><br>
	 Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.<br>
 <b>Алексеев Сергей Михайлович</b><br>
	 Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.<br>
 <b>Ильин Николай Васильевич</b><br>
	 Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор<br>
 <b>Михайлова Наталья Борисовна</b><br>
	 Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н<br>
 <b>Медведева Надежда Вадимовна</b><br>
	 Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.<br>
 <b>Манихас Георгий Моисеевич</b><br>
	 Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ<br>
 <b>Волошин Сергей Владимирович</b><br>
	 Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург<br>
 <b>Моисеенко Владимир Михайлович</b><br>
	 Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ<br>
 <b>Шнейдер Татьяна Владимировна</b><br>
	 Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области
</p>
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Главные научные кураторы программы и наблюдательный совет:

«Многоцентровая кооперативная проспективно-ретроспективная наблюдательная программа по оценке эффективности и безопасности лечения лимфомы Ходжкина в Северо-Западном Федеральном округе РФ» инициирована экспертами НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой и ФГБУ «НИИ онкологии им. Н. Н. Петрова» МЗ РФ и будет проводиться под руководством наблюдательного совета.

Главные научные кураторы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Моисеев Иван Сергеевич
Заместитель директора по науке, НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии ПСПб ГМУ им. академика И. П. Павлова, к.м.н.

Наблюдательный совет программы:

Афанасьев Борис Владимирович
Директор НИИ детской онкологии, гематологии и трансфузиологии им. Р. М. Горбачевой, заведующий кафедрой гематологии, трансфузиологии и трансплантологии СПб ГМУ им. академика И. П. Павлова, д.м.н., профессор
Беляев Алексей Михайлович
Директор ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, главный внештатный онколог Северо-Западного Федерального округа, заведующий кафедрой онкологии Северо-Западного государственного медицинского университета им. И. И. Мечникова, президент Ассоциации онкологов Северо-Запада, д.м.н., профессор
Зарицкий Андрей Юрьевич
Директор института гематологии ФМИЦ им. В. А. Алмазова, профессор кафедры факультетской терапии Санкт-Петербургского государственного медицинского университета им. акад. И. П. Павлова, д.м.н.
Алексеев Сергей Михайлович
Заместитель главного врача по гематологии ФГБУ «НИИ онкологии им. Н. Н. Петрова» Минздрава России, руководитель химиотерапевтическое отделение онкологии, гематологии и трансплантации костного мозга, к.м.н.
Ильин Николай Васильевич
Руководитель радиотерапевтического отделение № 1 Российского Научного Центра Радиологии и Хирургических Технологий, д.м.н., профессор
Михайлова Наталья Борисовна
Руководитель отдела онкологии и химиотерапии Института детской гематологии и трансплантологии им. Р. М. Горбачевой ПСПбГМУ им. ак. И. П. Павлова, к.м.н
Медведева Надежда Вадимовна
Руководитель Санкт-Петербургского городского центра онкогематологии на базе ГКБ № 31 заместитель главного врача по медицинской части врач-гематолог высшей квалификационной категории к.м.н.
Манихас Георгий Моисеевич
Главный врач ГКОД, главный внештатный специалист онколог Санкт-Петербурга, д.м.н., профессор, заслуженный врач РФ
Волошин Сергей Владимирович
Врач высшей категории, к.м.н., ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург
Моисеенко Владимир Михайлович
Руководитель Санкт-Петербургского клинического научно-практического центра специализированных видов медицинской помощи (онкологический), д.м.н., профессор, заслуженный врач РФ
Шнейдер Татьяна Владимировна
Заведующая онкогематологическим отделением №1 Ленинградской областной клинической больницы, главный внештатный гематолог Ленинградской области

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version in Russian) 3rd part [~DESCRIPTION] => [~NAME] => Name [~DEFAULT_VALUE] => ) [FULL_TEXT_RU] => Array ( [ID] => 42 [TIMESTAMP_X] => 2015-09-07 20:29:18 [IBLOCK_ID] => 2 [NAME] => Полный текст [ACTIVE] => Y [SORT] => 500 [CODE] => FULL_TEXT_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 42 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20077 [VALUE] => Array ( [TEXT] => <h2></h2> <h2 style="text-align: justify;">Вторая линия химиотерапии:</h2> <p style="text-align: justify;"> • Курсы химиотерапии ICE, IGEV, DHAP, бендамустин + брентуксимаб 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:<br> – IPS 1-3;<br> – Химиочувствительная опухоль (по крайней мере, ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:<br> – IPS 4;<br> – Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.<br> • При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Аутологичная трансплантация</h3> <p style="text-align: justify;"> Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра. </p> <h3 style="text-align: justify;">Поддержка брентуксимабом после аутологичной ТГСК</h3> <p style="text-align: justify;"> Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):<br> – рецидив позднее 1 года от диагноза;<br> – нет экстранодального поражения в рецидиве;<br> – полный ответ после 2-ой линии химиотерапии;<br> – нет bulky опухоли в рецидиве.<br> Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):<br> – рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;<br> – есть экстранодальное поражение в рецидиве;<br> – менее, чем полный ответ после 2-ой линии химиотерапии;<br> – есть bulky опухоль в рецидиве. </p> <h2 style="text-align: justify;">Третья линия химиотерапии:</h2> <p style="text-align: justify;"> • Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.<br> • При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.<br> <img width="982" alt="Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png" src="/upload/medialibrary/29d/vetka_protokola_dlya_vich_assotsiirovannoy_limfomy_khodzhkina_risunok_2_risunok_2_lechenie_patsientov_s_vich_infektsiey.png" height="1010" title="Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png"><br> Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.<br> • Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.<br> • Выполняется ПЭТ-КТ.<br> • При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.<br> • При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.<br> • При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.<br> • При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV&lt;6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV&gt;6 пациент переводится на вторую линию терапии.<br> • При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии. </p> <h2 style="text-align: justify;">Вторая линия химиотерапии:</h2> <p style="text-align: justify;"> • Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:<br> – IPS 1-3;<br> – Химиочувствительная опухоль (по крайней мере,<br> ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:<br> – IPS 4;<br> – Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).<br> • Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.<br> • При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии. </p> <h3 style="text-align: justify;">Аутологичная трансплантация</h3> <p style="text-align: justify;"> Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра. </p> <h3 style="text-align: justify;">Поддержка брентуксимабом после аутологичной ТГСК:</h3> <p style="text-align: justify;"> Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):<br> – рецидив позднее 1 года от диагноза;<br> – нет экстранодального поражения в рецидиве;<br> – полный ответ после 2-ой линии химиотерапии;<br> – нет bulky опухоли в рецидиве.<br> Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):<br> – рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;<br> – есть экстранодальное поражение в рецидиве;<br> – менее, чем полный ответ после 2-ой линии химиотерапии;<br> – есть bulky опухоль в рецидиве. </p> <h2 style="text-align: justify;">Третья линия химиотерапии:</h2> <p style="text-align: justify;"> • Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.<br> • При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК. </p> <h2 style="text-align: justify;">23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов</h2> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Схемы химиотерапии.</h3> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">Курс полихимиотерапии ABVD:</h3> <p style="text-align: justify;"> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;<br> • V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла. </p> <h3 style="text-align: justify;">Курс полихимиотерапии AVD:</h3> <p style="text-align: justify;"> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;<br> • D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP-14:</h3> <p style="text-align: justify;"> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;<br> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;<br> • P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP escalated:</h3> <p style="text-align: justify;"> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;<br> • E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;<br> • A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;<br> • P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP-14 с дакарбазином:</h3> <p style="text-align: justify;"> • Используется только при отсутсвии доступа к прокарбазину;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;<br> • A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;<br> • P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии BEACOPP escalated с дакарбазином:</h3> <p style="text-align: justify;"> • Используется только при отсутсвии доступа к прокарбазину;<br> • B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;<br> • E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;<br> • A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;<br> • O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;<br> • P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;<br> • P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;<br> • Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл. </p> <h3 style="text-align: justify;">Курс полихимиотерапии DHAP:</h3> <p style="text-align: justify;"> • D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;<br> • HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;<br> • P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;<br> Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови. </p> <h3 style="text-align: justify;">Курс полихимиотерапии ICE:</h3> <p style="text-align: justify;"> • I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;<br> • С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;<br> • E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;<br> Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови. </p> <h3 style="text-align: justify;">Курс полихимиотерапии IGEV:</h3> <p style="text-align: justify;"> • I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;<br> • GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;<br> • V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;<br> • преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Брентуксимаб:</h3> <p style="text-align: justify;"> • доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Брентуксимаб+бендамустин:</h3> <p style="text-align: justify;"> • брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;<br> • бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла. </p> <h3 style="text-align: justify;">Редукция доз химиопрепаратов при почечной недостаточности:</h3> <p style="text-align: justify;"> Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.<br> • блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина &lt;10 мл/мин – 50% дозы;<br> • доксорубицин: коррекция дозы не проводится;<br> • винбластин/винкристин: коррекция дозы не проводится;<br> • дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина &lt;30 мл/мин – 70% дозы;<br> • прокарбазин: клиренс креатинина &lt;50 мл/мин – 50% дозы;<br> • циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;<br> • этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина &lt;15 мл/мин – 50% дозы;<br> • цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина &lt;45 мл/мин – выбор альтернативной схемы;<br> • карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина &lt;20 мл/мин - выбор альтернативной схемы;<br> • цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина &lt;45мл/мин – выбор альтернативной схемы;<br> • ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина &lt;45мл/мин – выбор альтернативной схемы;<br> • гемцитабин: клиренс креатинина &lt;30 мл/мин – нет редукции или 75% дозы;<br> • винорельбин: коррекция дозы не проводится;<br> • бендамутин: коррекция дозы не проводится. </p> <h3 style="text-align: justify;">Сопроводительная терапия:</h3> <p style="text-align: justify;"> </p> <h3 style="text-align: justify;">ABVD/AVD:</h3> <p style="text-align: justify;"> • Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;<br> • Ондасетрон 8 мг в дни введения химиопрепаратов;<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;<br> • Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;<br> • Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам. </p> <h3 style="text-align: justify;">BEACOPP14/BEACOPPesc:</h3> <p style="text-align: justify;"> • Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">DHAP:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации<br> • Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">ICE:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации<br> • уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">IGEV:</h3> <p style="text-align: justify;"> • Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);<br> • Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;<br> • Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;<br> • Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.<br> Брентуксимаб+бендамустин:<br> • Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;<br> • Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;<br> • Омепразол 20-40 мг 2 раза в день весь период лечения;<br> • Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения<br> • Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;<br> • Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения. </p> <h3 style="text-align: justify;">Условия коррекции сроков начала следующего курса:</h3> <p style="text-align: justify;"> Начало следующего курса может быть отложено в случае:<br> • Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);<br> • Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);<br> • Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок &gt;70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;<br> • Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома. </p> <h2 style="text-align: justify;">24. СПИСОК ЛИТЕРАТУРЫ</h2> <p style="text-align: justify;"> 1. Bonadonna G, Zucali R, Monfardini S et al. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259.<br> 2. Cheson BD. Which Hodgkin’s patients in the Unites States should be treated with BEACOPP? Curr Hematol Malig Rep. 2014 Sep;9(3):222-226.<br> 3. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395.<br> 4. Eich HT, Diehl V, Görgen H et al. Intensified chemotherapy and dose-reduced involved-fi eld radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: fi nal analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-4206.<br> 5. Sieniawski M, Reineke T, Josting A et al. Assessment of male fertility in patients with Hodgkin’s lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19(10):1795-1801.<br> 6. Merli F, Luminari S, Gobbi PG et al. Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi. J Clin Oncol. 2016;34(11):1175-1181.<br> 7. Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799.<br> 8. Borchmann P, Haverkamp H, Diehl V et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin’s lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011;29(32):4234-4242.<br> 9. von Tresckow B, Plütschow A, Fuchs M et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012;30(9):907-913.<br> 10. Engert A, Plütschow A, Eich HT et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640-652.<br> 11. Meyer RM, Gospodarowicz MK, Connors JM et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med. 2012; 366(5):399-408.<br> 12. Eichenauer DA, Engert A. 2012; Advances in the treatment of Hodgkin lymphoma. Int J Hematol 96:535–543.<br> 13. Johnson P, Federico M, Kirkwood A et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. N Engl J Med. 2016;374(25):2419-2429.<br> 14. Engert A. ABVD or BEACOPP for Advanced Hodgkin Lymphoma. J Clin Oncol. 2016;34(11):1167-1169<br> 15. Uldrick TS, Little RF et al. How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. Blood. 2015;125(8):1226-1235.<br> 16. Press OW, Li H, Schöder H et al. US Intergroup Trial of Response-Adapted Th erapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016;34(17):2020-2027.<br> 17. Andreas Engert,Sandra J. Horning. 2011; Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics. Springer-Verlag, Berlin.<br> 18. Zinzani PL, Vitolo U, Viviani S et al. Safety and effi cacy of single-agent bendamustine aft er failure of brentuximab vedotin in patients with relapsed or refractory hodgkin’s lymphoma: experience with 27 patients. Clin Lymphoma Myeloma Leuk. 2015;15(7):404-408.<br> 19. Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.<br> 20. Moskowitz CH, Nimer SD, Glassman JR et al. The International Prognostic Index predicts for outcome following autologous stem cell transplantation in patients with relapsed and primary refractory intermediate-grade lymphoma. Bone Marrow Transplant. 1999;23(6):561-567.<br> 21. Satwani P, Ahn KW, Carreras J et al. A prognostic model predicting autologous transplantation outcomes in children, adolescents and young adults with Hodgkin lymphoma. Bone Marrow Transplant. 2015;50(11):1416-1423.<br> 22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.<br> 23. Cheson BD, Pfi stner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-586.<br> 24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP, бендамустин + брентуксимаб 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере, ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.
Vetka_protokola_dlya_VICh-assotsiirovannoy_limfomy_Khodzhkina_risunok_2_Risunok_2_Lechenie_patsientov_s_VICh_infektsiey.png
Химиотерапия проводится только на фоне высокоактивной антиретровирусной терапии (HAART), совместно с инфекционистом. Инфекционист может внести коррекцию в антиретровирусную терапию, в зависимости от сочетаемости препаратов с химиопрепаратами.
• Для всех стадий заболевания (I-IV) проводится 2 курса ABVD.
• Выполняется ПЭТ-КТ.
• При достижении ПЭТ(-) ПР для стадий I-IIA без неблагоприятных факторов проводится наблюдение.
• При достижении ПЭТ(-) ПР или ПЭТ(+) ЧО для стадий IIB-IV или при наличии неблагоприятных факторов проводится рандомизация со стратификацией риска по IPS между 4 курсами ABVD и AVD с промежуточной КТ после двух курсов.
• При достижении ПЭТ(+) ЧО для стадий I-IIA проводится радиотерапия 30 Gy и последующее наблюдение.
• При ПЭТ(+) статусе для стадий IIB-IV, размере лимфоузлов менее 2.5 см и SUV<6 после 4 курсов ABVD или AVD проводится радиотерапия 30 Gy, при размере лимфоузлов более 2.5 см или SUV>6 пациент переводится на вторую линию терапии.
• При наличии прогрессии на любом этапе лечения пациент переводится на вторую линию терапии.

Вторая линия химиотерапии:

• Курсы химиотерапии ICE, IGEV, DHAP 2 курса (на усмотрение лечебного учреждения) для следующих групп пациентов c:
– IPS 1-3;
– Химиочувствительная опухоль (по крайней мере,
ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса для пациентов с:
– IPS 4;
– Химиорезистентная опухоль (менее ЧО на 1-ой линии химиотерапии).
• Терапия брентуксимаб ± бендамустин 2 курса также доступна по желанию пациента и при наличии возможности учреждения проводить данный вид терапии.
• При наличии прогрессии на любом этапе лечения или отсутствия ЧО пациент переводится на вторую линию терапии.

Аутологичная трансплантация

Аутологичная трансплантация выполняется всем пациентам, получивших по крайней мере частичный ответ на 2-ой линии химиотерапии. Режим мобилизации стволовых клеток и режим кондиционирования оставляется на усмотрение трансплантационного центра.

Поддержка брентуксимабом после аутологичной ТГСК:

Поддержка не рекомендована для следующих пациентов при наличии всех факторов (благоприятный прогноз):
– рецидив позднее 1 года от диагноза;
– нет экстранодального поражения в рецидиве;
– полный ответ после 2-ой линии химиотерапии;
– нет bulky опухоли в рецидиве.
Поддержка может проводиться (на усмотрение лечащего учреждения) для пациентов, имеющих хотя бы 1 из факторов (неблагоприятный прогноз):
– рецидив ранее 1 года от диагноза или отсутствие полной ремиссии после 1-ой линии;
– есть экстранодальное поражение в рецидиве;
– менее, чем полный ответ после 2-ой линии химиотерапии;
– есть bulky опухоль в рецидиве.

Третья линия химиотерапии:

• Для всех пациентов рекомендована терапия брентуксимаб ± бендамустин 2 курса.
• При наличии ЧО или ПО после 2-х курсов пациент направляется на аллогенную ТГСК или лучшую доступную терапию при невозможности проведения аллоТГСК.

23. ПРИЛОЖЕНИЕ 2. Схемы химиотерапии и критерии изменения сроков введения и доз препаратов

Схемы химиотерапии.

Курс полихимиотерапии ABVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 60-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии AVD:

• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• V: винбластин: доза 6 мг/м2 вводится в/в струйно в дни 1 и 15 каждого 28-дневного цикла;
• D: дакарбазин: доза 375 мг/м2 вводится в/в 30-минутной инфузией в дни 1 и 15 каждого 28-дневного цикла.

Курс полихимиотерапии BEACOPP-14:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated:

• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: прокарбазин: доза 100 мг/м2 (округлить до 50 мг) принимается перорально в дни 1-7 каждого 21-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP-14 с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 14-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 14-дневного цикла;
• A: доксорубицин: доза 25 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• С: циклофосфамид: доза 650 мг/м2 вводится в/в струйно в день 1 каждого 14-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 14-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-8 каждого 14-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к в дни 8-13 каждого 14-дневного цикла, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии BEACOPP escalated с дакарбазином:

• Используется только при отсутсвии доступа к прокарбазину;
• B: блеомицин: доза 10 мг/м2 вводится в/в 15-минутной инфузией на 8 день каждого 21-дневного цикла;
• E: этопозид: доза 200 мг/м2 вводится в/в 1-часовой инфузией в дни 1, 2 и 3 каждого 21-дневного цикла;
• A: доксорубицин: доза 35 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• С: циклофосфамид: доза 1250 мг/м2 вводится в/в струйно в день 1 каждого 21-дневного цикла;
• O: винкристин: доза 1.4 мг/м2 (максимально 2 мг) вводится в/в струйно на 8 день каждого 21-дневного цикла;
• P: дакарбазин: доза 375 мг/м2 в/в 1-часовой инфузией в день 1 каждого 14-дневного цикла;
• P: преднизолон: доза 40 мг/м2 принимается перорально в дни 1-14 каждого 21-дневного цикла;
• Филграстим 5 мкг/кг вводится п/к с дня 8 ЛИБО при снижении нейтрофилов менее 1000/мкл (на усмотрение лечебного учреждения) до восстановления нейтрофилов выше 1000/мкл в течение 3 последовательных дней, введение пропускается при уровне лейкоцитов более 15 тыс. в мкл.

Курс полихимиотерапии DHAP:

• D: дексаметазон: доза 40 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 28-дневного цикла;
• HA: цитозар: доза 2000 мг/м2 два раза в день вводится в/в 2-часовой инфузией после окончания введения цисплатина каждого 28-дневного цикла;
• P: цисплатин: доза 100 мг/м2 вводится в/в 24-часовой инфузией в день 1 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии ICE:

• I: ифосфамид: доза 5 г/м2 вводится в/в 24-часовой инфузией в день 2 каждого 28-дневного цикла;
• С: карбоплатин: доза 400 мг/м2 вводится в/в 2-часовой инфузией в день 2 каждого 28-дневного цикла;
• E: этопозид: доза 100 мг/м2 вводится в/в 1-часовой инфузией в дни 1-3 каждого 28-дневного цикла;
Допустимо начало следующего цикла ранее 28 дня в случае восстановления показателей периферической крови.

Курс полихимиотерапии IGEV:

• I: ифосфамид: доза 2 г/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• GE: гемцитабин: доза 800 мг/м2 вводится в/в 2-часовой инфузией в дни 1-4 каждого 21-дневного цикла;
• V: винорельбин: доза 20 г/м2 вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• преднизолон: доза 100 мг вводится в/в 30-минутной инфузией или перорально в дни 1-4 каждого 21-дневного цикла.

Брентуксимаб:

• доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла.

Брентуксимаб+бендамустин:

• брентуксимаб: доза 1.8 мг/кг вводится в/в 30-минутной инфузией в день 1 каждого 21-дневного цикла;
• бендамустин: доза 90 мг/м2 вводится в/в 1-часовой инфузией в день 1 и 2 каждого 21-дневного цикла.

Редукция доз химиопрепаратов при почечной недостаточности:

Расчет клиренса креатинина будет проводится автоматически при первичной регистрации пациента и перед началом второй линии терапии по формуле Кокрофта-Гаута.
• блеомицин: клиренс креатинина 10-50 мл/мин – 75% дозы, клиренс креатинина <10 мл/мин – 50% дозы;
• доксорубицин: коррекция дозы не проводится;
• винбластин/винкристин: коррекция дозы не проводится;
• дакарбазин: клиренс креатинина 45-60 мл/мин – 80% дозы, клиренс креатинина 30-45 мл/мин – 75% дозы, клиренс креатинина <30 мл/мин – 70% дозы;
• прокарбазин: клиренс креатинина <50 мл/мин – 50% дозы;
• циклофосфамид: клиренс креатинина 10-20 мл/мин – 75% дозы;
• этопозид: клиренс креатинина 15-50 мл/мин – 75% дозы, клиренс креатинина <15 мл/мин – 50% дозы;
• цитарабин: клиренс креатинина 45-60 мл/мин – 60% дозы, клиренс креатинина 30-45 мл/мин – 50% дозы, клиренс креатинина <45 мл/мин – выбор альтернативной схемы;
• карбоплатин: клиренс креатинина 20-40 мл/мин – доза 250 мг/м2, клиренс креатинина <20 мл/мин - выбор альтернативной схемы;
• цисплатин: клиренс креатинина 45-60 мл/мин – 75% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• ифосфамид: клиренс креатинина 45-60 мл/мин – 70% дозы, клиренс креатинина <45мл/мин – выбор альтернативной схемы;
• гемцитабин: клиренс креатинина <30 мл/мин – нет редукции или 75% дозы;
• винорельбин: коррекция дозы не проводится;
• бендамутин: коррекция дозы не проводится.

Сопроводительная терапия:

ABVD/AVD:

• Внутривенная или пероральная гидратация не менее 1 литра в дни введения химиопрепаратов;
• Ондасетрон 8 мг в дни введения химиопрепаратов;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7, 15,21 каждого цикла;
• Антибактериальная профилактика ципрофлоксацином 500 мг 2 р\д ПО назначается только при наличии агранулоцитоза более 3 дней или фебрильной нейтропении на предыдущем курсе химиотерапии;
• Профилактика пневмоцистной пневмонии триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю назначается только ВИЧ-инфецированным пациентам.

BEACOPP14/BEACOPPesc:

• Внутривенная или пероральная гидратация не менее 1.5 литра/м2 в дни введения химиопрепаратов;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

DHAP:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• Маннитол 20% 40 мл/м2 за 3 часа и 30 минут до введения цисплатина. Маннитол 20% 100 мл при снижении диуреза менее чем 400 мл/м2/6 часов. Назначение петлевых диуретиков в период во время введения цисплатина запрещено.
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

ICE:

• Внутривенная гидратация не менее 3 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации
• уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

IGEV:

• Внутривенная гидратация не менее 1.5 литров/м2 в дни введения химиопрепаратов (50% – 0.9% NaCl, 50% – 5% глюкоза);
• Введение не менее 40 мл 10% KCl в день продленной инфузией или дробно в рамках гидратации;
• Уромитексан 5 г/м2 24-частовая инфузия одновременно с ифосфамидом;
• Ондасетрон 8 мг 2 раза в день в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Ципрофлоксацин 500 мг 2 раза в день весь период лечения (если не противоречит стандартам противоинфекционной профилактики учреждения);
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения;
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.
Брентуксимаб+бендамустин:
• Внутривенная или пероральная гидратация не менее 1.0 литра/м2 в дни введения бендамустина;
• Ондасетрон 8 мг в дни введения химиопрепаратов, допускается усиление дексаметазоном 4 мг или апрепитантом 80-125 мг;
• Омепразол 20-40 мг 2 раза в день весь период лечения;
• Триметопримом/сульфаметоксазолом 960 мг 2 р\д 3 раза в неделю весь период лечения
• Аллопуринол 300-600 мг (на усмотрение лечащего врача) в дни 1-7 каждого цикла;
• Для женщин – регивидон 1 т/сутки или босерелин/госерелин депо (на усмотрение лечащего врача) весь период лечения.

Условия коррекции сроков начала следующего курса:

Начало следующего курса может быть отложено в случае:
• Уровня нейтрофилов менее 1000/мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Уровня тромбоцитов менее 50000 /мкл на момент наличия цикла (если не связано с доказанным поражением костного мозга);
• Наличие тяжелой бактериальной или грибковой инфекции с сохраняющейся системной воспалительной реакцией (фебрильная лихорадка, С-реактивный белок >70 мг/л) или органной недостаточностью (дыхательная, сердечно-сосудистая, почечная или печеночная) на момент начала цикла;
• Уровень гемоглобина НЕ является основанием для переноса сроков начала следующего цикла, показана трансфузия эритроцитарных компонентов при наличии тяжелого анемического синдрома.

24. СПИСОК ЛИТЕРАТУРЫ

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22. Moskowitz CH, Nademanee A, Masszi T et al. Brentuximab vedotin as consolidation therapy aft er autologous stemcell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853-1862.
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24. Аль-Ради Л.С., Барях Е.А, Белоусова И.Э. и др. Клинические рекомендации по диагностике и лечению лимфопролиферативных заболеваний. Москва, 2014. Опубликовано: oncology-association.ru/docs/ recomend/2016/59klin-rek.pdf.

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Multicenter cooperative prospectiveretrospective observational program for diagnostics and treatment of Hodgkin disease in the North-Western District of Russian Federation (RNWOHG-HD1 Protocol, the full-text version in Russian) 3rd part