ISSN 1866-8836
Клеточная терапия и трансплантация
Изменить отображение страницы на: только анонсы
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It is probably true quite generally that in the history of human thinking
the most fruitful developments frequently take place at those points
where two different lines of thought meet. These lines may have their
roots in quite different parts of human culture, in different times or cultural
environments or different religious traditions; hence if they actually meet,
that is, if they are at least so much related to each other that a real interaction can
take place, then one may hope that new and interesting developments will follow.

Werner Heisenberg

Heisenberg, Werner: “The Role of Modern Physics in the Present Development
of Human Thinking”. 
Physics and Philosophy. The Revolution in Modern Science.
New York: Harper and Brothers Publishers, 1958, pp. 187-206, p. 187.

"Cellular Therapy and Transplantation" (CTT) is a new journal dedicated to creating a meeting point for different lines of thought in the fields of cellular and gene therapy and transplantation. We invite submissions on current issues and findings that help explain how degenerative diseases develop and how cures can be found. A lot of research has been undertaken in these areas recently, and our journal wishes to publish contributions that offer critical reflection on the developments that seem promising at this point in time.

In particular, CTT aims to present a selection of current research articles from Russian speaking countries. We seek to stay abreast of changes that can be expected from a fruitful interaction between the Russian speaking traditions and their neighboring cultures, such as those in the West.

Likewise, we feel that past developments merit critical attention, too; so we intend to publish, on a scale of one item per issue, relevant contributions that provide a reflection on issues in the medical history of CTT fields. For this inaugural issue, the historical contribution is the Raisa Gorbacheva Memorial Lecture given by Prof. Thomas Büchner at the Symposium on Hematopoietic Stem Cell Transplantation on the 110th anniversary of the Saint Petersburg State Medical I. Pavlov University, which took place on 21–22 September 2007.

We would like to thank the following colleagues for undertaking the peer reviews for this issue of CTT: Athanasius A. Anagnostou, Francis A. Ayuk, Ulrike Bacher, Vadim V. Baikov, Alexei B. Chukhlovin, Thomas Eiermann, Maite Hartwig, Nicolaus Kröger, Claudia Lange, Frank Marini, Florian Tögel, Ludmila S. Zoubarovskaya.

Our heartfelt thanks go to Mikhail Gorbachev and the Gorbachev Foundation, for providing us with a kind and most topical foreword. And last but not least, we wish to acknowledge funding by the German Research Foundation (DFG).

May the scientific community welcome this forum as an inviting opportunity for real interaction in the sense of Werner Heisenberg. We're looking forward to receiving your contributions.

" ["~DETAIL_TEXT"]=> string(3281) "

It is probably true quite generally that in the history of human thinking
the most fruitful developments frequently take place at those points
where two different lines of thought meet. These lines may have their
roots in quite different parts of human culture, in different times or cultural
environments or different religious traditions; hence if they actually meet,
that is, if they are at least so much related to each other that a real interaction can
take place, then one may hope that new and interesting developments will follow.

Werner Heisenberg

Heisenberg, Werner: “The Role of Modern Physics in the Present Development
of Human Thinking”. 
Physics and Philosophy. The Revolution in Modern Science.
New York: Harper and Brothers Publishers, 1958, pp. 187-206, p. 187.

"Cellular Therapy and Transplantation" (CTT) is a new journal dedicated to creating a meeting point for different lines of thought in the fields of cellular and gene therapy and transplantation. We invite submissions on current issues and findings that help explain how degenerative diseases develop and how cures can be found. A lot of research has been undertaken in these areas recently, and our journal wishes to publish contributions that offer critical reflection on the developments that seem promising at this point in time.

In particular, CTT aims to present a selection of current research articles from Russian speaking countries. We seek to stay abreast of changes that can be expected from a fruitful interaction between the Russian speaking traditions and their neighboring cultures, such as those in the West.

Likewise, we feel that past developments merit critical attention, too; so we intend to publish, on a scale of one item per issue, relevant contributions that provide a reflection on issues in the medical history of CTT fields. For this inaugural issue, the historical contribution is the Raisa Gorbacheva Memorial Lecture given by Prof. Thomas Büchner at the Symposium on Hematopoietic Stem Cell Transplantation on the 110th anniversary of the Saint Petersburg State Medical I. Pavlov University, which took place on 21–22 September 2007.

We would like to thank the following colleagues for undertaking the peer reviews for this issue of CTT: Athanasius A. Anagnostou, Francis A. Ayuk, Ulrike Bacher, Vadim V. Baikov, Alexei B. Chukhlovin, Thomas Eiermann, Maite Hartwig, Nicolaus Kröger, Claudia Lange, Frank Marini, Florian Tögel, Ludmila S. Zoubarovskaya.

Our heartfelt thanks go to Mikhail Gorbachev and the Gorbachev Foundation, for providing us with a kind and most topical foreword. And last but not least, we wish to acknowledge funding by the German Research Foundation (DFG).

May the scientific community welcome this forum as an inviting opportunity for real interaction in the sense of Werner Heisenberg. We're looking forward to receiving your contributions.

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Борис Владимирович Афанасьев
и Аксель Рольф Цандер

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Boris Vladimirovich Afanasyev
and Axel Rolf Zander

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12pt;">Вероятно, в порядке общего предположения можно сказать, что в истории<br> человеческого мышления наиболее плодотворными часто оказывались те<br> направления, где встречались два различных способа мышления.<br> Эти различные способы мышления, по-видимому, имеют свои корни<br> в различных областях человеческой культуры или в различных временах,<br> в различной культурной среде или в различных религиозных традициях.<br> Если они действительно встречаются, если по крайней мере они так<br> соотносятся друг с другом, что между ними устанавливается взаимодействие,<br> то можно надеяться, что последуют новые и интересные открытия.</span></i><br> </p> <p style="text-align: right;"> <i><span style="font-size: 12pt;"> </span></i> </p> <p style="text-align: right;"> <i><span style="font-size: 12pt;"> Вернер Гейзенберг</span></i> </p> <p style="text-align: right;"> </p> <p style="text-align: right;"> </p> <p style="text-align: right;"> <span style="font-size: 12pt;">В. Гейзенберг, «Роль новой физики в современном развитии человеческого мышления»<br> из «Физика и философии», М., Наука, 1989 (Перевод с немецкого И. А. Акчурина и Э. П. Андреева)</span> </p> <p> «Клеточная Терапия и Трансплантация» - новый журнал, посвященный созданию места встреч для различных направлений мысли в области клеточной и генной терапии, и трансплантации. Мы приглашаем присылать публикации, касающиеся имеющихся проблем и результатов, которые помогают объяснить, как развиваются дегенеративные заболевания, и как изыскать способы их лечения. За последнее время проведено множество исследований в этих областях, и наш журнал хотел бы публиковать статьи, которые дают критическое отражение разработок, которые на данный момент представляются перспективными. </p> <p> В частности, журнал КТТ имеет целью отбор статей о текущих исследованиях в русскоговорящих странах. Мы стремимся оставаться на уровне тех изменений, которые можно ждать от плодотворного взаимодействия между традициями изложения в России и в соседствующих культурах, например - на Западе. </p> <p> Аналогичным образом мы чувствуем, что прошлые разработки также заслуживают критического рассмотрения. Так что мы намерены публиковать (по одной теме в каждом номере) соответствующие публикации, отражающие вопросы истории медицины в области клеточной терапии и трансплантации. Для этого вводного выпуска такой публикацией на исторические темы является лекция памяти Раисы Горбачевой, представленная профессором Т. Бюхнером на Симпозиуме по трансплантации гемопоэтических стволовых клеток по случаю 110-й годовщины Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова, состоявшегося 21-22 сентября 2007 г. </p> <p> Мы хотели бы поблагодарить следующих коллег за рецензирование статей в данном выпуске журнала КТТ: Атанасия А.Анагносту, Фрэнсиса А.Айюка, Ульрику Бахер, Вадима В. Байкова, Алексея Б.Чухловина, Томаса Айермана, Майте Хартвиг, Николауса Крегера, Клаудию Ланге, Франка Марини, Флориана Тегеля, Людмилу С.Зубаровскую. </p> <p> Выражаем сердечную благодарность Михаилу Горбачеву и Фонду Горбачева за представление нам доброго и своевременного предисловия. Наконец, в заключение мы бы хотели особо поблагодарить Германский исследовательский Фонд за финансирование проекта. </p> <p> Мы надеемся, что научное сообщество воспримет этот форум, как приглашение к реальному взаимодействию в смысле высказывания Вернера Гейзенберга. Мы рассчитываем на поступление ваших публикаций. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6159) "

Вероятно, в порядке общего предположения можно сказать, что в истории
человеческого мышления наиболее плодотворными часто оказывались те
направления, где встречались два различных способа мышления.
Эти различные способы мышления, по-видимому, имеют свои корни
в различных областях человеческой культуры или в различных временах,
в различной культурной среде или в различных религиозных традициях.
Если они действительно встречаются, если по крайней мере они так
соотносятся друг с другом, что между ними устанавливается взаимодействие,
то можно надеяться, что последуют новые и интересные открытия.

Вернер Гейзенберг

В. Гейзенберг, «Роль новой физики в современном развитии человеческого мышления»
из «Физика и философии», М., Наука, 1989 (Перевод с немецкого И. А. Акчурина и Э. П. Андреева)

«Клеточная Терапия и Трансплантация» - новый журнал, посвященный созданию места встреч для различных направлений мысли в области клеточной и генной терапии, и трансплантации. Мы приглашаем присылать публикации, касающиеся имеющихся проблем и результатов, которые помогают объяснить, как развиваются дегенеративные заболевания, и как изыскать способы их лечения. За последнее время проведено множество исследований в этих областях, и наш журнал хотел бы публиковать статьи, которые дают критическое отражение разработок, которые на данный момент представляются перспективными.

В частности, журнал КТТ имеет целью отбор статей о текущих исследованиях в русскоговорящих странах. Мы стремимся оставаться на уровне тех изменений, которые можно ждать от плодотворного взаимодействия между традициями изложения в России и в соседствующих культурах, например - на Западе.

Аналогичным образом мы чувствуем, что прошлые разработки также заслуживают критического рассмотрения. Так что мы намерены публиковать (по одной теме в каждом номере) соответствующие публикации, отражающие вопросы истории медицины в области клеточной терапии и трансплантации. Для этого вводного выпуска такой публикацией на исторические темы является лекция памяти Раисы Горбачевой, представленная профессором Т. Бюхнером на Симпозиуме по трансплантации гемопоэтических стволовых клеток по случаю 110-й годовщины Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова, состоявшегося 21-22 сентября 2007 г.

Мы хотели бы поблагодарить следующих коллег за рецензирование статей в данном выпуске журнала КТТ: Атанасия А.Анагносту, Фрэнсиса А.Айюка, Ульрику Бахер, Вадима В. Байкова, Алексея Б.Чухловина, Томаса Айермана, Майте Хартвиг, Николауса Крегера, Клаудию Ланге, Франка Марини, Флориана Тегеля, Людмилу С.Зубаровскую.

Выражаем сердечную благодарность Михаилу Горбачеву и Фонду Горбачева за представление нам доброго и своевременного предисловия. Наконец, в заключение мы бы хотели особо поблагодарить Германский исследовательский Фонд за финансирование проекта.

Мы надеемся, что научное сообщество воспримет этот форум, как приглашение к реальному взаимодействию в смысле высказывания Вернера Гейзенберга. Мы рассчитываем на поступление ваших публикаций.

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Boris Vladimirovich Afanasyev
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Борис Владимирович Афанасьев
и Аксель Рольф Цандер

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Борис Владимирович Афанасьев
и Аксель Рольф Цандер

" } ["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(4) "8495" ["VALUE"]=> array(2) { ["TEXT"]=> string(6547) "<p style="text-align: right;"> <i><span style="font-size: 12pt;">Вероятно, в порядке общего предположения можно сказать, что в истории<br> человеческого мышления наиболее плодотворными часто оказывались те<br> направления, где встречались два различных способа мышления.<br> Эти различные способы мышления, по-видимому, имеют свои корни<br> в различных областях человеческой культуры или в различных временах,<br> в различной культурной среде или в различных религиозных традициях.<br> Если они действительно встречаются, если по крайней мере они так<br> соотносятся друг с другом, что между ними устанавливается взаимодействие,<br> то можно надеяться, что последуют новые и интересные открытия.</span></i><br> </p> <p style="text-align: right;"> <i><span style="font-size: 12pt;"> </span></i> </p> <p style="text-align: right;"> <i><span style="font-size: 12pt;"> Вернер Гейзенберг</span></i> </p> <p style="text-align: right;"> </p> <p style="text-align: right;"> </p> <p style="text-align: right;"> <span style="font-size: 12pt;">В. Гейзенберг, «Роль новой физики в современном развитии человеческого мышления»<br> из «Физика и философии», М., Наука, 1989 (Перевод с немецкого И. А. Акчурина и Э. П. Андреева)</span> </p> <p> «Клеточная Терапия и Трансплантация» - новый журнал, посвященный созданию места встреч для различных направлений мысли в области клеточной и генной терапии, и трансплантации. Мы приглашаем присылать публикации, касающиеся имеющихся проблем и результатов, которые помогают объяснить, как развиваются дегенеративные заболевания, и как изыскать способы их лечения. За последнее время проведено множество исследований в этих областях, и наш журнал хотел бы публиковать статьи, которые дают критическое отражение разработок, которые на данный момент представляются перспективными. </p> <p> В частности, журнал КТТ имеет целью отбор статей о текущих исследованиях в русскоговорящих странах. Мы стремимся оставаться на уровне тех изменений, которые можно ждать от плодотворного взаимодействия между традициями изложения в России и в соседствующих культурах, например - на Западе. </p> <p> Аналогичным образом мы чувствуем, что прошлые разработки также заслуживают критического рассмотрения. Так что мы намерены публиковать (по одной теме в каждом номере) соответствующие публикации, отражающие вопросы истории медицины в области клеточной терапии и трансплантации. Для этого вводного выпуска такой публикацией на исторические темы является лекция памяти Раисы Горбачевой, представленная профессором Т. Бюхнером на Симпозиуме по трансплантации гемопоэтических стволовых клеток по случаю 110-й годовщины Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова, состоявшегося 21-22 сентября 2007 г. </p> <p> Мы хотели бы поблагодарить следующих коллег за рецензирование статей в данном выпуске журнала КТТ: Атанасия А.Анагносту, Фрэнсиса А.Айюка, Ульрику Бахер, Вадима В. Байкова, Алексея Б.Чухловина, Томаса Айермана, Майте Хартвиг, Николауса Крегера, Клаудию Ланге, Франка Марини, Флориана Тегеля, Людмилу С.Зубаровскую. </p> <p> Выражаем сердечную благодарность Михаилу Горбачеву и Фонду Горбачева за представление нам доброго и своевременного предисловия. Наконец, в заключение мы бы хотели особо поблагодарить Германский исследовательский Фонд за финансирование проекта. </p> <p> Мы надеемся, что научное сообщество воспримет этот форум, как приглашение к реальному взаимодействию в смысле высказывания Вернера Гейзенберга. Мы рассчитываем на поступление ваших публикаций. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6159) "

Вероятно, в порядке общего предположения можно сказать, что в истории
человеческого мышления наиболее плодотворными часто оказывались те
направления, где встречались два различных способа мышления.
Эти различные способы мышления, по-видимому, имеют свои корни
в различных областях человеческой культуры или в различных временах,
в различной культурной среде или в различных религиозных традициях.
Если они действительно встречаются, если по крайней мере они так
соотносятся друг с другом, что между ними устанавливается взаимодействие,
то можно надеяться, что последуют новые и интересные открытия.

Вернер Гейзенберг

В. Гейзенберг, «Роль новой физики в современном развитии человеческого мышления»
из «Физика и философии», М., Наука, 1989 (Перевод с немецкого И. А. Акчурина и Э. П. Андреева)

«Клеточная Терапия и Трансплантация» - новый журнал, посвященный созданию места встреч для различных направлений мысли в области клеточной и генной терапии, и трансплантации. Мы приглашаем присылать публикации, касающиеся имеющихся проблем и результатов, которые помогают объяснить, как развиваются дегенеративные заболевания, и как изыскать способы их лечения. За последнее время проведено множество исследований в этих областях, и наш журнал хотел бы публиковать статьи, которые дают критическое отражение разработок, которые на данный момент представляются перспективными.

В частности, журнал КТТ имеет целью отбор статей о текущих исследованиях в русскоговорящих странах. Мы стремимся оставаться на уровне тех изменений, которые можно ждать от плодотворного взаимодействия между традициями изложения в России и в соседствующих культурах, например - на Западе.

Аналогичным образом мы чувствуем, что прошлые разработки также заслуживают критического рассмотрения. Так что мы намерены публиковать (по одной теме в каждом номере) соответствующие публикации, отражающие вопросы истории медицины в области клеточной терапии и трансплантации. Для этого вводного выпуска такой публикацией на исторические темы является лекция памяти Раисы Горбачевой, представленная профессором Т. Бюхнером на Симпозиуме по трансплантации гемопоэтических стволовых клеток по случаю 110-й годовщины Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова, состоявшегося 21-22 сентября 2007 г.

Мы хотели бы поблагодарить следующих коллег за рецензирование статей в данном выпуске журнала КТТ: Атанасия А.Анагносту, Фрэнсиса А.Айюка, Ульрику Бахер, Вадима В. Байкова, Алексея Б.Чухловина, Томаса Айермана, Майте Хартвиг, Николауса Крегера, Клаудию Ланге, Франка Марини, Флориана Тегеля, Людмилу С.Зубаровскую.

Выражаем сердечную благодарность Михаилу Горбачеву и Фонду Горбачева за представление нам доброго и своевременного предисловия. Наконец, в заключение мы бы хотели особо поблагодарить Германский исследовательский Фонд за финансирование проекта.

Мы надеемся, что научное сообщество воспримет этот форум, как приглашение к реальному взаимодействию в смысле высказывания Вернера Гейзенберга. Мы рассчитываем на поступление ваших публикаций.

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Вероятно, в порядке общего предположения можно сказать, что в истории
человеческого мышления наиболее плодотворными часто оказывались те
направления, где встречались два различных способа мышления.
Эти различные способы мышления, по-видимому, имеют свои корни
в различных областях человеческой культуры или в различных временах,
в различной культурной среде или в различных религиозных традициях.
Если они действительно встречаются, если по крайней мере они так
соотносятся друг с другом, что между ними устанавливается взаимодействие,
то можно надеяться, что последуют новые и интересные открытия.

Вернер Гейзенберг

В. Гейзенберг, «Роль новой физики в современном развитии человеческого мышления»
из «Физика и философии», М., Наука, 1989 (Перевод с немецкого И. А. Акчурина и Э. П. Андреева)

«Клеточная Терапия и Трансплантация» - новый журнал, посвященный созданию места встреч для различных направлений мысли в области клеточной и генной терапии, и трансплантации. Мы приглашаем присылать публикации, касающиеся имеющихся проблем и результатов, которые помогают объяснить, как развиваются дегенеративные заболевания, и как изыскать способы их лечения. За последнее время проведено множество исследований в этих областях, и наш журнал хотел бы публиковать статьи, которые дают критическое отражение разработок, которые на данный момент представляются перспективными.

В частности, журнал КТТ имеет целью отбор статей о текущих исследованиях в русскоговорящих странах. Мы стремимся оставаться на уровне тех изменений, которые можно ждать от плодотворного взаимодействия между традициями изложения в России и в соседствующих культурах, например - на Западе.

Аналогичным образом мы чувствуем, что прошлые разработки также заслуживают критического рассмотрения. Так что мы намерены публиковать (по одной теме в каждом номере) соответствующие публикации, отражающие вопросы истории медицины в области клеточной терапии и трансплантации. Для этого вводного выпуска такой публикацией на исторические темы является лекция памяти Раисы Горбачевой, представленная профессором Т. Бюхнером на Симпозиуме по трансплантации гемопоэтических стволовых клеток по случаю 110-й годовщины Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова, состоявшегося 21-22 сентября 2007 г.

Мы хотели бы поблагодарить следующих коллег за рецензирование статей в данном выпуске журнала КТТ: Атанасия А.Анагносту, Фрэнсиса А.Айюка, Ульрику Бахер, Вадима В. Байкова, Алексея Б.Чухловина, Томаса Айермана, Майте Хартвиг, Николауса Крегера, Клаудию Ланге, Франка Марини, Флориана Тегеля, Людмилу С.Зубаровскую.

Выражаем сердечную благодарность Михаилу Горбачеву и Фонду Горбачева за представление нам доброго и своевременного предисловия. Наконец, в заключение мы бы хотели особо поблагодарить Германский исследовательский Фонд за финансирование проекта.

Мы надеемся, что научное сообщество воспримет этот форум, как приглашение к реальному взаимодействию в смысле высказывания Вернера Гейзенберга. Мы рассчитываем на поступление ваших публикаций.

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Prof. Yaitsky, Rector of the University, Prof. Roumiantsev, Prof. Afanasyev, Prof. Zander, Ladies and Gentlemen,

Dear Prof. Afanasyev,

My congratulations for your important achievement, and for the great day you had yesterday with the opening of the new clinic, the Raisa Gorbacheva Memorial Institute of Children Hematology and Transplantation, also for your research team, for all your cooperators, supporters, and sponsors. You do not make much noise, but we all know what you created during the past two years. Thank you, and good wishes for a good cooperation in the future.

Gorbacheva.jpg






Raisa Maximovna Gorbacheva, 1999

Ladies and Gentlemen, were are assembled here in memory of Raisa Gorbacheva. In August 1999, I received a letter from Prof. Roumiantsev and Prof. Vladimirskaya from the Research Institute of Paediatric Haematology in Moscow. The letter said: "Raisa Gorbacheva was the first person in Russia who, in 1991, has supported us in our struggle with acute leukemia in children. She was the first initiator of the foundation of the International Association Hematologists of the World for Children. The department of bone marrow transplantation in our institute was in fact built only because of the support of the Gorbachev family and of Raisa Maximowna personally. During these 9 years, Raisa and the Gorbachev family helped us not only morally, but also financially, with the royalties from book publications authors by both herself and her husband, and of course by the Peace Nobel Prize award sum."

I know that this support is continuing until today, as we saw yesterday.

image002.jpg




1989 Symposium in Pushkinskie Gory on Acute Leukemia and Lymphoproliferative Diseases

In 1986, the Gorbachevs side by side visited East Berlin. And during the following years, Mikhail Gorbachev pursued the idea of “Glasnost” and “Perestrojka”, that turned out to eventually cause a revolution in our two countries, in Europe and in the world. Three years later, in 1989, I got my first opportunity to visit your country by an invitation to a hematology symposium to be held at “Pushkinskie Gory”. We started our trip in Moscow by bus and we had two excellent Russian piano-players in our group who played Chopin for us and Mussorgsky at the house of Mussorgsky's which we visited before we continued to Pushkinskie Gory. There we had a symposium on Acute Leukemia and Lymphoproliferative Diseases. I was asked to give a lecture on Acute Myeloid Leukemia. I started this lecture by thanking the organisers for inviting me, although I was a German. But they accepted this German and they gave us their friendship.

image003.jpg

On the left photo you can see Andrej Vorobiev, actually one of our teachers.





image004.jpg

Andrej Vorobiev, Mrs Büchner, Don Thomas (from left to right)



image005.jpg

Boris Afanasyev, 1989, another important teacher.




Let us now talk about Acute Myeloid Leukemia (AML), about the disease itself and the problems linked to the disease. AML is characterised by a bone marrow tightly packed with leukemic cells. All cells which produce normal blood cells have disappeared.

image006.jpg



Image 1. AML bone marrow


When we remove the leukemic cell burden by chemotherapy until bone marrow gets empty and does not contain any blood forming cells, only some tissue cells are left.

image007.jpg


Image 2. AML bone marrow, aplasia after chemotherapy

This is a chance for a normal cell population to recover so that a patient can go into a complete remission where she or he feels well and we are not able to detect leukemic cells any more, and the patient may even be cured, if not relapsing later. In 1969, all patients still died within two years, and half of the patients even died within the first five months.. This was the pre-chemotherapy era, again confirming AML to be a most aggressive and dreadful disease. 

image008.jpg



Image 3. AML bone marrow, complete remission after chemotherapy

The first of the two tables below shows the results in complete remissions (CR) and 4-5-year continuous complete remissions (CCR) in multicenter randomized trials for younger patients, and the second table represents the results for older patients.

image009.jpg

In 1981 and the following years, many reports in multicenter randomized trials were published. And we have to go into all these publications in order to learn our lessons. This is what those 20.000 patients have given us.

image010.jpg

image011.jpg

Mean percent complete remissions in 31 randomized multicenter trials and 19 882 patients increased over time from 66% to 72% in younger patients, and similarly from 42% to 51% in older patients. 

image012.jpg

For continuous complete AML remissions at 4-5 years, the cure rate increases from 17% to 34% in younger patients, a double cure rate. In older patients there is an increase from 11% to 15% only. So, in comparison to the younger patients group, older patients do worse.

image013.jpg

The German Acute Myeloid Leukemia Cooperative Group started its work in 1978. Our first observation was that patients who did not receive any post-remission chemotherapy have no chance of a longer relapse-free survival. In the following years we intensified our chemotherapy step-by-step by giving consolidation and maintenance. By double induction and maintenance, the cure rate of these patients was raised to 35%, which was, however, not enough. Yet the good point about this is that these are the results for patients of all age groups.

We tried to improve the results by further intensifying chemotherapy. By HAM-HAM induction, randomised against TAD-HAM, representing a difference in dosage of factor 2 there was no difference in the overall survival. And this lesson shows us that once a certain intensity of chemotherapy has been reached, we may not be able to further improve the results. Those may in fact be the limits of cytotoxic treatment. So we have to look for alternatives. This is true for patients of all ages.

The overall survival of older patients amounts to only half of the overall survival of younger patients. So the situation for older patients is two times worse. This is a very important finding because two thirds of our patients are 60 years of age or older.

image014.jpg

AML is a disease of older people. The treatment of older age AML is a challenge for the future. The challenge is to improve the results not only in the children, but also in the grandparents.

We also have to look at the chromosomes that show typical abnormalities in AML. These abnormalities give predictions for different outcomes in patients.

A favorable cytogenetic group is associated with a relatively long overall survival on the top and unfavorable cytogenetics predict for a short survival (on the bottom). And in between, three other groups of outcome in AML (AMLCG). So we can establish a hierarchy of classification on the basis of cytogenetics.

image015.jpg

image016.jpg

This slide shows that this classification is maintained in both age groups, in the younger patients on the left and also in the older patients on the right. But you see that in the older patients the general survival is significantly lower, which proves that the situation for older patients is worse.

We also have to look at the genes and their mutations as discovered more recently. We are in a position to find out particular genes and their mutations. This is especially important in the patients with normal karyotypes. Since half of the patients have normal karyotypes, we cannot classify them by cytogenetics.

There are some important mutations, such as mutations of the nucleophosmin1 gene in an acute myeloid leukemia (NPM), particularly when combined with the absence of an FLT3 mutation.

This combination really predicts a favorable outcome for patients of all ages.

image017.jpg

In contrast to other combinations of the two genes, we need this again for classification. And we need the mutations in the future for therapeutic targets, of course.

image018.jpg

This slide shows the steps of improvement of chemotherapy together with allogeneic transplantation. Allogeneic transplantation represents the most important alternative to chemotherapy. Moreover, allogeneic transplantation appears superior to chemotherapy. However, it is difficult to measure it. There are different approaches. One approach is Match Pair analysis. You see 84 transplantations compared to 84 chemotherapy patients in the Matched Pair system. And you see some superiorities which are not quite significant.

Furthermore, here, allogeneic transplantation appears highly superior to chemotherapy. However, you have to keep in mind that transplant patients are positively selected patients. In addition, they are younger than 60, in contrast to the chemotherapy patients, who are of all ages. However, allogeneic transplantation looks promising.

image019.jpg

Here we did additional comparisons and analyses of allogeneic transplantation. The slide presents Matched Pair Analysis of 98 chemotherapy patients. A transplant is highly superior in the probability to remain without relapse.

image020.jpg

Those patients mostly do not relapse. However, if you look at the overall survival of these patients they become superimposable. This teaches us that allogeneic transplantation in all adults is associated with considerable mortality. We need to find out how transplant associated mortality can be overcome. This would really bring us much forward.

image021.jpg

This could be done for instance by reduction in the Total Body Irradiation here at 8 Gy instead of 12 Gy. In this study it led to a high cure rate for the transplant patients, even in their overall survival. It looks like the transplant associated mortality was overcome in this study. And this is very encouraging. I heard from Hans-Jochem Kolb that this is also possible by reduction in chemotherapeutic conditioning of patients with similar results.

It is very promising also for our older patients. Patients even over 60 years old and even over 70 years old may be treated by allogeneic transplantation in the future.

image022.jpg

We also need better cooperation and we try to have it in the European Leukemia Network which is being funded by the European Commission in Brussels. In this network we combine a huge number of centres, of countries and of investigators.

We also created a network of multicenter therapeutic trials for AML. For such trials, researchers normally don't cooperate but rather compete with each other. But here they are cooperating using the instrument of a common standard arm.

The first symposium of the European Leukemia Network was in 2004. President Mikhail Gorbachev sent us a greeting address.

image023.jpg

The next annual meeting will be in January 2009. We are hoping for Mikhail Gorbachev to join us in this meeting and to speak to us. We like to learn from paediatricians.

My colleague, Professor Ritter, from our university, gave me this slide about AML-multicenter-BFM trial, the Berlin/ Frankfurt/ Munich trial. And you see a stepwise improvement of the results according to the optimisation. A similar picture as in the adults.

image024.jpg

Paediatricians have a lot to teach us and we appreciate learning from them. More than 15 years ago, while in St. Petersburg with Boris Afanasyev, Edith and I met a family, with a little girl just undergoing allogeneic transplantation from her sister. She is now a medical student.

image025.jpg

Ladies and Gentlemen, I hope I could give you a taste of the efforts required for helping patients with Acute Myeloid Leukemia, efforts of investigators, efforts of clinicians, and efforts of dedicated persons, their sponsorship, their organisation, their political work, let me say, their spirit. And this is the contribution of Raisa Gorbacheva. We will never forget Raisa Gorbacheva. We, our children, our grandchildren, and even history will not forget Raisa. 

Thank you. 


" ["~DETAIL_TEXT"]=> string(18444) "

Prof. Yaitsky, Rector of the University, Prof. Roumiantsev, Prof. Afanasyev, Prof. Zander, Ladies and Gentlemen,

Dear Prof. Afanasyev,

My congratulations for your important achievement, and for the great day you had yesterday with the opening of the new clinic, the Raisa Gorbacheva Memorial Institute of Children Hematology and Transplantation, also for your research team, for all your cooperators, supporters, and sponsors. You do not make much noise, but we all know what you created during the past two years. Thank you, and good wishes for a good cooperation in the future.

Gorbacheva.jpg






Raisa Maximovna Gorbacheva, 1999

Ladies and Gentlemen, were are assembled here in memory of Raisa Gorbacheva. In August 1999, I received a letter from Prof. Roumiantsev and Prof. Vladimirskaya from the Research Institute of Paediatric Haematology in Moscow. The letter said: "Raisa Gorbacheva was the first person in Russia who, in 1991, has supported us in our struggle with acute leukemia in children. She was the first initiator of the foundation of the International Association Hematologists of the World for Children. The department of bone marrow transplantation in our institute was in fact built only because of the support of the Gorbachev family and of Raisa Maximowna personally. During these 9 years, Raisa and the Gorbachev family helped us not only morally, but also financially, with the royalties from book publications authors by both herself and her husband, and of course by the Peace Nobel Prize award sum."

I know that this support is continuing until today, as we saw yesterday.

image002.jpg




1989 Symposium in Pushkinskie Gory on Acute Leukemia and Lymphoproliferative Diseases

In 1986, the Gorbachevs side by side visited East Berlin. And during the following years, Mikhail Gorbachev pursued the idea of “Glasnost” and “Perestrojka”, that turned out to eventually cause a revolution in our two countries, in Europe and in the world. Three years later, in 1989, I got my first opportunity to visit your country by an invitation to a hematology symposium to be held at “Pushkinskie Gory”. We started our trip in Moscow by bus and we had two excellent Russian piano-players in our group who played Chopin for us and Mussorgsky at the house of Mussorgsky's which we visited before we continued to Pushkinskie Gory. There we had a symposium on Acute Leukemia and Lymphoproliferative Diseases. I was asked to give a lecture on Acute Myeloid Leukemia. I started this lecture by thanking the organisers for inviting me, although I was a German. But they accepted this German and they gave us their friendship.

image003.jpg

On the left photo you can see Andrej Vorobiev, actually one of our teachers.





image004.jpg

Andrej Vorobiev, Mrs Büchner, Don Thomas (from left to right)



image005.jpg

Boris Afanasyev, 1989, another important teacher.




Let us now talk about Acute Myeloid Leukemia (AML), about the disease itself and the problems linked to the disease. AML is characterised by a bone marrow tightly packed with leukemic cells. All cells which produce normal blood cells have disappeared.

image006.jpg



Image 1. AML bone marrow


When we remove the leukemic cell burden by chemotherapy until bone marrow gets empty and does not contain any blood forming cells, only some tissue cells are left.

image007.jpg


Image 2. AML bone marrow, aplasia after chemotherapy

This is a chance for a normal cell population to recover so that a patient can go into a complete remission where she or he feels well and we are not able to detect leukemic cells any more, and the patient may even be cured, if not relapsing later. In 1969, all patients still died within two years, and half of the patients even died within the first five months.. This was the pre-chemotherapy era, again confirming AML to be a most aggressive and dreadful disease. 

image008.jpg



Image 3. AML bone marrow, complete remission after chemotherapy

The first of the two tables below shows the results in complete remissions (CR) and 4-5-year continuous complete remissions (CCR) in multicenter randomized trials for younger patients, and the second table represents the results for older patients.

image009.jpg

In 1981 and the following years, many reports in multicenter randomized trials were published. And we have to go into all these publications in order to learn our lessons. This is what those 20.000 patients have given us.

image010.jpg

image011.jpg

Mean percent complete remissions in 31 randomized multicenter trials and 19 882 patients increased over time from 66% to 72% in younger patients, and similarly from 42% to 51% in older patients. 

image012.jpg

For continuous complete AML remissions at 4-5 years, the cure rate increases from 17% to 34% in younger patients, a double cure rate. In older patients there is an increase from 11% to 15% only. So, in comparison to the younger patients group, older patients do worse.

image013.jpg

The German Acute Myeloid Leukemia Cooperative Group started its work in 1978. Our first observation was that patients who did not receive any post-remission chemotherapy have no chance of a longer relapse-free survival. In the following years we intensified our chemotherapy step-by-step by giving consolidation and maintenance. By double induction and maintenance, the cure rate of these patients was raised to 35%, which was, however, not enough. Yet the good point about this is that these are the results for patients of all age groups.

We tried to improve the results by further intensifying chemotherapy. By HAM-HAM induction, randomised against TAD-HAM, representing a difference in dosage of factor 2 there was no difference in the overall survival. And this lesson shows us that once a certain intensity of chemotherapy has been reached, we may not be able to further improve the results. Those may in fact be the limits of cytotoxic treatment. So we have to look for alternatives. This is true for patients of all ages.

The overall survival of older patients amounts to only half of the overall survival of younger patients. So the situation for older patients is two times worse. This is a very important finding because two thirds of our patients are 60 years of age or older.

image014.jpg

AML is a disease of older people. The treatment of older age AML is a challenge for the future. The challenge is to improve the results not only in the children, but also in the grandparents.

We also have to look at the chromosomes that show typical abnormalities in AML. These abnormalities give predictions for different outcomes in patients.

A favorable cytogenetic group is associated with a relatively long overall survival on the top and unfavorable cytogenetics predict for a short survival (on the bottom). And in between, three other groups of outcome in AML (AMLCG). So we can establish a hierarchy of classification on the basis of cytogenetics.

image015.jpg

image016.jpg

This slide shows that this classification is maintained in both age groups, in the younger patients on the left and also in the older patients on the right. But you see that in the older patients the general survival is significantly lower, which proves that the situation for older patients is worse.

We also have to look at the genes and their mutations as discovered more recently. We are in a position to find out particular genes and their mutations. This is especially important in the patients with normal karyotypes. Since half of the patients have normal karyotypes, we cannot classify them by cytogenetics.

There are some important mutations, such as mutations of the nucleophosmin1 gene in an acute myeloid leukemia (NPM), particularly when combined with the absence of an FLT3 mutation.

This combination really predicts a favorable outcome for patients of all ages.

image017.jpg

In contrast to other combinations of the two genes, we need this again for classification. And we need the mutations in the future for therapeutic targets, of course.

image018.jpg

This slide shows the steps of improvement of chemotherapy together with allogeneic transplantation. Allogeneic transplantation represents the most important alternative to chemotherapy. Moreover, allogeneic transplantation appears superior to chemotherapy. However, it is difficult to measure it. There are different approaches. One approach is Match Pair analysis. You see 84 transplantations compared to 84 chemotherapy patients in the Matched Pair system. And you see some superiorities which are not quite significant.

Furthermore, here, allogeneic transplantation appears highly superior to chemotherapy. However, you have to keep in mind that transplant patients are positively selected patients. In addition, they are younger than 60, in contrast to the chemotherapy patients, who are of all ages. However, allogeneic transplantation looks promising.

image019.jpg

Here we did additional comparisons and analyses of allogeneic transplantation. The slide presents Matched Pair Analysis of 98 chemotherapy patients. A transplant is highly superior in the probability to remain without relapse.

image020.jpg

Those patients mostly do not relapse. However, if you look at the overall survival of these patients they become superimposable. This teaches us that allogeneic transplantation in all adults is associated with considerable mortality. We need to find out how transplant associated mortality can be overcome. This would really bring us much forward.

image021.jpg

This could be done for instance by reduction in the Total Body Irradiation here at 8 Gy instead of 12 Gy. In this study it led to a high cure rate for the transplant patients, even in their overall survival. It looks like the transplant associated mortality was overcome in this study. And this is very encouraging. I heard from Hans-Jochem Kolb that this is also possible by reduction in chemotherapeutic conditioning of patients with similar results.

It is very promising also for our older patients. Patients even over 60 years old and even over 70 years old may be treated by allogeneic transplantation in the future.

image022.jpg

We also need better cooperation and we try to have it in the European Leukemia Network which is being funded by the European Commission in Brussels. In this network we combine a huge number of centres, of countries and of investigators.

We also created a network of multicenter therapeutic trials for AML. For such trials, researchers normally don't cooperate but rather compete with each other. But here they are cooperating using the instrument of a common standard arm.

The first symposium of the European Leukemia Network was in 2004. President Mikhail Gorbachev sent us a greeting address.

image023.jpg

The next annual meeting will be in January 2009. We are hoping for Mikhail Gorbachev to join us in this meeting and to speak to us. We like to learn from paediatricians.

My colleague, Professor Ritter, from our university, gave me this slide about AML-multicenter-BFM trial, the Berlin/ Frankfurt/ Munich trial. And you see a stepwise improvement of the results according to the optimisation. A similar picture as in the adults.

image024.jpg

Paediatricians have a lot to teach us and we appreciate learning from them. More than 15 years ago, while in St. Petersburg with Boris Afanasyev, Edith and I met a family, with a little girl just undergoing allogeneic transplantation from her sister. She is now a medical student.

image025.jpg

Ladies and Gentlemen, I hope I could give you a taste of the efforts required for helping patients with Acute Myeloid Leukemia, efforts of investigators, efforts of clinicians, and efforts of dedicated persons, their sponsorship, their organisation, their political work, let me say, their spirit. And this is the contribution of Raisa Gorbacheva. We will never forget Raisa Gorbacheva. We, our children, our grandchildren, and even history will not forget Raisa. 

Thank you. 


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Томас Бюхнер

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В статье отмечены большие заслуги Р. Горбачевой в борьбе с лейкозами у детей. Раиса Горбачева и ее супруг Михаил Горбачев сделали большой организационный и материальный вклад в лечение лейкозов у детей в России. Данный обзор касается также основных проблем лечения острого миелобластного лейкоза (ОМЛ)Б в том числе общей концепции миелоаблативной терапии. За четыре десятилетия были усовершенствованы терапевтические подходы, что привело к увеличению частоты полных ремиссий и общей выживаемости среди больных ОМЛ. Однако дальнейшая интенсификация обычного лечения не сопровождается возрастанием долгосрочной выживаемости больных. При использовании этого терапевтического подхода отмечено существенное снижение частоты выживания среди лиц старшего возраста (>60 лет). Недавний прогресс связан с использованием некоторых аберраций хромосом и генов для прогнозирования результатов лечения и выживаемости при ОМЛ. Так, мутации в гене нуклеофосмина 1 в отсутствии мутаций FLT3 является не зависящим от возраста прогностическим фактором благоприятного исхода ОМЛ. Значительный прогресс в лечении ОМЛ был достигнут при внедрении метода интенсивной химиотерапии с последующей аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эффективность этого подхода явно превышает эффект обычной терапии в аспекте безрецидивной выживаемости. Однако оценка сравнительной эффективности различных методов терапии может быть связана с рыдом статистических противоречий (например, неравноценного отбора больных при попарном анализе). Кроме того, алло-ТГСК связана со значительной смертностью, связанной с трансплантацией, что влияет на показатели общей выживаемости. Чтобы снизить раннюю смертность, могут рассматриваться варианты кондиционирования со сниженной интенсивностью, особенно для лиц старшего возраста. Большинство клинических испытаний при ОМЛ проводятся как мультицентрические испытания (например, с участием Европейской Лейкемической Сетевой Системы), что обеспечивает ускорение разработок в области повышения эффективности лечения ОМЛ.

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Thomas Büchner

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The article is introduced by a tribute to the huge merits of Mrs. Raisa Gorbacheva's anti-leukemia campaign. Raisa Gorbacheva and her husband, Mr. Michael Gorbachev, have contributed greatly to the arrangement and funding of childhood leukemia treatment in Russia. The review article also covers the basic issues to do with acute myeloid leukemia (AML) treatment, including the general concepts of myeloablative therapy. Over four decades, improvements in therapeutic approaches have resulted in a gradual increase in complete remission rates and general survival of AML patients. However, further intensification of conventional treatments failed to increase the patients' long-term survival. A significantly lower survival rate among older patients (>60 years of age) is found when using this approach. Recent developments are associated with the usage of chromosome and gene aberrations as valuable markers to predict the treatment results and survival in AML. For example, a mutated nucleophosmin 1 gene in the absence of a FLT3 mutation is an age-independent predictor of a favorable outcome in AML. Decisive progress in AML treatment has been achieved when applying intensive chemotherapy followed by allogeneic transplantation of hematopoietic stem cells (allo-HSCT). This approach is clearly superior to conventional therapy in terms of relapse-free survival. However, comparative efficiency for different therapies presents some statistical controversies (e.g., biased patient selection in Matched Pair analysis). Allo-HSCT is still associated with considerable transplant-associated mortality, thus affecting overall survival rates. To avoid early mortality, a reduced-intensity conditioning may be considered, especially for older patients. Most clinical trials in AML are performed as multicentre therapeutic trials (e.g., within the European Leukemia Network): thus providing faster progress in the development of a more efficient AML treatment.

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Thomas Büchner

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Thomas Büchner

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The article is introduced by a tribute to the huge merits of Mrs. Raisa Gorbacheva's anti-leukemia campaign. Raisa Gorbacheva and her husband, Mr. Michael Gorbachev, have contributed greatly to the arrangement and funding of childhood leukemia treatment in Russia. The review article also covers the basic issues to do with acute myeloid leukemia (AML) treatment, including the general concepts of myeloablative therapy. Over four decades, improvements in therapeutic approaches have resulted in a gradual increase in complete remission rates and general survival of AML patients. However, further intensification of conventional treatments failed to increase the patients' long-term survival. A significantly lower survival rate among older patients (>60 years of age) is found when using this approach. Recent developments are associated with the usage of chromosome and gene aberrations as valuable markers to predict the treatment results and survival in AML. For example, a mutated nucleophosmin 1 gene in the absence of a FLT3 mutation is an age-independent predictor of a favorable outcome in AML. Decisive progress in AML treatment has been achieved when applying intensive chemotherapy followed by allogeneic transplantation of hematopoietic stem cells (allo-HSCT). This approach is clearly superior to conventional therapy in terms of relapse-free survival. However, comparative efficiency for different therapies presents some statistical controversies (e.g., biased patient selection in Matched Pair analysis). Allo-HSCT is still associated with considerable transplant-associated mortality, thus affecting overall survival rates. To avoid early mortality, a reduced-intensity conditioning may be considered, especially for older patients. Most clinical trials in AML are performed as multicentre therapeutic trials (e.g., within the European Leukemia Network): thus providing faster progress in the development of a more efficient AML treatment.

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The article is introduced by a tribute to the huge merits of Mrs. Raisa Gorbacheva's anti-leukemia campaign. Raisa Gorbacheva and her husband, Mr. Michael Gorbachev, have contributed greatly to the arrangement and funding of childhood leukemia treatment in Russia. The review article also covers the basic issues to do with acute myeloid leukemia (AML) treatment, including the general concepts of myeloablative therapy. Over four decades, improvements in therapeutic approaches have resulted in a gradual increase in complete remission rates and general survival of AML patients. However, further intensification of conventional treatments failed to increase the patients' long-term survival. A significantly lower survival rate among older patients (>60 years of age) is found when using this approach. Recent developments are associated with the usage of chromosome and gene aberrations as valuable markers to predict the treatment results and survival in AML. For example, a mutated nucleophosmin 1 gene in the absence of a FLT3 mutation is an age-independent predictor of a favorable outcome in AML. Decisive progress in AML treatment has been achieved when applying intensive chemotherapy followed by allogeneic transplantation of hematopoietic stem cells (allo-HSCT). This approach is clearly superior to conventional therapy in terms of relapse-free survival. However, comparative efficiency for different therapies presents some statistical controversies (e.g., biased patient selection in Matched Pair analysis). Allo-HSCT is still associated with considerable transplant-associated mortality, thus affecting overall survival rates. To avoid early mortality, a reduced-intensity conditioning may be considered, especially for older patients. Most clinical trials in AML are performed as multicentre therapeutic trials (e.g., within the European Leukemia Network): thus providing faster progress in the development of a more efficient AML treatment.

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Томас Бюхнер

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Томас Бюхнер

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Горбачевой в борьбе с лейкозами у детей. Раиса Горбачева и ее супруг Михаил Горбачев сделали большой организационный и материальный вклад в лечение лейкозов у детей в России. Данный обзор касается также основных проблем лечения острого миелобластного лейкоза (ОМЛ)Б в том числе общей концепции миелоаблативной терапии. За четыре десятилетия были усовершенствованы терапевтические подходы, что привело к увеличению частоты полных ремиссий и общей выживаемости среди больных ОМЛ. Однако дальнейшая интенсификация обычного лечения не сопровождается возрастанием долгосрочной выживаемости больных. При использовании этого терапевтического подхода отмечено существенное снижение частоты выживания среди лиц старшего возраста (&gt;60 лет). Недавний прогресс связан с использованием некоторых аберраций хромосом и генов для прогнозирования результатов лечения и выживаемости при ОМЛ. Так, мутации в гене нуклеофосмина 1 в отсутствии мутаций FLT3 является не зависящим от возраста прогностическим фактором благоприятного исхода ОМЛ. Значительный прогресс в лечении ОМЛ был достигнут при внедрении метода интенсивной химиотерапии с последующей аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эффективность этого подхода явно превышает эффект обычной терапии в аспекте безрецидивной выживаемости. Однако оценка сравнительной эффективности различных методов терапии может быть связана с рыдом статистических противоречий (например, неравноценного отбора больных при попарном анализе). Кроме того, алло-ТГСК связана со значительной смертностью, связанной с трансплантацией, что влияет на показатели общей выживаемости. Чтобы снизить раннюю смертность, могут рассматриваться варианты кондиционирования со сниженной интенсивностью, особенно для лиц старшего возраста. Большинство клинических испытаний при ОМЛ проводятся как мультицентрические испытания (например, с участием Европейской Лейкемической Сетевой Системы), что обеспечивает ускорение разработок в области повышения эффективности лечения ОМЛ.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3825) "

В статье отмечены большие заслуги Р. Горбачевой в борьбе с лейкозами у детей. Раиса Горбачева и ее супруг Михаил Горбачев сделали большой организационный и материальный вклад в лечение лейкозов у детей в России. Данный обзор касается также основных проблем лечения острого миелобластного лейкоза (ОМЛ)Б в том числе общей концепции миелоаблативной терапии. За четыре десятилетия были усовершенствованы терапевтические подходы, что привело к увеличению частоты полных ремиссий и общей выживаемости среди больных ОМЛ. Однако дальнейшая интенсификация обычного лечения не сопровождается возрастанием долгосрочной выживаемости больных. При использовании этого терапевтического подхода отмечено существенное снижение частоты выживания среди лиц старшего возраста (>60 лет). Недавний прогресс связан с использованием некоторых аберраций хромосом и генов для прогнозирования результатов лечения и выживаемости при ОМЛ. Так, мутации в гене нуклеофосмина 1 в отсутствии мутаций FLT3 является не зависящим от возраста прогностическим фактором благоприятного исхода ОМЛ. Значительный прогресс в лечении ОМЛ был достигнут при внедрении метода интенсивной химиотерапии с последующей аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эффективность этого подхода явно превышает эффект обычной терапии в аспекте безрецидивной выживаемости. Однако оценка сравнительной эффективности различных методов терапии может быть связана с рыдом статистических противоречий (например, неравноценного отбора больных при попарном анализе). Кроме того, алло-ТГСК связана со значительной смертностью, связанной с трансплантацией, что влияет на показатели общей выживаемости. Чтобы снизить раннюю смертность, могут рассматриваться варианты кондиционирования со сниженной интенсивностью, особенно для лиц старшего возраста. Большинство клинических испытаний при ОМЛ проводятся как мультицентрические испытания (например, с участием Европейской Лейкемической Сетевой Системы), что обеспечивает ускорение разработок в области повышения эффективности лечения ОМЛ.

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В статье отмечены большие заслуги Р. Горбачевой в борьбе с лейкозами у детей. Раиса Горбачева и ее супруг Михаил Горбачев сделали большой организационный и материальный вклад в лечение лейкозов у детей в России. Данный обзор касается также основных проблем лечения острого миелобластного лейкоза (ОМЛ)Б в том числе общей концепции миелоаблативной терапии. За четыре десятилетия были усовершенствованы терапевтические подходы, что привело к увеличению частоты полных ремиссий и общей выживаемости среди больных ОМЛ. Однако дальнейшая интенсификация обычного лечения не сопровождается возрастанием долгосрочной выживаемости больных. При использовании этого терапевтического подхода отмечено существенное снижение частоты выживания среди лиц старшего возраста (>60 лет). Недавний прогресс связан с использованием некоторых аберраций хромосом и генов для прогнозирования результатов лечения и выживаемости при ОМЛ. Так, мутации в гене нуклеофосмина 1 в отсутствии мутаций FLT3 является не зависящим от возраста прогностическим фактором благоприятного исхода ОМЛ. Значительный прогресс в лечении ОМЛ был достигнут при внедрении метода интенсивной химиотерапии с последующей аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Эффективность этого подхода явно превышает эффект обычной терапии в аспекте безрецидивной выживаемости. Однако оценка сравнительной эффективности различных методов терапии может быть связана с рыдом статистических противоречий (например, неравноценного отбора больных при попарном анализе). Кроме того, алло-ТГСК связана со значительной смертностью, связанной с трансплантацией, что влияет на показатели общей выживаемости. Чтобы снизить раннюю смертность, могут рассматриваться варианты кондиционирования со сниженной интенсивностью, особенно для лиц старшего возраста. Большинство клинических испытаний при ОМЛ проводятся как мультицентрические испытания (например, с участием Европейской Лейкемической Сетевой Системы), что обеспечивает ускорение разработок в области повышения эффективности лечения ОМЛ.

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Introduction

Human leukocyte antigens (HLA), or the major histocompatibility complex represents a genetic system which plays a central role in the immune response, recognizing “own” and “foreign” cells, and presenting processed antigens to immunocompetent cells. This system is characterized by extreme polymorphism. The HLA gene complex is located at chromosome 6 (short arm), includes over 4000 base pairs, and consists of three gene groups (Class I, II, and III). According to the Classification of 2005, it includes 47 loci, encoding over 2000 known allelic variants [7]. Such an extreme polymorphism is stipulated by a necessity to withstand a huge number of evolving environmental antigens, and to maintain the genetic individuality of the human organism. Therefore, a search for two individuals with identical genetic characteristics is prone to sufficient problems.
   
At the same time, successful transplantation of unrelated hematopoietic stem cells (HSCT) is primarily determined by the genetic similarity between recipient and donor [2]. This highly technological therapeutic approach is successfully employed worldwide to treat many diseases, including different leukemias, combined immune deficiencies, generalized autoimmune diseases and so on. To carry out a selection of donor-recipient pairs, a network of regional HSC donor registries is arranged throughout the world, under active cooperation within this community. For several years, the Russian Registry has been cooperating with the Stefan Morsch Foundation [1], in performing mutual searches for donors for patients with hemoblastosis.

The aim of our study was to evaluate immunogenetic characteristics among HSC donors, including the populations from various Russian regions, as well as comparisons with appropriate data from German Registries.

befd73a94d.png

Materials and methods

Characteristics of the group under study

HLA typing for class A and B loci was performed on 1198 persons included in the Registry of potential bone marrow donors, based upon the Russian Research Institute of Hematology and Transfusion. Most of these cohorts were represented by regular blood donors. Small numbers of volunteers and relatives of the patients with hemoblastosis were also involved. In general, distribution for age and gender corresponds to appropriate parameters for blood donors, i.e., males prevailed in the samples (63%). With respect to age, the group mainly represents a cohort from 26 to 40 years (50%), followed by individuals of 40 to 50 years old (35.7%). The least numerous group was represented by persons 18 to 25 years old (14%). In Samara, Kirov, Rostov-upon-Don, and Nizhny Novgorod 161, 196, 347, and 817 persons respectively, were studied (Fig. 1). All these persons were active blood donors.

dab56709db.png

HLA Class I typing

Class A and B HLA typing was performed by serological techniques, in a standard microlymphocytotoxic test, using a panel of histotyping anti-leukocyte sera produced at Russian Institute of Hematology and Transfusion. 

Statistical analysis 

The prevalence of antigen (А) was calculated according to equation: А=n/N, where n is number of donors with given antigen, and N, total number of persons studied.

The prevalence of the gene (p) was determined by the following equation:

2008-1-en-Bubnova-Formula-1-300dpi-205px.png

where А is the prevalence of the appropriate antigen [4].
Haplotype frequency for the two genes  (Н) was estimated using the equation:

2008-1-en-Bubnova-Formula-2-300dpi-282px.png

where р₁ and р₂ are gene frequencies for HLA antigens, and ∆₁,₂ is an inter-allelic disequilibrium linkage.

The values of disequilibrium linkage (∆₁,₂) were calculated accordingly, using a formula from a four-field table (2x2 tables) [5]

2008-1-en-Bubnova-Formula-3-300dpi-475px.png

where a, b, c, and d comprise values in the fields of the tables; N = a+b+c+d, the volume of sample;
а = + + (number of donors in the given sample in whom both antigens of the given haplotype are present);
b = + – (number of donors in the given sample in whom the first of two antigens of the given haplotype is present);
c = – + (number of donors in the given sample in whom the second of two antigens of the given haplotype is present);
d =  – – (number of donors in the given sample in whom both antigens of the given haplotype are absent).
To evaluate the statistical significance of differences for HLA antigen frequencies between the groups, we used χ² criterion [10].

2008-1-en-Bubnova-Formula-4-300dpi-491px.png

where
a is the number of donors in group 1 with a given antigen,
b is the number of donors in group 1 without this antigen,
c is the number of donors in group 2 with a given antigen,
d is the number of donors in group 2 without this antigen,

n, the numbers of persons in the group,
/a•d – b•c/ – absolute value of difference,
0,5•n – correction for continuity in small samples.

The determination of the p level corresponding to the assessed χ² value was performed with computer software, taking into account one degree of freedom (df=1). With respect to the polyallelic nature of the HLA set, calculation of corrected p levels was carried out when testing the significance of differences for distribution of a given trait [8].

2008-1-en-Bubnova-Formula-5-300dpi-316px.png

where n is a number of traits studied.
χ² values exceeding 3,841 (corresponding to Р<0,05), were regarded as a stable borderline index for significant difference between the frequencies in the groups compared.

Results

As seen in Table 1, the HLA class I study at the St. Petersburg Registry reveals that among locus A specificities, A2 and A3 (48.9% and 28.7% respectively) are the most common specificities. When analyzing distributions in locus B antigens for the same populations, B7 and B35 are frequently represented (26.8% and 20.9% resp.; see Table 2).

d2c68b5329.png

The common incidence of these genes is characteristic of the general European population [3]. However, if compared with the German Registry [6], which is among the largest in the Europe, one may see that in spite of a general similarity, the frequency of some genes differs quite significantly. It concerns such locus A specificities as A1 (20.8% in St. Petersburg vs 28.9% in Germany), А9 (23.7% vs 20.6%), and А10 (19.7% vs 13.3%).

These differences are even more pronounced for locus B; for example B8, a quite common gene, occurs among Germans much more often than in the Russian Registry (20.3% and 12.4% resp.). Meanwhile, the frequencies of the В13 and В18 antigens that are rather common in St. Petersburg proved to occur half as often in the German population (11.7% vs 6.9%, and 14.9% vs 9.7%). The incidence of the B41 antigen was almost 3-fold higher in St. Petersburg than in Germany—thus suggesting a different distribution of some genes in Russia and Germany, in spite of the general similarity of both populations.

When studying haplotype incidence for A and B loci (Table 3), we have shown that the following haplotypes are the most common in the St. Petersburg Registry: А2-В7 (4.25%), А2-В35 (3.44%), and А3-В7 (3.31%); whereas А11-В35 and А25-В18 proved to be more rare (0.13% and 1.11% resp.).

03de4758dc.png

A comparative study of haplotype frequencies for two genes from the A and B loci in the Russian and German Registries (Table 3) has shown that their incidence is sufficiently different: the most common in St. Petersburg, the А2-В7 haplotype, is at the 5th position in the German sample, whereas the A1-B8 haplotype, which occurs most commonly in Germany and in a majority of European countries, occupies only 9th position in the population of St. Petersburg.

The absence of certain highly prevalent haplotypes is another important feature of the Russian Registry, thus being indicative for a more pronounced genetic heterogeneity in the local population, i.e., neither of the most common haplotypes in St. Petersburg is over-represented, as compared to the German population with 8.29% for A1-B8, 5.73% for A3-B7, or 4.65% for A2-B44. In St. Petersburg, the most common А2-В7 haplotype was found in 4.25% of cases.

Our results suggest that the distribution of HLA genes and haplotypes of the MHC complex in the St. Petersburg Registry shows gross similarities to the gene distribution in Western Europe. The St. Petersburg Registry, however, displays some specific features due to an altered frequency due to some antigenic specificity and more pronounced genetic heterogeneity among the populations represented in the Registry.

We analyzed the opportunities for unrelated donor matching for 52 patients with oncohematological disorders treated at the Institute clinics. Comparisons of phenotypically determined HLA sets for the patients with those represented in the donor Registry showed that HLA-A,B-compatible donors were found for 48% of the patients. When based on the patient’s phenotype, the ratio of class I-compatible donors for each patient proved to be 1 to 14, thus providing evidence in favor of finding a donor for the patients even within a relatively small registry of potential donors from the same region.
 
When comparing the frequencies of loci A and B specificities among the donors from Russian regions and Germany, the most pronounced differences, both for single antigens and haplotypes, were revealed between the general cohorts from the German Registry and the Russian Republican Registry (Fig. 2, Tables 2, 3). 

2008-1-en-Bubnova-Figure-2-72dpi-429px.png

That is, the most similar genetic characteristics are expressed in the donors from St. Petersburg and Nizhny Novgorod (Fig. 3). 

2008-1-en-Bubnova-Figure-3-72dpi-733px.png

Donors from the Samara Region are, for some characteristics, closer to German donors (Fig. 2), whereas the persons from Kirov possess some markers that are typical to Northern folk. Donors from Rostov-upon-Don represent a highly heterogeneous population with respect to their nationality, since this region is inhabited by Russians, as well as Ukrainians, Armenians, Greeks, etc. However, their immunogenetic features tend to be more similar to other representatives of the Russian Republican Register than to the German population. As seen in Table 3, containing a synopsis of 10 most common haplotypes, the А2-В7 haplotype is encountered most often in St. Petersburg, as well as in Rostov-upon-Don and Kirov. In Nizhny Novgorod, however, it holds 2nd position, whereas in Samara Region, a European A1-B8 haplotype is clearly prevalent (Fig. 4).

28007d5c86.png

This data confirms the need for an urgent expansion of the Russian Register for potential HSC donors, since the probability of finding a donor for Russian patients becomes sufficiently higher when the search is performed in a regional Registry. Taking into account the significant rate of current migration to Germany, a closer working cooperation would be desirable between the Russian and German Registries.

Discussion

HLA polymorphism has evolved since the very origin of human beings. Its evolution was influenced by many factors, as the immune system has undergone its development for effective protection against the invasion of potential pathogens, i.e., from viruses to pathogenic worms.

The ability for a rapid response to single pathogens is mediated by the adaptive immune system, including an appropriate scale of host responses provided by the HLA molecules, together with T and B cell receptors. The type of pathogens existing in the various geographic regions inhabited by different human populations may determine the selection of specific HLA gene products. Gene conversions, i.e., substitutions of existing nucleotide sequences of HLA genes with short segments from other HLA alleles or loci within the HLA complex, comprise the main source of biodiversity created within relatively short timelines (e.g., several centuries). This process reconstitutes an HLA gene repertoire for effective protection against pathogens that exist in steadily renewing environment.

Hence, the combined set of HLA gene products expressed in each human population is, mainly, a result of interactions with the flora and animals of the region inhabited by the population over centuries and millennia. Some cases of linkage disequilibrium observed with certain HLA genes reflect evolutionary advantages of appropriate gene-gene interactions.

A history of people inhabiting the region comprises the second important factor that determines the divergence of genetic features between the populations (the so-called "ancestor effect"). For example, А1-В8 is the most common haplotype in the German Registry. As suggested by G. Rodey [9], this genetic feature could be traced back to the Goths and ancient German tribes, whereas the А2-В7 haplotype (the most common in the St. Petersburg Registry) is typical for Vikings. This assumption seems quite probable, due to the close relations between North-Western Slaves and Vikings. The increased frequency of the A1, B8 haplotype in Samara may be due to the mass migration of Germans to the Volga Region, which has taken place since the times of Catherine the Great of Russia in XVIII century (Fig. 4).

As far as the broad phenotypic diversity that is characteristic of the Russian population is concerned, this could be directly connected with the vast habitation areas of Russian people and sharing these territories with other national groups.
 
Summarizing the above results, we may state that a search for donors for recipients living in other regions is associated with significant difficulties, irrespective of the Register size. However, such a search would be facilitated if the donor and the recipient originate from the same region.

Conclusions

1. When performing a comparative analysis of St. Petersburg and German Registries with other regional Russian Registries, we have revealed certain differences in frequencies of HLA genes and haplotypes (A and B loci).

2. The probability of a successful search for a histocompatible HSC donor is higher for a Registry in the country of recipients’ origin.

3. There is a need for the urgent expansion of the Russian HSC Donor Registry.

4. International cooperation between the Registries is necessary, especially when searching for donors for migrants from abroad.

References

1. Bubnova L.N., Beliaeva E.V., Berkos A.S., Nikolenko V.N. A registry of bone marrow donors. Transfusion Medicine 1995, №5, p.14-18. (In Russian)

2. Cleaver S. Donor work-up and transport of bone marrow recommendations and requirement for a standardized practice. Bone Marrow Transplantation 1997;20:621-629.

3. Goldman John M. Special report: Bone marrow transplants using volunteer donors-recommendations and requirements of a standardized practice throughout  the world (1994 update). Blood 1994;84:2833-2839.

4. Haldane J.B. The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 1956;20:309.

5. Mattius P.L., Ihde D., Piazza A., Cepellini R., Bodmer W.F. New approaches to the population genetic segregation analysis of the HLA system. In: Terasaki P.I. (ed): Histocompatibility Testing, 1970. Copenhagen: Munksgaard, 1970.

6. Müller C, Ehninger G., Goldmann S. Gene and haplotype frequency for the loci HLA- A, HLA- B, and HLA- DR based on over 13,000 German Blood Donors. Human Immunology 2003;64,1:137-151.

7. Marsh S., Albert E., Bodmer W., et al. Nomenclature for factors of the HLA system, 2004. Tissue Antigens 2005:65,4:301-370.

8. Pevnitsky L.A. Statistical evaluation of associations between HLA antigens and diseases. Vestnik RAMS. 1998, №7, p.48-51. (In Russian)

9. Rodey G. HLA Beyond tears. introduction to human histocompatibility. Durango, CO : De Novo Distributed by Pel-Freez, 2nd edition, 2000.

10. Svejgaard A., Ryder L.P. HLA and disease association: Detecting the strongest association. Tissue Antigens 1994;43:18-27.

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Introduction

Human leukocyte antigens (HLA), or the major histocompatibility complex represents a genetic system which plays a central role in the immune response, recognizing “own” and “foreign” cells, and presenting processed antigens to immunocompetent cells. This system is characterized by extreme polymorphism. The HLA gene complex is located at chromosome 6 (short arm), includes over 4000 base pairs, and consists of three gene groups (Class I, II, and III). According to the Classification of 2005, it includes 47 loci, encoding over 2000 known allelic variants [7]. Such an extreme polymorphism is stipulated by a necessity to withstand a huge number of evolving environmental antigens, and to maintain the genetic individuality of the human organism. Therefore, a search for two individuals with identical genetic characteristics is prone to sufficient problems.
   
At the same time, successful transplantation of unrelated hematopoietic stem cells (HSCT) is primarily determined by the genetic similarity between recipient and donor [2]. This highly technological therapeutic approach is successfully employed worldwide to treat many diseases, including different leukemias, combined immune deficiencies, generalized autoimmune diseases and so on. To carry out a selection of donor-recipient pairs, a network of regional HSC donor registries is arranged throughout the world, under active cooperation within this community. For several years, the Russian Registry has been cooperating with the Stefan Morsch Foundation [1], in performing mutual searches for donors for patients with hemoblastosis.

The aim of our study was to evaluate immunogenetic characteristics among HSC donors, including the populations from various Russian regions, as well as comparisons with appropriate data from German Registries.

befd73a94d.png

Materials and methods

Characteristics of the group under study

HLA typing for class A and B loci was performed on 1198 persons included in the Registry of potential bone marrow donors, based upon the Russian Research Institute of Hematology and Transfusion. Most of these cohorts were represented by regular blood donors. Small numbers of volunteers and relatives of the patients with hemoblastosis were also involved. In general, distribution for age and gender corresponds to appropriate parameters for blood donors, i.e., males prevailed in the samples (63%). With respect to age, the group mainly represents a cohort from 26 to 40 years (50%), followed by individuals of 40 to 50 years old (35.7%). The least numerous group was represented by persons 18 to 25 years old (14%). In Samara, Kirov, Rostov-upon-Don, and Nizhny Novgorod 161, 196, 347, and 817 persons respectively, were studied (Fig. 1). All these persons were active blood donors.

dab56709db.png

HLA Class I typing

Class A and B HLA typing was performed by serological techniques, in a standard microlymphocytotoxic test, using a panel of histotyping anti-leukocyte sera produced at Russian Institute of Hematology and Transfusion. 

Statistical analysis 

The prevalence of antigen (А) was calculated according to equation: А=n/N, where n is number of donors with given antigen, and N, total number of persons studied.

The prevalence of the gene (p) was determined by the following equation:

2008-1-en-Bubnova-Formula-1-300dpi-205px.png

where А is the prevalence of the appropriate antigen [4].
Haplotype frequency for the two genes  (Н) was estimated using the equation:

2008-1-en-Bubnova-Formula-2-300dpi-282px.png

where р₁ and р₂ are gene frequencies for HLA antigens, and ∆₁,₂ is an inter-allelic disequilibrium linkage.

The values of disequilibrium linkage (∆₁,₂) were calculated accordingly, using a formula from a four-field table (2x2 tables) [5]

2008-1-en-Bubnova-Formula-3-300dpi-475px.png

where a, b, c, and d comprise values in the fields of the tables; N = a+b+c+d, the volume of sample;
а = + + (number of donors in the given sample in whom both antigens of the given haplotype are present);
b = + – (number of donors in the given sample in whom the first of two antigens of the given haplotype is present);
c = – + (number of donors in the given sample in whom the second of two antigens of the given haplotype is present);
d =  – – (number of donors in the given sample in whom both antigens of the given haplotype are absent).
To evaluate the statistical significance of differences for HLA antigen frequencies between the groups, we used χ² criterion [10].

2008-1-en-Bubnova-Formula-4-300dpi-491px.png

where
a is the number of donors in group 1 with a given antigen,
b is the number of donors in group 1 without this antigen,
c is the number of donors in group 2 with a given antigen,
d is the number of donors in group 2 without this antigen,

n, the numbers of persons in the group,
/a•d – b•c/ – absolute value of difference,
0,5•n – correction for continuity in small samples.

The determination of the p level corresponding to the assessed χ² value was performed with computer software, taking into account one degree of freedom (df=1). With respect to the polyallelic nature of the HLA set, calculation of corrected p levels was carried out when testing the significance of differences for distribution of a given trait [8].

2008-1-en-Bubnova-Formula-5-300dpi-316px.png

where n is a number of traits studied.
χ² values exceeding 3,841 (corresponding to Р<0,05), were regarded as a stable borderline index for significant difference between the frequencies in the groups compared.

Results

As seen in Table 1, the HLA class I study at the St. Petersburg Registry reveals that among locus A specificities, A2 and A3 (48.9% and 28.7% respectively) are the most common specificities. When analyzing distributions in locus B antigens for the same populations, B7 and B35 are frequently represented (26.8% and 20.9% resp.; see Table 2).

d2c68b5329.png

The common incidence of these genes is characteristic of the general European population [3]. However, if compared with the German Registry [6], which is among the largest in the Europe, one may see that in spite of a general similarity, the frequency of some genes differs quite significantly. It concerns such locus A specificities as A1 (20.8% in St. Petersburg vs 28.9% in Germany), А9 (23.7% vs 20.6%), and А10 (19.7% vs 13.3%).

These differences are even more pronounced for locus B; for example B8, a quite common gene, occurs among Germans much more often than in the Russian Registry (20.3% and 12.4% resp.). Meanwhile, the frequencies of the В13 and В18 antigens that are rather common in St. Petersburg proved to occur half as often in the German population (11.7% vs 6.9%, and 14.9% vs 9.7%). The incidence of the B41 antigen was almost 3-fold higher in St. Petersburg than in Germany—thus suggesting a different distribution of some genes in Russia and Germany, in spite of the general similarity of both populations.

When studying haplotype incidence for A and B loci (Table 3), we have shown that the following haplotypes are the most common in the St. Petersburg Registry: А2-В7 (4.25%), А2-В35 (3.44%), and А3-В7 (3.31%); whereas А11-В35 and А25-В18 proved to be more rare (0.13% and 1.11% resp.).

03de4758dc.png

A comparative study of haplotype frequencies for two genes from the A and B loci in the Russian and German Registries (Table 3) has shown that their incidence is sufficiently different: the most common in St. Petersburg, the А2-В7 haplotype, is at the 5th position in the German sample, whereas the A1-B8 haplotype, which occurs most commonly in Germany and in a majority of European countries, occupies only 9th position in the population of St. Petersburg.

The absence of certain highly prevalent haplotypes is another important feature of the Russian Registry, thus being indicative for a more pronounced genetic heterogeneity in the local population, i.e., neither of the most common haplotypes in St. Petersburg is over-represented, as compared to the German population with 8.29% for A1-B8, 5.73% for A3-B7, or 4.65% for A2-B44. In St. Petersburg, the most common А2-В7 haplotype was found in 4.25% of cases.

Our results suggest that the distribution of HLA genes and haplotypes of the MHC complex in the St. Petersburg Registry shows gross similarities to the gene distribution in Western Europe. The St. Petersburg Registry, however, displays some specific features due to an altered frequency due to some antigenic specificity and more pronounced genetic heterogeneity among the populations represented in the Registry.

We analyzed the opportunities for unrelated donor matching for 52 patients with oncohematological disorders treated at the Institute clinics. Comparisons of phenotypically determined HLA sets for the patients with those represented in the donor Registry showed that HLA-A,B-compatible donors were found for 48% of the patients. When based on the patient’s phenotype, the ratio of class I-compatible donors for each patient proved to be 1 to 14, thus providing evidence in favor of finding a donor for the patients even within a relatively small registry of potential donors from the same region.
 
When comparing the frequencies of loci A and B specificities among the donors from Russian regions and Germany, the most pronounced differences, both for single antigens and haplotypes, were revealed between the general cohorts from the German Registry and the Russian Republican Registry (Fig. 2, Tables 2, 3). 

2008-1-en-Bubnova-Figure-2-72dpi-429px.png

That is, the most similar genetic characteristics are expressed in the donors from St. Petersburg and Nizhny Novgorod (Fig. 3). 

2008-1-en-Bubnova-Figure-3-72dpi-733px.png

Donors from the Samara Region are, for some characteristics, closer to German donors (Fig. 2), whereas the persons from Kirov possess some markers that are typical to Northern folk. Donors from Rostov-upon-Don represent a highly heterogeneous population with respect to their nationality, since this region is inhabited by Russians, as well as Ukrainians, Armenians, Greeks, etc. However, their immunogenetic features tend to be more similar to other representatives of the Russian Republican Register than to the German population. As seen in Table 3, containing a synopsis of 10 most common haplotypes, the А2-В7 haplotype is encountered most often in St. Petersburg, as well as in Rostov-upon-Don and Kirov. In Nizhny Novgorod, however, it holds 2nd position, whereas in Samara Region, a European A1-B8 haplotype is clearly prevalent (Fig. 4).

28007d5c86.png

This data confirms the need for an urgent expansion of the Russian Register for potential HSC donors, since the probability of finding a donor for Russian patients becomes sufficiently higher when the search is performed in a regional Registry. Taking into account the significant rate of current migration to Germany, a closer working cooperation would be desirable between the Russian and German Registries.

Discussion

HLA polymorphism has evolved since the very origin of human beings. Its evolution was influenced by many factors, as the immune system has undergone its development for effective protection against the invasion of potential pathogens, i.e., from viruses to pathogenic worms.

The ability for a rapid response to single pathogens is mediated by the adaptive immune system, including an appropriate scale of host responses provided by the HLA molecules, together with T and B cell receptors. The type of pathogens existing in the various geographic regions inhabited by different human populations may determine the selection of specific HLA gene products. Gene conversions, i.e., substitutions of existing nucleotide sequences of HLA genes with short segments from other HLA alleles or loci within the HLA complex, comprise the main source of biodiversity created within relatively short timelines (e.g., several centuries). This process reconstitutes an HLA gene repertoire for effective protection against pathogens that exist in steadily renewing environment.

Hence, the combined set of HLA gene products expressed in each human population is, mainly, a result of interactions with the flora and animals of the region inhabited by the population over centuries and millennia. Some cases of linkage disequilibrium observed with certain HLA genes reflect evolutionary advantages of appropriate gene-gene interactions.

A history of people inhabiting the region comprises the second important factor that determines the divergence of genetic features between the populations (the so-called "ancestor effect"). For example, А1-В8 is the most common haplotype in the German Registry. As suggested by G. Rodey [9], this genetic feature could be traced back to the Goths and ancient German tribes, whereas the А2-В7 haplotype (the most common in the St. Petersburg Registry) is typical for Vikings. This assumption seems quite probable, due to the close relations between North-Western Slaves and Vikings. The increased frequency of the A1, B8 haplotype in Samara may be due to the mass migration of Germans to the Volga Region, which has taken place since the times of Catherine the Great of Russia in XVIII century (Fig. 4).

As far as the broad phenotypic diversity that is characteristic of the Russian population is concerned, this could be directly connected with the vast habitation areas of Russian people and sharing these territories with other national groups.
 
Summarizing the above results, we may state that a search for donors for recipients living in other regions is associated with significant difficulties, irrespective of the Register size. However, such a search would be facilitated if the donor and the recipient originate from the same region.

Conclusions

1. When performing a comparative analysis of St. Petersburg and German Registries with other regional Russian Registries, we have revealed certain differences in frequencies of HLA genes and haplotypes (A and B loci).

2. The probability of a successful search for a histocompatible HSC donor is higher for a Registry in the country of recipients’ origin.

3. There is a need for the urgent expansion of the Russian HSC Donor Registry.

4. International cooperation between the Registries is necessary, especially when searching for donors for migrants from abroad.

References

1. Bubnova L.N., Beliaeva E.V., Berkos A.S., Nikolenko V.N. A registry of bone marrow donors. Transfusion Medicine 1995, №5, p.14-18. (In Russian)

2. Cleaver S. Donor work-up and transport of bone marrow recommendations and requirement for a standardized practice. Bone Marrow Transplantation 1997;20:621-629.

3. Goldman John M. Special report: Bone marrow transplants using volunteer donors-recommendations and requirements of a standardized practice throughout  the world (1994 update). Blood 1994;84:2833-2839.

4. Haldane J.B. The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 1956;20:309.

5. Mattius P.L., Ihde D., Piazza A., Cepellini R., Bodmer W.F. New approaches to the population genetic segregation analysis of the HLA system. In: Terasaki P.I. (ed): Histocompatibility Testing, 1970. Copenhagen: Munksgaard, 1970.

6. Müller C, Ehninger G., Goldmann S. Gene and haplotype frequency for the loci HLA- A, HLA- B, and HLA- DR based on over 13,000 German Blood Donors. Human Immunology 2003;64,1:137-151.

7. Marsh S., Albert E., Bodmer W., et al. Nomenclature for factors of the HLA system, 2004. Tissue Antigens 2005:65,4:301-370.

8. Pevnitsky L.A. Statistical evaluation of associations between HLA antigens and diseases. Vestnik RAMS. 1998, №7, p.48-51. (In Russian)

9. Rodey G. HLA Beyond tears. introduction to human histocompatibility. Durango, CO : De Novo Distributed by Pel-Freez, 2nd edition, 2000.

10. Svejgaard A., Ryder L.P. HLA and disease association: Detecting the strongest association. Tissue Antigens 1994;43:18-27.

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"728" [9]=> string(3) "729" } ["~DESCRIPTION"]=> array(10) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" [6]=> string(0) "" [7]=> string(0) "" [8]=> string(0) "" [9]=> string(0) "" } ["~NAME"]=> string(12) "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(4) "9460" ["VALUE"]=> array(2) { ["TEXT"]=> string(297) "<p class="Autor">Бубнова Л. Н., Зайцева Г. А., Ерохина Л. В., Беркос А. С., Реутова Н. В., Беляева Е. В.,<br> Петровская М. Н., Игнатова Н. К., Кудинова Э. Е., Минина В. М.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(269) "

Бубнова Л. Н., Зайцева Г. А., Ерохина Л. В., Беркос А. С., Реутова Н. В., Беляева Е. В.,
Петровская М. Н., Игнатова Н. К., Кудинова Э. Е., Минина В. М.

" ["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(4) "9461" ["VALUE"]=> array(2) { ["TEXT"]=> string(2653) "<p>Полиморфизм генетической системы HLA исключительно высок, поэтому поиск двух индивидуумов, обладающих идентичными генетическими характеристиками, связан со значительными трудностями. В то же время, успех трансплантации аллогенных неродственных ГСК прежде всего связан с генетической близостью реципиента и донора. Республиканский регистр, объединяющий базы данных, содержащих сведения о типированных донорах Российского и Кировского НИИ гематологии и трансфузиологии, станций переливания крови Нижнего Новгорода, Ростова-на-Дону, Самары, Первоуральска в течение нескольких лет сотрудничает с немецким регистром Стефана Морша, осуществляя взаимный поиск доноров для больных гемобластозами. При исследовании установлено, что наиболее выраженные различия как частот встречаемости отдельных антигенов, так и гаплотипов, обнаружены между представителями Регистра Германии и Республиканского Регистра в целом. Наиболее близкими друг другу генетическими характеристиками обладают доноры Санкт-Петербурга и Нижнего Новгорода. Доноры Самарского региона по отдельным характеристикам ближе к донорам Германии, а доноры из Кирова обладают рядом признаков, характерных для северных народов. Эти данные подтверждают необходимость срочного расширения нашего Регистра потенциальных доноров ГСК, поскольку вероятность нахождения донора для жителя России значительно увеличивается, если поиск осуществляется в собственном регистре.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2641) "

Полиморфизм генетической системы HLA исключительно высок, поэтому поиск двух индивидуумов, обладающих идентичными генетическими характеристиками, связан со значительными трудностями. В то же время, успех трансплантации аллогенных неродственных ГСК прежде всего связан с генетической близостью реципиента и донора. Республиканский регистр, объединяющий базы данных, содержащих сведения о типированных донорах Российского и Кировского НИИ гематологии и трансфузиологии, станций переливания крови Нижнего Новгорода, Ростова-на-Дону, Самары, Первоуральска в течение нескольких лет сотрудничает с немецким регистром Стефана Морша, осуществляя взаимный поиск доноров для больных гемобластозами. При исследовании установлено, что наиболее выраженные различия как частот встречаемости отдельных антигенов, так и гаплотипов, обнаружены между представителями Регистра Германии и Республиканского Регистра в целом. Наиболее близкими друг другу генетическими характеристиками обладают доноры Санкт-Петербурга и Нижнего Новгорода. Доноры Самарского региона по отдельным характеристикам ближе к донорам Германии, а доноры из Кирова обладают рядом признаков, характерных для северных народов. Эти данные подтверждают необходимость срочного расширения нашего Регистра потенциальных доноров ГСК, поскольку вероятность нахождения донора для жителя России значительно увеличивается, если поиск осуществляется в собственном регистре.

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Ludmila N. Bubnova1, Galina A. Zaitseva2, Ludmila V. Erokhina1, Andrej S. Berkos1, Natalija V. Reutova1, Elena V. Belyaeva1, Marina N. Petrovskaya3, Natalija K. Ignatova4, Ella Ye. Koudinova5, Vera M. Minina6


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1Russian Research Institute of Hematology and Transfusiology, St.Petersburg; 2Kirov Research Institute of Hematology and Blood Transfusion, Kirov; 3N.Ya.Klimova Nyzhegorodsky Blood Bank, Nyzhni Novgorod; 4Samara Regional Blood Bank, Samara;
5Rostov Regional Blood Bank, Rostov-on-Don; 6Sverdlovsk Blood Bank, Pervouralsk, Russia

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Genetic polymorphism in the HLA system is extremely high, thus rendering a search for individuals exhibiting identical genetic characteristics difficult. Meanwhile, successful allografting of unrelated donor hematopoietic stem cells (allo-HSCT) is determined mainly via genetic similarity between the recipient and donor. A Republican Register that unites the databases of HLA-typed donors from the Russian and Kirov Research Institutes of Hematology and Blood Transfusion, and the blood banks of Nyzhni Novgorod, Rostov-on-Don, Samara, and Pervouralsk has been cooperating for several years with the Stefan Morsch Registry in Germany, performing bilateral donor searches for patients with hemoblastosis.

The study has shown that the most pronounced differences in prevalence, both for certain antigens and their haplotypes, are observed between the general cohorts of the German and Russian Registers. Donors from St. Petersburg and Nyhzni Novgorod express maximal similarity in their genetic features. The donors from Samara Region are, for some characteristics, more related to German donors, whereas donors from Kirov possess some features that are typical to Northern folk. This data confirms an urgent need for expansion of the Russian Donor Registry, since the probability of finding a donor in the Russian population is sufficiently higher when performing the search in a local Registry.

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["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(4) "9499" ["VALUE"]=> array(2) { ["TEXT"]=> string(495) "<p class="Autor">Ludmila N. Bubnova<sup>1</sup>, Galina A. Zaitseva<sup>2</sup>, Ludmila V. Erokhina<sup>1</sup>, Andrej S. Berkos<sup>1</sup>, Natalija V. Reutova<sup>1</sup>, Elena V. Belyaeva<sup>1</sup>, Marina N. Petrovskaya<sup>3</sup>, Natalija K. Ignatova<sup>4</sup>, Ella Ye. Koudinova<sup>5</sup>, Vera M. Minina<sup>6</sup></p> <br> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(347) "

Ludmila N. Bubnova1, Galina A. Zaitseva2, Ludmila V. Erokhina1, Andrej S. Berkos1, Natalija V. Reutova1, Elena V. Belyaeva1, Marina N. Petrovskaya3, Natalija K. Ignatova4, Ella Ye. Koudinova5, Vera M. Minina6


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Ludmila N. Bubnova1, Galina A. Zaitseva2, Ludmila V. Erokhina1, Andrej S. Berkos1, Natalija V. Reutova1, Elena V. Belyaeva1, Marina N. Petrovskaya3, Natalija K. Ignatova4, Ella Ye. Koudinova5, Vera M. Minina6


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Genetic polymorphism in the HLA system is extremely high, thus rendering a search for individuals exhibiting identical genetic characteristics difficult. Meanwhile, successful allografting of unrelated donor hematopoietic stem cells (allo-HSCT) is determined mainly via genetic similarity between the recipient and donor. A Republican Register that unites the databases of HLA-typed donors from the Russian and Kirov Research Institutes of Hematology and Blood Transfusion, and the blood banks of Nyzhni Novgorod, Rostov-on-Don, Samara, and Pervouralsk has been cooperating for several years with the Stefan Morsch Registry in Germany, performing bilateral donor searches for patients with hemoblastosis.

The study has shown that the most pronounced differences in prevalence, both for certain antigens and their haplotypes, are observed between the general cohorts of the German and Russian Registers. Donors from St. Petersburg and Nyhzni Novgorod express maximal similarity in their genetic features. The donors from Samara Region are, for some characteristics, more related to German donors, whereas donors from Kirov possess some features that are typical to Northern folk. This data confirms an urgent need for expansion of the Russian Donor Registry, since the probability of finding a donor in the Russian population is sufficiently higher when performing the search in a local Registry.

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Genetic polymorphism in the HLA system is extremely high, thus rendering a search for individuals exhibiting identical genetic characteristics difficult. Meanwhile, successful allografting of unrelated donor hematopoietic stem cells (allo-HSCT) is determined mainly via genetic similarity between the recipient and donor. A Republican Register that unites the databases of HLA-typed donors from the Russian and Kirov Research Institutes of Hematology and Blood Transfusion, and the blood banks of Nyzhni Novgorod, Rostov-on-Don, Samara, and Pervouralsk has been cooperating for several years with the Stefan Morsch Registry in Germany, performing bilateral donor searches for patients with hemoblastosis.

The study has shown that the most pronounced differences in prevalence, both for certain antigens and their haplotypes, are observed between the general cohorts of the German and Russian Registers. Donors from St. Petersburg and Nyhzni Novgorod express maximal similarity in their genetic features. The donors from Samara Region are, for some characteristics, more related to German donors, whereas donors from Kirov possess some features that are typical to Northern folk. This data confirms an urgent need for expansion of the Russian Donor Registry, since the probability of finding a donor in the Russian population is sufficiently higher when performing the search in a local Registry.

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1Russian Research Institute of Hematology and Transfusiology, St.Petersburg; 2Kirov Research Institute of Hematology and Blood Transfusion, Kirov; 3N.Ya.Klimova Nyzhegorodsky Blood Bank, Nyzhni Novgorod; 4Samara Regional Blood Bank, Samara;
5Rostov Regional Blood Bank, Rostov-on-Don; 6Sverdlovsk Blood Bank, Pervouralsk, Russia

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1Russian Research Institute of Hematology and Transfusiology, St.Petersburg; 2Kirov Research Institute of Hematology and Blood Transfusion, Kirov; 3N.Ya.Klimova Nyzhegorodsky Blood Bank, Nyzhni Novgorod; 4Samara Regional Blood Bank, Samara;
5Rostov Regional Blood Bank, Rostov-on-Don; 6Sverdlovsk Blood Bank, Pervouralsk, Russia

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Бубнова Л. Н., Зайцева Г. А., Ерохина Л. В., Беркос А. С., Реутова Н. В., Беляева Е. В.,
Петровская М. Н., Игнатова Н. К., Кудинова Э. Е., Минина В. М.

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Бубнова Л. Н., Зайцева Г. А., Ерохина Л. В., Беркос А. С., Реутова Н. В., Беляева Е. В.,
Петровская М. Н., Игнатова Н. К., Кудинова Э. Е., Минина В. М.

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В то же время, успех трансплантации аллогенных неродственных ГСК прежде всего связан с генетической близостью реципиента и донора. Республиканский регистр, объединяющий базы данных, содержащих сведения о типированных донорах Российского и Кировского НИИ гематологии и трансфузиологии, станций переливания крови Нижнего Новгорода, Ростова-на-Дону, Самары, Первоуральска в течение нескольких лет сотрудничает с немецким регистром Стефана Морша, осуществляя взаимный поиск доноров для больных гемобластозами. При исследовании установлено, что наиболее выраженные различия как частот встречаемости отдельных антигенов, так и гаплотипов, обнаружены между представителями Регистра Германии и Республиканского Регистра в целом. Наиболее близкими друг другу генетическими характеристиками обладают доноры Санкт-Петербурга и Нижнего Новгорода. Доноры Самарского региона по отдельным характеристикам ближе к донорам Германии, а доноры из Кирова обладают рядом признаков, характерных для северных народов. 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Полиморфизм генетической системы HLA исключительно высок, поэтому поиск двух индивидуумов, обладающих идентичными генетическими характеристиками, связан со значительными трудностями. В то же время, успех трансплантации аллогенных неродственных ГСК прежде всего связан с генетической близостью реципиента и донора. Республиканский регистр, объединяющий базы данных, содержащих сведения о типированных донорах Российского и Кировского НИИ гематологии и трансфузиологии, станций переливания крови Нижнего Новгорода, Ростова-на-Дону, Самары, Первоуральска в течение нескольких лет сотрудничает с немецким регистром Стефана Морша, осуществляя взаимный поиск доноров для больных гемобластозами. При исследовании установлено, что наиболее выраженные различия как частот встречаемости отдельных антигенов, так и гаплотипов, обнаружены между представителями Регистра Германии и Республиканского Регистра в целом. Наиболее близкими друг другу генетическими характеристиками обладают доноры Санкт-Петербурга и Нижнего Новгорода. Доноры Самарского региона по отдельным характеристикам ближе к донорам Германии, а доноры из Кирова обладают рядом признаков, характерных для северных народов. Эти данные подтверждают необходимость срочного расширения нашего Регистра потенциальных доноров ГСК, поскольку вероятность нахождения донора для жителя России значительно увеличивается, если поиск осуществляется в собственном регистре.

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Полиморфизм генетической системы HLA исключительно высок, поэтому поиск двух индивидуумов, обладающих идентичными генетическими характеристиками, связан со значительными трудностями. В то же время, успех трансплантации аллогенных неродственных ГСК прежде всего связан с генетической близостью реципиента и донора. Республиканский регистр, объединяющий базы данных, содержащих сведения о типированных донорах Российского и Кировского НИИ гематологии и трансфузиологии, станций переливания крови Нижнего Новгорода, Ростова-на-Дону, Самары, Первоуральска в течение нескольких лет сотрудничает с немецким регистром Стефана Морша, осуществляя взаимный поиск доноров для больных гемобластозами. При исследовании установлено, что наиболее выраженные различия как частот встречаемости отдельных антигенов, так и гаплотипов, обнаружены между представителями Регистра Германии и Республиканского Регистра в целом. Наиболее близкими друг другу генетическими характеристиками обладают доноры Санкт-Петербурга и Нижнего Новгорода. Доноры Самарского региона по отдельным характеристикам ближе к донорам Германии, а доноры из Кирова обладают рядом признаков, характерных для северных народов. Эти данные подтверждают необходимость срочного расширения нашего Регистра потенциальных доноров ГСК, поскольку вероятность нахождения донора для жителя России значительно увеличивается, если поиск осуществляется в собственном регистре.

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Introduction

Allogeneic HCT is a curative treatment for a number of hematologic malignancies and genetic disorders. Despite the routine use of immunosuppressive agents that target T cells, such as calcineurin inhibitors, up to 50% of HCT recipients still experience significant graft-versus-host disease (GVHD) that requires treatment with high dose systemic steroids. The risk of mortality in patients who do not respond completely to initial therapy is very high, but complete response (CR) rates have remained at approximately 35%.

Animal models have established that the pathophysiology of GVHD can be conceived as a process with three phases, involving complex immunologic interactions between cellular effectors and soluble effectors, such as inflammatory cytokines (See Figure 1).

e79574e7d7.png

Figure 1. Phases of GVHD Pathophysiology.

The development of acute GVHD can be conceptualized in three sequential steps or phases: (1) activation of the antigen presenting cells (APCs); (2) donor T cell activation, proliferation, differentiation and migration; and (3) target tissue destruction. During phase 1, the release of inflammatory cytokines such as IL-1, IL-6, and especially, TNF-α, lead to increased expression of MHC antigens and adhesion molecules, which enhance host antigen presenting cells (APCs) to present allo-antigen to donor T cells. In phase 2, mature T cells from the donor, infused into an environment primed for immunologic activation, interact with host APCs, proliferate and differentiate into activated T cells, which release additional inflammatory cytokines. In phase 3, target organ damage results from the migration of cytotoxic T lymphocytes (CTLs) and natural killer cells into the tissues. In addition, monocytes, stimulated by lipopolysaccharide (LPS) translocated across damaged intestinal mucosa, secrete cytopathic amounts of inflammatory cytokines such as TNF-α, culminating in clinically evident GVHD.

One of the most important inflammatory cytokines in GVHD pathophysiology is tumor necrosis factor-alpha (TNFα), which mediates GVHD both through the amplification of donor immune response to host tissues as well as direct toxicity to target organs. These preclinical data served as the rationale to use anti-TNFα agents. Infliximab, a monoclonal antibody directed at TNFα, binds to both soluble and membrane-bound TNFα, resulting in clearance of both circulating TNFα and T cells. Etanercept, a soluble dimeric TNFα Receptor 2, competes for TNFα binding and renders it inactive. This mechanism of action combined with its relative ease of administration by subcutaneous injection and generally minor side effects, make etanercept attractive as primary GVHD therapy.

Results

We have recently published the results of our using etanercept in addition to high dose steroids as primary therapy for acute GVHD16.

The primary endpoint of the clinical trial was CR (resolution of all GVHD manifestations) at four weeks after the initiation of treatment. Patients treated with etanercept plus steroids were significantly more likely to achieve CR four weeks later than were patients treated with steroids alone [69% vs 33%, p<0.0001]. The benefit of etanercept persisted so that by 12 weeks after initiation of GVHD treatment, 77% of etanercept plus steroids patients had achieved CR compared to 50% of steroids alone patients (p=0.0009). We performed a univariate analysis comparing CR rates according to conditioning regimen (myeloablative vs reduced intensity), a factor known to influence GVHD17. A conditioning regimen did not impact CR rates in patients treated with etanercept plus steroids. In multivariate analyses the only two variables associated with increased likelihood of CR were the use of etanercept and a related donor stem cell source. Patient age, conditioning regimen, degree of HLA-match, and the day of onset of GVHD all had no statistically significant association with response.

The higher response rate seen in patients treated with etanercept plus steroids translated into improved survival at 100 days from initiation of GVHD treatment [etanercept plus steroids, 82% vs steroids alone, 66%, p=0.04]. At 6 months from initiation of treatment a higher proportion of patients treated with etanercept plus steroids were still alive (69%), compared to 55% of patients treated with steroids alone, but this difference did not meet the criteria for statistical significance [p=0.08].

Because of the trend towards an increased proportion of unrelated donor transplants in the group treated with steroids alone, we analyzed the results by stem cell source. The superiority of etanercept was evident in transplant recipients from both related donors [79% vs 39%, p=0.001] and unrelated donors [53% vs 26%, p=0.0005]. This latter difference is particularly noteworthy, because studies have shown that acute GVHD in recipients of unrelated donor transplants is more difficult to treat than GVHD in recipients of related donor transplants. The time to CR was significantly faster in recipients of related donor transplants who were treated with etanercept plus steroids, but by 12 weeks nearly equivalent proportions of patients in both groups achieved a CR (etanercept plus steroids, 80%, steroids alone 70%). It is therefore not surprising that survival six months from initiation of GVHD treatment was similar in both treatment groups. Recipients of unrelated donor transplants who failed to achieve a CR by day 28 were likely to never achieve CR, thus translating into a survival advantage six months later. Importantly, the infection rates in the first 100 days from initiation of GVHD treatment were not different between patients treated with etanercept plus steroids or treated with steroids alone for bacterial, invasive fungal or viral infections. There were no mycobacterial infections observed in any patients.

Discussion

Current standards for the treatment of acute GVHD rely primarily on steroids alone as initial therapy and reserve additional agents for steroid refractory disease. Previous studies in steroid refractory GVHD have shown that anti-TNFα agents have significant efficacy but the majority of patients still die from GVHD or its complications. Our results show that the combination of etanercept plus steroids as initial treatment for GVHD results in significantly better CR rates four weeks later compared to steroids alone. These CRs were durable and could not be explained by differences in the steroid dose at four weeks. Of note, etanercept plus steroids improved the outcome for recipients of both related donor and unrelated donor transplants which translated into significantly improved survival at six months for unrelated donor transplant recipients. The improvements in outcome were realized without an increased incidence of serious infections, chronic GVHD or relapse.

Animal studies have demonstrated that TNFα plays a critical role in both the gastrointestinal tract18,19 and the skin, but its role in the liver is more controversial. Our data confirm mechanistic studies of GVHD pathophysiology in animal models that have delineated both TNFα dependent and TNFα independent pathways of disease because TNFα inhibition increases response rates but does not completely eliminate GVHD. All patients who received etanercept also received steroids, and therefore the relative importance of these pathways in clinical GVHD remains to be determined in future studies.

One potential concern regarding the use of TNF-inhibitors to treat GVHD is an increased risk of infections, particularly mycobacterial and fungal infections. Invasive Aspergillus infections have been associated with use of the anti-TNFα monoclonal antibody infliximab for treatment of GVHD in two retrospective studies involving a total of 32 patients. Although the overall incidence of infection was significant—as would be expected in patients with GVHD receiving high dose steroids—we did not observe any significant difference in infection rates, including fungal infections, in patients also treated with etanercept. The discrepancy between the two studies may be due to potential differences in the mechanism of action of the two drugs: infliximab can induce systemic elimination and clearance of monocytes and macrophages that express membrane-bound TNFα, whereas etanercept does not. In addition, the recent availability of more effective prophylactic agents against a broad range of fungal species may have contained the overall infectious risk. We also did not observe increased morbidity and mortality from etanercept in patients who developed gram-positive infections, which differs from prior reports in other disease settings.

If these data are confirmed in other multi-center trials, we may well be able to use inhibition of TNF-α as an important adjunct to therapy for GVHD that one day may be able to reduce or even eliminate the need for prolonged high-dose steroids in some patients.

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9. Korngold R, Marini JC, de Baca ME, Murphy GF, Giles-Komar J. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant 2003;9:292-303.

10.Jacobsohn DA, Hallick J, Anders V, McMillan S, Morris L, Vogelsang GB. Infliximab for steroid-refractory acute GVHD: a case series. Am J Hematol 2003;74:119-24.

11.Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004;104:649-54.

12. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007;82:45-52.

13. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica 2004;89:1352-9.

14. Sieper J, Van Den Brande J. Diverse effects of infliximab and etanercept on T lymphocytes. Semin Arthritis Rheum 2005;34(Suppl1):23-7.

15. Dhillon S, Lyseng-Williamson KA, Scott LJ. Etanercept: a review of its use in the management of rheumatoid arthritis. Drugs 2007;67:1211-41.

16. Levine JE, Paczesny SS, Mineishi SS, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470.

17. Levine JE, Uberti JP, Ayash L, et al. Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. Biol Blood Marrow Transplant 2003;9:189-97.

18. Brown GR, Lee EL, Thiele DL. TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms. J Immunol 2003;170:5082-8.

19. Hattori K, Hirano T, Miyajima H, et al. Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies. Blood 1998;91:4051-5.

20. Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med 1987;166:1280-9.

21. Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med 2004;19:320-34.

22. Marty FM, Lee SJ, Fahey MM, et al. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood 2003;102:2768-76.

23. Ehlers S. Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept? Clin Infect Dis 2005;41 Suppl 3:S199-203.

24. Fisher CJ, Jr., Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334:1697-702.

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Introduction

Allogeneic HCT is a curative treatment for a number of hematologic malignancies and genetic disorders. Despite the routine use of immunosuppressive agents that target T cells, such as calcineurin inhibitors, up to 50% of HCT recipients still experience significant graft-versus-host disease (GVHD) that requires treatment with high dose systemic steroids. The risk of mortality in patients who do not respond completely to initial therapy is very high, but complete response (CR) rates have remained at approximately 35%.

Animal models have established that the pathophysiology of GVHD can be conceived as a process with three phases, involving complex immunologic interactions between cellular effectors and soluble effectors, such as inflammatory cytokines (See Figure 1).

e79574e7d7.png

Figure 1. Phases of GVHD Pathophysiology.

The development of acute GVHD can be conceptualized in three sequential steps or phases: (1) activation of the antigen presenting cells (APCs); (2) donor T cell activation, proliferation, differentiation and migration; and (3) target tissue destruction. During phase 1, the release of inflammatory cytokines such as IL-1, IL-6, and especially, TNF-α, lead to increased expression of MHC antigens and adhesion molecules, which enhance host antigen presenting cells (APCs) to present allo-antigen to donor T cells. In phase 2, mature T cells from the donor, infused into an environment primed for immunologic activation, interact with host APCs, proliferate and differentiate into activated T cells, which release additional inflammatory cytokines. In phase 3, target organ damage results from the migration of cytotoxic T lymphocytes (CTLs) and natural killer cells into the tissues. In addition, monocytes, stimulated by lipopolysaccharide (LPS) translocated across damaged intestinal mucosa, secrete cytopathic amounts of inflammatory cytokines such as TNF-α, culminating in clinically evident GVHD.

One of the most important inflammatory cytokines in GVHD pathophysiology is tumor necrosis factor-alpha (TNFα), which mediates GVHD both through the amplification of donor immune response to host tissues as well as direct toxicity to target organs. These preclinical data served as the rationale to use anti-TNFα agents. Infliximab, a monoclonal antibody directed at TNFα, binds to both soluble and membrane-bound TNFα, resulting in clearance of both circulating TNFα and T cells. Etanercept, a soluble dimeric TNFα Receptor 2, competes for TNFα binding and renders it inactive. This mechanism of action combined with its relative ease of administration by subcutaneous injection and generally minor side effects, make etanercept attractive as primary GVHD therapy.

Results

We have recently published the results of our using etanercept in addition to high dose steroids as primary therapy for acute GVHD16.

The primary endpoint of the clinical trial was CR (resolution of all GVHD manifestations) at four weeks after the initiation of treatment. Patients treated with etanercept plus steroids were significantly more likely to achieve CR four weeks later than were patients treated with steroids alone [69% vs 33%, p<0.0001]. The benefit of etanercept persisted so that by 12 weeks after initiation of GVHD treatment, 77% of etanercept plus steroids patients had achieved CR compared to 50% of steroids alone patients (p=0.0009). We performed a univariate analysis comparing CR rates according to conditioning regimen (myeloablative vs reduced intensity), a factor known to influence GVHD17. A conditioning regimen did not impact CR rates in patients treated with etanercept plus steroids. In multivariate analyses the only two variables associated with increased likelihood of CR were the use of etanercept and a related donor stem cell source. Patient age, conditioning regimen, degree of HLA-match, and the day of onset of GVHD all had no statistically significant association with response.

The higher response rate seen in patients treated with etanercept plus steroids translated into improved survival at 100 days from initiation of GVHD treatment [etanercept plus steroids, 82% vs steroids alone, 66%, p=0.04]. At 6 months from initiation of treatment a higher proportion of patients treated with etanercept plus steroids were still alive (69%), compared to 55% of patients treated with steroids alone, but this difference did not meet the criteria for statistical significance [p=0.08].

Because of the trend towards an increased proportion of unrelated donor transplants in the group treated with steroids alone, we analyzed the results by stem cell source. The superiority of etanercept was evident in transplant recipients from both related donors [79% vs 39%, p=0.001] and unrelated donors [53% vs 26%, p=0.0005]. This latter difference is particularly noteworthy, because studies have shown that acute GVHD in recipients of unrelated donor transplants is more difficult to treat than GVHD in recipients of related donor transplants. The time to CR was significantly faster in recipients of related donor transplants who were treated with etanercept plus steroids, but by 12 weeks nearly equivalent proportions of patients in both groups achieved a CR (etanercept plus steroids, 80%, steroids alone 70%). It is therefore not surprising that survival six months from initiation of GVHD treatment was similar in both treatment groups. Recipients of unrelated donor transplants who failed to achieve a CR by day 28 were likely to never achieve CR, thus translating into a survival advantage six months later. Importantly, the infection rates in the first 100 days from initiation of GVHD treatment were not different between patients treated with etanercept plus steroids or treated with steroids alone for bacterial, invasive fungal or viral infections. There were no mycobacterial infections observed in any patients.

Discussion

Current standards for the treatment of acute GVHD rely primarily on steroids alone as initial therapy and reserve additional agents for steroid refractory disease. Previous studies in steroid refractory GVHD have shown that anti-TNFα agents have significant efficacy but the majority of patients still die from GVHD or its complications. Our results show that the combination of etanercept plus steroids as initial treatment for GVHD results in significantly better CR rates four weeks later compared to steroids alone. These CRs were durable and could not be explained by differences in the steroid dose at four weeks. Of note, etanercept plus steroids improved the outcome for recipients of both related donor and unrelated donor transplants which translated into significantly improved survival at six months for unrelated donor transplant recipients. The improvements in outcome were realized without an increased incidence of serious infections, chronic GVHD or relapse.

Animal studies have demonstrated that TNFα plays a critical role in both the gastrointestinal tract18,19 and the skin, but its role in the liver is more controversial. Our data confirm mechanistic studies of GVHD pathophysiology in animal models that have delineated both TNFα dependent and TNFα independent pathways of disease because TNFα inhibition increases response rates but does not completely eliminate GVHD. All patients who received etanercept also received steroids, and therefore the relative importance of these pathways in clinical GVHD remains to be determined in future studies.

One potential concern regarding the use of TNF-inhibitors to treat GVHD is an increased risk of infections, particularly mycobacterial and fungal infections. Invasive Aspergillus infections have been associated with use of the anti-TNFα monoclonal antibody infliximab for treatment of GVHD in two retrospective studies involving a total of 32 patients. Although the overall incidence of infection was significant—as would be expected in patients with GVHD receiving high dose steroids—we did not observe any significant difference in infection rates, including fungal infections, in patients also treated with etanercept. The discrepancy between the two studies may be due to potential differences in the mechanism of action of the two drugs: infliximab can induce systemic elimination and clearance of monocytes and macrophages that express membrane-bound TNFα, whereas etanercept does not. In addition, the recent availability of more effective prophylactic agents against a broad range of fungal species may have contained the overall infectious risk. We also did not observe increased morbidity and mortality from etanercept in patients who developed gram-positive infections, which differs from prior reports in other disease settings.

If these data are confirmed in other multi-center trials, we may well be able to use inhibition of TNF-α as an important adjunct to therapy for GVHD that one day may be able to reduce or even eliminate the need for prolonged high-dose steroids in some patients.

References

1. Chao NJ, Chen BJ. Prophylaxis and treatment of acute graft-versus-host disease. Semin Hematol 2006; 43:32-41.

2. Leisenring WM, Martin PJ, Peterdorf EW, et al. An acute graft-versus-host disease activity index to predict survival after hematopoietic cell translpantation with myeloablative conditioning regimens. Blood 2006; 108:749-55.

3. Van Lint MT, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day +5 responders and no advantage for nonresponders recieving anti-thymocate globulin, Blood 2006;107:4177-81.

4. MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant 2002;8:387-94.

5. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood 1990;76:1464-72.

6. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990;75:1024-30.

7. Reddy P, Ferrara JL. Immunobiology of acute graft-versus-host disease. Blood Rev 2003;17:187-94.

8. Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 2002;8:575-81.

9. Korngold R, Marini JC, de Baca ME, Murphy GF, Giles-Komar J. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant 2003;9:292-303.

10.Jacobsohn DA, Hallick J, Anders V, McMillan S, Morris L, Vogelsang GB. Infliximab for steroid-refractory acute GVHD: a case series. Am J Hematol 2003;74:119-24.

11.Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004;104:649-54.

12. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007;82:45-52.

13. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica 2004;89:1352-9.

14. Sieper J, Van Den Brande J. Diverse effects of infliximab and etanercept on T lymphocytes. Semin Arthritis Rheum 2005;34(Suppl1):23-7.

15. Dhillon S, Lyseng-Williamson KA, Scott LJ. Etanercept: a review of its use in the management of rheumatoid arthritis. Drugs 2007;67:1211-41.

16. Levine JE, Paczesny SS, Mineishi SS, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood. 2008;111:2470.

17. Levine JE, Uberti JP, Ayash L, et al. Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. Biol Blood Marrow Transplant 2003;9:189-97.

18. Brown GR, Lee EL, Thiele DL. TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms. J Immunol 2003;170:5082-8.

19. Hattori K, Hirano T, Miyajima H, et al. Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies. Blood 1998;91:4051-5.

20. Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med 1987;166:1280-9.

21. Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med 2004;19:320-34.

22. Marty FM, Lee SJ, Fahey MM, et al. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood 2003;102:2768-76.

23. Ehlers S. Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept? Clin Infect Dis 2005;41 Suppl 3:S199-203.

24. Fisher CJ, Jr., Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334:1697-702.

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Феррара Дж., Левин Дж.Э.

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Болезнь «трансплантат против хозяина» (РТПХ) является основной причиной заболеваемости после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Многочисленные доклинические исследования показали, что фактор некроза опухолей (TNFα) представляет собой важный эффектор РТПХ в условиях эксперимента. Стандартная терапия острой РТПХ с применением высоких доз стероидных гормонов приводит к полному клиническому ответу у 35% больных. В то же время у больных, леченных препаратом «этанерсепт» и стероидами, чаще достигался полный клинический эффект, нежели у больных, леченных лишь стероидами (соответственно, 69% и 33%, Р=0,0001). Это различие наблюдалось у реципиентов при ТГСК как от родственных, так и неродственных доноров. Уровни TNF R1 (биомаркера активности РТПХ) в плазме были повышенными в начале РТПХ и значительно снижались только у больных с полным клиническим ответом на лечение. Делается вывод о том, что этанерсепт в комбинации со стероидными гормонами в качестве исходной терапии острой РТПХ приводит к значительному возрастанию частоты полного клинического эффекта от лечения. Таким образом, медикаментозная блокада цитокинов может в будущем стать важным элементом лечения РТПХ.

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James L.M. Ferrara, M.D. 1,2 and John E. Levine, M.D.1,2

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1Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan; 2Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan


Address correspondence:
Dr. Ferrara at 1500 E. Medical Center Dr., 5303 Cancer Center, Ann Arbor, Michigan, 48109-0941
or at Ferrara@spam is badumich.edu

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Graft-versus-host disease (GVHD) is a principal cause of morbidity following allogeneic hematopoietic cell transplantation (HCT). Multiple pre-clinical studies have shown that tumor necrosis factor-α (TNFα) is an important effector of experimental GVHD. Patients treated with etanercept and steroids were more likely to achieve complete response than were patients treated with steroids alone. This difference was observed in HCT recipients of both related donors and unrelated donors. Cytokine blockade may become an important element of treatment for GVHD in the future.

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James L.M. Ferrara, M.D. 1,2 and John E. Levine, M.D.1,2

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James L.M. Ferrara, M.D. 1,2 and John E. Levine, M.D.1,2

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Graft-versus-host disease (GVHD) is a principal cause of morbidity following allogeneic hematopoietic cell transplantation (HCT). Multiple pre-clinical studies have shown that tumor necrosis factor-α (TNFα) is an important effector of experimental GVHD. Patients treated with etanercept and steroids were more likely to achieve complete response than were patients treated with steroids alone. This difference was observed in HCT recipients of both related donors and unrelated donors. Cytokine blockade may become an important element of treatment for GVHD in the future.

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Graft-versus-host disease (GVHD) is a principal cause of morbidity following allogeneic hematopoietic cell transplantation (HCT). Multiple pre-clinical studies have shown that tumor necrosis factor-α (TNFα) is an important effector of experimental GVHD. Patients treated with etanercept and steroids were more likely to achieve complete response than were patients treated with steroids alone. This difference was observed in HCT recipients of both related donors and unrelated donors. Cytokine blockade may become an important element of treatment for GVHD in the future.

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1Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan; 2Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan


Address correspondence:
Dr. Ferrara at 1500 E. Medical Center Dr., 5303 Cancer Center, Ann Arbor, Michigan, 48109-0941
or at Ferrara@spam is badumich.edu

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1Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan; 2Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan


Address correspondence:
Dr. Ferrara at 1500 E. Medical Center Dr., 5303 Cancer Center, Ann Arbor, Michigan, 48109-0941
or at Ferrara@spam is badumich.edu

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(РТПХ) является основной причиной заболеваемости после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). 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Болезнь «трансплантат против хозяина» (РТПХ) является основной причиной заболеваемости после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Многочисленные доклинические исследования показали, что фактор некроза опухолей (TNFα) представляет собой важный эффектор РТПХ в условиях эксперимента. Стандартная терапия острой РТПХ с применением высоких доз стероидных гормонов приводит к полному клиническому ответу у 35% больных. В то же время у больных, леченных препаратом «этанерсепт» и стероидами, чаще достигался полный клинический эффект, нежели у больных, леченных лишь стероидами (соответственно, 69% и 33%, Р=0,0001). Это различие наблюдалось у реципиентов при ТГСК как от родственных, так и неродственных доноров. Уровни TNF R1 (биомаркера активности РТПХ) в плазме были повышенными в начале РТПХ и значительно снижались только у больных с полным клиническим ответом на лечение. Делается вывод о том, что этанерсепт в комбинации со стероидными гормонами в качестве исходной терапии острой РТПХ приводит к значительному возрастанию частоты полного клинического эффекта от лечения. Таким образом, медикаментозная блокада цитокинов может в будущем стать важным элементом лечения РТПХ.

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Болезнь «трансплантат против хозяина» (РТПХ) является основной причиной заболеваемости после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Многочисленные доклинические исследования показали, что фактор некроза опухолей (TNFα) представляет собой важный эффектор РТПХ в условиях эксперимента. Стандартная терапия острой РТПХ с применением высоких доз стероидных гормонов приводит к полному клиническому ответу у 35% больных. В то же время у больных, леченных препаратом «этанерсепт» и стероидами, чаще достигался полный клинический эффект, нежели у больных, леченных лишь стероидами (соответственно, 69% и 33%, Р=0,0001). Это различие наблюдалось у реципиентов при ТГСК как от родственных, так и неродственных доноров. Уровни TNF R1 (биомаркера активности РТПХ) в плазме были повышенными в начале РТПХ и значительно снижались только у больных с полным клиническим ответом на лечение. Делается вывод о том, что этанерсепт в комбинации со стероидными гормонами в качестве исходной терапии острой РТПХ приводит к значительному возрастанию частоты полного клинического эффекта от лечения. Таким образом, медикаментозная блокада цитокинов может в будущем стать важным элементом лечения РТПХ.

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Introduction

Acute Myeloid Leukemia (AML) represents as highly heterogeneous disorder with very variable clinical courses and response to chemotherapy. Long term survival ranges from >80% in Acute Promyelocytic Leukemia (APL) with the (15;17)/PML-RARA translocation to <10% in cases with complex aberrations (≥3 chromosomal abnormalities). Additionally, the internal tandem duplications/length mutations within the FLT3-gene (FLT3-ITD/LM) confer an extremely adverse prognostic impact [43,33], whereas isolated mutations in the Nucleophosmin (NPM1) gene in normal karyotype cases are predictive for a more favorable prognosis [11].

Due to these variances in outcome, the prospective determination of the intensity of treatment in AML is a major task. This applies especially to the indications for allogeneic stem cell transplantation (SCT), as the benefit of the graft versus leukemia (GvL) effect has to be balanced against the risks of transplant-associated morbidity and mortality (TRM) in each individual case.

A broad panel of diagnostic methods is necessary to meet the demands of an optimized risk stratification which forms basis for the decision for SCT: Cytogenetic abnormalities are identified by chromosomal banding analyses in ~55% of patients with AML and represent the strongest known prognostic parameters in AML [2,42]. In the remaining 45% of patients where no chromosomal abnormalities can be identified, molecular strategies based on diverse polymerase chain reaction (PCR) techniques allow a more detailed risk stratification in >80% of all cases [29].

Early cytomorphological assessment of bone marrow blast reduction after induction therapy contributes additional prognostic information [22]. This can be combined with multiparameter flow cytometry (MFC), as the quantification of cells with a leukemia associated immunophenotype (LAIP) before and after induction therapy allows an early and very sensitive evaluation of the response to treatment [23]. Quantitative PCR can also be helpful in evaluating the response to therapy at an early timepoint [35]. During follow-up of the disease, the quantification of the minimal residual disease (MRD) load by PCR and MFC permits the detection of impending relapse on a molecular level before clinical or morphological manifestation [16,28].

Thus, the indication for allogeneic SCT in AML requires not only a broad panel of laboratory methods but also has high demands for the knowledge and interpretation of a variety of cytogenetic and molecular markers. To further increase insights into this complex panel of criteria that are relevant for the decision for allogeneic SCT in AML, this work intends to give an overview of the relevant diagnostic methods and markers which can support this complex decision process.

Cytomorphological criteria

The performance of bone marrow cytomorphology shortly after the end of induction allows an assessment of early blast clearance in AML patients. A reduction of blasts <10% on day 16 after the start of induction (“day 16 blasts”) was demonstrated to represent a favorable prognostic parameter. In contrast, the persistence of higher blast percentages at this time-point is a negative prognostic sign and should always provoke the question whether there might be an indication for allo-SCT [31,22].

Cytogenetic criteria

Chromosome banding analyses still play a central role for sub-classification and determination of prognosis in AML [5,40]. To verify the results obtained by chromosome banding and to further clarify more complex aberrations, several fluorescence in situ hybridization (FISH) techniques (e.g. interphase FISH, metaphase FISH, 24-color FISH/SKY) can additionally be performed. Further, interphase FISH provides a higher sensitivity, as 100-200 cells can be evaluated without problems in comparison to 20-25 metaphases by chromosomal banding [18].

The karyotypes allow separation of AML patients into three prognostic relevant groups: The favorable subgroup is represented by the recurrent reciprocal translocations t(15;17)/PML-RARA, t(8;21)/AML1-ETO, and inv(16)/CBFB-MYH11 from the first hierarchy of the WHO classification [20]. Due to the favorable outcome which is achieved by standard therapy in these cytogenetic subgroups, allogeneic SCT is not performed in first complete remission anymore. However, in the case of relapse, allogenic SCT also remains an option in these subgroups [8,16,44].

The second prognostically intermediate subgroup contains patients with a normal karyotype or certain distinct aberrations—e.g. trisomy 8—which do not confer a specific prognostic impact. However, the subgroup of patients with a normal karyotype can be separated into several subentities on the basis of diverse molecular markers, so the indication for SCT can be further determined and differentiated even in this heterogeneous group.

The third prognostically unfavorable subgroup includes unbalanced karyotypes, characterized by gain or loss of whole chromosomes or chromosomal regions. Patients with anomalies of chromosomes 3—e.g. an inversion inv(3)/t(3;3)(q21q26)—or structural or numerical abnormalities of chromosome 7 are also part of this group. Complex aberrant karyotypes which are defined as >3 chromosomal anomalies are found in 10-15% of all AML cases. Conventional chemotherapy achieves stable remissions only rarely [4]. Complex aberrations are interpreted as result of multistep leukemogenesis and show similarities to solid tumors with respect to the pathomechanisms and the inferior response to cytotoxic therapy [36]. Another example are the 11q23/MLL-rearrangements, which occur often in therapy induced AML (t-AML) after treatment with topoisomerase-II inhibitors such as Etoposide.

All these prognostically unfavorable subgroups are characterized by relapse rates of up to 80%. Whereas allogeneic SCT was shown to result in survival of >40%, intensive chemotherapy or high dose chemotherapy followed by autologous stem cell support results in long time survival of only 15-20% in these subgroups. Therefore, diagnosis of the respective karyotypes should in all cases be followed by early planning of allogeneic SCT if possible [41].  

Previously, it had been thought that secondary AML (s-AML) after MDS and therapy associated AML are per se associated with inferior outcome. However, recent studies showed that prognostically unfavorable karyotypes are more frequent in these subgroups, but that prognosis of the individual karyotypes does not differ from the corresponding cytogenetic alterations in de novo AML [30,27]. However, stable disease free survival of >30% has been achieved in s-AML after MDS by allogeneic SCT in some studies [9], and dose reduced conditioning protocols might further improve these results [25].

Molecular criteria

From molecular the aspect, the subgroup of patients with a normal karyotype is composed of a large spectrum of diverse mutations that are associated with distinct prognostic profiles: Length mutations/internal tandem duplications of the FLT3 gene (FLT3-LM/ITD), which are represented by insertions of a few hundred base pairs, are found in ~40% of all patients with normal karyotype [34,45]. Prognosis is dismal, and stable remissions after standard chemotherapy protocols are only seen occasionally [8]. With allogeneic SCT, survival could be improved from 20-25% up to 45-50% in some studies [3,32].

In contrast, isolated mutations of the NPM1 gene are prognostically favorable. They are detected in ~50% of all patients and represent the most frequent molecular marker in AML with a specific association to normal karyotype. The respective mutation is represented by diverse subtypes of a 4 base pair insertion and results in a disturbed function of a tumor suppressor pathway [11].

Recently, Schlenk et al. demonstrated that patients with isolated NPM1-mutations without evidence of FLT3-length mutations and with a normal karyotype do not benefit from allogeneic SCT in first remission. However, when the FLT3-LM and the NPM1-mutation occur in coincidence, outcome was improved when allogeneic SCT was performed [32].

Other mutations are relevant as well, e.g. mutations of the CEPBA-gene. Due to the favorable prognosis their isolated presence should exclude SCT from first-line treatment concepts in first remission [32].

The spectrum of molecular markers being able to allow a more differentiated indication for SCT in normal karyotype AML is continuously increasing: Mutations within the MLL-gene (partial tandem duplications, MLL-PTD) are prognostically unfavorable [10] and represent a further indication for SCT [32]. Thus, molecular screening in patients with a normal karyotype is of high priority for the decision for SCT. (Table 1 provides an overview on the prognostic relevant subgroups in AML on the basis of cytogenetic and molecular markers.)

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Minimal residual disease criteria

Minimal residual disease (MRD) diagnostics are of increasing importance for the definition of therapeutic strategies in AML. The highest level of sensitivity (up to 10-5-10-6) is provided by quantitative PCR or nested PCR [39].

In the reciprocal transcript fusions t(15;17)/PML-RARA, t(8;21)/AML1-ETO, and inv(16)/CBFB-MYH11 quantitative real-time-PCR can be used to assess the reduction of the leukemic cell load after therapy. A persistence of the transcript [17] or a minor decrease [35] are predictive for a significantly enhanced relapse risk. Although these balanced translocations play a minor role in SCT nowadays, as patients can be cured by standard chemotherapy in many cases, increases of the particular molecular markers might be detected 3-6 months before the cytomorphological manifestation of relapse and can still represent an indication for allogeneic SCT.

So far quantitative PCR is available for part of the known molecular mutations only, but efforts are being made to develop such quantification strategies for other markers also. In some studies of limited size it was shown that the NPM1 mutations represent a stable MRD parameter which can be followed quantitatively by real-time PCR [7,14]. For patients with the FLT3-LM, follow-up monitoring can be performed by semi-quantitative PCR [34] or by quantitative methods after design of patient-specific primers due to the heterogeneity of the mutations [38]. For some markers, e.g. for mutations within the loop of the FLT3 tyrosine kinase domain (TKD), assays for quantitative monitoring [37] are being developed, so the spectrum of molecular markers being suitable for MRD is continuously expanding.

Another useful method for MRD studies in AML is provided by multiparameter flow cytometry (MFC), as a leukemia associated immunphenotype (LAIP) can be determined in 95% of all patients [6,24,15,21]. Sensitivities of up to 10-2-10-4 are achieved [12] which also allows MRD monitoring in patients where there are no molecular markers for MRD studies available. Numerous studies demonstrated that the LAIP positive cells show an increase before morphological relapse occurs. Therefore, an increase of LAIP positive cells after therapy should always raise concern and can represent an indication for allogeneic SCT [26]. (Figure 1 shows an algorithm for the decision process to allogeneic SCT in AML.)

e4c6ee370c.png

Hierarchy of diagnostic methods

To allow a most efficient flow of methods and an optimized risk stratification in the decision process towards allogeneic SCT, the diverse methods should be seen in the context of the whole panel, and hierarchies between the diverse methods should be used to guide the more specific techniques. Cytomorphological results raising suspicion for the balanced transcripts t(15;17)/PML-RARA, t(8;21)/AML1-ETO, or inv(16)/CBFB-MYH11 should immediately be followed by the corresponding interphase FISH or PCR analyses for confirmation of subtypes.

When chromosomal banding shows numerical or structural aberrations, the appropriate interphase FISH probes for confirmation and clarification of the results should be selected accordingly. Additionally, interphase FISH can be integrated in the MRD panel due to the higher sensitivity of 1:100–1:200 cells [1]. In normal karyotype cases, molecular screening, e.g., for the NPM1 and FLT3-LM, should be initiated. This might be completed by analyses for the CEBPA mutations, MLL-PTD, or FLT3-TKD, as these markers all are associated with normal karyotype and are essential for risk stratification in the indication to SCT [32]. The determination of the individual LAIP provides a solid basis for later follow-up to detect relapse at the earliest possible timepoint for eventual early planning of SCT.

Conclusions

Therapeutic concepts in AML try to adapt the intensity of therapy to the individual relapse risk. In poor-risk patients, allogeneic SCT is the therapy of choice, whereas in patients with a good prognosis such as the favorable reciprocal translocations, allogeneic SCT is restricted to impending or manifest relapse [8]. This risk stratification is possible only on the basis of patient-specific biological parameters and an exact subclassification of AML cases according to distinct cytogenetic and molecular markers. Further, indications for allogeneic SCT should include the results of MRD diagnostics, as persistence or increase of molecular markers might be an indication for a change of therapy towards SCT.

Thus, therapeutic decisions and the indications for allogeneic SCT require a multimodal diagnostic approach composed by a combination of cytogenetics, FISH, molecular genetics, and MRD diagnostics based on real time PCR and MFC.

However, many questions still require clarification. The combination of diverse markers might be relevant, as prognosis might differ from patients with isolated mutations. Examples are provided by the coincidence of the PML-RARA mutation with the FLT3-LM where prognosis is more unfavorable than in patients with an isolated t(15;17) [13], or by the coincidence of FLT3-LM and NPM1mutations [11]. These overlaps between the diverse genetic subgroups can be responsible for variations in the clinical outcome which are seen in distinct AML subentities and need further investigation.

Further, results should be provided as soon as possible after diagnosis of AML to pave the way to allogeneic SCT in poor-risk cases. Novel methods such as gene expression profiling with microarrays, which allow the simultaneous analysis of thousands of genes, might allow an even more detailed risk stratification and prognostication within the shortest time in the near future [19] which would also facilitate the indication for allogeneic SCT. Drug specific sensitivity assays based on gene expression analyses might soon offer more exact predictions concerning the expected success of the planned chemotherapy [30].

In conclusion, an optimized indication for allogeneic SCT in AML requires the interaction of a broad panel of diagnostic methods, which should be open for new developments to pave the way to an easier, safer, and faster risk stratification in this complex disorder.

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Introduction

Acute Myeloid Leukemia (AML) represents as highly heterogeneous disorder with very variable clinical courses and response to chemotherapy. Long term survival ranges from >80% in Acute Promyelocytic Leukemia (APL) with the (15;17)/PML-RARA translocation to <10% in cases with complex aberrations (≥3 chromosomal abnormalities). Additionally, the internal tandem duplications/length mutations within the FLT3-gene (FLT3-ITD/LM) confer an extremely adverse prognostic impact [43,33], whereas isolated mutations in the Nucleophosmin (NPM1) gene in normal karyotype cases are predictive for a more favorable prognosis [11].

Due to these variances in outcome, the prospective determination of the intensity of treatment in AML is a major task. This applies especially to the indications for allogeneic stem cell transplantation (SCT), as the benefit of the graft versus leukemia (GvL) effect has to be balanced against the risks of transplant-associated morbidity and mortality (TRM) in each individual case.

A broad panel of diagnostic methods is necessary to meet the demands of an optimized risk stratification which forms basis for the decision for SCT: Cytogenetic abnormalities are identified by chromosomal banding analyses in ~55% of patients with AML and represent the strongest known prognostic parameters in AML [2,42]. In the remaining 45% of patients where no chromosomal abnormalities can be identified, molecular strategies based on diverse polymerase chain reaction (PCR) techniques allow a more detailed risk stratification in >80% of all cases [29].

Early cytomorphological assessment of bone marrow blast reduction after induction therapy contributes additional prognostic information [22]. This can be combined with multiparameter flow cytometry (MFC), as the quantification of cells with a leukemia associated immunophenotype (LAIP) before and after induction therapy allows an early and very sensitive evaluation of the response to treatment [23]. Quantitative PCR can also be helpful in evaluating the response to therapy at an early timepoint [35]. During follow-up of the disease, the quantification of the minimal residual disease (MRD) load by PCR and MFC permits the detection of impending relapse on a molecular level before clinical or morphological manifestation [16,28].

Thus, the indication for allogeneic SCT in AML requires not only a broad panel of laboratory methods but also has high demands for the knowledge and interpretation of a variety of cytogenetic and molecular markers. To further increase insights into this complex panel of criteria that are relevant for the decision for allogeneic SCT in AML, this work intends to give an overview of the relevant diagnostic methods and markers which can support this complex decision process.

Cytomorphological criteria

The performance of bone marrow cytomorphology shortly after the end of induction allows an assessment of early blast clearance in AML patients. A reduction of blasts <10% on day 16 after the start of induction (“day 16 blasts”) was demonstrated to represent a favorable prognostic parameter. In contrast, the persistence of higher blast percentages at this time-point is a negative prognostic sign and should always provoke the question whether there might be an indication for allo-SCT [31,22].

Cytogenetic criteria

Chromosome banding analyses still play a central role for sub-classification and determination of prognosis in AML [5,40]. To verify the results obtained by chromosome banding and to further clarify more complex aberrations, several fluorescence in situ hybridization (FISH) techniques (e.g. interphase FISH, metaphase FISH, 24-color FISH/SKY) can additionally be performed. Further, interphase FISH provides a higher sensitivity, as 100-200 cells can be evaluated without problems in comparison to 20-25 metaphases by chromosomal banding [18].

The karyotypes allow separation of AML patients into three prognostic relevant groups: The favorable subgroup is represented by the recurrent reciprocal translocations t(15;17)/PML-RARA, t(8;21)/AML1-ETO, and inv(16)/CBFB-MYH11 from the first hierarchy of the WHO classification [20]. Due to the favorable outcome which is achieved by standard therapy in these cytogenetic subgroups, allogeneic SCT is not performed in first complete remission anymore. However, in the case of relapse, allogenic SCT also remains an option in these subgroups [8,16,44].

The second prognostically intermediate subgroup contains patients with a normal karyotype or certain distinct aberrations—e.g. trisomy 8—which do not confer a specific prognostic impact. However, the subgroup of patients with a normal karyotype can be separated into several subentities on the basis of diverse molecular markers, so the indication for SCT can be further determined and differentiated even in this heterogeneous group.

The third prognostically unfavorable subgroup includes unbalanced karyotypes, characterized by gain or loss of whole chromosomes or chromosomal regions. Patients with anomalies of chromosomes 3—e.g. an inversion inv(3)/t(3;3)(q21q26)—or structural or numerical abnormalities of chromosome 7 are also part of this group. Complex aberrant karyotypes which are defined as >3 chromosomal anomalies are found in 10-15% of all AML cases. Conventional chemotherapy achieves stable remissions only rarely [4]. Complex aberrations are interpreted as result of multistep leukemogenesis and show similarities to solid tumors with respect to the pathomechanisms and the inferior response to cytotoxic therapy [36]. Another example are the 11q23/MLL-rearrangements, which occur often in therapy induced AML (t-AML) after treatment with topoisomerase-II inhibitors such as Etoposide.

All these prognostically unfavorable subgroups are characterized by relapse rates of up to 80%. Whereas allogeneic SCT was shown to result in survival of >40%, intensive chemotherapy or high dose chemotherapy followed by autologous stem cell support results in long time survival of only 15-20% in these subgroups. Therefore, diagnosis of the respective karyotypes should in all cases be followed by early planning of allogeneic SCT if possible [41].  

Previously, it had been thought that secondary AML (s-AML) after MDS and therapy associated AML are per se associated with inferior outcome. However, recent studies showed that prognostically unfavorable karyotypes are more frequent in these subgroups, but that prognosis of the individual karyotypes does not differ from the corresponding cytogenetic alterations in de novo AML [30,27]. However, stable disease free survival of >30% has been achieved in s-AML after MDS by allogeneic SCT in some studies [9], and dose reduced conditioning protocols might further improve these results [25].

Molecular criteria

From molecular the aspect, the subgroup of patients with a normal karyotype is composed of a large spectrum of diverse mutations that are associated with distinct prognostic profiles: Length mutations/internal tandem duplications of the FLT3 gene (FLT3-LM/ITD), which are represented by insertions of a few hundred base pairs, are found in ~40% of all patients with normal karyotype [34,45]. Prognosis is dismal, and stable remissions after standard chemotherapy protocols are only seen occasionally [8]. With allogeneic SCT, survival could be improved from 20-25% up to 45-50% in some studies [3,32].

In contrast, isolated mutations of the NPM1 gene are prognostically favorable. They are detected in ~50% of all patients and represent the most frequent molecular marker in AML with a specific association to normal karyotype. The respective mutation is represented by diverse subtypes of a 4 base pair insertion and results in a disturbed function of a tumor suppressor pathway [11].

Recently, Schlenk et al. demonstrated that patients with isolated NPM1-mutations without evidence of FLT3-length mutations and with a normal karyotype do not benefit from allogeneic SCT in first remission. However, when the FLT3-LM and the NPM1-mutation occur in coincidence, outcome was improved when allogeneic SCT was performed [32].

Other mutations are relevant as well, e.g. mutations of the CEPBA-gene. Due to the favorable prognosis their isolated presence should exclude SCT from first-line treatment concepts in first remission [32].

The spectrum of molecular markers being able to allow a more differentiated indication for SCT in normal karyotype AML is continuously increasing: Mutations within the MLL-gene (partial tandem duplications, MLL-PTD) are prognostically unfavorable [10] and represent a further indication for SCT [32]. Thus, molecular screening in patients with a normal karyotype is of high priority for the decision for SCT. (Table 1 provides an overview on the prognostic relevant subgroups in AML on the basis of cytogenetic and molecular markers.)

52ac7633aa.png

Minimal residual disease criteria

Minimal residual disease (MRD) diagnostics are of increasing importance for the definition of therapeutic strategies in AML. The highest level of sensitivity (up to 10-5-10-6) is provided by quantitative PCR or nested PCR [39].

In the reciprocal transcript fusions t(15;17)/PML-RARA, t(8;21)/AML1-ETO, and inv(16)/CBFB-MYH11 quantitative real-time-PCR can be used to assess the reduction of the leukemic cell load after therapy. A persistence of the transcript [17] or a minor decrease [35] are predictive for a significantly enhanced relapse risk. Although these balanced translocations play a minor role in SCT nowadays, as patients can be cured by standard chemotherapy in many cases, increases of the particular molecular markers might be detected 3-6 months before the cytomorphological manifestation of relapse and can still represent an indication for allogeneic SCT.

So far quantitative PCR is available for part of the known molecular mutations only, but efforts are being made to develop such quantification strategies for other markers also. In some studies of limited size it was shown that the NPM1 mutations represent a stable MRD parameter which can be followed quantitatively by real-time PCR [7,14]. For patients with the FLT3-LM, follow-up monitoring can be performed by semi-quantitative PCR [34] or by quantitative methods after design of patient-specific primers due to the heterogeneity of the mutations [38]. For some markers, e.g. for mutations within the loop of the FLT3 tyrosine kinase domain (TKD), assays for quantitative monitoring [37] are being developed, so the spectrum of molecular markers being suitable for MRD is continuously expanding.

Another useful method for MRD studies in AML is provided by multiparameter flow cytometry (MFC), as a leukemia associated immunphenotype (LAIP) can be determined in 95% of all patients [6,24,15,21]. Sensitivities of up to 10-2-10-4 are achieved [12] which also allows MRD monitoring in patients where there are no molecular markers for MRD studies available. Numerous studies demonstrated that the LAIP positive cells show an increase before morphological relapse occurs. Therefore, an increase of LAIP positive cells after therapy should always raise concern and can represent an indication for allogeneic SCT [26]. (Figure 1 shows an algorithm for the decision process to allogeneic SCT in AML.)

e4c6ee370c.png

Hierarchy of diagnostic methods

To allow a most efficient flow of methods and an optimized risk stratification in the decision process towards allogeneic SCT, the diverse methods should be seen in the context of the whole panel, and hierarchies between the diverse methods should be used to guide the more specific techniques. Cytomorphological results raising suspicion for the balanced transcripts t(15;17)/PML-RARA, t(8;21)/AML1-ETO, or inv(16)/CBFB-MYH11 should immediately be followed by the corresponding interphase FISH or PCR analyses for confirmation of subtypes.

When chromosomal banding shows numerical or structural aberrations, the appropriate interphase FISH probes for confirmation and clarification of the results should be selected accordingly. Additionally, interphase FISH can be integrated in the MRD panel due to the higher sensitivity of 1:100–1:200 cells [1]. In normal karyotype cases, molecular screening, e.g., for the NPM1 and FLT3-LM, should be initiated. This might be completed by analyses for the CEBPA mutations, MLL-PTD, or FLT3-TKD, as these markers all are associated with normal karyotype and are essential for risk stratification in the indication to SCT [32]. The determination of the individual LAIP provides a solid basis for later follow-up to detect relapse at the earliest possible timepoint for eventual early planning of SCT.

Conclusions

Therapeutic concepts in AML try to adapt the intensity of therapy to the individual relapse risk. In poor-risk patients, allogeneic SCT is the therapy of choice, whereas in patients with a good prognosis such as the favorable reciprocal translocations, allogeneic SCT is restricted to impending or manifest relapse [8]. This risk stratification is possible only on the basis of patient-specific biological parameters and an exact subclassification of AML cases according to distinct cytogenetic and molecular markers. Further, indications for allogeneic SCT should include the results of MRD diagnostics, as persistence or increase of molecular markers might be an indication for a change of therapy towards SCT.

Thus, therapeutic decisions and the indications for allogeneic SCT require a multimodal diagnostic approach composed by a combination of cytogenetics, FISH, molecular genetics, and MRD diagnostics based on real time PCR and MFC.

However, many questions still require clarification. The combination of diverse markers might be relevant, as prognosis might differ from patients with isolated mutations. Examples are provided by the coincidence of the PML-RARA mutation with the FLT3-LM where prognosis is more unfavorable than in patients with an isolated t(15;17) [13], or by the coincidence of FLT3-LM and NPM1mutations [11]. These overlaps between the diverse genetic subgroups can be responsible for variations in the clinical outcome which are seen in distinct AML subentities and need further investigation.

Further, results should be provided as soon as possible after diagnosis of AML to pave the way to allogeneic SCT in poor-risk cases. Novel methods such as gene expression profiling with microarrays, which allow the simultaneous analysis of thousands of genes, might allow an even more detailed risk stratification and prognostication within the shortest time in the near future [19] which would also facilitate the indication for allogeneic SCT. Drug specific sensitivity assays based on gene expression analyses might soon offer more exact predictions concerning the expected success of the planned chemotherapy [30].

In conclusion, an optimized indication for allogeneic SCT in AML requires the interaction of a broad panel of diagnostic methods, which should be open for new developments to pave the way to an easier, safer, and faster risk stratification in this complex disorder.

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Поэтому оптимизация показаний к ГАСК при ОМЛ требует, прежде всего, определения индивидуального риска рецидива. При этом прогноз основывается на различных хромосомных и молекулярных аберрациях. Необходима широкая панель диагностических приемов, чтобы обеспечить такую субклассификацию и стратификацию по прогнозу, а именно: цитоморфологические, цитогенетические, молекулярно-генетические методы и иммунофенотипирование посредством мультипарамерической проточной цитометрии. Эти методы должны рассматриваться не как изолированные технологии, а как часть интегральной сети иерархий и взаимодействий. Неблагоприятным прогностическим маркером считается наличие несбалансированных кариотипов с утратой или наличием лишних хромосом или их крупных фрагментов. Приводятся примеры сочетаний маркеров высокого риска для обоснования четких показаний к алло-ТГСК, например аномалий хромосомы 7, сложных аберраций (&gt;3 хромосомных аномалий) или мутаций по протяженности FLT3. 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Хартвиг М., Цандер Р.А., Хаферлах Е. , Фезе Б., Крегер Н., Бахер У.

" ["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(4) "9236" ["VALUE"]=> array(2) { ["TEXT"]=> string(3734) "<p>Показания к аллогенной трансплантации стволовых клеток (алло-ТГСК) при остром миелобластном лейкозе (ОМЛ) представляют серьезные трудности из-за клинической и генетической гетерогенности данного заболевания. Поэтому оптимизация показаний к ГАСК при ОМЛ требует, прежде всего, определения индивидуального риска рецидива. При этом прогноз основывается на различных хромосомных и молекулярных аберрациях. Необходима широкая панель диагностических приемов, чтобы обеспечить такую субклассификацию и стратификацию по прогнозу, а именно: цитоморфологические, цитогенетические, молекулярно-генетические методы и иммунофенотипирование посредством мультипарамерической проточной цитометрии. Эти методы должны рассматриваться не как изолированные технологии, а как часть интегральной сети иерархий и взаимодействий. Неблагоприятным прогностическим маркером считается наличие несбалансированных кариотипов с утратой или наличием лишних хромосом или их крупных фрагментов. Приводятся примеры сочетаний маркеров высокого риска для обоснования четких показаний к алло-ТГСК, например аномалий хромосомы 7, сложных аберраций (&gt;3 хромосомных аномалий) или мутаций по протяженности FLT3. Напротив, относительно благоприятные реципрокные транслокации, такие, как t(15;17)/<em>PML</em><em>-</em><em>RARA</em> или t(8;21)/<em>AML</em><em>1-</em><em>ETO</em><em> </em>и inv(16)/<em>CBFB</em><em>-</em><em>MYH</em><em>11</em>, мутации гена<strong> </strong><em>NPM</em><em>1</em>. Не являются показанием к ТГСК в первой ремиссии, в связи с достаточно хорошим прогнозом при проведении стандартной терапии. В дальнейшем показания к ТГСК должны включать в себя результаты оценки минимальной остаточной болезни (МОБ) посредством полимеразной цепной реакции (ПЦР) или проточной цитометрии. Новые аспекты безопасной и быстрой стратификации по риску для оптимизации показаний к ТГСК при ОМЛ могут быть выработаны на основе новых технологий, таких, как оценка профилей экспрессии множества генов с помощью микроэрреев (биочипов). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3550) "

Показания к аллогенной трансплантации стволовых клеток (алло-ТГСК) при остром миелобластном лейкозе (ОМЛ) представляют серьезные трудности из-за клинической и генетической гетерогенности данного заболевания. Поэтому оптимизация показаний к ГАСК при ОМЛ требует, прежде всего, определения индивидуального риска рецидива. При этом прогноз основывается на различных хромосомных и молекулярных аберрациях. Необходима широкая панель диагностических приемов, чтобы обеспечить такую субклассификацию и стратификацию по прогнозу, а именно: цитоморфологические, цитогенетические, молекулярно-генетические методы и иммунофенотипирование посредством мультипарамерической проточной цитометрии. Эти методы должны рассматриваться не как изолированные технологии, а как часть интегральной сети иерархий и взаимодействий. Неблагоприятным прогностическим маркером считается наличие несбалансированных кариотипов с утратой или наличием лишних хромосом или их крупных фрагментов. Приводятся примеры сочетаний маркеров высокого риска для обоснования четких показаний к алло-ТГСК, например аномалий хромосомы 7, сложных аберраций (>3 хромосомных аномалий) или мутаций по протяженности FLT3. Напротив, относительно благоприятные реципрокные транслокации, такие, как t(15;17)/PML-RARA или t(8;21)/AML1-ETO и inv(16)/CBFB-MYH11, мутации гена NPM1. Не являются показанием к ТГСК в первой ремиссии, в связи с достаточно хорошим прогнозом при проведении стандартной терапии. В дальнейшем показания к ТГСК должны включать в себя результаты оценки минимальной остаточной болезни (МОБ) посредством полимеразной цепной реакции (ПЦР) или проточной цитометрии. Новые аспекты безопасной и быстрой стратификации по риску для оптимизации показаний к ТГСК при ОМЛ могут быть выработаны на основе новых технологий, таких, как оценка профилей экспрессии множества генов с помощью микроэрреев (биочипов).

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Maite Hartwig1, Axel Rolf Zander1, Torsten Haferlach2, Boris Fehse1,3,Nicolaus Kröger1, Ulrike Bacher1*

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1Interdisciplinary Clinic for Stem Cell Transplantation, University Medical Center Hamburg, Germany; 2MLL, Munich Leukemia Laboratory, Munich, Germany; 3Experimental Pediatric Oncology and Hematology, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany


Correspondence:
*Dr. med. Ulrike Bacher, MD, Interdisciplinary Clinic for Stem Cell Transplantation,
University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany


Tel. 00494428034154, Fax. 00494428038097, Email: u.bacher@uke.de

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The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. 

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Maite Hartwig1, Axel Rolf Zander1, Torsten Haferlach2, Boris Fehse1,3,Nicolaus Kröger1, Ulrike Bacher1*

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The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. 

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The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling. 

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1Interdisciplinary Clinic for Stem Cell Transplantation, University Medical Center Hamburg, Germany; 2MLL, Munich Leukemia Laboratory, Munich, Germany; 3Experimental Pediatric Oncology and Hematology, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany


Correspondence:
*Dr. med. Ulrike Bacher, MD, Interdisciplinary Clinic for Stem Cell Transplantation,
University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany


Tel. 00494428034154, Fax. 00494428038097, Email: u.bacher@uke.de

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1Interdisciplinary Clinic for Stem Cell Transplantation, University Medical Center Hamburg, Germany; 2MLL, Munich Leukemia Laboratory, Munich, Germany; 3Experimental Pediatric Oncology and Hematology, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany


Correspondence:
*Dr. med. Ulrike Bacher, MD, Interdisciplinary Clinic for Stem Cell Transplantation,
University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany


Tel. 00494428034154, Fax. 00494428038097, Email: u.bacher@uke.de

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Хартвиг М., Цандер Р.А., Хаферлах Е. , Фезе Б., Крегер Н., Бахер У.

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Напротив, относительно благоприятные реципрокные транслокации, такие, как t(15;17)/<em>PML</em><em>-</em><em>RARA</em> или t(8;21)/<em>AML</em><em>1-</em><em>ETO</em><em> </em>и inv(16)/<em>CBFB</em><em>-</em><em>MYH</em><em>11</em>, мутации гена<strong> </strong><em>NPM</em><em>1</em>. Не являются показанием к ТГСК в первой ремиссии, в связи с достаточно хорошим прогнозом при проведении стандартной терапии. В дальнейшем показания к ТГСК должны включать в себя результаты оценки минимальной остаточной болезни (МОБ) посредством полимеразной цепной реакции (ПЦР) или проточной цитометрии. Новые аспекты безопасной и быстрой стратификации по риску для оптимизации показаний к ТГСК при ОМЛ могут быть выработаны на основе новых технологий, таких, как оценка профилей экспрессии множества генов с помощью микроэрреев (биочипов). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3550) "

Показания к аллогенной трансплантации стволовых клеток (алло-ТГСК) при остром миелобластном лейкозе (ОМЛ) представляют серьезные трудности из-за клинической и генетической гетерогенности данного заболевания. Поэтому оптимизация показаний к ГАСК при ОМЛ требует, прежде всего, определения индивидуального риска рецидива. При этом прогноз основывается на различных хромосомных и молекулярных аберрациях. Необходима широкая панель диагностических приемов, чтобы обеспечить такую субклассификацию и стратификацию по прогнозу, а именно: цитоморфологические, цитогенетические, молекулярно-генетические методы и иммунофенотипирование посредством мультипарамерической проточной цитометрии. Эти методы должны рассматриваться не как изолированные технологии, а как часть интегральной сети иерархий и взаимодействий. Неблагоприятным прогностическим маркером считается наличие несбалансированных кариотипов с утратой или наличием лишних хромосом или их крупных фрагментов. Приводятся примеры сочетаний маркеров высокого риска для обоснования четких показаний к алло-ТГСК, например аномалий хромосомы 7, сложных аберраций (>3 хромосомных аномалий) или мутаций по протяженности FLT3. Напротив, относительно благоприятные реципрокные транслокации, такие, как t(15;17)/PML-RARA или t(8;21)/AML1-ETO и inv(16)/CBFB-MYH11, мутации гена NPM1. Не являются показанием к ТГСК в первой ремиссии, в связи с достаточно хорошим прогнозом при проведении стандартной терапии. В дальнейшем показания к ТГСК должны включать в себя результаты оценки минимальной остаточной болезни (МОБ) посредством полимеразной цепной реакции (ПЦР) или проточной цитометрии. Новые аспекты безопасной и быстрой стратификации по риску для оптимизации показаний к ТГСК при ОМЛ могут быть выработаны на основе новых технологий, таких, как оценка профилей экспрессии множества генов с помощью микроэрреев (биочипов).

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Introduction

Generally, the treatment of children with advanced stages or relapses of malignant disorders consists of high-dose chemotherapy, or, sometimes, radiotherapy with follow-up autologous transplantation of hematopoietic stem cells (HSCs). Multiple courses of intensive chemo and/or radiotherapy result in damage to the bone marrow cells involving all natural factors of antimicrobial defense, resulting in the patients' susceptibility to a wide spectrum of opportunistic infections. During the early post-transplant period, these infections and appropriate therapeutic approaches are determined by neutropenia. After transplant engraftment, the risk of severe bacterial infections becomes greatly reduced.

For most patients, engraftment of peripheral blood stem cell (PBSC) autotransplant occurs relatively early: average neutrophil counts of > 500/μl are observed by 11 days; increase in platelets to > 20 000 is reached by 12 days. However, for about 5% of the patients transplanted with autologous HSCs, a delayed reconstitution of neutrophils and platelets is observed, which is explained mostly by a low dosage of transplanted CD34+ cells per kg of patient's body weight [1, 2].

A highly attractive method of choice to shorten the period of hematopoietic reconstitution after transplantation of HSCs is being developed at present, i.e., a simultaneous autotransplantation of mesenchymal stem cells (MSCs).

The main source of MSCs is bone marrow, which contains only 1-2 of these cells per 10000 of nucleated cells [3, 4, 5]. They have a fibroblast-like morphology and form specific fibroblast colony-forming units (CFU-F) when cultured in vitro. MSCs possess great proliferative capacity; and the cells obtained from young bone marrow donors are able to divide some 24-40 times, and to expand the cell population by up to 1 million times [6, 7, 8]. Phenotypic characterization of MSCs has shown that these cells are negative for hematopoietic markers (CD34, CD45, CD14, CD31, CD133), and positive for CD44, СD105 (SH2), CD166, CD73 (SH3), CD140 antigens [5, 9]. MSCs are multipotential progenitors and possess high plasticity. After cultivation in vitro and implantation, mesenchymal cells are able to differentiate into bone, cartilaginous, muscular, adipose tissues, and bone marrow stromal cells, as controlled by local factors and the microenvironment of the implantation area [5, 9, 10, 11, 12].

In such a way, MSCs give rise to bone marrow stromal cells that support hematopoiesis, by means of cytokine production (e.g., IL1, IL6, IL7, IL8, IL11, IL12, IL14), as well as Flt-3 ligand and SCF, which induces G-CSF and GM-CSF production [4, 9, 13]. Moreover, MSCs greatly support in vitro formation of megakaryocytes and platelet cells [14]. This work concerns the issues of hematopoiesis reconstitution in children with oncohematological disorders. Autologous transplantation of HSCs has been recommended for these patients, but after HSCs mobilization and collection the amounts of CD34+ cells per kg were not sufficient for fast engraftment. Co-transplantation with MSCs was applied for these patients.

Patients and methods

Patients: Twenty-four children were involved in our investigation. All of them were initially included in the protocol of treatment in BRCPOH and had neoplastic disorders at an advanced stage (II-IV), i.e., Hodgkin’s disease (HD), non-Hodgkin's lymphomas and Ewing's sarcomas. Autologous transplantation of HSCs formed a part of the standard treatment protocols for these diseases. After collection of HSCs, we detected an insufficiency in all of these patients of CD34+ cells (≤ 2,5 x106/kg) in transplants, due to either weak mobilization response induced by G-CSF, or excessive weight. The study was performed over a relatively long time period (June 2003 to May 2005). After obtaining written consent from the patients or their parents, autologous transplantation of MSCs was applied to seven adolescents, in addition to PBSC autotransplantation (five patients) and bone marrow autotransplantation (two cases), to investigate the influence of MSCs upon the rates of autotransplant engraftment.

Eleven patients were auto-transplanted with PBSC (control group 1), and the six patients transplanted with bone marrow without MSCs autotransplantation were considered as control group 2.

Mobilization and collection of HSCs: PBSC mobilization in patients was carried out using G-CSF Granocyte (Sanofi – Aventis, France), according to the following schedule: G-CSF, 10 μg/kg within 24 hours subcutaneously for 5 to 10 days, depending on the body mass of the patients. The lymphocyte counts were observed on a daily basis. PBSCs were harvested when the lymphocyte numbers exceeded ≥ 25 х 106/ml. A blood cell separator "CS-3000+" (Baxter, USA) was used for stem cell apheresis.

The CD34+ cell numbers in the transplant were detected by flow cytometry (FACScan, Becton Dickinson, USA).

Mesenchymal stem cells:
Up to 30–50 days before the planned PBSC auto-transplantation, 20–50ml portions of autologous bone marrow were taken under anesthesia via bone marrow puncture. Mononuclear cells were separated in Histopaque medium with a buoyant density of 1.077 (Sigma, USA), then twice washed in Hanks solution, re-suspended in Iscove’s Modified Dulbecco Medium (IMDM) with 10% FBS (Sigma, USA), and transferred into 175cm2 flasks filled with 30ml medium, at a concentration of 2-3 x 106/ml. The cells were incubated under 37оC at 5% СО2. Non-adherent cells were removed every 48 hours during the medium replacement. After reaching 80–90% confluence at the flask surface, the cells were detached with 0.25% trypsin-EDTA, and 1x10 cells were transferred into a new flask (passage 1). Several passages were carried out in a similar way. Thei in vitro expanded cells were identified by flow cytometry for the presence of typical MSC surface markers (CD105, CD90, CD140), and the absence of hematopoietic cells markers (CD34, CD45, CD14).

CFU-F analysis:
To perform CFU-F counts, the mononuclear cells were isolated from bone marrow samples, and re-suspended in a full medium that contained IMDM supplemented with 15% FBS, L-glutamine, 2-mercaptoethanol and hydrocortisone (all reagents from Sigma, USA). Cell suspensions were then transferred into 60-mm Petri dishes. The cells were cultivated for 14 days (37оC, 5% СО2). After methanol fixation, the resulting colonies were stained according to Giemsa, and counted with inverted microscopy.

Statistical analysis:
The data obtained was treated using STATISTICA 6.0 software. When analyzing the transplant parameters, the statistical significance of the differences between the groups was evaluated by the Mann-Whitney test. The degrees of correlations between the parameters were evaluated by the Spearman test.

Results

Isaikina_tab1.png

Patients' characteristics:
In Table 1, we present the characteristics of seven patients involved in the experimental group who obtained additional infusions of MSCs. The age of these patients was 13 to 17 years; male/female ratio was 5:2. Two patients were diagnosed as Hodgkin’s disease (HD), stages II and IV; two patients suffered with non-Hodgkin B-type lymphomas, stage III and IV, two of patients had Ewing's sarcoma, and one had forward mediastinal germinoma, IV stage. Treatment of all the patients started in accordance with the protocols approved in BRCPOH (for Hodgkin’s disease, DAL HD 95, for Ewing’s sarcoma, ММCU-99, for Non-Hodgkin’s lymphoma, BFM-95 Rez, for germinoma, MAKEI-96). The numbers of chemotherapy cycles depended on the specific therapy response, relapse development, and the absence of a response to therapy; and varied from 4 to 10 cycles.

In addition to low CD34+ cell numbers in the transplant, the stabilization of the main disease in two weeks and Karnovsky Status >80% served as criteria for inclusion into this investigation. Two patients were in complete remission state, stabilization of the process was determined in two other patients, and there was no response to induction therapy in three adolescents.

In patients with Hodgkin’s disease, upon conditioning before autotransplantation of HSC, a high-dose polychemotherapy block BEAM was used (carmustin 300 mg/m2+ Ara-C 800 mg/m2+ etoposid 400 mg/m2+ меlphalan 140 mg/m2); in Ewing’s sarcoma, TioBuM-140 (tiophosphamide 600 mg/m2+ busulphan 16 mg/kg + меlphalan 140 mg/m2); with Non-Hodgkin’s lymphomas BuVPEnd (busulphan 480 mg/m2+ VP-16 900 mg/m2+ endoxan 4500 mg/m2), and in germinomas BuM-140 (busulphan 480 mg/m2+ меlphalan 140 mg/m2).

Table 2 shows the characteristics of the 17 patients involved in control group 1 (11 pts) and control group 2 (6 pts), who were subjected to autologous HSCT only.

Isaikina_tab2.png

Ex vivo MSCs expansion for autologous transplantation

For subsequent infusion together with autologous HSCs, the MSCs were cultured in vitro until the necessary amount had been obtained, depending on the body weight of each patient. Cells from passages 1 to 4 were used for autotransplantation in our patients. All mesenchymal cells obtained in vitro were morphologically homogeneous and exhibited a fibroblast-like shape in the monolayer at the surface of flasks. When re-suspended after trypsinization, they were large and rounded with a round nucleus, and they were three-fold larger than the neutrophils.

Isaikina_tab3.png

The main parameters of growth dynamics for MSCs obtained from the patients' mononuclear cells in vitro are listed in Table 3. About 25.7 ± 2.8 ml of the bone marrow was utilized in order to obtain the MSCs. Of this volume, we yielded as many as 486.43 ± 108.61 х 106 mononuclear cells. A 90% confluence cell layer was obtained in the primary culture at about 17 ± 2 days of incubation. The cells were then detached from the flasks' surface and counted (first passage). An average of 17.14 ± 4.38 х 106 of MSCs were obtained after cell growth in primary culture.

After bone marrow collection, CFU-F analysis was carried out for all patients. This test allowed us to detect the relative number of MSCs (proliferative cells active in culture) among the nucleated cell fraction, isolated from patients' bone marrow probes. The CFU-F number was about 5.26 ± 0.6 colonies per 105 bone marrow mononuclear cells.

Thus, the MSC number did increase ~103 times after incubation in the primary culture. After several passages were carried out, and the MSCs were incubated in subculture, their amount became ~104 times higher. Fig.1 represents the MSCs growth dynamics in subculture for each patient.

Fig. 2 reflects the correlation between the numbers of initial MSCs in the bone marrow able to proliferate and to form colonies in culture (CFU-F number), and MSCs number obtained from the primary culture before they underwent subcultures (r = 0.77; р = 0.04).

Isaikina_fig1.pngIsaikina_fig2.png

Data analysis revealed a statistically reliable dependence between the high-dose chemotherapy cycles number received by patients before bone marrow collection and the time taken for MSCs growth until a monolayer in primary culture was formed (r = 0,79, p = 0,03).

These results display the reduction of MSCs proliferative activity after chemo or radiotherapy.

HSCs and MSCs transplantation

Table 4 represents the HSCs and additional MSCs transplant characteristics for each patient. 5 children who had received PBSC as a transplant a median of 4.6 (range 3.0–6.9) х 108 /kg of nucleated cells were transfused including a median of 1.14 (range 0.64–1.3) х 106 /kg of CD34+ cells. Two patients who had received autologous bone marrow as a transplant 2.5 х 106 /kg and 8.1 х 106 /kg of nucleated cells were transfused including 1.0 х 106 /kg and 0.8 х 106 /kg of CD34+ cells, correspondingly. The median number of expanded MSCs reinfused into a patient was 0.6 (range 0.3–1.1) х 106 MSCs/kg in one hour after HSCs transplantation. Cells detached from the flasks' surface with the trypsine were washed twice in Hanks solution, counted and re-suspended in 20 ml of 0.9% NaCl solution. Intravenous injection of the cell suspension into the patient was performed within 5 minutes. The phenotype and sterility of the cell probes were analyzed.

Cells from passage 4 were used in 4 patients, cells from passage 2, in two patients. For one patient with IV stage HD, who had received 10 blocks of high-dose chemotherapy, MSCs from the first passage were used, in view of their weak proliferation activity, and, as a consequence, with prolonged growth in the main culture over 27 days, and attenuated cell proliferation after the first passage.

Isaikina_tab4.png

Hematopoietic engraftment after co-transplantation of HSCs and MSCs

Table 4 represents the results concerning the reconstitution of neutrophils and red blood cells after HSCs reinfusion for all patients. Five patients who received the MSCs infusion, in addition to autologous PBSC transplantation, and all patients in the control group had obtained 5 μg/kg of G-CSF, starting from the fifth day after transplantation until transplant engraftment. In the case of co-transplantation with MSCs, the median time of neutrophil recovery to ≥ 500/μl was on day 10 (range, 9 to 11), and ≥1000/μl was on day 11 (range, 10 to 13). These rates of neutrophil reconstitution are higher when compared to control group 1, where the median time of neutrophil recovery to ≥ 500/μl was on day 13 (range, 11 to 15), ≥ 1000/μl was on day 14 (range, 13 to 19).

Reconstitution of red blood cells was determined by the appearance of ≥ 1‰ of reticulocytes in the peripheral blood. This value was also higher in the experimental group with MSCs infusion compared to control group 1, and median red cells recovery was on day 10 (range 9 to 12) and on day 14 (range, 11 to 17) respectively.

In two children with co-transplantation of MSCs and autologous bone marrow, neutrophil recovery ≥ 500/μl in peripheral blood analysis was detected for both patients on day 14, ≥ 1000/μl on day 16 and day 14, the reticulocytes number ≥ 1‰ was on day 16 and on day 14, correspondingly. These rates of reconstitution are higher when compared to the autologous bone marrow transplantation in control group 2 (without MSCs infusion), where a median neutrophil recovery ≥ 500/μl was observed on day 24 (range 18 to 32), ≥ 1000/μl on day 25 (range 20 to 35) and median reticulocytes number ≥ 1‰ recovery was observed on day 26 (range 17 to 28).

Discussion

In our present work, we have for the first time proposed the viability of the curative potential for MSCs obtained from the bone marrow of children with oncohematological disorders, who have been pre-treated with high-dose polychemotherapy and radiotherapy. This investigation was undertaken in order to design a therapeutic strategy of MSCs application for hematopoietic support, and the reduction of the neutropenic period after an autologous transplantation of HSCs in children with insufficient amounts of CD34+ cells/kg.

The biological aspects of mesenchymal stem cells are still under intensive investigation. In spite of scarce experimental data, bone marrow-derived MSCs are increasingly being used in clinical settings. In most cases, either MSCs from healthy donors are cultured and expanded for use in allogenic co-transplantations with HSCs, or autologous MSCs are employed as implants for treatment of some non-oncological conditions, e.g., bone or cartilaginous disorders.

MSC's ability to support hematopoiesis in vitro has been shown experimentally by many workers, when co-culturing MSCs and HSCs. Mesenchymal stem cells are considered the precursors of stromal stem cells, osteoblasts, adipocytes, and endothelial cells that form areas of hematopoiesis-inducing microenvironment in bone marrow, thus supporting production of leucocytes, red blood cells and platelets [15, 16]. On one hand their effects upon hematopoietic precursors are exerted via secretion of soluble cytokines, chemokines, peptides, mediators and hormones and, on other hand, by formation of extracellular matrix from collagen, fibronectin and laminin molecules that provide homing and adhesion of hematopoietic cells. Interleukin-6 (IL-6), IL-1, IL-7, IL-8, SCF, Flt-3-ligand, colony-stimulating factors (CSFs), thrombopoietin, insulin-like growth factor, and transforming growth factor (TGF) are permanently synthesized by stromal cells, thus supporting the stability of blood cell counts within steady limits. IL-1 is the main inducer of cytokine production, whereas TGF is able to inhibit hematopoiesis [17].

Some studies concerning the capacity of cultivated MSCs to support human hematopoiesis in vitro have revealed that, on contact with MSCs, both primitive hematopoietic precursors and committed cells are able to proliferate, thus maintaining their ability for self-replication and differentiation in renewing hematopoietic tissues [18]. The role of stromal cells is especially important due to their ability to prevent HSCs apoptosis [19, 20].

Graça Almeida-Porada et al, in their work on the influence of in vitro cultivated stromal cells on HSCs engraftment, used a xenogeneic model of prenatal transplantation of human cells into sheep embryos. They showed that in cases of human HSCs and MSCs co-transplantation, earlier and higher levels of donor cells in blood were attained. Moreover, HSCs engraftment was more effective with a combined treatment than HSCs transplantation alone [21]. Investigations of human hematopoietic cells from umbilical blood and MSCs co-transplantation into NOD/SCID mice confirmed the importance of MSCs in fast and stable hematopoietic cell engraftment decisively [22].
At the present time, limited data has been published concerning the application of hematopoietic and mesenchymal cell co-transplantation in clinics in order to shorten the period of neutropenia post-transplant in patients with malignant disorders. To our knowledge, no publications exist that concern the results of autologous MSCs utilization aiming to support fast and prolonged engraftment of HSCs auto-transplants in children with oncological and hematological diseases.

The issues of delayed reconstitution of granulocytes and platelets after HSCs autotransplantation still exist, however. A problem with autotransplant rejection still remains, and, in most cases, it occurs due to low doses of transplanted CD34+ cells/kg [1, 2]. At present, all studies on the application of autologous HSCs and MSCs co-transplantation within different groups of patients deal with high doses of CD34+ cells/kg in transplants: e.g., patients with breast tumors received an average of 13.9 х 106 CD34+ cells/kg, according to Кос О. et al (2000)[9]. For related allogenic PBSC transplantation to patients with malignant hematological diseases Lazarus HM et al (2005) employed a mean 5.0х106 CD34+ cells/kg [23]. And in the case of HSCs allogenic transplantation following T-cell depletion, D Cilloni et al (2000) transfused ≥ 2.2 х 106 CD34+ cells/kg [24]. However, numerous observations in large cohorts of patients with PBSC autotransplants suggest high levels of CD34+ in the transplant to be among the most important factors that affect neutrophil recovery after prescribed myeloablative therapy. A standard threshold dose of CD34+cells/kg weight for engraftment of autotransplant and hematopoiesis reconstitution is ≥ 2.5 х 106 cells/kg [25, 26, 27], and, at infusion doses over 5 х 106 CD34+cells/kg, the duration of cytopenia is noticeably reduced [28, 29, 30].

The main idea of our pilot study was to demonstrate the efficacy of supplementary autologous MSCs transplantation, in order to accelerate hematopoietic stem cells engraftment at low doses of CD34+ cells in transplants obtained by leukapheresis: i.e., 0.64–1.3 х 106 CD34+ cells/kg in PBSC autotransplant, and 0.8–1.0 х 106 CD34+ cells/kg in bone marrow autotransplants. An analysis of the resulting data revealed a significant reduction in the post-transplantation cytopenia period for the patients with MSCs co-transplantation after sub-optimal CD34+ cells mobilization, when compared to the control group. In particular, neutrophil reconstitution ≥ 500/μl was found at 9–11 days compared to 11–15, platelet increase ≥ 10000/μl, in 10–13 days as compared to 13–19 in controls, and red cells increased at 9–12 days against 11–17 days in the control group. In this case, it enabled us to avoid the commonly accepted procedure of repeated attempts at PBSC collection, or harvesting considerable bone marrow volumes in case of insufficient CD34+ cell numbers in grafts upon primary harvesting. This is important for the patients who have undergone multiple cycles of chemotherapy or high-dose radiotherapy before autotransplantation, because the negative influence of chemo and radiotherapy on CD34+ cell number is well documented. Bensinger et al (1994) have revealed that each cycle of chemotherapy results in reduction of CD34+ cell numbers by 0.2 х 106 cells during leukapheresis for patients without radiotherapy. Meanwhile, a round of radiotherapy results in CD34+ cells number reduction by 1,8 х 106  after PBSC collection [25].

A number of publications have demonstrated that bone marrow stroma suffers significantly as a result of high-dose chemotherapy or radiotherapy [31,32]. Stromal cells (4–5 week cultures) from the patients after conditioning with busulphan and cyclophosphamide are able to produce monolayers in only 20% of cases, in comparison with 80% in healthy donors [33], and it is not always possible to obtain enough MSCs in vitro for infusion into patients [24].

Our data also confirms a reduced MSCs proliferation capacity after chemotherapy or radiotherapy in our patients. This trend is supported by high correlation coefficient (r = 0.79, p = 0.03) between the numbers of previously received high-dose chemotherapy cycles, and MSCs expansion rate.

In our work we evaluated the functional state of stromal cells by their ability to proliferate in children with supplementary MSCs transplantation. To this purpose, CFU-F analysis was performed. The average CFU-F numbers in bone marrow of the patients was 5.26 ± 0.52 per 105 mononuclear cells. This number was considerably lower when compared to the results of CFU-F analysis in healthy donors [34]. In spite of this, the application of this MSC isolation method from bone marrow, and the technology of cell expansion considered by Кос О.[9], we expanded the primary amounts of MSCs by ~104 times. Thus we obtained sufficient amounts of MSCs within a mean of 36,6 ± 6,3 days after bone marrow aspiration.

Moreover, analysis of our data shows that MSCs infusion is already efficient at MSCs dose 0.3 х 106 cells/kg, thus being quite important in cases of MSCs expansion at limited times elapsing from MSCs aspiration to co-transplantation.

As a result of our pilot study, we confirmed that autologous MSCs co-transplantation may accelerate engraftment of HSCs transplants with low numbers of CD34+ cells/kg when treating children with malignancies. Expansion of MSC in sufficient amounts is an acceptable option in auto-transplants for children after they received prolonged myelotoxic therapy and radiotherapy.

References

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Introduction

Generally, the treatment of children with advanced stages or relapses of malignant disorders consists of high-dose chemotherapy, or, sometimes, radiotherapy with follow-up autologous transplantation of hematopoietic stem cells (HSCs). Multiple courses of intensive chemo and/or radiotherapy result in damage to the bone marrow cells involving all natural factors of antimicrobial defense, resulting in the patients' susceptibility to a wide spectrum of opportunistic infections. During the early post-transplant period, these infections and appropriate therapeutic approaches are determined by neutropenia. After transplant engraftment, the risk of severe bacterial infections becomes greatly reduced.

For most patients, engraftment of peripheral blood stem cell (PBSC) autotransplant occurs relatively early: average neutrophil counts of > 500/μl are observed by 11 days; increase in platelets to > 20 000 is reached by 12 days. However, for about 5% of the patients transplanted with autologous HSCs, a delayed reconstitution of neutrophils and platelets is observed, which is explained mostly by a low dosage of transplanted CD34+ cells per kg of patient's body weight [1, 2].

A highly attractive method of choice to shorten the period of hematopoietic reconstitution after transplantation of HSCs is being developed at present, i.e., a simultaneous autotransplantation of mesenchymal stem cells (MSCs).

The main source of MSCs is bone marrow, which contains only 1-2 of these cells per 10000 of nucleated cells [3, 4, 5]. They have a fibroblast-like morphology and form specific fibroblast colony-forming units (CFU-F) when cultured in vitro. MSCs possess great proliferative capacity; and the cells obtained from young bone marrow donors are able to divide some 24-40 times, and to expand the cell population by up to 1 million times [6, 7, 8]. Phenotypic characterization of MSCs has shown that these cells are negative for hematopoietic markers (CD34, CD45, CD14, CD31, CD133), and positive for CD44, СD105 (SH2), CD166, CD73 (SH3), CD140 antigens [5, 9]. MSCs are multipotential progenitors and possess high plasticity. After cultivation in vitro and implantation, mesenchymal cells are able to differentiate into bone, cartilaginous, muscular, adipose tissues, and bone marrow stromal cells, as controlled by local factors and the microenvironment of the implantation area [5, 9, 10, 11, 12].

In such a way, MSCs give rise to bone marrow stromal cells that support hematopoiesis, by means of cytokine production (e.g., IL1, IL6, IL7, IL8, IL11, IL12, IL14), as well as Flt-3 ligand and SCF, which induces G-CSF and GM-CSF production [4, 9, 13]. Moreover, MSCs greatly support in vitro formation of megakaryocytes and platelet cells [14]. This work concerns the issues of hematopoiesis reconstitution in children with oncohematological disorders. Autologous transplantation of HSCs has been recommended for these patients, but after HSCs mobilization and collection the amounts of CD34+ cells per kg were not sufficient for fast engraftment. Co-transplantation with MSCs was applied for these patients.

Patients and methods

Patients: Twenty-four children were involved in our investigation. All of them were initially included in the protocol of treatment in BRCPOH and had neoplastic disorders at an advanced stage (II-IV), i.e., Hodgkin’s disease (HD), non-Hodgkin's lymphomas and Ewing's sarcomas. Autologous transplantation of HSCs formed a part of the standard treatment protocols for these diseases. After collection of HSCs, we detected an insufficiency in all of these patients of CD34+ cells (≤ 2,5 x106/kg) in transplants, due to either weak mobilization response induced by G-CSF, or excessive weight. The study was performed over a relatively long time period (June 2003 to May 2005). After obtaining written consent from the patients or their parents, autologous transplantation of MSCs was applied to seven adolescents, in addition to PBSC autotransplantation (five patients) and bone marrow autotransplantation (two cases), to investigate the influence of MSCs upon the rates of autotransplant engraftment.

Eleven patients were auto-transplanted with PBSC (control group 1), and the six patients transplanted with bone marrow without MSCs autotransplantation were considered as control group 2.

Mobilization and collection of HSCs: PBSC mobilization in patients was carried out using G-CSF Granocyte (Sanofi – Aventis, France), according to the following schedule: G-CSF, 10 μg/kg within 24 hours subcutaneously for 5 to 10 days, depending on the body mass of the patients. The lymphocyte counts were observed on a daily basis. PBSCs were harvested when the lymphocyte numbers exceeded ≥ 25 х 106/ml. A blood cell separator "CS-3000+" (Baxter, USA) was used for stem cell apheresis.

The CD34+ cell numbers in the transplant were detected by flow cytometry (FACScan, Becton Dickinson, USA).

Mesenchymal stem cells:
Up to 30–50 days before the planned PBSC auto-transplantation, 20–50ml portions of autologous bone marrow were taken under anesthesia via bone marrow puncture. Mononuclear cells were separated in Histopaque medium with a buoyant density of 1.077 (Sigma, USA), then twice washed in Hanks solution, re-suspended in Iscove’s Modified Dulbecco Medium (IMDM) with 10% FBS (Sigma, USA), and transferred into 175cm2 flasks filled with 30ml medium, at a concentration of 2-3 x 106/ml. The cells were incubated under 37оC at 5% СО2. Non-adherent cells were removed every 48 hours during the medium replacement. After reaching 80–90% confluence at the flask surface, the cells were detached with 0.25% trypsin-EDTA, and 1x10 cells were transferred into a new flask (passage 1). Several passages were carried out in a similar way. Thei in vitro expanded cells were identified by flow cytometry for the presence of typical MSC surface markers (CD105, CD90, CD140), and the absence of hematopoietic cells markers (CD34, CD45, CD14).

CFU-F analysis:
To perform CFU-F counts, the mononuclear cells were isolated from bone marrow samples, and re-suspended in a full medium that contained IMDM supplemented with 15% FBS, L-glutamine, 2-mercaptoethanol and hydrocortisone (all reagents from Sigma, USA). Cell suspensions were then transferred into 60-mm Petri dishes. The cells were cultivated for 14 days (37оC, 5% СО2). After methanol fixation, the resulting colonies were stained according to Giemsa, and counted with inverted microscopy.

Statistical analysis:
The data obtained was treated using STATISTICA 6.0 software. When analyzing the transplant parameters, the statistical significance of the differences between the groups was evaluated by the Mann-Whitney test. The degrees of correlations between the parameters were evaluated by the Spearman test.

Results

Isaikina_tab1.png

Patients' characteristics:
In Table 1, we present the characteristics of seven patients involved in the experimental group who obtained additional infusions of MSCs. The age of these patients was 13 to 17 years; male/female ratio was 5:2. Two patients were diagnosed as Hodgkin’s disease (HD), stages II and IV; two patients suffered with non-Hodgkin B-type lymphomas, stage III and IV, two of patients had Ewing's sarcoma, and one had forward mediastinal germinoma, IV stage. Treatment of all the patients started in accordance with the protocols approved in BRCPOH (for Hodgkin’s disease, DAL HD 95, for Ewing’s sarcoma, ММCU-99, for Non-Hodgkin’s lymphoma, BFM-95 Rez, for germinoma, MAKEI-96). The numbers of chemotherapy cycles depended on the specific therapy response, relapse development, and the absence of a response to therapy; and varied from 4 to 10 cycles.

In addition to low CD34+ cell numbers in the transplant, the stabilization of the main disease in two weeks and Karnovsky Status >80% served as criteria for inclusion into this investigation. Two patients were in complete remission state, stabilization of the process was determined in two other patients, and there was no response to induction therapy in three adolescents.

In patients with Hodgkin’s disease, upon conditioning before autotransplantation of HSC, a high-dose polychemotherapy block BEAM was used (carmustin 300 mg/m2+ Ara-C 800 mg/m2+ etoposid 400 mg/m2+ меlphalan 140 mg/m2); in Ewing’s sarcoma, TioBuM-140 (tiophosphamide 600 mg/m2+ busulphan 16 mg/kg + меlphalan 140 mg/m2); with Non-Hodgkin’s lymphomas BuVPEnd (busulphan 480 mg/m2+ VP-16 900 mg/m2+ endoxan 4500 mg/m2), and in germinomas BuM-140 (busulphan 480 mg/m2+ меlphalan 140 mg/m2).

Table 2 shows the characteristics of the 17 patients involved in control group 1 (11 pts) and control group 2 (6 pts), who were subjected to autologous HSCT only.

Isaikina_tab2.png

Ex vivo MSCs expansion for autologous transplantation

For subsequent infusion together with autologous HSCs, the MSCs were cultured in vitro until the necessary amount had been obtained, depending on the body weight of each patient. Cells from passages 1 to 4 were used for autotransplantation in our patients. All mesenchymal cells obtained in vitro were morphologically homogeneous and exhibited a fibroblast-like shape in the monolayer at the surface of flasks. When re-suspended after trypsinization, they were large and rounded with a round nucleus, and they were three-fold larger than the neutrophils.

Isaikina_tab3.png

The main parameters of growth dynamics for MSCs obtained from the patients' mononuclear cells in vitro are listed in Table 3. About 25.7 ± 2.8 ml of the bone marrow was utilized in order to obtain the MSCs. Of this volume, we yielded as many as 486.43 ± 108.61 х 106 mononuclear cells. A 90% confluence cell layer was obtained in the primary culture at about 17 ± 2 days of incubation. The cells were then detached from the flasks' surface and counted (first passage). An average of 17.14 ± 4.38 х 106 of MSCs were obtained after cell growth in primary culture.

After bone marrow collection, CFU-F analysis was carried out for all patients. This test allowed us to detect the relative number of MSCs (proliferative cells active in culture) among the nucleated cell fraction, isolated from patients' bone marrow probes. The CFU-F number was about 5.26 ± 0.6 colonies per 105 bone marrow mononuclear cells.

Thus, the MSC number did increase ~103 times after incubation in the primary culture. After several passages were carried out, and the MSCs were incubated in subculture, their amount became ~104 times higher. Fig.1 represents the MSCs growth dynamics in subculture for each patient.

Fig. 2 reflects the correlation between the numbers of initial MSCs in the bone marrow able to proliferate and to form colonies in culture (CFU-F number), and MSCs number obtained from the primary culture before they underwent subcultures (r = 0.77; р = 0.04).

Isaikina_fig1.pngIsaikina_fig2.png

Data analysis revealed a statistically reliable dependence between the high-dose chemotherapy cycles number received by patients before bone marrow collection and the time taken for MSCs growth until a monolayer in primary culture was formed (r = 0,79, p = 0,03).

These results display the reduction of MSCs proliferative activity after chemo or radiotherapy.

HSCs and MSCs transplantation

Table 4 represents the HSCs and additional MSCs transplant characteristics for each patient. 5 children who had received PBSC as a transplant a median of 4.6 (range 3.0–6.9) х 108 /kg of nucleated cells were transfused including a median of 1.14 (range 0.64–1.3) х 106 /kg of CD34+ cells. Two patients who had received autologous bone marrow as a transplant 2.5 х 106 /kg and 8.1 х 106 /kg of nucleated cells were transfused including 1.0 х 106 /kg and 0.8 х 106 /kg of CD34+ cells, correspondingly. The median number of expanded MSCs reinfused into a patient was 0.6 (range 0.3–1.1) х 106 MSCs/kg in one hour after HSCs transplantation. Cells detached from the flasks' surface with the trypsine were washed twice in Hanks solution, counted and re-suspended in 20 ml of 0.9% NaCl solution. Intravenous injection of the cell suspension into the patient was performed within 5 minutes. The phenotype and sterility of the cell probes were analyzed.

Cells from passage 4 were used in 4 patients, cells from passage 2, in two patients. For one patient with IV stage HD, who had received 10 blocks of high-dose chemotherapy, MSCs from the first passage were used, in view of their weak proliferation activity, and, as a consequence, with prolonged growth in the main culture over 27 days, and attenuated cell proliferation after the first passage.

Isaikina_tab4.png

Hematopoietic engraftment after co-transplantation of HSCs and MSCs

Table 4 represents the results concerning the reconstitution of neutrophils and red blood cells after HSCs reinfusion for all patients. Five patients who received the MSCs infusion, in addition to autologous PBSC transplantation, and all patients in the control group had obtained 5 μg/kg of G-CSF, starting from the fifth day after transplantation until transplant engraftment. In the case of co-transplantation with MSCs, the median time of neutrophil recovery to ≥ 500/μl was on day 10 (range, 9 to 11), and ≥1000/μl was on day 11 (range, 10 to 13). These rates of neutrophil reconstitution are higher when compared to control group 1, where the median time of neutrophil recovery to ≥ 500/μl was on day 13 (range, 11 to 15), ≥ 1000/μl was on day 14 (range, 13 to 19).

Reconstitution of red blood cells was determined by the appearance of ≥ 1‰ of reticulocytes in the peripheral blood. This value was also higher in the experimental group with MSCs infusion compared to control group 1, and median red cells recovery was on day 10 (range 9 to 12) and on day 14 (range, 11 to 17) respectively.

In two children with co-transplantation of MSCs and autologous bone marrow, neutrophil recovery ≥ 500/μl in peripheral blood analysis was detected for both patients on day 14, ≥ 1000/μl on day 16 and day 14, the reticulocytes number ≥ 1‰ was on day 16 and on day 14, correspondingly. These rates of reconstitution are higher when compared to the autologous bone marrow transplantation in control group 2 (without MSCs infusion), where a median neutrophil recovery ≥ 500/μl was observed on day 24 (range 18 to 32), ≥ 1000/μl on day 25 (range 20 to 35) and median reticulocytes number ≥ 1‰ recovery was observed on day 26 (range 17 to 28).

Discussion

In our present work, we have for the first time proposed the viability of the curative potential for MSCs obtained from the bone marrow of children with oncohematological disorders, who have been pre-treated with high-dose polychemotherapy and radiotherapy. This investigation was undertaken in order to design a therapeutic strategy of MSCs application for hematopoietic support, and the reduction of the neutropenic period after an autologous transplantation of HSCs in children with insufficient amounts of CD34+ cells/kg.

The biological aspects of mesenchymal stem cells are still under intensive investigation. In spite of scarce experimental data, bone marrow-derived MSCs are increasingly being used in clinical settings. In most cases, either MSCs from healthy donors are cultured and expanded for use in allogenic co-transplantations with HSCs, or autologous MSCs are employed as implants for treatment of some non-oncological conditions, e.g., bone or cartilaginous disorders.

MSC's ability to support hematopoiesis in vitro has been shown experimentally by many workers, when co-culturing MSCs and HSCs. Mesenchymal stem cells are considered the precursors of stromal stem cells, osteoblasts, adipocytes, and endothelial cells that form areas of hematopoiesis-inducing microenvironment in bone marrow, thus supporting production of leucocytes, red blood cells and platelets [15, 16]. On one hand their effects upon hematopoietic precursors are exerted via secretion of soluble cytokines, chemokines, peptides, mediators and hormones and, on other hand, by formation of extracellular matrix from collagen, fibronectin and laminin molecules that provide homing and adhesion of hematopoietic cells. Interleukin-6 (IL-6), IL-1, IL-7, IL-8, SCF, Flt-3-ligand, colony-stimulating factors (CSFs), thrombopoietin, insulin-like growth factor, and transforming growth factor (TGF) are permanently synthesized by stromal cells, thus supporting the stability of blood cell counts within steady limits. IL-1 is the main inducer of cytokine production, whereas TGF is able to inhibit hematopoiesis [17].

Some studies concerning the capacity of cultivated MSCs to support human hematopoiesis in vitro have revealed that, on contact with MSCs, both primitive hematopoietic precursors and committed cells are able to proliferate, thus maintaining their ability for self-replication and differentiation in renewing hematopoietic tissues [18]. The role of stromal cells is especially important due to their ability to prevent HSCs apoptosis [19, 20].

Graça Almeida-Porada et al, in their work on the influence of in vitro cultivated stromal cells on HSCs engraftment, used a xenogeneic model of prenatal transplantation of human cells into sheep embryos. They showed that in cases of human HSCs and MSCs co-transplantation, earlier and higher levels of donor cells in blood were attained. Moreover, HSCs engraftment was more effective with a combined treatment than HSCs transplantation alone [21]. Investigations of human hematopoietic cells from umbilical blood and MSCs co-transplantation into NOD/SCID mice confirmed the importance of MSCs in fast and stable hematopoietic cell engraftment decisively [22].
At the present time, limited data has been published concerning the application of hematopoietic and mesenchymal cell co-transplantation in clinics in order to shorten the period of neutropenia post-transplant in patients with malignant disorders. To our knowledge, no publications exist that concern the results of autologous MSCs utilization aiming to support fast and prolonged engraftment of HSCs auto-transplants in children with oncological and hematological diseases.

The issues of delayed reconstitution of granulocytes and platelets after HSCs autotransplantation still exist, however. A problem with autotransplant rejection still remains, and, in most cases, it occurs due to low doses of transplanted CD34+ cells/kg [1, 2]. At present, all studies on the application of autologous HSCs and MSCs co-transplantation within different groups of patients deal with high doses of CD34+ cells/kg in transplants: e.g., patients with breast tumors received an average of 13.9 х 106 CD34+ cells/kg, according to Кос О. et al (2000)[9]. For related allogenic PBSC transplantation to patients with malignant hematological diseases Lazarus HM et al (2005) employed a mean 5.0х106 CD34+ cells/kg [23]. And in the case of HSCs allogenic transplantation following T-cell depletion, D Cilloni et al (2000) transfused ≥ 2.2 х 106 CD34+ cells/kg [24]. However, numerous observations in large cohorts of patients with PBSC autotransplants suggest high levels of CD34+ in the transplant to be among the most important factors that affect neutrophil recovery after prescribed myeloablative therapy. A standard threshold dose of CD34+cells/kg weight for engraftment of autotransplant and hematopoiesis reconstitution is ≥ 2.5 х 106 cells/kg [25, 26, 27], and, at infusion doses over 5 х 106 CD34+cells/kg, the duration of cytopenia is noticeably reduced [28, 29, 30].

The main idea of our pilot study was to demonstrate the efficacy of supplementary autologous MSCs transplantation, in order to accelerate hematopoietic stem cells engraftment at low doses of CD34+ cells in transplants obtained by leukapheresis: i.e., 0.64–1.3 х 106 CD34+ cells/kg in PBSC autotransplant, and 0.8–1.0 х 106 CD34+ cells/kg in bone marrow autotransplants. An analysis of the resulting data revealed a significant reduction in the post-transplantation cytopenia period for the patients with MSCs co-transplantation after sub-optimal CD34+ cells mobilization, when compared to the control group. In particular, neutrophil reconstitution ≥ 500/μl was found at 9–11 days compared to 11–15, platelet increase ≥ 10000/μl, in 10–13 days as compared to 13–19 in controls, and red cells increased at 9–12 days against 11–17 days in the control group. In this case, it enabled us to avoid the commonly accepted procedure of repeated attempts at PBSC collection, or harvesting considerable bone marrow volumes in case of insufficient CD34+ cell numbers in grafts upon primary harvesting. This is important for the patients who have undergone multiple cycles of chemotherapy or high-dose radiotherapy before autotransplantation, because the negative influence of chemo and radiotherapy on CD34+ cell number is well documented. Bensinger et al (1994) have revealed that each cycle of chemotherapy results in reduction of CD34+ cell numbers by 0.2 х 106 cells during leukapheresis for patients without radiotherapy. Meanwhile, a round of radiotherapy results in CD34+ cells number reduction by 1,8 х 106  after PBSC collection [25].

A number of publications have demonstrated that bone marrow stroma suffers significantly as a result of high-dose chemotherapy or radiotherapy [31,32]. Stromal cells (4–5 week cultures) from the patients after conditioning with busulphan and cyclophosphamide are able to produce monolayers in only 20% of cases, in comparison with 80% in healthy donors [33], and it is not always possible to obtain enough MSCs in vitro for infusion into patients [24].

Our data also confirms a reduced MSCs proliferation capacity after chemotherapy or radiotherapy in our patients. This trend is supported by high correlation coefficient (r = 0.79, p = 0.03) between the numbers of previously received high-dose chemotherapy cycles, and MSCs expansion rate.

In our work we evaluated the functional state of stromal cells by their ability to proliferate in children with supplementary MSCs transplantation. To this purpose, CFU-F analysis was performed. The average CFU-F numbers in bone marrow of the patients was 5.26 ± 0.52 per 105 mononuclear cells. This number was considerably lower when compared to the results of CFU-F analysis in healthy donors [34]. In spite of this, the application of this MSC isolation method from bone marrow, and the technology of cell expansion considered by Кос О.[9], we expanded the primary amounts of MSCs by ~104 times. Thus we obtained sufficient amounts of MSCs within a mean of 36,6 ± 6,3 days after bone marrow aspiration.

Moreover, analysis of our data shows that MSCs infusion is already efficient at MSCs dose 0.3 х 106 cells/kg, thus being quite important in cases of MSCs expansion at limited times elapsing from MSCs aspiration to co-transplantation.

As a result of our pilot study, we confirmed that autologous MSCs co-transplantation may accelerate engraftment of HSCs transplants with low numbers of CD34+ cells/kg when treating children with malignancies. Expansion of MSC in sufficient amounts is an acceptable option in auto-transplants for children after they received prolonged myelotoxic therapy and radiotherapy.

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В нашем исследовании участвовали 24 ребёнка, у которых после взятия гемопоэтических стволовых клеток (ГСК) было низкое содержание CD34 + клеток в аутотрансплантате <br> (≤ 2 x106/кг). Аутологичная котрансплантация МСК применялась у 7 подростков, а в качестве контроля  служили 17 пациентов, которым были введены только ГСК. Число циклов полихимиотерапии зависело от специфического ответа на терапию, развития рецидива, невосприимчивости к терапии, и варьировало от 4 до 10 циклов. МСК были изолированы из костного мозга (КМ) пациентов за 30 - 50 дней до аутологичной трансплантации и были размножены in vitro. Анализ CFU-F был выполнен для всех пациентов.<br> <br> Статистический анализ был выполнен с помощью программного обеспечения STATISTICA 6.0. Достоверность различий результатов в группах при анализе параметров оценивали по тесту Mann-Whitney,  и степень корреляции между параметрами – с помощью теста Spearman. </p> <h3>Результаты</h3> <h3> <p> В среднем 25 ± 6.9 мл костного мозга было использовано, чтобы получить МСК. Число CFU-F составляло 5.26 ± 0.6 колоний на 105 мононуклеарных клеток костного мозга. Число МСК для каждого пациента возрастало в среднем в 104 раз(а) после размножения in vitro. Анализ данных показал статистически достоверную зависимость между числом циклов высокодозной химиотерапии, полученной пациентами до сбора клеток костного мозга и сроками роста МСК, до формирования монослоя в первичной культуре (r = 0,79, p = 0,03). <br> <br> Среднее число МСК, введенных больным, было равно 0.6 (от 0.3 до - 1.1) х 106 МСК /кг в течение 1 часа после трансплантации ГСК. В случае котрансплантации МСК, раннее восстановление нейтрофилов  происходило через 10 дней (от 9 до 11 дней), по сравнению с 13 днями (11 - 15 дней) в группе контроля (р = 0,002). Повышение доли ретикулоцитов свыше ≥ 1 ‰ наблюдалось, соответственно, через 10 дней (от 9 до 12 дней) при ТМСК и 14 дней в контроле (от 11 до 17 дней, р = 0.004). </p> </h3> <h3>Заключение</h3> <p> Выявлено ускоренное приживление трансплантанта ГСК при низком числе CD34 + клеток/кг в случае аутологичной (совместной ко-трансплантации МСК у детей со злокачественными заболеваниями. 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Исайкина Я., Минаковская Н., Алейникова О.

" ["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(4) "9635" ["VALUE"]=> array(2) { ["TEXT"]=> string(4854) "<p class="bodytext"> Исследование предпринято, чтобы изучить возможности применения мезенхимальных стволовых клеток (МСК) для поддержки гемопоэза и сокращения периода нейтропении после аутологичной трансплантации гемопоэтических стволовых клеток (ГСК) детям с онкогематологическими заболеваниями и недостаточностью CD34+ клеток в трансплантате. В нашем исследовании участвовали 24 ребёнка, у которых после взятия гемопоэтических стволовых клеток (ГСК) было низкое содержание CD34 + клеток в аутотрансплантате <br> (≤ 2 x106/кг). Аутологичная котрансплантация МСК применялась у 7 подростков, а в качестве контроля  служили 17 пациентов, которым были введены только ГСК. Число циклов полихимиотерапии зависело от специфического ответа на терапию, развития рецидива, невосприимчивости к терапии, и варьировало от 4 до 10 циклов. МСК были изолированы из костного мозга (КМ) пациентов за 30 - 50 дней до аутологичной трансплантации и были размножены in vitro. Анализ CFU-F был выполнен для всех пациентов.<br> <br> Статистический анализ был выполнен с помощью программного обеспечения STATISTICA 6.0. Достоверность различий результатов в группах при анализе параметров оценивали по тесту Mann-Whitney,  и степень корреляции между параметрами – с помощью теста Spearman. </p> <h3>Результаты</h3> <h3> <p> В среднем 25 ± 6.9 мл костного мозга было использовано, чтобы получить МСК. Число CFU-F составляло 5.26 ± 0.6 колоний на 105 мононуклеарных клеток костного мозга. Число МСК для каждого пациента возрастало в среднем в 104 раз(а) после размножения in vitro. Анализ данных показал статистически достоверную зависимость между числом циклов высокодозной химиотерапии, полученной пациентами до сбора клеток костного мозга и сроками роста МСК, до формирования монослоя в первичной культуре (r = 0,79, p = 0,03). <br> <br> Среднее число МСК, введенных больным, было равно 0.6 (от 0.3 до - 1.1) х 106 МСК /кг в течение 1 часа после трансплантации ГСК. В случае котрансплантации МСК, раннее восстановление нейтрофилов  происходило через 10 дней (от 9 до 11 дней), по сравнению с 13 днями (11 - 15 дней) в группе контроля (р = 0,002). Повышение доли ретикулоцитов свыше ≥ 1 ‰ наблюдалось, соответственно, через 10 дней (от 9 до 12 дней) при ТМСК и 14 дней в контроле (от 11 до 17 дней, р = 0.004). </p> </h3> <h3>Заключение</h3> <p> Выявлено ускоренное приживление трансплантанта ГСК при низком числе CD34 + клеток/кг в случае аутологичной (совместной ко-трансплантации МСК у детей со злокачественными заболеваниями. Эта возможность имеется для детей, которые подверглись продолжительной миелотоксической и радиационной терапии для увеличения количества МСК до оптимального для совместной трансплантации. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4742) "

Исследование предпринято, чтобы изучить возможности применения мезенхимальных стволовых клеток (МСК) для поддержки гемопоэза и сокращения периода нейтропении после аутологичной трансплантации гемопоэтических стволовых клеток (ГСК) детям с онкогематологическими заболеваниями и недостаточностью CD34+ клеток в трансплантате. В нашем исследовании участвовали 24 ребёнка, у которых после взятия гемопоэтических стволовых клеток (ГСК) было низкое содержание CD34 + клеток в аутотрансплантате
(≤ 2 x106/кг). Аутологичная котрансплантация МСК применялась у 7 подростков, а в качестве контроля  служили 17 пациентов, которым были введены только ГСК. Число циклов полихимиотерапии зависело от специфического ответа на терапию, развития рецидива, невосприимчивости к терапии, и варьировало от 4 до 10 циклов. МСК были изолированы из костного мозга (КМ) пациентов за 30 - 50 дней до аутологичной трансплантации и были размножены in vitro. Анализ CFU-F был выполнен для всех пациентов.

Статистический анализ был выполнен с помощью программного обеспечения STATISTICA 6.0. Достоверность различий результатов в группах при анализе параметров оценивали по тесту Mann-Whitney,  и степень корреляции между параметрами – с помощью теста Spearman.

Результаты

В среднем 25 ± 6.9 мл костного мозга было использовано, чтобы получить МСК. Число CFU-F составляло 5.26 ± 0.6 колоний на 105 мононуклеарных клеток костного мозга. Число МСК для каждого пациента возрастало в среднем в 104 раз(а) после размножения in vitro. Анализ данных показал статистически достоверную зависимость между числом циклов высокодозной химиотерапии, полученной пациентами до сбора клеток костного мозга и сроками роста МСК, до формирования монослоя в первичной культуре (r = 0,79, p = 0,03).

Среднее число МСК, введенных больным, было равно 0.6 (от 0.3 до - 1.1) х 106 МСК /кг в течение 1 часа после трансплантации ГСК. В случае котрансплантации МСК, раннее восстановление нейтрофилов  происходило через 10 дней (от 9 до 11 дней), по сравнению с 13 днями (11 - 15 дней) в группе контроля (р = 0,002). Повышение доли ретикулоцитов свыше ≥ 1 ‰ наблюдалось, соответственно, через 10 дней (от 9 до 12 дней) при ТМСК и 14 дней в контроле (от 11 до 17 дней, р = 0.004).

Заключение

Выявлено ускоренное приживление трансплантанта ГСК при низком числе CD34 + клеток/кг в случае аутологичной (совместной ко-трансплантации МСК у детей со злокачественными заболеваниями. Эта возможность имеется для детей, которые подверглись продолжительной миелотоксической и радиационной терапии для увеличения количества МСК до оптимального для совместной трансплантации.

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Yanina Isaikina, Nina Minakovskaya, Olga Aleinikova

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Belarusian Research Centre for Pediatric Oncology and Hematology, Minsk, Belarus

Tel. +375 17 202 40 89, fax 202-42-22, e-mail: yaninai@mail.ru

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Aim

This investigation was undertaken to study the possibility for the application of mesenchymal stem cells (MSCs) for hematopoiesis support and reduction of the neutropenia period after autologous HSCs transplantation for children with oncohematological disorders and graft insufficiency of CD34+ cells/kg.

Patients and methods

24 children, who after collection of hematopoietic stem cells (HSCs) had low numbers of CD34+ (≤ 2,5 x106/kg) in autotransplant, were involved in our investigation. Autologous co-transplantation of MSCs was used for 7 adolescents; and 17 patients who were only given HSCs represented a control. The number of polychemotherapy cycles depended on the specific therapy response, relapse development, and the refractory to therapy, and varied from 4 to 10 cycles. MSCs were isolated from the bone marrow (BM) of patients up to 30–50 days before the autologous transplantation and expanded in vitro. CFU-F analysis was carried out for all patients. Statistical analysis was carried out with the help of STATISTICA 6.0 software. Difference reliability in groups during transplant parameters analysis was evaluated by the Mann-Whitney test, and the correlation degree between parameters by the Spearman test.

Results

About 25 ± 6.9 ml of bone marrow was utilized in order to obtain MSCs. The CFU-F number was about 5.26 ± 0.6 colonies per 105 bone marrow mononuclear cells. The MSCs number had increased an average ~104 times after expansion in vitro for each patient. The data analysis revealed a statistically reliable dependence between the high-dose chemotherapy cycles number received by patients before bone marrow collection and MSCs growth time until a monolayer in primary culture (r = 0.79, p = 0.03) formed. The median number of MSCs reinfused into the patient was 0.6 (range 0.3–1.1) х 106 MSCs/kg in one hour after HSCs transplantation. In the case of co-transplantation, the MSCs neutrophil recovery > 500/µl was in 10 days (range, 9 to 11 days), ≥ 1000/µl in 11days (range, 10 to13 days) compared to 13 days (range, 11 to 15 days), and 14 days (range, 13 to19 days) respectively, in the control group (р = 0.002 and р = 0.001 correspondingly). A reticulocyte number of ≥ 1‰ was observed by 10 days (range 9 to 12 days) and 14 days (range 11 to 17 days), respectively (р = 0.004).

Conclusion

We determined an accelerated engraftment of HSCs transplant with low number CD34+ cells/kg in cases of autologous MSCs co-transplantation for children with malignant disorders. This approach is possible for children who have undergone prolonged myelotoxic and radiotherapy to expanse MSCs to efficient for co-transplantation volume.

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Yanina Isaikina, Nina Minakovskaya, Olga Aleinikova

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Yanina Isaikina, Nina Minakovskaya, Olga Aleinikova

" } ["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(4) "9651" ["VALUE"]=> array(2) { ["TEXT"]=> string(2974) "<h3>Aim</h3> <p> This investigation was undertaken to study the possibility for the application of mesenchymal stem cells (MSCs) for hematopoiesis support and reduction of the neutropenia period after autologous HSCs transplantation for children with oncohematological disorders and graft insufficiency of CD34+ cells/kg.</p> <h3>Patients and methods</h3> <p>24 children, who after collection of hematopoietic stem cells (HSCs) had low numbers of CD34+ (≤ 2,5 x10<sup>6</sup>/kg) in autotransplant, were involved in our investigation. Autologous co-transplantation of MSCs was used for 7 adolescents; and 17 patients who were only given HSCs represented a control. The number of polychemotherapy cycles depended on the specific therapy response, relapse development, and the refractory to therapy, and varied from 4 to 10 cycles. MSCs were isolated from the bone marrow (BM) of patients up to 30–50 days before the autologous transplantation and expanded in vitro. CFU-F analysis was carried out for all patients. Statistical analysis was carried out with the help of STATISTICA 6.0 software. Difference reliability in groups during transplant parameters analysis was evaluated by the Mann-Whitney test, and the correlation degree between parameters by the Spearman test. </p> <h3>Results</h3> <p>About 25 ± 6.9 ml of bone marrow was utilized in order to obtain MSCs. The CFU-F number was about 5.26 ± 0.6 colonies per 10<sup>5</sup> bone marrow mononuclear cells. The MSCs number had increased an average ~10<sup>4</sup> times after expansion <em>in vitro</em> for each patient. The data analysis revealed a statistically reliable dependence between the high-dose chemotherapy cycles number received by patients before bone marrow collection and MSCs growth time until a monolayer in primary culture (r = 0.79, p = 0.03) formed. The median number of MSCs reinfused into the patient was 0.6 (range 0.3–1.1) х 10<sup>6</sup> MSCs/kg in one hour after HSCs transplantation. In the case of co-transplantation, the MSCs neutrophil recovery &gt; 500/µl was in 10 days (range, 9 to 11 days), ≥ 1000/µl in 11days (range, 10 to13 days) compared to 13 days (range, 11 to 15 days), and 14 days (range, 13 to19 days) respectively, in the control group (р = 0.002 and р = 0.001 correspondingly). A reticulocyte number of ≥ 1‰ was observed by 10 days (range 9 to 12 days) and 14 days (range 11 to 17 days), respectively (р = 0.004). </p> <h3>Conclusion</h3> <p>We determined an accelerated engraftment of HSCs transplant with low number CD34+ cells/kg in cases of autologous MSCs co-transplantation for children with malignant disorders. This approach is possible for children who have undergone prolonged myelotoxic and radiotherapy to expanse MSCs to efficient for co-transplantation volume. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2814) "

Aim

This investigation was undertaken to study the possibility for the application of mesenchymal stem cells (MSCs) for hematopoiesis support and reduction of the neutropenia period after autologous HSCs transplantation for children with oncohematological disorders and graft insufficiency of CD34+ cells/kg.

Patients and methods

24 children, who after collection of hematopoietic stem cells (HSCs) had low numbers of CD34+ (≤ 2,5 x106/kg) in autotransplant, were involved in our investigation. Autologous co-transplantation of MSCs was used for 7 adolescents; and 17 patients who were only given HSCs represented a control. The number of polychemotherapy cycles depended on the specific therapy response, relapse development, and the refractory to therapy, and varied from 4 to 10 cycles. MSCs were isolated from the bone marrow (BM) of patients up to 30–50 days before the autologous transplantation and expanded in vitro. CFU-F analysis was carried out for all patients. Statistical analysis was carried out with the help of STATISTICA 6.0 software. Difference reliability in groups during transplant parameters analysis was evaluated by the Mann-Whitney test, and the correlation degree between parameters by the Spearman test.

Results

About 25 ± 6.9 ml of bone marrow was utilized in order to obtain MSCs. The CFU-F number was about 5.26 ± 0.6 colonies per 105 bone marrow mononuclear cells. The MSCs number had increased an average ~104 times after expansion in vitro for each patient. The data analysis revealed a statistically reliable dependence between the high-dose chemotherapy cycles number received by patients before bone marrow collection and MSCs growth time until a monolayer in primary culture (r = 0.79, p = 0.03) formed. The median number of MSCs reinfused into the patient was 0.6 (range 0.3–1.1) х 106 MSCs/kg in one hour after HSCs transplantation. In the case of co-transplantation, the MSCs neutrophil recovery > 500/µl was in 10 days (range, 9 to 11 days), ≥ 1000/µl in 11days (range, 10 to13 days) compared to 13 days (range, 11 to 15 days), and 14 days (range, 13 to19 days) respectively, in the control group (р = 0.002 and р = 0.001 correspondingly). A reticulocyte number of ≥ 1‰ was observed by 10 days (range 9 to 12 days) and 14 days (range 11 to 17 days), respectively (р = 0.004).

Conclusion

We determined an accelerated engraftment of HSCs transplant with low number CD34+ cells/kg in cases of autologous MSCs co-transplantation for children with malignant disorders. This approach is possible for children who have undergone prolonged myelotoxic and radiotherapy to expanse MSCs to efficient for co-transplantation volume.

" ["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(2814) "

Aim

This investigation was undertaken to study the possibility for the application of mesenchymal stem cells (MSCs) for hematopoiesis support and reduction of the neutropenia period after autologous HSCs transplantation for children with oncohematological disorders and graft insufficiency of CD34+ cells/kg.

Patients and methods

24 children, who after collection of hematopoietic stem cells (HSCs) had low numbers of CD34+ (≤ 2,5 x106/kg) in autotransplant, were involved in our investigation. Autologous co-transplantation of MSCs was used for 7 adolescents; and 17 patients who were only given HSCs represented a control. The number of polychemotherapy cycles depended on the specific therapy response, relapse development, and the refractory to therapy, and varied from 4 to 10 cycles. MSCs were isolated from the bone marrow (BM) of patients up to 30–50 days before the autologous transplantation and expanded in vitro. CFU-F analysis was carried out for all patients. Statistical analysis was carried out with the help of STATISTICA 6.0 software. Difference reliability in groups during transplant parameters analysis was evaluated by the Mann-Whitney test, and the correlation degree between parameters by the Spearman test.

Results

About 25 ± 6.9 ml of bone marrow was utilized in order to obtain MSCs. The CFU-F number was about 5.26 ± 0.6 colonies per 105 bone marrow mononuclear cells. The MSCs number had increased an average ~104 times after expansion in vitro for each patient. The data analysis revealed a statistically reliable dependence between the high-dose chemotherapy cycles number received by patients before bone marrow collection and MSCs growth time until a monolayer in primary culture (r = 0.79, p = 0.03) formed. The median number of MSCs reinfused into the patient was 0.6 (range 0.3–1.1) х 106 MSCs/kg in one hour after HSCs transplantation. In the case of co-transplantation, the MSCs neutrophil recovery > 500/µl was in 10 days (range, 9 to 11 days), ≥ 1000/µl in 11days (range, 10 to13 days) compared to 13 days (range, 11 to 15 days), and 14 days (range, 13 to19 days) respectively, in the control group (р = 0.002 and р = 0.001 correspondingly). A reticulocyte number of ≥ 1‰ was observed by 10 days (range 9 to 12 days) and 14 days (range 11 to 17 days), respectively (р = 0.004).

Conclusion

We determined an accelerated engraftment of HSCs transplant with low number CD34+ cells/kg in cases of autologous MSCs co-transplantation for children with malignant disorders. This approach is possible for children who have undergone prolonged myelotoxic and radiotherapy to expanse MSCs to efficient for co-transplantation volume.

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Belarusian Research Centre for Pediatric Oncology and Hematology, Minsk, Belarus

Tel. +375 17 202 40 89, fax 202-42-22, e-mail: yaninai@mail.ru

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Belarusian Research Centre for Pediatric Oncology and Hematology, Minsk, Belarus

Tel. +375 17 202 40 89, fax 202-42-22, e-mail: yaninai@mail.ru

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Исайкина Я., Минаковская Н., Алейникова О.

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Исайкина Я., Минаковская Н., Алейникова О.

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string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "737" [1]=> string(3) "738" [2]=> string(3) "739" [3]=> string(3) "740" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(4) { [0]=> string(104) "мезенхимальные стволовые клетки" [1]=> string(130) "колониеобразующие единицы фибробластов (КОЕ-Ф)" [2]=> string(93) "совместная трансплантация" [3]=> string(97) "гемопоэтическое приживление" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["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(4) "9635" ["VALUE"]=> array(2) { ["TEXT"]=> string(4854) "<p class="bodytext"> Исследование предпринято, чтобы изучить возможности применения мезенхимальных стволовых клеток (МСК) для поддержки гемопоэза и сокращения периода нейтропении после аутологичной трансплантации гемопоэтических стволовых клеток (ГСК) детям с онкогематологическими заболеваниями и недостаточностью CD34+ клеток в трансплантате. В нашем исследовании участвовали 24 ребёнка, у которых после взятия гемопоэтических стволовых клеток (ГСК) было низкое содержание CD34 + клеток в аутотрансплантате <br> (≤ 2 x106/кг). Аутологичная котрансплантация МСК применялась у 7 подростков, а в качестве контроля  служили 17 пациентов, которым были введены только ГСК. Число циклов полихимиотерапии зависело от специфического ответа на терапию, развития рецидива, невосприимчивости к терапии, и варьировало от 4 до 10 циклов. МСК были изолированы из костного мозга (КМ) пациентов за 30 - 50 дней до аутологичной трансплантации и были размножены in vitro. Анализ CFU-F был выполнен для всех пациентов.<br> <br> Статистический анализ был выполнен с помощью программного обеспечения STATISTICA 6.0. Достоверность различий результатов в группах при анализе параметров оценивали по тесту Mann-Whitney,  и степень корреляции между параметрами – с помощью теста Spearman. </p> <h3>Результаты</h3> <h3> <p> В среднем 25 ± 6.9 мл костного мозга было использовано, чтобы получить МСК. Число CFU-F составляло 5.26 ± 0.6 колоний на 105 мононуклеарных клеток костного мозга. Число МСК для каждого пациента возрастало в среднем в 104 раз(а) после размножения in vitro. Анализ данных показал статистически достоверную зависимость между числом циклов высокодозной химиотерапии, полученной пациентами до сбора клеток костного мозга и сроками роста МСК, до формирования монослоя в первичной культуре (r = 0,79, p = 0,03). <br> <br> Среднее число МСК, введенных больным, было равно 0.6 (от 0.3 до - 1.1) х 106 МСК /кг в течение 1 часа после трансплантации ГСК. В случае котрансплантации МСК, раннее восстановление нейтрофилов  происходило через 10 дней (от 9 до 11 дней), по сравнению с 13 днями (11 - 15 дней) в группе контроля (р = 0,002). Повышение доли ретикулоцитов свыше ≥ 1 ‰ наблюдалось, соответственно, через 10 дней (от 9 до 12 дней) при ТМСК и 14 дней в контроле (от 11 до 17 дней, р = 0.004). </p> </h3> <h3>Заключение</h3> <p> Выявлено ускоренное приживление трансплантанта ГСК при низком числе CD34 + клеток/кг в случае аутологичной (совместной ко-трансплантации МСК у детей со злокачественными заболеваниями. Эта возможность имеется для детей, которые подверглись продолжительной миелотоксической и радиационной терапии для увеличения количества МСК до оптимального для совместной трансплантации. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4742) "

Исследование предпринято, чтобы изучить возможности применения мезенхимальных стволовых клеток (МСК) для поддержки гемопоэза и сокращения периода нейтропении после аутологичной трансплантации гемопоэтических стволовых клеток (ГСК) детям с онкогематологическими заболеваниями и недостаточностью CD34+ клеток в трансплантате. В нашем исследовании участвовали 24 ребёнка, у которых после взятия гемопоэтических стволовых клеток (ГСК) было низкое содержание CD34 + клеток в аутотрансплантате
(≤ 2 x106/кг). Аутологичная котрансплантация МСК применялась у 7 подростков, а в качестве контроля  служили 17 пациентов, которым были введены только ГСК. Число циклов полихимиотерапии зависело от специфического ответа на терапию, развития рецидива, невосприимчивости к терапии, и варьировало от 4 до 10 циклов. МСК были изолированы из костного мозга (КМ) пациентов за 30 - 50 дней до аутологичной трансплантации и были размножены in vitro. Анализ CFU-F был выполнен для всех пациентов.

Статистический анализ был выполнен с помощью программного обеспечения STATISTICA 6.0. Достоверность различий результатов в группах при анализе параметров оценивали по тесту Mann-Whitney,  и степень корреляции между параметрами – с помощью теста Spearman.

Результаты

В среднем 25 ± 6.9 мл костного мозга было использовано, чтобы получить МСК. Число CFU-F составляло 5.26 ± 0.6 колоний на 105 мононуклеарных клеток костного мозга. Число МСК для каждого пациента возрастало в среднем в 104 раз(а) после размножения in vitro. Анализ данных показал статистически достоверную зависимость между числом циклов высокодозной химиотерапии, полученной пациентами до сбора клеток костного мозга и сроками роста МСК, до формирования монослоя в первичной культуре (r = 0,79, p = 0,03).

Среднее число МСК, введенных больным, было равно 0.6 (от 0.3 до - 1.1) х 106 МСК /кг в течение 1 часа после трансплантации ГСК. В случае котрансплантации МСК, раннее восстановление нейтрофилов  происходило через 10 дней (от 9 до 11 дней), по сравнению с 13 днями (11 - 15 дней) в группе контроля (р = 0,002). Повышение доли ретикулоцитов свыше ≥ 1 ‰ наблюдалось, соответственно, через 10 дней (от 9 до 12 дней) при ТМСК и 14 дней в контроле (от 11 до 17 дней, р = 0.004).

Заключение

Выявлено ускоренное приживление трансплантанта ГСК при низком числе CD34 + клеток/кг в случае аутологичной (совместной ко-трансплантации МСК у детей со злокачественными заболеваниями. Эта возможность имеется для детей, которые подверглись продолжительной миелотоксической и радиационной терапии для увеличения количества МСК до оптимального для совместной трансплантации.

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Исследование предпринято, чтобы изучить возможности применения мезенхимальных стволовых клеток (МСК) для поддержки гемопоэза и сокращения периода нейтропении после аутологичной трансплантации гемопоэтических стволовых клеток (ГСК) детям с онкогематологическими заболеваниями и недостаточностью CD34+ клеток в трансплантате. В нашем исследовании участвовали 24 ребёнка, у которых после взятия гемопоэтических стволовых клеток (ГСК) было низкое содержание CD34 + клеток в аутотрансплантате
(≤ 2 x106/кг). Аутологичная котрансплантация МСК применялась у 7 подростков, а в качестве контроля  служили 17 пациентов, которым были введены только ГСК. Число циклов полихимиотерапии зависело от специфического ответа на терапию, развития рецидива, невосприимчивости к терапии, и варьировало от 4 до 10 циклов. МСК были изолированы из костного мозга (КМ) пациентов за 30 - 50 дней до аутологичной трансплантации и были размножены in vitro. Анализ CFU-F был выполнен для всех пациентов.

Статистический анализ был выполнен с помощью программного обеспечения STATISTICA 6.0. Достоверность различий результатов в группах при анализе параметров оценивали по тесту Mann-Whitney,  и степень корреляции между параметрами – с помощью теста Spearman.

Результаты

В среднем 25 ± 6.9 мл костного мозга было использовано, чтобы получить МСК. Число CFU-F составляло 5.26 ± 0.6 колоний на 105 мононуклеарных клеток костного мозга. Число МСК для каждого пациента возрастало в среднем в 104 раз(а) после размножения in vitro. Анализ данных показал статистически достоверную зависимость между числом циклов высокодозной химиотерапии, полученной пациентами до сбора клеток костного мозга и сроками роста МСК, до формирования монослоя в первичной культуре (r = 0,79, p = 0,03).

Среднее число МСК, введенных больным, было равно 0.6 (от 0.3 до - 1.1) х 106 МСК /кг в течение 1 часа после трансплантации ГСК. В случае котрансплантации МСК, раннее восстановление нейтрофилов  происходило через 10 дней (от 9 до 11 дней), по сравнению с 13 днями (11 - 15 дней) в группе контроля (р = 0,002). Повышение доли ретикулоцитов свыше ≥ 1 ‰ наблюдалось, соответственно, через 10 дней (от 9 до 12 дней) при ТМСК и 14 дней в контроле (от 11 до 17 дней, р = 0.004).

Заключение

Выявлено ускоренное приживление трансплантанта ГСК при низком числе CD34 + клеток/кг в случае аутологичной (совместной ко-трансплантации МСК у детей со злокачественными заболеваниями. Эта возможность имеется для детей, которые подверглись продолжительной миелотоксической и радиационной терапии для увеличения количества МСК до оптимального для совместной трансплантации.

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Introduction

With modern chemotherapy, the vast majority of HL (formerly, Hodgkin's disease) patients achieve CR, and approximately 70% to 90% will be alive and free of disease at 5 years. However, 10 to 30% of HL patients have primary refractory disease, or relapse after their first CR. Survival rates are significantly worse for these patients. Treatment with alternative second-line chemotherapy regimens yields 5 to 10-year survival rates of only 20% to 32% [1-6]. Randomized trials confirmed the benefit of HDC as compared to second-line therapy with respect to event-free/FFTF survival [7,8]. In recent years, the use of peripheral blood as a source of autologous hematopoietic progenitor cells, together with advances in supportive care have significantly reduced transplant-associated morbidity and mortality—which further strengthens the appeal of HDC. HDC is currently a standard treatment modality in patients with sensitive relapse of HL [9,10]. The advantages in cases of primary refractory or multiple relapsing HL are questionable, though the use of HDC in this patient category is justified by the absence of effective alternatives.

According to the European Group for Blood and Marrow Transplantation (EBMT) registry, about 1200–1300 transplants are performed in HL patients in Western Europe annually, in contrast to Eastern Europe and, still more so, to the former USSR republics, where this effective treatment is much less common in spite of a similar proportion of relapsed/refractory HL patients. This situation may in part be explained by a generally low level of transplantation activity due to inadequate technical facilities and funding: cf., the number of transplantations per 10 million population in recent years was 60 in Belarus, 15 in Russia and 1 in the Ukraine (i.e., the total number of transplantations of any kind and for any reason in all 3 countries was approximately 290–300). It should be noted that there are some subjective reasons too, including a lack of information about the efficacy and safety of HDC as performed at local centers.

Materials and methods

The primary objective of this study was to assess the efficacy (OS, relapse-free survival [RFS], FFTF survival) and safety (early post-transplant mortality) of HDC with ASCT for patients with poor prognosis HL at centers of former USSR republics. The secondary objective was to assess the treatment efficacy with respect to the disease course (multiple relapse, primary refractory disease, early relapse).

We analyzed retrospective data of 184 patients who, due to a poor prognosis for HL received HDC with autologous progenitor cells from peripheral blood (PBSC) and/or bone marrow (BM) rescue between January 1990 and March 2003. Only data from centers that met the EBMT criteria for safety and transplantation activity (> 20 autologous transplantations per year) were included in the analysis. The following centers supplied their data:

1. Bone Marrow Transplantation Department, N. N. Blokhin Cancer Research Center, RAMS, Moscow, Russian Federation

2. Republican Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus

3. Hematology, Transfusiology and Transplantology Department, St. Petersburg State Medical I. Pavlov University, Russian Federation
4. Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine.

Patients were selected for this study if they received HDC within the above-mentioned interval (01.1990–03.2003) due to poor-prognosis HL. The patients' mean age at the time of ASCT was 27 years (11 to 56 years). The study group consisted of 89 males and 95 females.

Most of the patients had primary refractory or early relapsing disease. Patient characteristics are shown in tables 1 and 2.

2008-1-en-Ptushkin-Table-1-72dpi-571px.png

2008-1-en-Ptushkin-Table-2-72dpi-653px.png

Of 50 patients with early relapses, 27 received HDC after the failure of one or more second-line regimens. Because there were few patients (9) receiving HDC after their first late relapse, they were joined into a single group together with patients having multiple relapses.

Most patients (n=156; 85%) were treated with one of the second-line combination chemotherapy regimens for disease "debulking" before HDC (remission reinduction). The reinduction consisted of (hereinafter total doses per chemotherapy cycle are specified): dexamethazone, carmustine 60 mg/m2, etoposide 800–1000 mg/m2, cytarabine 800–1000 mg/m2, melphalan 20 mg/m2 (dexa-BEAM) in 100 (54%) patients, and dexamethazone, cisplatin 100 mg/m2, cytarabin 4 g/m2 (DHAP) in 31 (17%). The remaining 25 (14%) of patients were treated with other regimens.

The majority of patients (149 from 184; 81%) received conditioning chemotherapy with BEAM (carmustine 300 mg/m2, etoposide 1 g/m2, cytarabine 1 g/m2, melphalan 140 mg/m2), 20 patients (11%) received CBV (cyclophosphamide 6 g/m2, carmustin 350–500 mg/m2, etoposide 1–1.5 g/m2 + mitoxanthrone 50 mg/m2), and 11 (6%) received other high-dose regimens; 4 (2%) of patients were given two HDC courses.

Most of the patients (152/184) were rescued with peripheral blood progenitor cells (n=99; 54%) or a combination of PBSC and BM (n=53; 29%). BM was the only source of autologous stem cells in the remaining 32 (17%) patients. BM as a source of stem cells was used (solely or in combination with PBSC) basically before PBSC mobilization, and collection became a routine procedure in the transplant center (1990–1995 y.y.). After this period PBSC mobilization (G-CSF with or without chemotherapy) and collection were performed in all patients, and combined transplant (BM + PBSC) was used only in poor-mobilized patients.

Definitions and statistical analysis

Primary refractory disease was defined as disease progression on adequate first-line chemotherapy, inability to achieve a CR/CRu at the completion of first-line chemotherapy+/-radiotherapy, or a relapse within 3 months after CR/CRu achievement. Early relapse was defined as a relapse occurring within 3 to 12 months after CR or Cru; late relapse was defined as a relapse occurring at >12 months after attainment of CR or CRu. Multiple relapses were defined as more than one relapse in the same patient. Patients with one relapse receiving HDC after failure of one or more second-line regimens were defined as those having resistant relapse even if they responded to a reinduction of remission.

OS was defined as the time from the date of remission reinduction (if any) or HDC initiation (in the remaining patients) until death from any cause, or until the last follow-up visit. FFTF survival was estimated from the same date until the first event (failure to achieve CR or CRu after HDC, death from any cause, relapse) or until the last follow-up visit. RFS was calculated only in patients achieving CR/Cru, and was defined as the time from CR/CRu until relapse or the last follow-up visit.

Survival time distributions were calculated using the productlimit method of Kaplan and Meier. Comparisons of this time to event distributions were made using the log-rank test.

Results

Response to chemotherapy and survival rates

Following the reinduction of chemotherapy 33 from 156 (21.2%) patients were in CR, 6 (3.8%) were in CRu and 73 (46.8%) achieved partial response (PR). Stabilization was achieved in 20 (12.8%), and disease progression in 24 (15.4%) patients. HDC increased CR and CRu rates to 57.4% (106 from 184 patients) and 10.8% (20/184), respectively. PR rate was 15.9% (29/184). Disease stabilization and disease progression were reported in 10.8% (n=20) and 5.1% (n=9) of patients, respectively.

At final analysis after a median follow-up of 30 months (3 to 139 months) the 5-year OS was 60%, RFS was 69.7% and FFTF survival was 41.5%. All participating centers had comparable results in respect of long-term outcomes (Figs. 1–3).

2008-1-en-Ptushkin-Figure-1-72dpi-674px.png2008-1-en-Ptushkin-Figure-2-72dpi-573px.png

2008-1-en-Ptushkin-Figure-3-72dpi-574px.png

The analysis showed a difference in FFTF with respect to disease status (p=0.029). However, the 5-year survival reached 35% even in patients with primary refractory disease. In patients with early relapse and with multiple relapses/late relapse, the 5-year survival rates were 41.6% and 46.4%, respectively (Fig. 4).

2008-1-en-Ptushkin-Figure-4-72dpi-574px.png

We analyzed the FFTF for a small group of 23 patients receiving HDC separately, according to the most accepted standard indication i.e., the first early sensitive relapse (CR or PR achievement after reinduction of remission in the absence of any other second-line chemotherapy). The 5-year FFTF in this cohort of patients was 59.2%.

2008-1-en-Ptushkin-Figure-5-72dpi-575px.png

Hematological recovery
Median duration of neutropenia < 0.5x109/l was 13 days (8 to 90 days), and was different (p=0.0035) with respect to the type of transplant (22 days in patients receiving BM transplant vs. 13 days in patients receiving PBSC vs. 16 days in the combined transplant group). The median time to platelet transfusion-independent recovery status was 13 days (6 to 90 days), and also dependant on the transplant type (23, 14 and 18 days for BM, PBSC and combined transplants, respectively, p=0.015).

Toxicity
Early post-transplant mortality (100-days) was 5.4 % (10 patients), and decreased considerably in patients receiving HDC over recent years: cf. 16% during 1990–1995 versus 3.6% in 1995–2000 and 1.4% in 2000–2003 (Fig. 6).

2008-1-en-Ptushkin-Figure-6-72dpi-714px.png

Discussion

In most economically developed countries HDC is given mainly to patients with the highest chance of cure (patients in first sensitive relapse). Unfortunately, in the former USSR republics this treatment modality was until recently either not offered to patients at all or was considered by physicians as the "last chance" to be taken after the failure of all other salvage modalities. Today we have sufficient reason to revise this approach shared by the oncologists and hematologists of former USSR countries, and to adjust the indication of HDC to worldwide standards (use of HDC mainly in patients in first sensitive relapse). The HDC performed at selected transplant centers of former USSR countries resulted in long-term FFTF survival in 35%–46.4% of patients with poor-prognosis HL, depending upon disease course. As previously suggested by others [11], HDC is a preferred treatment modality not only for patients with sensitive relapse, but also for patients with primary refractory HL, because there is no alternative effective treatment yet. Our results have shown that a proportion of patients with primary refractory HL (5-year FFTF survival 35%) or multiple relapses of HL (5-year FFTF survival 46.4%) do well. However, we should like to mention that the prevalence of patients with primary resistance, multiple relapses, and resistant relapses reflects to a certain extent the opinion of oncologists and hematologists from former USSR republics about HDC. Unfortunately, HDC (especially as conducted at local clinics) is considered in these countries a highly toxic and "experimental" therapy that is indicated only in cases of absolute resistance to standard salvage treatment. As demonstrated by our findings, the experience of actively functioning transplantation centers in former USSR republics together with an improvement in supportive care have led to a considerable reduction in early post-transplant death rates.

Conclusion

Our analysis demonstrated that a more than 10-year experience in HDC in HL patients with poor prognosis at certified clinics of former USSR countries resulted in treatment outcomes that were compatible with those achieved at leading centers.

References

1. Santoro A, Viviani S, Villarreal C, et al. Salvage chemotherapy in Hodgkin's disease irradiation failures: superiority of doxorubicin-containing regimens over MOPP. Cancer Treat Rep 1986;70:343.

2. Rodriguet MG, Schoppe WD, Fuchs R. Lomustine, etoposide, vindesine, and dexamethasone (CEVD) in Hodgkin's disease refractory to cyclophosphamide, vincristine, procarbacine, and prednisone (COPP) and doxorubicine, bleomycin, vinblastine, and darcarbazine (ABVD): a multi-center trial of the German Hodgkin`s study group. Cancer Treat Rep 1987;71:1203.

3. Pfreundschuh M, Rueffer U, Lathan B, et al. Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group. J Clin Oncol 1994;12:580.

4. Hagemeister F, Tannir N, McLaughlin P, et al. MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin's disease. J Clin Oncol 1987;5:556.

5. Velasquez WS, Jagannath S, Hagemeister FB. Dexamethasone, high-dose ara-C and cisplatin as salvage treatment for relapsing Hodgkin`s disease. Proc Am Soc Hematol 1986;68:242.

6. Ferme C, Bastion Y, Lepage E, et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin's disease. Ann Oncol 1995;6:543.

7. Linch D, Winfield D, Goldstone A, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet 1993;341:1051.

8. Schmitz N, Sextro M, Pfistner B. HDR-1: high-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin's disease (HD): final results of a randomized GHSG and EBMT trial (HD-R1). Proc Am Soc Clin Oncol 1999;18[Suppl  5]:18.

9. Diehl V, Mauch PM, Harris NL. Chapter 45: Lymphomas, 45.6: Hodgkin's Disease in Cancer: Principles and Practice of Oncology, 6th Edition; ed. DeVita TD, Hellman S, Rosenberg SA. Lippincott Williams & Wilkins, 2001.

10. Mauch PM, Weiss L, Armitage JO. Hodgkin’s disease in Cancer Medicine, 6th Edition; ed Holland J, Frei E. BC Decker Inc, Hamilton, London, 2003: 2182.

11. Josting A, Schmitz N. Relapsed refractory Hodgkin's disease, in "Insights into 25 years of clinical trials of the GHSG", Munich, 2004, 89-99.

" ["~DETAIL_TEXT"]=> string(16492) "

Introduction

With modern chemotherapy, the vast majority of HL (formerly, Hodgkin's disease) patients achieve CR, and approximately 70% to 90% will be alive and free of disease at 5 years. However, 10 to 30% of HL patients have primary refractory disease, or relapse after their first CR. Survival rates are significantly worse for these patients. Treatment with alternative second-line chemotherapy regimens yields 5 to 10-year survival rates of only 20% to 32% [1-6]. Randomized trials confirmed the benefit of HDC as compared to second-line therapy with respect to event-free/FFTF survival [7,8]. In recent years, the use of peripheral blood as a source of autologous hematopoietic progenitor cells, together with advances in supportive care have significantly reduced transplant-associated morbidity and mortality—which further strengthens the appeal of HDC. HDC is currently a standard treatment modality in patients with sensitive relapse of HL [9,10]. The advantages in cases of primary refractory or multiple relapsing HL are questionable, though the use of HDC in this patient category is justified by the absence of effective alternatives.

According to the European Group for Blood and Marrow Transplantation (EBMT) registry, about 1200–1300 transplants are performed in HL patients in Western Europe annually, in contrast to Eastern Europe and, still more so, to the former USSR republics, where this effective treatment is much less common in spite of a similar proportion of relapsed/refractory HL patients. This situation may in part be explained by a generally low level of transplantation activity due to inadequate technical facilities and funding: cf., the number of transplantations per 10 million population in recent years was 60 in Belarus, 15 in Russia and 1 in the Ukraine (i.e., the total number of transplantations of any kind and for any reason in all 3 countries was approximately 290–300). It should be noted that there are some subjective reasons too, including a lack of information about the efficacy and safety of HDC as performed at local centers.

Materials and methods

The primary objective of this study was to assess the efficacy (OS, relapse-free survival [RFS], FFTF survival) and safety (early post-transplant mortality) of HDC with ASCT for patients with poor prognosis HL at centers of former USSR republics. The secondary objective was to assess the treatment efficacy with respect to the disease course (multiple relapse, primary refractory disease, early relapse).

We analyzed retrospective data of 184 patients who, due to a poor prognosis for HL received HDC with autologous progenitor cells from peripheral blood (PBSC) and/or bone marrow (BM) rescue between January 1990 and March 2003. Only data from centers that met the EBMT criteria for safety and transplantation activity (> 20 autologous transplantations per year) were included in the analysis. The following centers supplied their data:

1. Bone Marrow Transplantation Department, N. N. Blokhin Cancer Research Center, RAMS, Moscow, Russian Federation

2. Republican Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus

3. Hematology, Transfusiology and Transplantology Department, St. Petersburg State Medical I. Pavlov University, Russian Federation
4. Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine.

Patients were selected for this study if they received HDC within the above-mentioned interval (01.1990–03.2003) due to poor-prognosis HL. The patients' mean age at the time of ASCT was 27 years (11 to 56 years). The study group consisted of 89 males and 95 females.

Most of the patients had primary refractory or early relapsing disease. Patient characteristics are shown in tables 1 and 2.

2008-1-en-Ptushkin-Table-1-72dpi-571px.png

2008-1-en-Ptushkin-Table-2-72dpi-653px.png

Of 50 patients with early relapses, 27 received HDC after the failure of one or more second-line regimens. Because there were few patients (9) receiving HDC after their first late relapse, they were joined into a single group together with patients having multiple relapses.

Most patients (n=156; 85%) were treated with one of the second-line combination chemotherapy regimens for disease "debulking" before HDC (remission reinduction). The reinduction consisted of (hereinafter total doses per chemotherapy cycle are specified): dexamethazone, carmustine 60 mg/m2, etoposide 800–1000 mg/m2, cytarabine 800–1000 mg/m2, melphalan 20 mg/m2 (dexa-BEAM) in 100 (54%) patients, and dexamethazone, cisplatin 100 mg/m2, cytarabin 4 g/m2 (DHAP) in 31 (17%). The remaining 25 (14%) of patients were treated with other regimens.

The majority of patients (149 from 184; 81%) received conditioning chemotherapy with BEAM (carmustine 300 mg/m2, etoposide 1 g/m2, cytarabine 1 g/m2, melphalan 140 mg/m2), 20 patients (11%) received CBV (cyclophosphamide 6 g/m2, carmustin 350–500 mg/m2, etoposide 1–1.5 g/m2 + mitoxanthrone 50 mg/m2), and 11 (6%) received other high-dose regimens; 4 (2%) of patients were given two HDC courses.

Most of the patients (152/184) were rescued with peripheral blood progenitor cells (n=99; 54%) or a combination of PBSC and BM (n=53; 29%). BM was the only source of autologous stem cells in the remaining 32 (17%) patients. BM as a source of stem cells was used (solely or in combination with PBSC) basically before PBSC mobilization, and collection became a routine procedure in the transplant center (1990–1995 y.y.). After this period PBSC mobilization (G-CSF with or without chemotherapy) and collection were performed in all patients, and combined transplant (BM + PBSC) was used only in poor-mobilized patients.

Definitions and statistical analysis

Primary refractory disease was defined as disease progression on adequate first-line chemotherapy, inability to achieve a CR/CRu at the completion of first-line chemotherapy+/-radiotherapy, or a relapse within 3 months after CR/CRu achievement. Early relapse was defined as a relapse occurring within 3 to 12 months after CR or Cru; late relapse was defined as a relapse occurring at >12 months after attainment of CR or CRu. Multiple relapses were defined as more than one relapse in the same patient. Patients with one relapse receiving HDC after failure of one or more second-line regimens were defined as those having resistant relapse even if they responded to a reinduction of remission.

OS was defined as the time from the date of remission reinduction (if any) or HDC initiation (in the remaining patients) until death from any cause, or until the last follow-up visit. FFTF survival was estimated from the same date until the first event (failure to achieve CR or CRu after HDC, death from any cause, relapse) or until the last follow-up visit. RFS was calculated only in patients achieving CR/Cru, and was defined as the time from CR/CRu until relapse or the last follow-up visit.

Survival time distributions were calculated using the productlimit method of Kaplan and Meier. Comparisons of this time to event distributions were made using the log-rank test.

Results

Response to chemotherapy and survival rates

Following the reinduction of chemotherapy 33 from 156 (21.2%) patients were in CR, 6 (3.8%) were in CRu and 73 (46.8%) achieved partial response (PR). Stabilization was achieved in 20 (12.8%), and disease progression in 24 (15.4%) patients. HDC increased CR and CRu rates to 57.4% (106 from 184 patients) and 10.8% (20/184), respectively. PR rate was 15.9% (29/184). Disease stabilization and disease progression were reported in 10.8% (n=20) and 5.1% (n=9) of patients, respectively.

At final analysis after a median follow-up of 30 months (3 to 139 months) the 5-year OS was 60%, RFS was 69.7% and FFTF survival was 41.5%. All participating centers had comparable results in respect of long-term outcomes (Figs. 1–3).

2008-1-en-Ptushkin-Figure-1-72dpi-674px.png2008-1-en-Ptushkin-Figure-2-72dpi-573px.png

2008-1-en-Ptushkin-Figure-3-72dpi-574px.png

The analysis showed a difference in FFTF with respect to disease status (p=0.029). However, the 5-year survival reached 35% even in patients with primary refractory disease. In patients with early relapse and with multiple relapses/late relapse, the 5-year survival rates were 41.6% and 46.4%, respectively (Fig. 4).

2008-1-en-Ptushkin-Figure-4-72dpi-574px.png

We analyzed the FFTF for a small group of 23 patients receiving HDC separately, according to the most accepted standard indication i.e., the first early sensitive relapse (CR or PR achievement after reinduction of remission in the absence of any other second-line chemotherapy). The 5-year FFTF in this cohort of patients was 59.2%.

2008-1-en-Ptushkin-Figure-5-72dpi-575px.png

Hematological recovery
Median duration of neutropenia < 0.5x109/l was 13 days (8 to 90 days), and was different (p=0.0035) with respect to the type of transplant (22 days in patients receiving BM transplant vs. 13 days in patients receiving PBSC vs. 16 days in the combined transplant group). The median time to platelet transfusion-independent recovery status was 13 days (6 to 90 days), and also dependant on the transplant type (23, 14 and 18 days for BM, PBSC and combined transplants, respectively, p=0.015).

Toxicity
Early post-transplant mortality (100-days) was 5.4 % (10 patients), and decreased considerably in patients receiving HDC over recent years: cf. 16% during 1990–1995 versus 3.6% in 1995–2000 and 1.4% in 2000–2003 (Fig. 6).

2008-1-en-Ptushkin-Figure-6-72dpi-714px.png

Discussion

In most economically developed countries HDC is given mainly to patients with the highest chance of cure (patients in first sensitive relapse). Unfortunately, in the former USSR republics this treatment modality was until recently either not offered to patients at all or was considered by physicians as the "last chance" to be taken after the failure of all other salvage modalities. Today we have sufficient reason to revise this approach shared by the oncologists and hematologists of former USSR countries, and to adjust the indication of HDC to worldwide standards (use of HDC mainly in patients in first sensitive relapse). The HDC performed at selected transplant centers of former USSR countries resulted in long-term FFTF survival in 35%–46.4% of patients with poor-prognosis HL, depending upon disease course. As previously suggested by others [11], HDC is a preferred treatment modality not only for patients with sensitive relapse, but also for patients with primary refractory HL, because there is no alternative effective treatment yet. Our results have shown that a proportion of patients with primary refractory HL (5-year FFTF survival 35%) or multiple relapses of HL (5-year FFTF survival 46.4%) do well. However, we should like to mention that the prevalence of patients with primary resistance, multiple relapses, and resistant relapses reflects to a certain extent the opinion of oncologists and hematologists from former USSR republics about HDC. Unfortunately, HDC (especially as conducted at local clinics) is considered in these countries a highly toxic and "experimental" therapy that is indicated only in cases of absolute resistance to standard salvage treatment. As demonstrated by our findings, the experience of actively functioning transplantation centers in former USSR republics together with an improvement in supportive care have led to a considerable reduction in early post-transplant death rates.

Conclusion

Our analysis demonstrated that a more than 10-year experience in HDC in HL patients with poor prognosis at certified clinics of former USSR countries resulted in treatment outcomes that were compatible with those achieved at leading centers.

References

1. Santoro A, Viviani S, Villarreal C, et al. Salvage chemotherapy in Hodgkin's disease irradiation failures: superiority of doxorubicin-containing regimens over MOPP. Cancer Treat Rep 1986;70:343.

2. Rodriguet MG, Schoppe WD, Fuchs R. Lomustine, etoposide, vindesine, and dexamethasone (CEVD) in Hodgkin's disease refractory to cyclophosphamide, vincristine, procarbacine, and prednisone (COPP) and doxorubicine, bleomycin, vinblastine, and darcarbazine (ABVD): a multi-center trial of the German Hodgkin`s study group. Cancer Treat Rep 1987;71:1203.

3. Pfreundschuh M, Rueffer U, Lathan B, et al. Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group. J Clin Oncol 1994;12:580.

4. Hagemeister F, Tannir N, McLaughlin P, et al. MIME chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) as treatment for recurrent Hodgkin's disease. J Clin Oncol 1987;5:556.

5. Velasquez WS, Jagannath S, Hagemeister FB. Dexamethasone, high-dose ara-C and cisplatin as salvage treatment for relapsing Hodgkin`s disease. Proc Am Soc Hematol 1986;68:242.

6. Ferme C, Bastion Y, Lepage E, et al. The MINE regimen as intensive salvage chemotherapy for relapsed and refractory Hodgkin's disease. Ann Oncol 1995;6:543.

7. Linch D, Winfield D, Goldstone A, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet 1993;341:1051.

8. Schmitz N, Sextro M, Pfistner B. HDR-1: high-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin's disease (HD): final results of a randomized GHSG and EBMT trial (HD-R1). Proc Am Soc Clin Oncol 1999;18[Suppl  5]:18.

9. Diehl V, Mauch PM, Harris NL. Chapter 45: Lymphomas, 45.6: Hodgkin's Disease in Cancer: Principles and Practice of Oncology, 6th Edition; ed. DeVita TD, Hellman S, Rosenberg SA. Lippincott Williams & Wilkins, 2001.

10. Mauch PM, Weiss L, Armitage JO. Hodgkin’s disease in Cancer Medicine, 6th Edition; ed Holland J, Frei E. BC Decker Inc, Hamilton, London, 2003: 2182.

11. Josting A, Schmitz N. Relapsed refractory Hodgkin's disease, in "Insights into 25 years of clinical trials of the GHSG", Munich, 2004, 89-99.

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Retrospective analysis of data from four transplantation centers in Belarus, Russia and the Ukraine" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(3592) "<h3>Ретроспективный анализ данных из четырех центров трансплантации в Беларуси, России и Украине.</h3> <p class="bodytext">Высокодозная химиотерапия (ВХТ) с поддерживающей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК) является рутинным подходом к лечению рецидивирующей или рефрактерной к лечению больных  с болезнью Ходжкина (лимфогранулематозом). К сожалению, ВХТ с ТГСК нечасто проводится в республиках бывшего СССР, в частности, из-за отсутствия информации об эффективности и безопасности такого лечения при его проведении в местных центрах.   </p> <p class="bodytext">Мы проанализировали исходы лечения 184 больных, получавших ауто-ТГСК в наших центрах с января 1990 г. по март 2003 г. У большинства больных была установлена первично-рефрактерная болезнь (44,8%), ранние (27,2%) или множественные (21,6%) рецидивы заболевания. Рестадирование выявило заболевание III—IV степени в 69%, В-симптомы – в 53% случаев. До проведения ауто-ТГСК больные получали, в среднем, 9 (от 2 до 34) курсов стандартной химиотерапии.           <br /><br />Высокодозная химиотерапия приводила к полному или предположительно полному ответу (CR/CRu) в 68,2% случаев, при общем 5-летнем выживании у 60% больных, выживаемость без неудачи лечения (FFTF) составляла 41,5% при среднем сроке наблюдения 30 мес. (от 3 до 139 мес.). При оценке статуса заболевания, средние показатели пятилетнего FFTF была 35% среди больных с первично-рефрактерной болезнью, 46,4% - у больных с множественными рецидивами, и 59,2% у больных с ранними химиочувствительными рецидивами. Частота ранней гибели больных была 5,4%, но продемонстрировала тенденцию к значительному снижению в течению последних лет (1,4% в 2000-2003 гг.). 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int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "9826" ["VALUE"]=> array(2) { ["TEXT"]=> string(369) "<p class="Autor">Птушкин В. В., Афанасьев Б. В., Жуков Н. В., Усс А. Л., Караманешт Е. Е., Миланович Н. Ф., Михайлова Н. Б., Коренкова И. С., Миненко С. В., Демина Е. А., Змачинский В. А., Пугачев А. А., Бородкин С. В.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(347) "

Птушкин В. В., Афанасьев Б. В., Жуков Н. В., Усс А. Л., Караманешт Е. Е., Миланович Н. Ф., Михайлова Н. Б., Коренкова И. С., Миненко С. В., Демина Е. А., Змачинский В. А., Пугачев А. А., Бородкин С. В.

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Ретроспективный анализ данных из четырех центров трансплантации в Беларуси, России и Украине.

Высокодозная химиотерапия (ВХТ) с поддерживающей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК) является рутинным подходом к лечению рецидивирующей или рефрактерной к лечению больных  с болезнью Ходжкина (лимфогранулематозом). К сожалению, ВХТ с ТГСК нечасто проводится в республиках бывшего СССР, в частности, из-за отсутствия информации об эффективности и безопасности такого лечения при его проведении в местных центрах.  

Мы проанализировали исходы лечения 184 больных, получавших ауто-ТГСК в наших центрах с января 1990 г. по март 2003 г. У большинства больных была установлена первично-рефрактерная болезнь (44,8%), ранние (27,2%) или множественные (21,6%) рецидивы заболевания. Рестадирование выявило заболевание III—IV степени в 69%, В-симптомы – в 53% случаев. До проведения ауто-ТГСК больные получали, в среднем, 9 (от 2 до 34) курсов стандартной химиотерапии.          

Высокодозная химиотерапия приводила к полному или предположительно полному ответу (CR/CRu) в 68,2% случаев, при общем 5-летнем выживании у 60% больных, выживаемость без неудачи лечения (FFTF) составляла 41,5% при среднем сроке наблюдения 30 мес. (от 3 до 139 мес.). При оценке статуса заболевания, средние показатели пятилетнего FFTF была 35% среди больных с первично-рефрактерной болезнью, 46,4% - у больных с множественными рецидивами, и 59,2% у больных с ранними химиочувствительными рецидивами. Частота ранней гибели больных была 5,4%, но продемонстрировала тенденцию к значительному снижению в течению последних лет (1,4% в 2000-2003 гг.). Таким образом, ВХТ с поддерживающей ауто-ТГСК, проведенная в трансплантационных центрах республик бывшего СССР, связана с низкой смертностью и удовлетворительными показателями выживаемости у больных с первично-рефрактерной или рецидивирующей болезнью Ходжкина.

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Ptushkin V. V.1, Afanasyev B. V.3, Zhukov N. V.1, Uss A. L.2, Karamanesht E. E.4, Milanovich N. F.2, Mikhaylova N. B.3,
Korenkova I. S.4, Minenko S. V.1, Demina E. A.1, Zmachinski V. A.2, Pugachev A. A.3, Borodkin S. V.4

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1Bone Marrow Transplantation Department, N. N. Blokhin Cancer Research Center, RAMS, Moscow, RF; 2Republican Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus; 3R.M.Gorbacheva Memorial Institute of Children Hematology and Transplantation, and Hematology, Transfusiology and Transplantology Department, St. Petersburg State Medical I. Pavlov University,
Russian Federation; 4Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine


Presenting author
Ptushkin Vadim Vadimovich
Postal address
117997, Leninsky prospect, 117, Moscow, Federal Center of Pediatric Hematology/Oncology/Immunology, Ministry of Health and Social Development, Russia. Head, Department of Clinical Oncology, Telephone +7-903-199-51-69,  Fax +7-495-937-50-24,
E-mail: vadimvadim@spam is badinbox.ru

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High-dose chemotherapy (HDC) with autologous stem cell transplantation support is a routine treatment approach for relapsed or refractory Hodgkin's lymphoma (HL) patients. Unfortunately, HDC is much less common in the former USSR republics; among other reasons due to a lack of information about the efficacy and safety of this treatment as performed at local centers.

We analyzed the outcome for 184 HL patients receiving HDC in the former USSR republics between January 1990 and March 2003. Most patients had primary refractory disease (44.8%), early (27.2%) or multiple (21.6%) relapses. Restaging revealed stage III–IV disease in 69%, and B-symptoms in 53% of cases. The patients received a mean of 9 (2 to 34) courses of standard chemotherapy prior to HDC.

HDC yielded complete response or complete response uncertain (CR/CRu) in 68.2% of cases, and the 5-year overall survival (OS) rate was 60%; freedom from treatment failure (FFTF) survival was 41.5% with a median follow-up of 30 months (3 to 139 months). As estimated with respect to disease status, the 5-year FFTF was 35% among patients with primary refractory disease, 46.4% in patients with multiple relapses, and 59.2% in patients with early sensitive relapse. The early death rate was 5.4%, but has demonstrated a considerable decreasing trend over recent years (1.4% in 2000–2003). The HDC with autologous hematopoietic stem cell rescue procedure performed at transplant centers in the former USSR republics is associated with low mortality and satisfactory FFTF for patients with primary refractory or relapsed Hodgkin's disease.

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Ptushkin V. V.1, Afanasyev B. V.3, Zhukov N. V.1, Uss A. L.2, Karamanesht E. E.4, Milanovich N. F.2, Mikhaylova N. B.3,
Korenkova I. S.4, Minenko S. V.1, Demina E. A.1, Zmachinski V. A.2, Pugachev A. A.3, Borodkin S. V.4

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High-dose chemotherapy (HDC) with autologous stem cell transplantation support is a routine treatment approach for relapsed or refractory Hodgkin's lymphoma (HL) patients. Unfortunately, HDC is much less common in the former USSR republics; among other reasons due to a lack of information about the efficacy and safety of this treatment as performed at local centers.

We analyzed the outcome for 184 HL patients receiving HDC in the former USSR republics between January 1990 and March 2003. Most patients had primary refractory disease (44.8%), early (27.2%) or multiple (21.6%) relapses. Restaging revealed stage III–IV disease in 69%, and B-symptoms in 53% of cases. The patients received a mean of 9 (2 to 34) courses of standard chemotherapy prior to HDC.

HDC yielded complete response or complete response uncertain (CR/CRu) in 68.2% of cases, and the 5-year overall survival (OS) rate was 60%; freedom from treatment failure (FFTF) survival was 41.5% with a median follow-up of 30 months (3 to 139 months). As estimated with respect to disease status, the 5-year FFTF was 35% among patients with primary refractory disease, 46.4% in patients with multiple relapses, and 59.2% in patients with early sensitive relapse. The early death rate was 5.4%, but has demonstrated a considerable decreasing trend over recent years (1.4% in 2000–2003). The HDC with autologous hematopoietic stem cell rescue procedure performed at transplant centers in the former USSR republics is associated with low mortality and satisfactory FFTF for patients with primary refractory or relapsed Hodgkin's disease.

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We analyzed the outcome for 184 HL patients receiving HDC in the former USSR republics between January 1990 and March 2003. Most patients had primary refractory disease (44.8%), early (27.2%) or multiple (21.6%) relapses. Restaging revealed stage III–IV disease in 69%, and B-symptoms in 53% of cases. The patients received a mean of 9 (2 to 34) courses of standard chemotherapy prior to HDC.

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Pavlov University, <br>Russian Federation; <sup>4</sup>Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine </p> <br> <p class="bodytext"><b>Presenting author</b> <br> Ptushkin Vadim Vadimovich <br> <b>Postal address</b><br> 117997, Leninsky prospect, 117, Moscow, Federal Center of Pediatric Hematology/Oncology/Immunology, Ministry of Health and Social Development, Russia. Head, Department of Clinical Oncology, Telephone +7-903-199-51-69,  Fax +7-495-937-50-24, <br>E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.zehmqzehmqDmrfsb2vy');">vadimvadim@<span style="display:none;">spam is bad</span>inbox.ru</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1061) "

1Bone Marrow Transplantation Department, N. N. Blokhin Cancer Research Center, RAMS, Moscow, RF; 2Republican Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus; 3R.M.Gorbacheva Memorial Institute of Children Hematology and Transplantation, and Hematology, Transfusiology and Transplantology Department, St. Petersburg State Medical I. Pavlov University,
Russian Federation; 4Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine


Presenting author
Ptushkin Vadim Vadimovich
Postal address
117997, Leninsky prospect, 117, Moscow, Federal Center of Pediatric Hematology/Oncology/Immunology, Ministry of Health and Social Development, Russia. Head, Department of Clinical Oncology, Telephone +7-903-199-51-69,  Fax +7-495-937-50-24,
E-mail: vadimvadim@spam is badinbox.ru

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1Bone Marrow Transplantation Department, N. N. Blokhin Cancer Research Center, RAMS, Moscow, RF; 2Republican Center for Hematology and Bone Marrow Transplantation, Minsk, Belarus; 3R.M.Gorbacheva Memorial Institute of Children Hematology and Transplantation, and Hematology, Transfusiology and Transplantology Department, St. Petersburg State Medical I. Pavlov University,
Russian Federation; 4Kiev Center for Bone Marrow Transplantation, Kiev, Ukraine


Presenting author
Ptushkin Vadim Vadimovich
Postal address
117997, Leninsky prospect, 117, Moscow, Federal Center of Pediatric Hematology/Oncology/Immunology, Ministry of Health and Social Development, Russia. Head, Department of Clinical Oncology, Telephone +7-903-199-51-69,  Fax +7-495-937-50-24,
E-mail: vadimvadim@spam is badinbox.ru

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поддерживающей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК) является рутинным подходом к лечению рецидивирующей или рефрактерной к лечению больных  с болезнью Ходжкина (лимфогранулематозом). К сожалению, ВХТ с ТГСК нечасто проводится в республиках бывшего СССР, в частности, из-за отсутствия информации об эффективности и безопасности такого лечения при его проведении в местных центрах.   </p> <p class="bodytext">Мы проанализировали исходы лечения 184 больных, получавших ауто-ТГСК в наших центрах с января 1990 г. по март 2003 г. У большинства больных была установлена первично-рефрактерная болезнь (44,8%), ранние (27,2%) или множественные (21,6%) рецидивы заболевания. Рестадирование выявило заболевание III—IV степени в 69%, В-симптомы – в 53% случаев. До проведения ауто-ТГСК больные получали, в среднем, 9 (от 2 до 34) курсов стандартной химиотерапии.           <br /><br />Высокодозная химиотерапия приводила к полному или предположительно полному ответу (CR/CRu) в 68,2% случаев, при общем 5-летнем выживании у 60% больных, выживаемость без неудачи лечения (FFTF) составляла 41,5% при среднем сроке наблюдения 30 мес. (от 3 до 139 мес.). При оценке статуса заболевания, средние показатели пятилетнего FFTF была 35% среди больных с первично-рефрактерной болезнью, 46,4% - у больных с множественными рецидивами, и 59,2% у больных с ранними химиочувствительными рецидивами. Частота ранней гибели больных была 5,4%, но продемонстрировала тенденцию к значительному снижению в течению последних лет (1,4% в 2000-2003 гг.). Таким образом, ВХТ с поддерживающей ауто-ТГСК, проведенная в трансплантационных центрах республик бывшего СССР, связана с низкой смертностью и удовлетворительными показателями выживаемости у больных с первично-рефрактерной или рецидивирующей болезнью Ходжкина. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3524) "

Ретроспективный анализ данных из четырех центров трансплантации в Беларуси, России и Украине.

Высокодозная химиотерапия (ВХТ) с поддерживающей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК) является рутинным подходом к лечению рецидивирующей или рефрактерной к лечению больных  с болезнью Ходжкина (лимфогранулематозом). К сожалению, ВХТ с ТГСК нечасто проводится в республиках бывшего СССР, в частности, из-за отсутствия информации об эффективности и безопасности такого лечения при его проведении в местных центрах.  

Мы проанализировали исходы лечения 184 больных, получавших ауто-ТГСК в наших центрах с января 1990 г. по март 2003 г. У большинства больных была установлена первично-рефрактерная болезнь (44,8%), ранние (27,2%) или множественные (21,6%) рецидивы заболевания. Рестадирование выявило заболевание III—IV степени в 69%, В-симптомы – в 53% случаев. До проведения ауто-ТГСК больные получали, в среднем, 9 (от 2 до 34) курсов стандартной химиотерапии.          

Высокодозная химиотерапия приводила к полному или предположительно полному ответу (CR/CRu) в 68,2% случаев, при общем 5-летнем выживании у 60% больных, выживаемость без неудачи лечения (FFTF) составляла 41,5% при среднем сроке наблюдения 30 мес. (от 3 до 139 мес.). При оценке статуса заболевания, средние показатели пятилетнего FFTF была 35% среди больных с первично-рефрактерной болезнью, 46,4% - у больных с множественными рецидивами, и 59,2% у больных с ранними химиочувствительными рецидивами. Частота ранней гибели больных была 5,4%, но продемонстрировала тенденцию к значительному снижению в течению последних лет (1,4% в 2000-2003 гг.). Таким образом, ВХТ с поддерживающей ауто-ТГСК, проведенная в трансплантационных центрах республик бывшего СССР, связана с низкой смертностью и удовлетворительными показателями выживаемости у больных с первично-рефрактерной или рецидивирующей болезнью Ходжкина.

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Ретроспективный анализ данных из четырех центров трансплантации в Беларуси, России и Украине.

Высокодозная химиотерапия (ВХТ) с поддерживающей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК) является рутинным подходом к лечению рецидивирующей или рефрактерной к лечению больных  с болезнью Ходжкина (лимфогранулематозом). К сожалению, ВХТ с ТГСК нечасто проводится в республиках бывшего СССР, в частности, из-за отсутствия информации об эффективности и безопасности такого лечения при его проведении в местных центрах.  

Мы проанализировали исходы лечения 184 больных, получавших ауто-ТГСК в наших центрах с января 1990 г. по март 2003 г. У большинства больных была установлена первично-рефрактерная болезнь (44,8%), ранние (27,2%) или множественные (21,6%) рецидивы заболевания. Рестадирование выявило заболевание III—IV степени в 69%, В-симптомы – в 53% случаев. До проведения ауто-ТГСК больные получали, в среднем, 9 (от 2 до 34) курсов стандартной химиотерапии.          

Высокодозная химиотерапия приводила к полному или предположительно полному ответу (CR/CRu) в 68,2% случаев, при общем 5-летнем выживании у 60% больных, выживаемость без неудачи лечения (FFTF) составляла 41,5% при среднем сроке наблюдения 30 мес. (от 3 до 139 мес.). При оценке статуса заболевания, средние показатели пятилетнего FFTF была 35% среди больных с первично-рефрактерной болезнью, 46,4% - у больных с множественными рецидивами, и 59,2% у больных с ранними химиочувствительными рецидивами. Частота ранней гибели больных была 5,4%, но продемонстрировала тенденцию к значительному снижению в течению последних лет (1,4% в 2000-2003 гг.). Таким образом, ВХТ с поддерживающей ауто-ТГСК, проведенная в трансплантационных центрах республик бывшего СССР, связана с низкой смертностью и удовлетворительными показателями выживаемости у больных с первично-рефрактерной или рецидивирующей болезнью Ходжкина.

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Introduction

The broad application of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still limited by the immunological recognition and destruction of host tissues, termed graft-versus-host disease (GVHD). The role of inflammatory cytokines and their impact on immune effectors (mainly CD4+ and CD8+ T cells) has been extensively studied in the context of the GVHD occurring after standard myeloablative allo-SCT. Reduced-intensity conditioning (RIC) regimens are being increasingly used with allo-SCT. RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on the outcome remain unknown. Moreover, the graft versus leukemia reaction (GVLR) was closely associated with GVHD.

However, recent data suggests that GVHD pathophysiology is likely to involve more complex interactions, where antigen-presenting cells, especially dendritic cells (DCs), may play a major role at the time of initiation of acute GVHD [9-10, 13].

The success of allogeneic stem cell transplantation owes much to improvements in the immunosuppressive regimens that prevent GVHD and reduce graft rejection risk. Previous studies have shown that the removal of T-cells from the graft via ex vivo T-cell depletion resulted in a dramatic decrease in aGVHD. This has been shown to be associated with a significant increase in graft failure and the risk of relapse, even in studies in which T-cell add-back has been investigated. An alternative strategy is to provide for in vivo T-cell depletion by using anti-thymocyte globulin (ATG) as a part of the conditioning regimen.
The common belief is that ATG's efficacy relies on its capacity to deplete T-lymphocytes, but the polyclonal nature of ATG is reflected in its diverse effects on the immune system: (1) T-cell depletion of blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; (2) modulation of key cell surface molecules that mediate leukocyte/endothelium interactions; (3) induction of apoptosis in B-cell lineages; (4) interference with dendritic cell functional properties; and (5) induction of regulatory T-cells and natural killer T-cells [9-13]. As a consequence, ATG provides a multifaceted immunomodulation, thus paving the way for future applications and suggesting that the use of ATG should be included in the immunosuppressive therapeutic armamentarium, thereby helping to reduce the incidence of graft rejection and GVHD.

Until now there has been no satisfactory evidence of these ATG benefits in such patients, because the decrease of graft rejection probability and GVHD severity could have been connected with an increasing relapse rate [2, 5]. Thus, in our study we have evaluated the application of ATG within conditioning regimens for increasing effectiveness of HSCT.

Materials and methods

There were 109 patients enrolled, who underwent 112 hematopoietic stem cell transplantations (HSCT) from related and unrelated donors at the Bone Marrow Transplantation Department at Saint-Petersburg Pavlov State Medical University from October 2000 until June 2006.

Patients were divided into two groups to test the use of ATG in conditioning regimens: (1) the experimental group, where ATG was used at a dosage of 16–120 mg/kg per cycle; this group enrolled 74 patients with 74 allo-SCT, and (2) the control group, where ATG was not used in conditioning regimens; it included 35 patients with 38 allo-SCT. Patient characteristics are listed in Table 1.

Zalyalov_tab01.png

Combinations of immunosuppressive drugs were employed, in accordance with international HSCT protocols, for GVHD prophylaxis in the post-transplant period. CsA was administered at 3–5 mg/kg, starting on Day 1 before HSCT, until Day 150–180 post-transplant depending on biochemical parameters and CsA concentrations in the blood plasma.

The main criteria of engraftment were the recovery of neutrophil levels to >0.5 х109/L during 3 consequent days without using CSF, an increase in platelet counts to >20х109/L, and an elevation of blood hemoglobin to>80 g/L without blood transfusions.

Results and discussion

According to many studies, the probability of graft rejection post-HSCT varies from 1% to 5%. In patients with aplastic anemia with multiple transfusions in their history, this event may be as high as 43% [3]. Adding ATG to the conditioning regimens in such patients could decrease graft rejection rates up to 9% [6].

In our study we have shown that an intensification of graft rejection prophylaxis with ATG helps to reduce the rate of such complications. In the experimental group, primary graft rejection was revealed in 3 patients (4%). Two patients (3%) developed late graft rejection after Day +100. The use of ATG in their conditioning regimens showed a positive correlation with decreased graft rejection rate, when compared with the control group: 7% vs. 24% (р=0.01), respectively (Table 2).

The results also show a significant reduction of graft rejection risk in association with ATG use in unrelated allo-HSCT (р=0.02). In patients treated with ATG in unrelated allo-SCT, the graft rejection rate was 5%, whereas the probability of such complications in the control group was 6 times higher, presenting in 29% of cases. However, ATG effectiveness for prevention of graft rejection in related allo-HSCTs is less obvious (р> 0.05).

A relatively high incidence of transplant rejection in our study, as compared with other data from literature, may be connected with some clinical features of most patients, who were continuously pretreated before HSCT, or transplanted during incomplete clinical remissions. A group of standard-risk patients (CR1/CP1) did not exceed 19% of the allo-HSCT group under study (Table 1).

Acute GVHD is one of the main complications after allo-SCT and occurs in 30% of cases. In allo-HCT from unrelated HLA-matched donors, the probability of aGVHD increases to 80% [1]. Clinical signs of aGVHD are considered to reflect only a part of recipient immunological response to donor cell injection. Another component of immune response in HSCT is presented by GVL (graft-versus-leukemia) reaction, which develops in parallel with aGVHD. Thereby, aGVHD is a biological marker of the anti-relapse effects of donor cells in allo-HSCT. Lymphocytes, recovered from bone marrow, could identify antigenic determinants expressed on leukemic cells, and eliminate them quite effectively. However, despite the complete HLA-compatibility of donor and recipient, donor-derived immune cells could also detect minor histocompatibility antigens (MHA) on the host cells, and induce an acute graft-versus-host reaction. Meanwhile, the usage of ATG in conditioning regimens for preventing such complications helps to decrease the aGVHD risk to 14%, comparing with 24% in control (Table 2).

Zalyalov_tab02.png

According to the literature, severe aGVHD develops more often in patients with unrelated allo-SCT compared with transplantations from related donors. In many cases it is associated with mismatches for minor histocompatibility antigens. We have shown, however, that among patients without ATG, occurrence of severe aGVHD (grade III–IV) was similar for cases of related versus unrelated transplants. There were no cases of severe aGVHD when using ATG in related allo-SCT, whereas in patients without ATG, aGVHD of grade III–IV occurred in 20.8% of cases. Additionally, a two-fold decrease in severe aGVHD rates among ATG-treated patients, as compared with the control group, was shown after unrelated allo-SCT, i.e., 16.6% vs. 40%, respectively. However, due to low numbers of patients with related HSCT in the ATG group, and unrelated HSCT in the control group, these results are not statistically significant (р> 0.05).

In recent years, it has been realized that absolute myeloablation is not an obligate condition for engraftment, and the immunoadaptive cytostatic action of donor cells in most cases may exceed the cytostatic effects of radio and chemotherapy [2, 4, 5, 7, 8]. These observations justified an increasing popularity of reduced toxicity regimens in clinical practice, because of their low toxic effects on bone marrow and other organs, and higher tolerability in aged patients with concomitant diseases.

Comparing the rates of relapse and/or progression within a period of 4 years after HCT in the main and control groups, we have not observed any increase in such complications among patients with ATG (29%) vs. patients without ATG (47%) (Fig.1).

2008-1-en-Zalyalov-Figure-1-72dpi-795px.png

According to our data, the application of reduced toxicity regimens with ATG contributes to a significantly lower risk of relapse/progression within a period of 3 years when compared with the control group: 35% and 67%, respectively (р= 0.03), whereas such a difference was not so evident among the patients after myeloablative conditioning regimens: 27% vs. 36% (р= 0.6).

Overall four-year survival in patients with ATG was 39%, while in the control group it was under 28% (Fig. 2).

2008-1-en-Zalyalov-Figure-2-72dpi-765px.png

In summary, ATG use in the experimental group provided a decrease in the death rate in the early post-transplant period, due to a reduction of graft rejection rates and milder aGVHD severity, as compared with patients from the control group who didn’t receive ATG.

Conclusions

1. Administration of anti-thymocyte globulin (ATG) contributes to an increased four-year overall survival rate of 39%, as compared with 28% among the patients of the control group who did not receive ATG.

2. Addition of ATG to conditioning regimens reduces the probability of graft rejection.

3. ATG administration is associated with decreased rates of severe aGVHD (grade III–IV).

4. ATG application does not lead to increased relapse rates.

References

1. Zubarovskaya L.S., Fregatova L.M., Afanasyev B.V. Hematopoetic stem cells transplantation in hemoblastosis. Clinical Oncohematology. Ed. Volkova M.A. Мoscow, 2001. P.479–494. (In Russian)

2. Bacigalupo A., Lamparelli T., Bruzzi P. et al. Antithymocyte globulin for preventing graft-versus-host disease in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO) Blood 2001, 98;2942–2947.

3. Dulley F.L., et al. The role of low dose busulfan (Bu) (4mg/kg) with cyclophosphamide (Cy) as a conditioning regimen for severe aplastic anaemia (SAA). Biol. Blood Marrow Transplantation 2003:9–88.

4. Finke J., Bertz H., Schmoor C., et al. Allogeneic bone marrow transplantation from unrelated donors using in vivo anti T-cell globulin. Br.J.Haematol. 2000;11:303–313.

5. Mohty M., Bay J.-O., Faucher C., Choufi B., Bilger K. et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin–based reduced-intensity preparative regime. Blood  2003,102:470–476.

6. Paquette R.L., Tebyani N., Frane M., Ireland P., Ho W.G., Champlin R.E., Nimer S.D. Long-Term Outcome of aplastic anemia in adults treated with antithymocyte globulin: comparison with bone marrow transplantation.
Blood 1995,85:283–290.

7. Remberger M. et al.  Association between pretransplant Thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors. Bone Marrow Transplantation 2002;29:391–397.

8. Zander A.R., Zabelina T., Kroger N., et al. Use of a five-agent GvHD prevention regimen in recipients of unrelated donor marrow. Bone Marrow Transplantation 1999;23:889–893.

9. Mohty M., Gaugler B. Inflammatory cytokines and dendritic cells in acute graft-versus-host disease after allogeneic stem cell transplantation. Cytokine Growth Factor Rev. 2008 Feb;19:53–63.

10. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007; 21:1387–1394.

11. Mohty M. Dendritic cells and acute graft-versus-host disease after allogeneic stem cell transplantation. Leuk. Lymphoma 2007;48:1696– 1701.

12. Zand M.S., Vo T., Huggins J., Felgar R., Liesveld J., Pellegrin T., Bozorgzadeh A., Sanz I., Briggs B.J. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways.  Transplantation 2005;79:1507–1515.

13. Naujokat C., Berges C., Fuchs D., Sadeghi M., Opelz G., Daniel V. Antithymocyte globulins suppress dendritic cell function by multiple mechanisms. Transplantation 2007; 83:485–497.

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Introduction

The broad application of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still limited by the immunological recognition and destruction of host tissues, termed graft-versus-host disease (GVHD). The role of inflammatory cytokines and their impact on immune effectors (mainly CD4+ and CD8+ T cells) has been extensively studied in the context of the GVHD occurring after standard myeloablative allo-SCT. Reduced-intensity conditioning (RIC) regimens are being increasingly used with allo-SCT. RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on the outcome remain unknown. Moreover, the graft versus leukemia reaction (GVLR) was closely associated with GVHD.

However, recent data suggests that GVHD pathophysiology is likely to involve more complex interactions, where antigen-presenting cells, especially dendritic cells (DCs), may play a major role at the time of initiation of acute GVHD [9-10, 13].

The success of allogeneic stem cell transplantation owes much to improvements in the immunosuppressive regimens that prevent GVHD and reduce graft rejection risk. Previous studies have shown that the removal of T-cells from the graft via ex vivo T-cell depletion resulted in a dramatic decrease in aGVHD. This has been shown to be associated with a significant increase in graft failure and the risk of relapse, even in studies in which T-cell add-back has been investigated. An alternative strategy is to provide for in vivo T-cell depletion by using anti-thymocyte globulin (ATG) as a part of the conditioning regimen.
The common belief is that ATG's efficacy relies on its capacity to deplete T-lymphocytes, but the polyclonal nature of ATG is reflected in its diverse effects on the immune system: (1) T-cell depletion of blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis; (2) modulation of key cell surface molecules that mediate leukocyte/endothelium interactions; (3) induction of apoptosis in B-cell lineages; (4) interference with dendritic cell functional properties; and (5) induction of regulatory T-cells and natural killer T-cells [9-13]. As a consequence, ATG provides a multifaceted immunomodulation, thus paving the way for future applications and suggesting that the use of ATG should be included in the immunosuppressive therapeutic armamentarium, thereby helping to reduce the incidence of graft rejection and GVHD.

Until now there has been no satisfactory evidence of these ATG benefits in such patients, because the decrease of graft rejection probability and GVHD severity could have been connected with an increasing relapse rate [2, 5]. Thus, in our study we have evaluated the application of ATG within conditioning regimens for increasing effectiveness of HSCT.

Materials and methods

There were 109 patients enrolled, who underwent 112 hematopoietic stem cell transplantations (HSCT) from related and unrelated donors at the Bone Marrow Transplantation Department at Saint-Petersburg Pavlov State Medical University from October 2000 until June 2006.

Patients were divided into two groups to test the use of ATG in conditioning regimens: (1) the experimental group, where ATG was used at a dosage of 16–120 mg/kg per cycle; this group enrolled 74 patients with 74 allo-SCT, and (2) the control group, where ATG was not used in conditioning regimens; it included 35 patients with 38 allo-SCT. Patient characteristics are listed in Table 1.

Zalyalov_tab01.png

Combinations of immunosuppressive drugs were employed, in accordance with international HSCT protocols, for GVHD prophylaxis in the post-transplant period. CsA was administered at 3–5 mg/kg, starting on Day 1 before HSCT, until Day 150–180 post-transplant depending on biochemical parameters and CsA concentrations in the blood plasma.

The main criteria of engraftment were the recovery of neutrophil levels to >0.5 х109/L during 3 consequent days without using CSF, an increase in platelet counts to >20х109/L, and an elevation of blood hemoglobin to>80 g/L without blood transfusions.

Results and discussion

According to many studies, the probability of graft rejection post-HSCT varies from 1% to 5%. In patients with aplastic anemia with multiple transfusions in their history, this event may be as high as 43% [3]. Adding ATG to the conditioning regimens in such patients could decrease graft rejection rates up to 9% [6].

In our study we have shown that an intensification of graft rejection prophylaxis with ATG helps to reduce the rate of such complications. In the experimental group, primary graft rejection was revealed in 3 patients (4%). Two patients (3%) developed late graft rejection after Day +100. The use of ATG in their conditioning regimens showed a positive correlation with decreased graft rejection rate, when compared with the control group: 7% vs. 24% (р=0.01), respectively (Table 2).

The results also show a significant reduction of graft rejection risk in association with ATG use in unrelated allo-HSCT (р=0.02). In patients treated with ATG in unrelated allo-SCT, the graft rejection rate was 5%, whereas the probability of such complications in the control group was 6 times higher, presenting in 29% of cases. However, ATG effectiveness for prevention of graft rejection in related allo-HSCTs is less obvious (р> 0.05).

A relatively high incidence of transplant rejection in our study, as compared with other data from literature, may be connected with some clinical features of most patients, who were continuously pretreated before HSCT, or transplanted during incomplete clinical remissions. A group of standard-risk patients (CR1/CP1) did not exceed 19% of the allo-HSCT group under study (Table 1).

Acute GVHD is one of the main complications after allo-SCT and occurs in 30% of cases. In allo-HCT from unrelated HLA-matched donors, the probability of aGVHD increases to 80% [1]. Clinical signs of aGVHD are considered to reflect only a part of recipient immunological response to donor cell injection. Another component of immune response in HSCT is presented by GVL (graft-versus-leukemia) reaction, which develops in parallel with aGVHD. Thereby, aGVHD is a biological marker of the anti-relapse effects of donor cells in allo-HSCT. Lymphocytes, recovered from bone marrow, could identify antigenic determinants expressed on leukemic cells, and eliminate them quite effectively. However, despite the complete HLA-compatibility of donor and recipient, donor-derived immune cells could also detect minor histocompatibility antigens (MHA) on the host cells, and induce an acute graft-versus-host reaction. Meanwhile, the usage of ATG in conditioning regimens for preventing such complications helps to decrease the aGVHD risk to 14%, comparing with 24% in control (Table 2).

Zalyalov_tab02.png

According to the literature, severe aGVHD develops more often in patients with unrelated allo-SCT compared with transplantations from related donors. In many cases it is associated with mismatches for minor histocompatibility antigens. We have shown, however, that among patients without ATG, occurrence of severe aGVHD (grade III–IV) was similar for cases of related versus unrelated transplants. There were no cases of severe aGVHD when using ATG in related allo-SCT, whereas in patients without ATG, aGVHD of grade III–IV occurred in 20.8% of cases. Additionally, a two-fold decrease in severe aGVHD rates among ATG-treated patients, as compared with the control group, was shown after unrelated allo-SCT, i.e., 16.6% vs. 40%, respectively. However, due to low numbers of patients with related HSCT in the ATG group, and unrelated HSCT in the control group, these results are not statistically significant (р> 0.05).

In recent years, it has been realized that absolute myeloablation is not an obligate condition for engraftment, and the immunoadaptive cytostatic action of donor cells in most cases may exceed the cytostatic effects of radio and chemotherapy [2, 4, 5, 7, 8]. These observations justified an increasing popularity of reduced toxicity regimens in clinical practice, because of their low toxic effects on bone marrow and other organs, and higher tolerability in aged patients with concomitant diseases.

Comparing the rates of relapse and/or progression within a period of 4 years after HCT in the main and control groups, we have not observed any increase in such complications among patients with ATG (29%) vs. patients without ATG (47%) (Fig.1).

2008-1-en-Zalyalov-Figure-1-72dpi-795px.png

According to our data, the application of reduced toxicity regimens with ATG contributes to a significantly lower risk of relapse/progression within a period of 3 years when compared with the control group: 35% and 67%, respectively (р= 0.03), whereas such a difference was not so evident among the patients after myeloablative conditioning regimens: 27% vs. 36% (р= 0.6).

Overall four-year survival in patients with ATG was 39%, while in the control group it was under 28% (Fig. 2).