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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.

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.

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.

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.

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.

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. 

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.

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.

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. 

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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. 

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.

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.

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. 

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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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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. 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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.

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.

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:

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

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]

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].

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].

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).

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.).

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). 

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

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).

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.

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.

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:

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

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]

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].

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].

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).

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.).

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). 

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

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).

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. 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</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).

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 tract^18,19 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).

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 tract^18,19 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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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.)

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.)

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.)

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.)

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 Fehse^1,3,Nicolaus Kröger¹, Ulrike Bacher^1*

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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 Fehse^1,3,Nicolaus Kröger¹, Ulrike Bacher^1*

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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

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.

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.

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).

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.

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

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.

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.

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).

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.

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.

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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. 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 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. </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 10⁵ bone marrow mononuclear cells. The MSCs number had increased an average ~10⁴ 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 10⁶ 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.

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).

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).

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%.

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).

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.

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).

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).

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%.

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).

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.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "9806" ["VALUE"]=> string(28) "10.3205/ctt2008-05-30-002-en" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(28) "10.3205/ctt2008-05-30-002-en" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "9901" ["VALUE"]=> array(2) { ["TEXT"]=> string(580) "<p class="Autor">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, <br>Korenkova I. S.⁴, Minenko S. V.¹, Demina E. A.¹, Zmachinski V. A.², Pugachev A. A.³, Borodkin S. V.⁴</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(396) "

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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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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array(2) { ["TEXT"]=> string(580) "<p class="Autor">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, <br>Korenkova I. S.⁴, Minenko S. V.¹, Demina E. A.¹, Zmachinski V. A.², Pugachev A. A.³, Borodkin S. V.⁴</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(396) "

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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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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Pavlov University, <br>Russian Federation; ⁴Kiev 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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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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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.

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).

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).

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).

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.

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).

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).

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).

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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Р., Ганапиев Б. А., Потапенко В. Г., Михайлова Н. Б., Афанасьев Б. В.<p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(152) "

Залялов Ю. Р., Ганапиев Б. А., Потапенко В. Г., Михайлова Н. Б., Афанасьев Б. В.

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Основными ранними осложнениями алло-ТГСК являются острая РТПХ и реакция отторжения трансплантата. В нашем исследовании проанализирована возможность развития этих ранних осложнений у 109 больных с различными онкогематологическими заболеваниями. Проведены 112 алло-ТГСК от родственных и неродственных доноров при миелоаблативных или немиелоаблативных режимах кондиционирования с введением антитимоцитарного глобулина (АТГ) или без него. Применение АТГ обеспечивает эффективный контроль при РТПХ без повышения риска рецидива основного заболевания и снижает вероятность отторжения трансплантата до 7%. В целом, использование АТГ, по нашим данным, связано с эффективным снижением риска ранних посттрансплантационных осложнений. Введение АТГ приводит к повышению средней 4-летней выживаемости больных до 39% по сравнению с 28% в контрольной группе.

Применение АТГ ассоциировано со снижением частоты развития тяжелых форм РТПХ (III-IV степени). Кроме того, использование АТГ не сопровождается возрастанием частоты рецидивов. Таким образом, применение АТГ у трансплантационных больных обеспечивает снижение гибели больных в раннем посттрансплантационном периоде в связи со снижением риска отторжения трансплантата и тяжести РТПХ по сравнению с контрольной группой, в которой больные не получали АТГ.

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Zalyalov Y. R., Ganapiev B. A., Potapenko V. G., Mikhailova N. B., Afanasyev B. V.

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R. M.Gorbacheva Memorial Institute of Hematology and Transplantology, and Department of Hematology, Transfusiology and Transplantology, St. Petersburg State Medical I. Pavlov University

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Acute GVHD and graft rejection are the main early complications of allo-SCT. In our research, we analyzed the probability of development of early complications in 109 patients with different oncohematological diseases. We evaluated the results of 112 allo-SCTs from related and unrelated donors subjected to myeloablative and nonmyeloablative conditioning regimens, either with or without ATG. The usage of ATG provides effective control over aGVHD, without increasing the risk of a relapse of the basic disease, and reduces the probability of graft rejection to 7%. Consequently, our data on ATG application in allo-HSCT demonstrates its ability to effectively decrease the risk of early complications post-transplant, thus favoring an increase of 4-year overall survival, in comparison to the control group, where ATG was not used.

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Acute GVHD and graft rejection are the main early complications of allo-SCT. In our research, we analyzed the probability of development of early complications in 109 patients with different oncohematological diseases. We evaluated the results of 112 allo-SCTs from related and unrelated donors subjected to myeloablative and nonmyeloablative conditioning regimens, either with or without ATG. The usage of ATG provides effective control over aGVHD, without increasing the risk of a relapse of the basic disease, and reduces the probability of graft rejection to 7%. Consequently, our data on ATG application in allo-HSCT demonstrates its ability to effectively decrease the risk of early complications post-transplant, thus favoring an increase of 4-year overall survival, in comparison to the control group, where ATG was not used.

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В нашем исследовании проанализирована возможность развития этих ранних осложнений у 109 больных с различными онкогематологическими заболеваниями. Проведены 112 алло-ТГСК от родственных и неродственных доноров при миелоаблативных или немиелоаблативных режимах кондиционирования с введением антитимоцитарного глобулина (АТГ) или без него. Применение АТГ обеспечивает эффективный контроль при РТПХ без повышения риска рецидива основного заболевания и снижает вероятность отторжения трансплантата до 7%. В целом, использование АТГ, по нашим данным, связано с эффективным снижением риска ранних посттрансплантационных осложнений. Введение АТГ приводит к повышению средней 4-летней выживаемости больных до 39% по сравнению с 28% в контрольной группе. </p> <p class="bodytext">Применение АТГ ассоциировано со снижением частоты развития тяжелых форм РТПХ (III-IV степени). Кроме того, использование АТГ не сопровождается возрастанием частоты рецидивов. Таким образом, применение АТГ у трансплантационных больных обеспечивает снижение гибели больных в раннем посттрансплантационном периоде в связи со снижением риска отторжения трансплантата и тяжести РТПХ по сравнению с контрольной группой, в которой больные не получали АТГ. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2434) "

Основными ранними осложнениями алло-ТГСК являются острая РТПХ и реакция отторжения трансплантата. В нашем исследовании проанализирована возможность развития этих ранних осложнений у 109 больных с различными онкогематологическими заболеваниями. Проведены 112 алло-ТГСК от родственных и неродственных доноров при миелоаблативных или немиелоаблативных режимах кондиционирования с введением антитимоцитарного глобулина (АТГ) или без него. Применение АТГ обеспечивает эффективный контроль при РТПХ без повышения риска рецидива основного заболевания и снижает вероятность отторжения трансплантата до 7%. В целом, использование АТГ, по нашим данным, связано с эффективным снижением риска ранних посттрансплантационных осложнений. Введение АТГ приводит к повышению средней 4-летней выживаемости больных до 39% по сравнению с 28% в контрольной группе.

Применение АТГ ассоциировано со снижением частоты развития тяжелых форм РТПХ (III-IV степени). Кроме того, использование АТГ не сопровождается возрастанием частоты рецидивов. Таким образом, применение АТГ у трансплантационных больных обеспечивает снижение гибели больных в раннем посттрансплантационном периоде в связи со снижением риска отторжения трансплантата и тяжести РТПХ по сравнению с контрольной группой, в которой больные не получали АТГ.

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Основными ранними осложнениями алло-ТГСК являются острая РТПХ и реакция отторжения трансплантата. В нашем исследовании проанализирована возможность развития этих ранних осложнений у 109 больных с различными онкогематологическими заболеваниями. Проведены 112 алло-ТГСК от родственных и неродственных доноров при миелоаблативных или немиелоаблативных режимах кондиционирования с введением антитимоцитарного глобулина (АТГ) или без него. Применение АТГ обеспечивает эффективный контроль при РТПХ без повышения риска рецидива основного заболевания и снижает вероятность отторжения трансплантата до 7%. В целом, использование АТГ, по нашим данным, связано с эффективным снижением риска ранних посттрансплантационных осложнений. Введение АТГ приводит к повышению средней 4-летней выживаемости больных до 39% по сравнению с 28% в контрольной группе.

Применение АТГ ассоциировано со снижением частоты развития тяжелых форм РТПХ (III-IV степени). Кроме того, использование АТГ не сопровождается возрастанием частоты рецидивов. Таким образом, применение АТГ у трансплантационных больных обеспечивает снижение гибели больных в раннем посттрансплантационном периоде в связи со снижением риска отторжения трансплантата и тяжести РТПХ по сравнению с контрольной группой, в которой больные не получали АТГ.

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Introduction

The basic criterion for choosing a particular method of treatment in medicine ought to be its effectiveness concerning the disease. This approach should be used for managing the patient: choosing the most effective method despite the cost. However, in many cases the high cost of a method combined with debatable effectiveness challenges their use and development, as well as their state financing.

Therefore, the aim of the study was to find some logical evaluation procedures of the treatment cost of HCT.

Materials and methods

There were 209 patients enrolled in the study, who received autologous HCT, and allogenic related and unrelated HCT from 1998 to 2005. There were 91 patients (43.5%) aged from 1 to 66 years with allo-HCT, among them 57 from unrelated donors and 34 from related donors; 118 patients (56.5%) had auto-HCT.

Using their medical charts we performed the treatment efficacy analysis and treatment cost analysis for these aforementioned patients. Clinical effectiveness was assessed using a 2-year overall survival. Evaluation of the total cost and its components in related and unrelated allo-HCT, and assessment of allo-HCT cost under myeloablative and reduced toxicity regimens was also performed. We have independently analyzed the cost of HCT with and without complications. There was an attempt to reveal the statistically justified clinical and cost parameters that influenced HCT effectiveness. The results were analyzed using parametric and non-parametric statistics; data were assessed with regression analysis [1-3].

Results

The result of data analysis suggests using the total cost of HCT. The expression for total HCT cost can be expressed like this:

Сexam – the cost of laboratory examinations performed while the patient is in the clinic. This depends on the disease and duration of in-patient period.

С_p/d – the cost of one patient day. This value is stable and calculated by the clinic's statistics department.

N_d – the duration of in-patient period. This depends on disease severity and complications.

С_transph – the cost of transfusions per day (24 hours). This also depends on disease severity, and complications that require blood transfusions.

С_cond – the cost of a conditioning regimen. This value is stable.

С_drug – the cost of drugs per day (24 h). Dependent on disease severity.

С_infus – the cost of apheresis and storage of BM and PBSC. This value is stable.

С_{donor search} – this value should be considered only in unrelated allo-HCT; it corresponds to the cost of a donor search in international donor registers.

Before the model's construction, which could be a function of clinical, cost and other parameters, it is reasonable to perform exploratory statistical analysis. The aim of such analysis is to reveal the statistically significant influence on the outcome of such features as: sex of patient, diagnosis, type of HCT, donor sex, source of hematopoietic stem cells (BM or PBSC), presence of relapse or progression, complications, particularly infections that require blood transfusions, conditioning regimen, age at HCT, and/or presence of GVHD. According to the character of the clinical parameters, we used analysis of continuous and category variables.

Our first step was to perform non-random difference of central tendency of continuous variables analysis (1). Table 1 presents the continuous variables that help to reveal a significant difference in groups by patient status.

Additionally, we analyzed the clinical, continuous and category variables influencing the HCT effectiveness. The statistically significant influence on HCT outcome caused:

•   HCT type – autologous or allogenic (р=0.002),
•  presence of relapse or progression (р=0.048),
•  presence of blood transfusions complications (р=0.003),
•  type of conditioning regimen: myeloablative or reduced toxicity (р=0.023).

The exploratory statistical analysis performed helps to form the group of continuous and category variables that can be used as predictors for regression modeling of patient status according to clinical and cost parameters.

The construction of a regression model with dependent variables, simulating dichotomous category variables and independent variables creates the need for logistic regression. Logistic regression connects event probability (one of the events of disease outcome variables) with independent variables (predictors), the impact of which was described in the previous section. Considering that the dependent variable is measured by probability mass, and independent variables include continuous and category parameters, it is necessary to make a functional transformation of the independent variables into the interval 0 – 1. Such functional transformation is done by function (2).

This is called the logistic, with Z parameter. 

The parameter Z=B₁X₁+B₂X₂+B₃X₃+B₄X₄+B₅X₅ connects independent variables (predictors).

The procedure of both logistic regression construction and standard regression includes three steps:

Creation of a logistic regression model,

Evaluation of the significance of weight factors in the formula (B₁, B₂, B₃, B₅),

Assessment of model stability.

By means of SPSS, using step-type variants of logistic regression to include or exclude parameters from the model and Wald criterion, we obtained the model, the  parameters of which are stated in Table 2.

According to the formula (2) the parameter

Formula (3) includes:

X₁ – total cost of blood transfusions

X₂ – the cost of blood transfusions per 24 h.

X₃ – the cost of drugs.

X₄ – conditioning regimen

   X₄=0 in reduced toxicity regimen,

   X₄=1 in myeloablative regimen,

X₅ – relapse before HCT

   X₅=0 no relapse before HCT,

   X₅=1 presence of relapse before HCT.

Since the total cost of blood transfusions is obtained via the multiplication of the cost of blood transfusions per 24 h on the number of patient days, X₁=X₂*N_d, formula (3) can be expressed like this:

As stated in Table 2, the model has non-random parameters with p<=0.05.

The quality of patient status prognosis could be assessed using the Table of forecast classification (Table 3)

The values in Table 3 characterize the power of testing (probability of status Alive prediction in present alive condition) and its specificity (probability of status Dead prediction in present dead condition). Thus the power of forecast is 93.5% and its specificity is 63.6%. The probability of a correct forecast is 81.1%.

The stability of the model should be checked using other samples, but we currently have no such data, so practical statistics recommends repeating the analysis using only a part of data for model creation, with the other part of data acting as the model validity check. In our study we embraced this approach.

All data were randomly divided into two parts using the Bernoulli distribution. The first part (selected observations) included approximately 70% of the data, the second (unselected observations) the remaining data. The first sample was used in a logistic regression procedure for model creation, while the other was used to check its validity. The model had the same parameters as described above, and its stability was confirmed using the Table of classification (Table 4), created independently for the two samples.

As is clear from the data in Table 4, test power and specificity between Selected observations and Unselected observations have different meanings. Such differences are caused by random variations. The absence of non-randomness for such differences can be assessed by Fischer's test. In this case:

For observation Alive give the opportunity p = 0.1594,
for observation Dead give the opportunity p = 0.7081.

Both opportunities show the absence of differences in the columns of classification table, i.e., the absence of differences in diagnostics of the two samples, the first of which was used for the model construction, and the second, which was used as a control.

A number of parameters were revealed during the aforementioned analysis, which are either related or independent from the disease outcome.

If the parameters are not connected with patient status, the central tendencies, obtained during common analysis of study predictors [see formula (1)], should be used for their characteristic. Considering abnormality of studied random values distribution, the median could be considered a central tendency.

The value of the parameters connected with patient status should be obtained by means of a regression model. The logistic function (2) possesses the value 0.5 under Z=0. This value corresponds with the situation when patient status is determined with probability 0.5. To obtain a more strict forecast condition Z>0 or Z<0 according to the target status value should be met.

We then set the value Z=0 to search for minimal expenses for HCT. Then from formula (4) we get:

On the left side of an equation are the cost parameters, and on the right side are the clinical parameters.

For different treatment variants (k), which are fed into the right side of equation (5), we could calculate weighting values, given by equation:

Estimated values for k are shown in Table 5.

Using the data from Table 5 for k and setting the median for X₂ or X₃ we can calculate the minimal expenses, which depend on patient status, and which patients will be alive with probability 0.5 (i.e., 50%)

There could be 2 variants of calculation:

1. We set median for X₂ (the median of cost of blood transfusions per 24 h under known clinical parameters), and the second parameter is calculated like this:

2. We set median for X₃ (i.e., the median for total drug cost), and the second parameter is calculated like this:

In summary, a model for calculating minimal acceptable cost of predictors was created, having a non-random impact on HCT outcome, under which the probability of positive outcome is 50%. The calculation of minimal total cost of HCT, under which there is 50% survival, is possible by data substitution on formula (1).

Discussion

The transplantation of hematopoietic stem cells is one of the high-technology treatment methods, thus it is rather expensive due to demand for contribution to international directives (GMP, EBMT).

According to the literature, the cost of allo-HCT can vary from US $100,000 to $250,000 [4-9]; cost differences are caused by local features in different countries, considering economic factors, labor costs, drug costs, etc. M. van Agthoven et al. (2002) [10] reviewed  the results of allo-HCT in patients with acute leukemia (ALL and AML) for 2 years. In patients who survived, the cost of allo-BMT from HLA-matched related donors was approximately EUR 103,509, and the cost of allo-PBSCT was EUR 105,906. The cost of allo-BMT from HLA-matched unrelated donor was approximately EUR 173,587, where 1/3 of this sum was spent on a donor search.

According to the literature, the main components of clinical expenses in HCT are outgoings on drugs (38.9%);

33.7% of clinical expenses are due to the cost of patient days;
7.5% is for blood transfusions;
5.8% for laboratory examinations;
5.6% for microbiological examinations;
1.4% for radiology, and
1,9% are other expenses [11].

In our study the aforementioned components of HCT costs were analyzed on statistically significant influences on death rate after HCT and were included in a suggested model of cost assessment, which provide 50% survival.

Despite of the importance of the studied problem and limiting role of high cost of HCT in its routine use in clinical practice in some countries, at the moment there is no method for analysis that can definitely justify its cost, and moreover there are no approaches to predict the influence of expenses on disease outcome.

Considering these facts the suggested method for statistically justified assessment of HCT cost, which helps to connect clinical parameters influencing treatment cost, as well as forecast minimal accessible cost of HCT, in which 50% is achieved, could be used for evaluation of necessary financing for this treatment method.

References

1. Dubno P.U. Using SPSS for treatment of statistical data. Мoscow: LLC Publishing house AST: NT Press, 2004, 221 p. (In Russian)

2. Nasledov A.D. Computer analysis of data in psychology and social sciences. St. Petersburg: Piter, 2005, 416 p. (In Russian)

3. Robert H. Fletcher, Suzanne W. Fletcher, E. Wagner. Clinical Epidemiology: The Essentials. Moscow: Media Sphera, 1998, 352 p. (In Russian)

4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol. 1984,7(3):273-278.

5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol. 1996,14(5):1413-1420.

6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J. 1991,104(916):303-305.

7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with  acute myeloid leukaemia in first remission. Bone Marrow Transplant. 1992,10(4):323-329.

8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic  transplantation. Bone Marrow Transplant. 1998,21(Suppl.3):S92-S98.

9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a children’s hospital. Bone Marrow Transplant. 1998 Jan;21(2):195-203.

10. van Agthoven M, Groot MT, Verdonck LF, et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant. 2002 Aug;30(4):243-51.

11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812.

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Introduction

The basic criterion for choosing a particular method of treatment in medicine ought to be its effectiveness concerning the disease. This approach should be used for managing the patient: choosing the most effective method despite the cost. However, in many cases the high cost of a method combined with debatable effectiveness challenges their use and development, as well as their state financing.

Therefore, the aim of the study was to find some logical evaluation procedures of the treatment cost of HCT.

Materials and methods

There were 209 patients enrolled in the study, who received autologous HCT, and allogenic related and unrelated HCT from 1998 to 2005. There were 91 patients (43.5%) aged from 1 to 66 years with allo-HCT, among them 57 from unrelated donors and 34 from related donors; 118 patients (56.5%) had auto-HCT.

Using their medical charts we performed the treatment efficacy analysis and treatment cost analysis for these aforementioned patients. Clinical effectiveness was assessed using a 2-year overall survival. Evaluation of the total cost and its components in related and unrelated allo-HCT, and assessment of allo-HCT cost under myeloablative and reduced toxicity regimens was also performed. We have independently analyzed the cost of HCT with and without complications. There was an attempt to reveal the statistically justified clinical and cost parameters that influenced HCT effectiveness. The results were analyzed using parametric and non-parametric statistics; data were assessed with regression analysis [1-3].

Results

The result of data analysis suggests using the total cost of HCT. The expression for total HCT cost can be expressed like this:

Сexam – the cost of laboratory examinations performed while the patient is in the clinic. This depends on the disease and duration of in-patient period.

С_p/d – the cost of one patient day. This value is stable and calculated by the clinic's statistics department.

N_d – the duration of in-patient period. This depends on disease severity and complications.

С_transph – the cost of transfusions per day (24 hours). This also depends on disease severity, and complications that require blood transfusions.

С_cond – the cost of a conditioning regimen. This value is stable.

С_drug – the cost of drugs per day (24 h). Dependent on disease severity.

С_infus – the cost of apheresis and storage of BM and PBSC. This value is stable.

С_{donor search} – this value should be considered only in unrelated allo-HCT; it corresponds to the cost of a donor search in international donor registers.

Before the model's construction, which could be a function of clinical, cost and other parameters, it is reasonable to perform exploratory statistical analysis. The aim of such analysis is to reveal the statistically significant influence on the outcome of such features as: sex of patient, diagnosis, type of HCT, donor sex, source of hematopoietic stem cells (BM or PBSC), presence of relapse or progression, complications, particularly infections that require blood transfusions, conditioning regimen, age at HCT, and/or presence of GVHD. According to the character of the clinical parameters, we used analysis of continuous and category variables.

Our first step was to perform non-random difference of central tendency of continuous variables analysis (1). Table 1 presents the continuous variables that help to reveal a significant difference in groups by patient status.

Additionally, we analyzed the clinical, continuous and category variables influencing the HCT effectiveness. The statistically significant influence on HCT outcome caused:

•   HCT type – autologous or allogenic (р=0.002),
•  presence of relapse or progression (р=0.048),
•  presence of blood transfusions complications (р=0.003),
•  type of conditioning regimen: myeloablative or reduced toxicity (р=0.023).

The exploratory statistical analysis performed helps to form the group of continuous and category variables that can be used as predictors for regression modeling of patient status according to clinical and cost parameters.

The construction of a regression model with dependent variables, simulating dichotomous category variables and independent variables creates the need for logistic regression. Logistic regression connects event probability (one of the events of disease outcome variables) with independent variables (predictors), the impact of which was described in the previous section. Considering that the dependent variable is measured by probability mass, and independent variables include continuous and category parameters, it is necessary to make a functional transformation of the independent variables into the interval 0 – 1. Such functional transformation is done by function (2).

This is called the logistic, with Z parameter. 

The parameter Z=B₁X₁+B₂X₂+B₃X₃+B₄X₄+B₅X₅ connects independent variables (predictors).

The procedure of both logistic regression construction and standard regression includes three steps:

Creation of a logistic regression model,

Evaluation of the significance of weight factors in the formula (B₁, B₂, B₃, B₅),

Assessment of model stability.

By means of SPSS, using step-type variants of logistic regression to include or exclude parameters from the model and Wald criterion, we obtained the model, the  parameters of which are stated in Table 2.

According to the formula (2) the parameter

Formula (3) includes:

X₁ – total cost of blood transfusions

X₂ – the cost of blood transfusions per 24 h.

X₃ – the cost of drugs.

X₄ – conditioning regimen

   X₄=0 in reduced toxicity regimen,

   X₄=1 in myeloablative regimen,

X₅ – relapse before HCT

   X₅=0 no relapse before HCT,

   X₅=1 presence of relapse before HCT.

Since the total cost of blood transfusions is obtained via the multiplication of the cost of blood transfusions per 24 h on the number of patient days, X₁=X₂*N_d, formula (3) can be expressed like this:

As stated in Table 2, the model has non-random parameters with p<=0.05.

The quality of patient status prognosis could be assessed using the Table of forecast classification (Table 3)

The values in Table 3 characterize the power of testing (probability of status Alive prediction in present alive condition) and its specificity (probability of status Dead prediction in present dead condition). Thus the power of forecast is 93.5% and its specificity is 63.6%. The probability of a correct forecast is 81.1%.

The stability of the model should be checked using other samples, but we currently have no such data, so practical statistics recommends repeating the analysis using only a part of data for model creation, with the other part of data acting as the model validity check. In our study we embraced this approach.

All data were randomly divided into two parts using the Bernoulli distribution. The first part (selected observations) included approximately 70% of the data, the second (unselected observations) the remaining data. The first sample was used in a logistic regression procedure for model creation, while the other was used to check its validity. The model had the same parameters as described above, and its stability was confirmed using the Table of classification (Table 4), created independently for the two samples.

As is clear from the data in Table 4, test power and specificity between Selected observations and Unselected observations have different meanings. Such differences are caused by random variations. The absence of non-randomness for such differences can be assessed by Fischer's test. In this case:

For observation Alive give the opportunity p = 0.1594,
for observation Dead give the opportunity p = 0.7081.

Both opportunities show the absence of differences in the columns of classification table, i.e., the absence of differences in diagnostics of the two samples, the first of which was used for the model construction, and the second, which was used as a control.

A number of parameters were revealed during the aforementioned analysis, which are either related or independent from the disease outcome.

If the parameters are not connected with patient status, the central tendencies, obtained during common analysis of study predictors [see formula (1)], should be used for their characteristic. Considering abnormality of studied random values distribution, the median could be considered a central tendency.

The value of the parameters connected with patient status should be obtained by means of a regression model. The logistic function (2) possesses the value 0.5 under Z=0. This value corresponds with the situation when patient status is determined with probability 0.5. To obtain a more strict forecast condition Z>0 or Z<0 according to the target status value should be met.

We then set the value Z=0 to search for minimal expenses for HCT. Then from formula (4) we get:

On the left side of an equation are the cost parameters, and on the right side are the clinical parameters.

For different treatment variants (k), which are fed into the right side of equation (5), we could calculate weighting values, given by equation:

Estimated values for k are shown in Table 5.

Using the data from Table 5 for k and setting the median for X₂ or X₃ we can calculate the minimal expenses, which depend on patient status, and which patients will be alive with probability 0.5 (i.e., 50%)

There could be 2 variants of calculation:

1. We set median for X₂ (the median of cost of blood transfusions per 24 h under known clinical parameters), and the second parameter is calculated like this:

2. We set median for X₃ (i.e., the median for total drug cost), and the second parameter is calculated like this:

In summary, a model for calculating minimal acceptable cost of predictors was created, having a non-random impact on HCT outcome, under which the probability of positive outcome is 50%. The calculation of minimal total cost of HCT, under which there is 50% survival, is possible by data substitution on formula (1).

Discussion

The transplantation of hematopoietic stem cells is one of the high-technology treatment methods, thus it is rather expensive due to demand for contribution to international directives (GMP, EBMT).

According to the literature, the cost of allo-HCT can vary from US $100,000 to $250,000 [4-9]; cost differences are caused by local features in different countries, considering economic factors, labor costs, drug costs, etc. M. van Agthoven et al. (2002) [10] reviewed  the results of allo-HCT in patients with acute leukemia (ALL and AML) for 2 years. In patients who survived, the cost of allo-BMT from HLA-matched related donors was approximately EUR 103,509, and the cost of allo-PBSCT was EUR 105,906. The cost of allo-BMT from HLA-matched unrelated donor was approximately EUR 173,587, where 1/3 of this sum was spent on a donor search.

According to the literature, the main components of clinical expenses in HCT are outgoings on drugs (38.9%);

33.7% of clinical expenses are due to the cost of patient days;
7.5% is for blood transfusions;
5.8% for laboratory examinations;
5.6% for microbiological examinations;
1.4% for radiology, and
1,9% are other expenses [11].

In our study the aforementioned components of HCT costs were analyzed on statistically significant influences on death rate after HCT and were included in a suggested model of cost assessment, which provide 50% survival.

Despite of the importance of the studied problem and limiting role of high cost of HCT in its routine use in clinical practice in some countries, at the moment there is no method for analysis that can definitely justify its cost, and moreover there are no approaches to predict the influence of expenses on disease outcome.

Considering these facts the suggested method for statistically justified assessment of HCT cost, which helps to connect clinical parameters influencing treatment cost, as well as forecast minimal accessible cost of HCT, in which 50% is achieved, could be used for evaluation of necessary financing for this treatment method.

References

1. Dubno P.U. Using SPSS for treatment of statistical data. Мoscow: LLC Publishing house AST: NT Press, 2004, 221 p. (In Russian)

2. Nasledov A.D. Computer analysis of data in psychology and social sciences. St. Petersburg: Piter, 2005, 416 p. (In Russian)

3. Robert H. Fletcher, Suzanne W. Fletcher, E. Wagner. Clinical Epidemiology: The Essentials. Moscow: Media Sphera, 1998, 352 p. (In Russian)

4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol. 1984,7(3):273-278.

5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol. 1996,14(5):1413-1420.

6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J. 1991,104(916):303-305.

7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with  acute myeloid leukaemia in first remission. Bone Marrow Transplant. 1992,10(4):323-329.

8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic  transplantation. Bone Marrow Transplant. 1998,21(Suppl.3):S92-S98.

9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a children’s hospital. Bone Marrow Transplant. 1998 Jan;21(2):195-203.

10. van Agthoven M, Groot MT, Verdonck LF, et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant. 2002 Aug;30(4):243-51.

11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812.

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Д. А. Багге, Б. И. Смирнов, Б. В. Афанасьев

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Институт гематологии и трансплантологии им. Р. М. Горбачевой и кафедра гематологии, трансфузиологии и трансплантологии Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова

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Модель логистической регрессии позволяет рассчитать минимально допустимую стоимость ТГСК, при которой возможно достижение 50% положительного эффекта. В исследование вошли 209 пациентов перенесших аутологичную, аллогенную родственную и неродственную ТГСК. Было определено неслучайное влияние на исход ТГСК параметров стоимости и различных медицинских факторов, в том числе возраста и пола пациента, типа донора (родственный/неродственный), источника стволовых клеток (из костного мозга или периферической крови). В стоимость процедуры ТГСК включались расходы на пребывание больного в стационаре (число койко-дней), стоимость лабораторного обследования, расходы на кондиционирующую терапию, стоимость лекарственных препаратов в посттрансплантационном периоде, расходы на аферез и заготовку костного мозга или периферических стволовых клеток, а также стоимость поиска донора (при неродственных ТГСК). Применение режимов кондиционирования со сниженной интенсивностью дозы и миелоаблативных режимов, наличие или отсутствие рецидива, а также стоимость медикаментов и трансфузиологического пособия статистически значимо влияли на исход ТГСК, что позволило рассчитать весовые коэффициенты и связать показатели стоимости и клинические параметры. Это дает возможность рассчитать минимально допустимую стоимость ТГСК.

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Dmitry A. Bagge, Boris I. Smirnov, Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10279" ["VALUE"]=> array(2) { ["TEXT"]=> string(160) "<p>R. M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, and St. Petersburg State Medical I. Pavlov University, Russia</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(148) "

R. M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, and St. Petersburg State Medical I. Pavlov University, Russia

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10280" ["VALUE"]=> array(2) { ["TEXT"]=> string(833) "<p>The logistic regression model allows the calculation of the minimal acceptable cost of HCT, having non-random impact on HCT outcome, under which the probability of a positive outcome is 50%. There were 209 patients enrolled in the study, who received autologous HCT, and allogenic related and unrelated HCT. The non-random cost and medical parameters connected with patient status were defined before HCT and HCT outcomes. The application of reduced toxicity (RTCR) or myeloablative conditioning regimens (MCR), the presence of relapse before HCT, and the cost of drugs and blood transfusion all have an influence on the outcome, and the weight coefficients of these parameters were calculated. This allows the connection of costs and clinical parameters, and the calculation of the minimal acceptable cost of HCT.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(821) "

The logistic regression model allows the calculation of the minimal acceptable cost of HCT, having non-random impact on HCT outcome, under which the probability of a positive outcome is 50%. There were 209 patients enrolled in the study, who received autologous HCT, and allogenic related and unrelated HCT. The non-random cost and medical parameters connected with patient status were defined before HCT and HCT outcomes. The application of reduced toxicity (RTCR) or myeloablative conditioning regimens (MCR), the presence of relapse before HCT, and the cost of drugs and blood transfusion all have an influence on the outcome, and the weight coefficients of these parameters were calculated. This allows the connection of costs and clinical parameters, and the calculation of the minimal acceptable cost of HCT.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10259" ["VALUE"]=> string(117) "The logistic regression model in the statistical justification of the cost of hematopoietic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(117) "The logistic regression model in the statistical justification of the cost of hematopoietic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10316" ["VALUE"]=> array(2) { ["TEXT"]=> string(36216) "<h3>Введение</h3> <p class="bodytext"> Главным основополагающим критерием выбора того или иного вида лечения в медицине должна являться эффективность его воздействия на возникшее заболевание. Руководствуясь этим принципом, следует подходить к лечению пациента, независимо от того, насколько дорогостоящим окажется самый эффективный при данном виде заболевания способ лечения. Однако, часто необоснованно высокая стоимость при однозначно не доказанной клинической эффективности того или иного вида лечения ставит под сомнение применение и дальнейшее развитие, а также государственное финансирование этих методов. </p> <p class="bodytext"> В соответствии с этим, в данной работе ставится задача найти обоснованные методы оценки стоимости лечения ТГСК. </p> <h3>Материал и методы исследования</h3> <p class="bodytext"> Исследование проводилось на группе из 209 пациентов, перенесших аутологичную ТГСК, аллогенную родственную и неродственную ТГСК с 1998 по 2005 год. Группа состояла из 91 (43,5%) пациента в возрасте от 1 до 66 лет, подвергшихся аллоТГСК, из  них  у 57 пациентов - от неродственного донора, у 34 пациентов от родственного донора, а 118 (56,5%) пациентов перенесли аутоТГСК.<br> <br> На основании клинических историй болезни проводили анализ эффективности лечения и анализ стоимости лечения вышеуказанных пациентов. Клиническую эффективность оценивали по результатам общей выживаемости за двухлетний период. Проводили оценку общей стоимости, а также различных составляющих стоимости лечения при аутологичной и аллогенной, родственной и неродственной ТГСК, оценку стоимости  аллоТГСК при миелоаблативных и немиелоаблативнных режимах кондиционирования; отдельно определяли стоимость осложненной ТГСК, и ТГСК протекавшей с/без осложнений.<strong> </strong>В работе сделана попытка выявить статистически обоснованные клинические и стоимостные показатели, влияющие на эффективность применения ТГСК. Полученные результаты были проанализированы с применением методов параметрической и непараметрической статистики, проведен регрессионный анализ полученных данных [1-3]. </p> <h3>Результаты исследования</h3> <p class="bodytext"> В результате анализа данных было предложено выражение общей стоимости ТГСК. Выражение общей стоимости ТГСК выглядит следующим образом: </p> <p> <img width="570" alt="2008-1-ru-Bagge-Formula-1-72dpi-814px.jpg" src="/upload/medialibrary/0f4/2008_1_ru_bagge_formula_1_72dpi_814px.jpg" height="62" title="2008-1-ru-Bagge-Formula-1-72dpi-814px.jpg"><br> </p> <p class="bodytext"> C_обс – стоимость лабораторного обследования, которое проводится при нахождении пациента в клинике. Величина, зависящая от характера заболевания и продолжительности нахождения пациента в стационаре. </p> <p class="bodytext"> С_к/д – стоимость нахождения пациента в условиях стационара в течение 1-го к/д. Это величина - фиксированная и рассчитывается статистическими отделами стационаров. </p> <p class="bodytext"> N_сут –длительность нахождения пациента в стационаре. Эта величина, будет зависеть от тяжести заболевания и наличия осложнений. </p> <p class="bodytext"> С_трансф – стоимость трансфузиологического пособия в сутки. Эта величина, также зависит от тяжести заболевания и наличия осложнений требующих гемотрансфузий. </p> <p class="bodytext"> С_конд – стоимость режима кондиционирования.  </p> <p class="bodytext"> С_конд – величина - фиксированная. </p> <p class="bodytext"> С_препар – стоимость  медикаментов в сутки. Зависит от тяжести течения заболевания. </p> <p class="bodytext"> С_инфуз – стоимость заготовки и инфузии КМ или ПСК. Величина фиксированная. </p> <p class="bodytext"> С_{поиск донора}– стоимость следует учитывать только при неродственной аллогенной ТГСК, соответствует стоимости поиска в международном регистре доноров. </p> <p class="bodytext"> Перед построением модели, которая может быть представлена как функция от клинических, стоимостных и других параметров, целесообразно выполнить разведочный статистический анализ. Целью данного анализа было выявление статистически достоверного влияния на исход заболевания следующих характеристик: пол пациента, диагноз, вид ТГСК, пол донора, использование в качестве трансплантата КМ или ПСКК, наличие рецидива или прогрессии, наличие осложнений в общем, и в частности - инфекционных, требующих гемотрансфузий, режима кондиционирования, возраста при ТГСК, наличия РТПХ. В зависимости от характера клинических характеристик были использованы методы анализа непрерывных и категориальных переменных. </p> <p class="bodytext"> На первом этапе был проведен анализ неслучайного различия центральных тенденций непрерывных переменных выражения (1). В табл. 1  приведены непрерывные параметры, которые выявили значимое различие в группах, сформированных по значению статуса пациента. </p> <p> <img width="614" alt="2008-1-ru-Bagge-Fig1.jpg" src="/upload/medialibrary/ba8/2008_1_ru_bagge_fig1.jpg" height="151" title="2008-1-ru-Bagge-Fig1.jpg"><br> </p> <p class="bodytext"> Далее были проанализированы клинические непрерывные и категориальные параметры влияющие на эффективность ТГСК. Статистически значимое влияние на исход ТГСК оказывали: </p> <p class="bodytext"> • вид ТГСК – аутологичная или аллогенная (р=0,002),<br> • наличие рецидива или прогрессии (р=0,048),<br> • наличие трансфузиологических осложнений (р=0,003),<br> • вид режима кондиционирования – миело или немиелоаблативный (р=0,023). </p> <p class="bodytext"> Выполненный разведочный анализ позволяет сформировать группу непрерывных и категориальных переменных, которые могут быть использованы в качестве предикторов при построении регрессионной модели статуса пациента в зависимости от клинических и стоимостных параметров. </p> <p class="bodytext"> Построение регрессионной модели с зависимой переменной, имеющей вид дихотомической категориальной переменной и независимыми переменными, представленными, приводит к необходимости использовать логистическую регрессию. Логистическая регрессия связывает вероятность наступления события (одного из событий переменной исход заболевания) с независимыми переменными (предикторами), влияние которых на независимую переменную выявлено в предыдущем разделе. Поскольку зависимая переменная оценивается вероятностной мерой, а независимые переменные включают категориальные и непрерывные параметры, необходимо выполнить функциональное преобразование независимых переменных к интервалу 0 – 1. Указанное функциональное преобразование выполняется функцией (2). </p> <p> <img width="215" alt="2008-1-ru-Bagge-Formula-2-72dpi-307px.jpg" src="/upload/medialibrary/682/2008_1_ru_bagge_formula_2_72dpi_307px.jpg" height="95" title="2008-1-ru-Bagge-Formula-2-72dpi-307px.jpg"><br> </p> <p class="bodytext"> которая называется логистической, с параметром <em>Z</em>.  </p> <p class="bodytext"> Параметр Z=<em>B</em>₁<em>X</em>₁+<em>B</em>₂<em>X</em>₂+<em>B</em>₃<em>X</em>₃+<em>B</em>₄<em>X</em>₄+<em>B</em><em>₅X</em><em>₅</em> связывает независимые переменные (предикторы). </p> <p class="bodytext"> Процедура построения логистической регрессии включает, как и обычная регрессия, три основные этапа:<br> • Получение модели логистической регрессии,<br> • Оценка значимостей полученных весовых коэффициентов уравнения (<em>B</em>₁, <em>B</em>₂, <em>B</em>₃, <em>B</em>₅),<br> • Определение устойчивости модели. </p> <p class="bodytext"> С помощью статистического пакета SPSS, используя пошаговые варианты логистической регрессии на включение и исключение параметров из модели и применение критерия Вальда была получена модель со следующими параметрами (Табл. 2). </p> <p> <img width="602" alt="2008-1-ru-Bagge-Table-2-72dpi-1003px-unsharp.jpg" src="/upload/medialibrary/cde/2008_1_ru_bagge_table_2_72dpi_1003px_unsharp.jpg" height="288" title="2008-1-ru-Bagge-Table-2-72dpi-1003px-unsharp.jpg"><br> </p> <p class="bodytext"> В соответствии с выражением (2) параметр </p> <p> <img width="650" alt="2008-1-ru-Bagge-Formula-3-72dpi-928px.jpg" src="/upload/medialibrary/f74/2008_1_ru_bagge_formula_3_72dpi_928px.jpg" height="61" title="2008-1-ru-Bagge-Formula-3-72dpi-928px.jpg"><br> </p> <p class="bodytext"> В выражение (3) входят: </p> <p class="bodytext"> <em>X</em>₁ – общая стоимость трансфузиологического пособия </p> <p class="bodytext"> <em>X</em>₂ - стоимость трансфузиологического пособия в сутки. </p> <p class="bodytext"> <em>X</em>₃ – стоимость медикаментов. </p> <p class="bodytext"> <em>X</em>₄– режим кондиционирования </p> <p class="bodytext"> <em>   X</em>₄=0 при немиелоаблативном режиме кондиционирования, </p> <p class="bodytext"> <em>   X</em>₄=1 при миелоаблативном режиме кондиционирования, </p> <p class="bodytext"> <em>X</em>₅ – рецидив перед ТГСК </p> <p class="bodytext"> <em>   X</em>₅=0 при отсутствии рецидива перед ТГСК, </p> <p class="bodytext"> <em>   X</em>₅=1 при наличии рецидива. </p> <p class="bodytext"> В связи с тем, что общая стоимость трансфузиологического пособия получена путем умножения стоимости трансфузиологического пособия в сутки на количество койко-дней, X₁=X₂*N_сут. Тогда выражение (3) принимает вид: </p> <p> <img width="694" alt="2008-1-ru-Bagge-Formula-4-72dpi-991px.jpg" src="/upload/medialibrary/b44/2008_1_ru_bagge_formula_4_72dpi_991px.jpg" height="63" title="2008-1-ru-Bagge-Formula-4-72dpi-991px.jpg"><br> </p> <p class="bodytext"> Как видно из табл. 2, модель обладает неслучайными параметрами, значимости которых p&lt;=0,05. </p> <p class="bodytext"> Качество прогноза статуса пациента может быть оценено с помощью таблицы классификации предсказания (см. табл. 3) </p> <p> <img width="473" alt="2008-1-ru-Bagge-Table-3-72dpi-788px.jpg" src="/upload/medialibrary/007/2008_1_ru_bagge_table_3_72dpi_788px.jpg" height="199" title="2008-1-ru-Bagge-Table-3-72dpi-788px.jpg"><br> </p> <p class="bodytext"> Значения табл. 3. характеризуют мощность теста (вероятность предсказания состояния «Жив» при наблюдаемом состоянии «Жив») и специфичность теста (вероятность предсказания «Умер» при  наблюдаемом состоянии «Умер»). Как видно из табл. 3 мощность  прогноза составляет 93,5%, а специфичность - 63,6%. При этом вероятность правильного прогноза составляет 81,1%. </p> <p class="bodytext"> Устойчивость полученной модели необходимо проверить на другой выборке, однако таких данных нет, поэтому прикладная статистика рекомендует выполнить повторный анализ, используя для построения модели только часть данных, другую часть использовать для проверки валидности построенной модели. Так поступили и в этом случае. </p> <p class="bodytext"> Весь массив данных был случайным образом с использованием распределения Бернулли разделен на две части. В первую (отобранные наблюдения) помещено примерно 70% данных, а во вторую (неотобранные наблюдения) - остальные. Первая выборка была использована в процедуре логистической регрессии для построения модели, а вторая – для проверки ее валидности. Модель была получена с такими же параметрами, как описано выше, а устойчивость ее подтверждена с помощью таблицы классификации (табл. 4), построенной раздельно для двух выборок. </p> <p> <img width="610" alt="2008-1-ru-Bagge-Table-4-72dpi-1016px.jpg" src="/upload/medialibrary/fce/2008_1_ru_bagge_table_4_72dpi_1016px.jpg" height="272" title="2008-1-ru-Bagge-Table-4-72dpi-1016px.jpg"><br> </p> <p class="bodytext"> Как видно из табл. 4, мощность и специфичность в выборках «отобранные значения» и «неотобранные значения» имеют различные величины. Эти различия обусловлены случайными вариациями. Отсутствие неслучайности различий может быть оценено с помощью теста Фишера, который в данном случае: </p> <p class="bodytext">   Для наблюдения «Жив» дает вероятность p = 0,1594, </p> <p class="bodytext">   Для наблюдения «Умер» дает вероятность p = 0,7081. </p> <p class="bodytext"> Обе вероятности говорят об отсутствии различий в столбцах классификационной таблицы, т.е. об отсутствии различия в диагносте двух выборок, первой, по которой строилась модель и второй, по которой она проверялась. </p> <p class="bodytext"> Выполненный в предыдущих разделах анализ выявил параметры зависящие от исхода заболевания и не зависящие от него. </p> <p class="bodytext"> Если параметры не связаны со статусом пациента, для их характеристики следует воспользоваться центральными тенденциями, полученными в результате общего анализа исследуемых предикторов представленных в выражении (1). Ввиду ненормальности распределений рассматриваемых случайных величин такой центральной тенденцией может выступить медиана. </p> <p class="bodytext"> Значения параметров, связанных со статусом, следует получить из регрессионной модели. Логистическая функция (2) принимает значение 0,5 при <em>Z</em>=0. Это значение соответствует ситуации, когда статус пациента определяется с вероятностью 0,5. Для получения более определенного прогноза должно выполняться условие Z&gt;0 или Z&lt;0 в зависимости от искомого значения статуса. </p> <p class="bodytext"> Примем Z=0 как значение для поиска минимальных затрат на ТГСК. Тогда из выражения (4) получим: </p> <p> <img width="676" alt="2008-1-ru-Bagge-Formula-5-72dpi-969px-corr.jpg" src="/upload/medialibrary/d46/2008_1_ru_bagge_formula_5_72dpi_969px_corr.jpg" height="65" title="2008-1-ru-Bagge-Formula-5-72dpi-969px-corr.jpg"><br> </p> <p class="bodytext"> В левой части уравнения находятся стоимостные параметры, а в правой клинические. </p> <p class="bodytext"> Для различных вариантов терапии (k), которые задаются правой частью уравнения (5) можно вычислить весовые значения, задаваемые уравнением: </p> <p class="bodytext"> <em>k</em>= 2,159*<em>X</em>₄+2,059*<em>X</em>₅. </p> <p class="bodytext"> Расчетные значения<em> </em><em>k</em> приведены в таблице 5. </p> <p> <img width="478" alt="2008-1-ru-Bagge-Table-5-72dpi-797px.jpg" src="/upload/medialibrary/e7e/2008_1_ru_bagge_table_5_72dpi_797px.jpg" height="263" title="2008-1-ru-Bagge-Table-5-72dpi-797px.jpg"><br> </p> <p class="bodytext"> Используя данные табл. 5 значений <em>к</em> и задав медиану для X₂ или X_3, можно вычислить минимальные значения стоимостей, зависящих от статуса, при которых больные будут живы с вероятностью 0,5 (т.е. 50%) </p> <p class="bodytext"> Возможны два варианта вычисления: </p> <p class="bodytext"> 1. Задается медиана X₂ (медиана стоимости трансфузиологического пособия в сутки при известных клинических параметрах), а второй параметр вычисляется как </p> <p> <img width="337" alt="2008-1-ru-Bagge-Calculation-1-72dpi-481px.jpg" src="/upload/medialibrary/8b6/2008_1_ru_bagge_calculation_1_72dpi_481px.jpg" height="99" title="2008-1-ru-Bagge-Calculation-1-72dpi-481px.jpg"><br> </p> <p class="bodytext"> 2. Задается медиана X₃ (т.е. медиана общей стоимости препаратов), а второй параметр вычисляется как </p> <p> <img width="261" alt="2008-1-ru-Bagge-Calculation-2-72dpi-373px.jpg" src="/upload/medialibrary/c17/2008_1_ru_bagge_calculation_2_72dpi_373px.jpg" height="97" title="2008-1-ru-Bagge-Calculation-2-72dpi-373px.jpg"><br> </p> <p class="bodytext">Таким образом, была получена модель расчета минимально допустимой стоимости предикторов имевших неслучайное воздействие на исход проведение ТГСК при котором вероятность наступления положительного исхода равна 50%. Подсчет минимальной общей стоимости ТГСК, при которой возможно достижение 50% выживаемости, становится возможным при подстановке полученных данных в выражение (1). </p> <h3>Обсуждение</h3> <p class="bodytext">Трансплантация гемопоэтических стволовых клеток относится к высокотехнологичным методам лечения. Это подразумевает необходимость значительных финансовых затрат, связанных с ее проведением в соответствии с требованиями международных стандартов (good medical practice-GMP, EBMT). </p> <p class="bodytext">Стоимость алло-ТГСК по литературным данным может составлять от 100 000 до 250 000 долларов США [4-9]; расхождения в стоимости связаны с особенностями   проведения ТГСК в различных странах с учетом их экономических факторов, стоимости оплаты труда, стоимости медикаментов и т.п. В работе M. van Agthoven et al. (2002) [<a href="1-1-bagge-etal-2008may28.html?&amp;L=1#c302" title="Внутренняя ссылка открывается в текущем окне" class="internal-link">10</a>] прослежены результаты алло-ТГСК у больных острыми лейкозаи (ОМЛ и ОЛЛ) за 2 года. У выживших пациентов стоимость аллоТКМ от HLA-совместимого родственного донора составила 103 509 евро, аллоТПСКК – 105 906 евро. Стоимость алло-ТГСК от неродственного донора была равна 173 587 евро, причем 1/3 этой суммы приходится на поиск донора. </p> <p class="bodytext">По данным зарубежных авторов, наибольшую долю общих госпитальных затрат при ТГСК составляют расходы на лекарственные препараты (38,9%); </p> <p class="bodytext">33,7% общих госпитальных затрат – расходы на пребывание больного в стационаре;<br />7,5% - трансфузиологическое пособие; <br />5,8% - лабораторно-диагностические исследования;<br />5,6% - микробиологические исследования;<br />1,4% - радиология; <br />1,9% составляют другие расходы [11]. <br /><br />В нашей работе представленные составляющие стоимости были проанализированы на предмет статистически достоверного влияния на летальность после ТГСК и включены в предложенную модель прогностическую модель оценки стоимости, при которой возможно достижение 50% выживаемости. </p> <p class="bodytext">Несмотря на важность рассматриваемого вопроса, а также лимитирующее воздействие высокой стоимости ТГСК на широкое внедрение этого метода в некоторых странах, в настоящий момент не существует метода анализа достоверно обосновывающего стоимость его стоимость, тем более не существует способов прогнозировать влияние затраченных денег на исход заболевания. </p> <p class="bodytext">В связи с вышеизложенным, представленный способ статистически обоснованной оценки стоимости ТГСК, позволяющий связать имеющиеся клинические параметры, влияющие на стоимость лечения, а также прогнозировать минимально возможную стоимость ТГСК, при которой достигается 50%-ный положительный эффект, может быть предложен для оценки необходимого финансирования данного вида лечения.</p> <h3>Литература</h3> <p class="bodytext">1. Дубно П.Ю. Обработка статистической информации с помощью SPSS. - М.: ООО «Издательство АСТ»: «НТ Пресс», 2004, 221 с. </p> <p class="bodytext">2. Наследов А.Д. Компьютерный анализ данных в психологии и социальных науках. – СПб.: Питер, 2005, 416 с. </p> <p class="bodytext">3. Флетчер Р., Флетчер С., Вагнер Э. Клиническая эпидемиология. Основы доказательной медицины. (перевод с англ.). Москва: Медиа-Сфера. 1998. – 352 с.</p> <p class="bodytext">4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol., 1984, 7 (3): 273-278. </p> <p class="bodytext">5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol., 1996, 14(5): 1413-1420. </p> <p class="bodytext">6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J., 1991, 104 (916): 303-305. </p> <p class="bodytext">7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission. Bone Marrow Transplant., 1992, 10(4):323-329. </p> <p class="bodytext">8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic transplantation. Bone Marrow Transplant., 1998, 21 (Suppl.3): S92-S98. </p> <p class="bodytext">9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a chidren’s hospital. Bone Marrow Transplant., 1998, 21:195-203.</p> <p class="bodytext">10. van Agthoven M., Groot M.T., Verdonck L.F. et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant., 2002, 30(4):243-251.11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med., 1989, 321(12): 807-812.  </p> <p class="bodytext"> 11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(32592) "

Введение

Главным основополагающим критерием выбора того или иного вида лечения в медицине должна являться эффективность его воздействия на возникшее заболевание. Руководствуясь этим принципом, следует подходить к лечению пациента, независимо от того, насколько дорогостоящим окажется самый эффективный при данном виде заболевания способ лечения. Однако, часто необоснованно высокая стоимость при однозначно не доказанной клинической эффективности того или иного вида лечения ставит под сомнение применение и дальнейшее развитие, а также государственное финансирование этих методов.

В соответствии с этим, в данной работе ставится задача найти обоснованные методы оценки стоимости лечения ТГСК.

Материал и методы исследования

Исследование проводилось на группе из 209 пациентов, перенесших аутологичную ТГСК, аллогенную родственную и неродственную ТГСК с 1998 по 2005 год. Группа состояла из 91 (43,5%) пациента в возрасте от 1 до 66 лет, подвергшихся аллоТГСК, из  них  у 57 пациентов - от неродственного донора, у 34 пациентов от родственного донора, а 118 (56,5%) пациентов перенесли аутоТГСК.

На основании клинических историй болезни проводили анализ эффективности лечения и анализ стоимости лечения вышеуказанных пациентов. Клиническую эффективность оценивали по результатам общей выживаемости за двухлетний период. Проводили оценку общей стоимости, а также различных составляющих стоимости лечения при аутологичной и аллогенной, родственной и неродственной ТГСК, оценку стоимости  аллоТГСК при миелоаблативных и немиелоаблативнных режимах кондиционирования; отдельно определяли стоимость осложненной ТГСК, и ТГСК протекавшей с/без осложнений. В работе сделана попытка выявить статистически обоснованные клинические и стоимостные показатели, влияющие на эффективность применения ТГСК. Полученные результаты были проанализированы с применением методов параметрической и непараметрической статистики, проведен регрессионный анализ полученных данных [1-3].

Результаты исследования

В результате анализа данных было предложено выражение общей стоимости ТГСК. Выражение общей стоимости ТГСК выглядит следующим образом:

C_обс – стоимость лабораторного обследования, которое проводится при нахождении пациента в клинике. Величина, зависящая от характера заболевания и продолжительности нахождения пациента в стационаре.

С_к/д – стоимость нахождения пациента в условиях стационара в течение 1-го к/д. Это величина - фиксированная и рассчитывается статистическими отделами стационаров.

N_сут – длительность нахождения пациента в стационаре. Эта величина, будет зависеть от тяжести заболевания и наличия осложнений.

С_трансф – стоимость трансфузиологического пособия в сутки. Эта величина, также зависит от тяжести заболевания и наличия осложнений требующих гемотрансфузий.

С_конд – стоимость режима кондиционирования. 

С_конд – величина - фиксированная.

С_препар – стоимость  медикаментов в сутки. Зависит от тяжести течения заболевания.

С_инфуз – стоимость заготовки и инфузии КМ или ПСК. Величина фиксированная.

С_{поиск донора} – стоимость следует учитывать только при неродственной аллогенной ТГСК, соответствует стоимости поиска в международном регистре доноров.

Перед построением модели, которая может быть представлена как функция от клинических, стоимостных и других параметров, целесообразно выполнить разведочный статистический анализ. Целью данного анализа было выявление статистически достоверного влияния на исход заболевания следующих характеристик: пол пациента, диагноз, вид ТГСК, пол донора, использование в качестве трансплантата КМ или ПСКК, наличие рецидива или прогрессии, наличие осложнений в общем, и в частности - инфекционных, требующих гемотрансфузий, режима кондиционирования, возраста при ТГСК, наличия РТПХ. В зависимости от характера клинических характеристик были использованы методы анализа непрерывных и категориальных переменных.

На первом этапе был проведен анализ неслучайного различия центральных тенденций непрерывных переменных выражения (1). В табл. 1  приведены непрерывные параметры, которые выявили значимое различие в группах, сформированных по значению статуса пациента.

Далее были проанализированы клинические непрерывные и категориальные параметры влияющие на эффективность ТГСК. Статистически значимое влияние на исход ТГСК оказывали:

• вид ТГСК – аутологичная или аллогенная (р=0,002),
• наличие рецидива или прогрессии (р=0,048),
• наличие трансфузиологических осложнений (р=0,003),
• вид режима кондиционирования – миело или немиелоаблативный (р=0,023).

Выполненный разведочный анализ позволяет сформировать группу непрерывных и категориальных переменных, которые могут быть использованы в качестве предикторов при построении регрессионной модели статуса пациента в зависимости от клинических и стоимостных параметров.

Построение регрессионной модели с зависимой переменной, имеющей вид дихотомической категориальной переменной и независимыми переменными, представленными, приводит к необходимости использовать логистическую регрессию. Логистическая регрессия связывает вероятность наступления события (одного из событий переменной исход заболевания) с независимыми переменными (предикторами), влияние которых на независимую переменную выявлено в предыдущем разделе. Поскольку зависимая переменная оценивается вероятностной мерой, а независимые переменные включают категориальные и непрерывные параметры, необходимо выполнить функциональное преобразование независимых переменных к интервалу 0 – 1. Указанное функциональное преобразование выполняется функцией (2).

которая называется логистической, с параметром Z. 

Параметр Z=B₁X₁+B₂X₂+B₃X₃+B₄X₄+B₅X₅ связывает независимые переменные (предикторы).

Процедура построения логистической регрессии включает, как и обычная регрессия, три основные этапа:
• Получение модели логистической регрессии,
• Оценка значимостей полученных весовых коэффициентов уравнения (B₁, B₂, B₃, B₅),
• Определение устойчивости модели.

С помощью статистического пакета SPSS, используя пошаговые варианты логистической регрессии на включение и исключение параметров из модели и применение критерия Вальда была получена модель со следующими параметрами (Табл. 2).

В соответствии с выражением (2) параметр

В выражение (3) входят:

X₁ – общая стоимость трансфузиологического пособия

X₂ - стоимость трансфузиологического пособия в сутки.

X₃ – стоимость медикаментов.

X₄ – режим кондиционирования

   X₄=0 при немиелоаблативном режиме кондиционирования,

   X₄=1 при миелоаблативном режиме кондиционирования,

X₅ – рецидив перед ТГСК

   X₅=0 при отсутствии рецидива перед ТГСК,

   X₅=1 при наличии рецидива.

В связи с тем, что общая стоимость трансфузиологического пособия получена путем умножения стоимости трансфузиологического пособия в сутки на количество койко-дней, X₁=X₂*N_сут. Тогда выражение (3) принимает вид:

Как видно из табл. 2, модель обладает неслучайными параметрами, значимости которых p<=0,05.

Качество прогноза статуса пациента может быть оценено с помощью таблицы классификации предсказания (см. табл. 3)

Значения табл. 3. характеризуют мощность теста (вероятность предсказания состояния «Жив» при наблюдаемом состоянии «Жив») и специфичность теста (вероятность предсказания «Умер» при  наблюдаемом состоянии «Умер»). Как видно из табл. 3 мощность  прогноза составляет 93,5%, а специфичность - 63,6%. При этом вероятность правильного прогноза составляет 81,1%.

Устойчивость полученной модели необходимо проверить на другой выборке, однако таких данных нет, поэтому прикладная статистика рекомендует выполнить повторный анализ, используя для построения модели только часть данных, другую часть использовать для проверки валидности построенной модели. Так поступили и в этом случае.

Весь массив данных был случайным образом с использованием распределения Бернулли разделен на две части. В первую (отобранные наблюдения) помещено примерно 70% данных, а во вторую (неотобранные наблюдения) - остальные. Первая выборка была использована в процедуре логистической регрессии для построения модели, а вторая – для проверки ее валидности. Модель была получена с такими же параметрами, как описано выше, а устойчивость ее подтверждена с помощью таблицы классификации (табл. 4), построенной раздельно для двух выборок.

Как видно из табл. 4, мощность и специфичность в выборках «отобранные значения» и «неотобранные значения» имеют различные величины. Эти различия обусловлены случайными вариациями. Отсутствие неслучайности различий может быть оценено с помощью теста Фишера, который в данном случае:

  Для наблюдения «Жив» дает вероятность p = 0,1594,

  Для наблюдения «Умер» дает вероятность p = 0,7081.

Обе вероятности говорят об отсутствии различий в столбцах классификационной таблицы, т.е. об отсутствии различия в диагносте двух выборок, первой, по которой строилась модель и второй, по которой она проверялась.

Выполненный в предыдущих разделах анализ выявил параметры зависящие от исхода заболевания и не зависящие от него.

Если параметры не связаны со статусом пациента, для их характеристики следует воспользоваться центральными тенденциями, полученными в результате общего анализа исследуемых предикторов представленных в выражении (1). Ввиду ненормальности распределений рассматриваемых случайных величин такой центральной тенденцией может выступить медиана.

Значения параметров, связанных со статусом, следует получить из регрессионной модели. Логистическая функция (2) принимает значение 0,5 при Z=0. Это значение соответствует ситуации, когда статус пациента определяется с вероятностью 0,5. Для получения более определенного прогноза должно выполняться условие Z>0 или Z<0 в зависимости от искомого значения статуса.

Примем Z=0 как значение для поиска минимальных затрат на ТГСК. Тогда из выражения (4) получим:

В левой части уравнения находятся стоимостные параметры, а в правой клинические.

Для различных вариантов терапии (k), которые задаются правой частью уравнения (5) можно вычислить весовые значения, задаваемые уравнением:

k= 2,159*X₄+2,059*X₅.

Расчетные значения k приведены в таблице 5.

Используя данные табл. 5 значений к и задав медиану для X₂ или X_3, можно вычислить минимальные значения стоимостей, зависящих от статуса, при которых больные будут живы с вероятностью 0,5 (т.е. 50%)

Возможны два варианта вычисления:

1. Задается медиана X₂ (медиана стоимости трансфузиологического пособия в сутки при известных клинических параметрах), а второй параметр вычисляется как

2. Задается медиана X₃ (т.е. медиана общей стоимости препаратов), а второй параметр вычисляется как

Таким образом, была получена модель расчета минимально допустимой стоимости предикторов имевших неслучайное воздействие на исход проведение ТГСК при котором вероятность наступления положительного исхода равна 50%. Подсчет минимальной общей стоимости ТГСК, при которой возможно достижение 50% выживаемости, становится возможным при подстановке полученных данных в выражение (1).

Обсуждение

Трансплантация гемопоэтических стволовых клеток относится к высокотехнологичным методам лечения. Это подразумевает необходимость значительных финансовых затрат, связанных с ее проведением в соответствии с требованиями международных стандартов (good medical practice-GMP, EBMT).

Стоимость алло-ТГСК по литературным данным может составлять от 100 000 до 250 000 долларов США [4-9]; расхождения в стоимости связаны с особенностями   проведения ТГСК в различных странах с учетом их экономических факторов, стоимости оплаты труда, стоимости медикаментов и т.п. В работе M. van Agthoven et al. (2002) [10] прослежены результаты алло-ТГСК у больных острыми лейкозаи (ОМЛ и ОЛЛ) за 2 года. У выживших пациентов стоимость аллоТКМ от HLA-совместимого родственного донора составила 103 509 евро, аллоТПСКК – 105 906 евро. Стоимость алло-ТГСК от неродственного донора была равна 173 587 евро, причем 1/3 этой суммы приходится на поиск донора.

По данным зарубежных авторов, наибольшую долю общих госпитальных затрат при ТГСК составляют расходы на лекарственные препараты (38,9%);

33,7% общих госпитальных затрат – расходы на пребывание больного в стационаре;
7,5% - трансфузиологическое пособие;
5,8% - лабораторно-диагностические исследования;
5,6% - микробиологические исследования;
1,4% - радиология;
1,9% составляют другие расходы [11].

В нашей работе представленные составляющие стоимости были проанализированы на предмет статистически достоверного влияния на летальность после ТГСК и включены в предложенную модель прогностическую модель оценки стоимости, при которой возможно достижение 50% выживаемости.

Несмотря на важность рассматриваемого вопроса, а также лимитирующее воздействие высокой стоимости ТГСК на широкое внедрение этого метода в некоторых странах, в настоящий момент не существует метода анализа достоверно обосновывающего стоимость его стоимость, тем более не существует способов прогнозировать влияние затраченных денег на исход заболевания.

В связи с вышеизложенным, представленный способ статистически обоснованной оценки стоимости ТГСК, позволяющий связать имеющиеся клинические параметры, влияющие на стоимость лечения, а также прогнозировать минимально возможную стоимость ТГСК, при которой достигается 50%-ный положительный эффект, может быть предложен для оценки необходимого финансирования данного вида лечения.

Литература

1. Дубно П.Ю. Обработка статистической информации с помощью SPSS. - М.: ООО «Издательство АСТ»: «НТ Пресс», 2004, 221 с.

2. Наследов А.Д. Компьютерный анализ данных в психологии и социальных науках. – СПб.: Питер, 2005, 416 с.

3. Флетчер Р., Флетчер С., Вагнер Э. Клиническая эпидемиология. Основы доказательной медицины. (перевод с англ.). Москва: Медиа-Сфера. 1998. – 352 с.

4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol., 1984, 7 (3): 273-278.

5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol., 1996, 14(5): 1413-1420.

6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J., 1991, 104 (916): 303-305.

7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission. Bone Marrow Transplant., 1992, 10(4):323-329.

8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic transplantation. Bone Marrow Transplant., 1998, 21 (Suppl.3): S92-S98.

9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a chidren’s hospital. Bone Marrow Transplant., 1998, 21:195-203.

10. van Agthoven M., Groot M.T., Verdonck L.F. et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant., 2002, 30(4):243-251.11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med., 1989, 321(12): 807-812. 

11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812.

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Dmitry A. Bagge, Boris I. Smirnov, Boris V. Afanasyev

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Dmitry A. Bagge, Boris I. Smirnov, Boris V. Afanasyev

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The logistic regression model allows the calculation of the minimal acceptable cost of HCT, having non-random impact on HCT outcome, under which the probability of a positive outcome is 50%. There were 209 patients enrolled in the study, who received autologous HCT, and allogenic related and unrelated HCT. The non-random cost and medical parameters connected with patient status were defined before HCT and HCT outcomes. The application of reduced toxicity (RTCR) or myeloablative conditioning regimens (MCR), the presence of relapse before HCT, and the cost of drugs and blood transfusion all have an influence on the outcome, and the weight coefficients of these parameters were calculated. This allows the connection of costs and clinical parameters, and the calculation of the minimal acceptable cost of HCT.

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The logistic regression model allows the calculation of the minimal acceptable cost of HCT, having non-random impact on HCT outcome, under which the probability of a positive outcome is 50%. There were 209 patients enrolled in the study, who received autologous HCT, and allogenic related and unrelated HCT. The non-random cost and medical parameters connected with patient status were defined before HCT and HCT outcomes. The application of reduced toxicity (RTCR) or myeloablative conditioning regimens (MCR), the presence of relapse before HCT, and the cost of drugs and blood transfusion all have an influence on the outcome, and the weight coefficients of these parameters were calculated. This allows the connection of costs and clinical parameters, and the calculation of the minimal acceptable cost of HCT.

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R. M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, and St. Petersburg State Medical I. Pavlov University, Russia

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R. M. Gorbacheva Memorial Institute of Children Hematology and Transplantation, and St. Petersburg State Medical I. Pavlov University, Russia

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В исследование вошли 209 пациентов перенесших аутологичную, аллогенную родственную и неродственную ТГСК. Было определено неслучайное влияние на исход ТГСК параметров стоимости и различных медицинских факторов, в том числе возраста и пола пациента, типа донора (родственный/неродственный), источника стволовых клеток (из костного мозга или периферической крови). В стоимость процедуры ТГСК включались расходы на пребывание больного в стационаре (число койко-дней), стоимость лабораторного обследования, расходы на кондиционирующую терапию, стоимость лекарственных препаратов в посттрансплантационном периоде, расходы на аферез и заготовку костного мозга или периферических стволовых клеток, а также стоимость поиска донора (при неродственных ТГСК). Применение режимов кондиционирования со сниженной интенсивностью дозы и миелоаблативных режимов, наличие или отсутствие рецидива, а также стоимость медикаментов и трансфузиологического пособия статистически значимо влияли на исход ТГСК, что позволило рассчитать весовые коэффициенты и связать показатели стоимости и клинические параметры. Это дает возможность рассчитать минимально допустимую стоимость ТГСК.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2433) "

Модель логистической регрессии позволяет рассчитать минимально допустимую стоимость ТГСК, при которой возможно достижение 50% положительного эффекта. В исследование вошли 209 пациентов перенесших аутологичную, аллогенную родственную и неродственную ТГСК. Было определено неслучайное влияние на исход ТГСК параметров стоимости и различных медицинских факторов, в том числе возраста и пола пациента, типа донора (родственный/неродственный), источника стволовых клеток (из костного мозга или периферической крови). В стоимость процедуры ТГСК включались расходы на пребывание больного в стационаре (число койко-дней), стоимость лабораторного обследования, расходы на кондиционирующую терапию, стоимость лекарственных препаратов в посттрансплантационном периоде, расходы на аферез и заготовку костного мозга или периферических стволовых клеток, а также стоимость поиска донора (при неродственных ТГСК). Применение режимов кондиционирования со сниженной интенсивностью дозы и миелоаблативных режимов, наличие или отсутствие рецидива, а также стоимость медикаментов и трансфузиологического пособия статистически значимо влияли на исход ТГСК, что позволило рассчитать весовые коэффициенты и связать показатели стоимости и клинические параметры. Это дает возможность рассчитать минимально допустимую стоимость ТГСК.

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Модель логистической регрессии позволяет рассчитать минимально допустимую стоимость ТГСК, при которой возможно достижение 50% положительного эффекта. В исследование вошли 209 пациентов перенесших аутологичную, аллогенную родственную и неродственную ТГСК. Было определено неслучайное влияние на исход ТГСК параметров стоимости и различных медицинских факторов, в том числе возраста и пола пациента, типа донора (родственный/неродственный), источника стволовых клеток (из костного мозга или периферической крови). В стоимость процедуры ТГСК включались расходы на пребывание больного в стационаре (число койко-дней), стоимость лабораторного обследования, расходы на кондиционирующую терапию, стоимость лекарственных препаратов в посттрансплантационном периоде, расходы на аферез и заготовку костного мозга или периферических стволовых клеток, а также стоимость поиска донора (при неродственных ТГСК). Применение режимов кондиционирования со сниженной интенсивностью дозы и миелоаблативных режимов, наличие или отсутствие рецидива, а также стоимость медикаментов и трансфузиологического пособия статистически значимо влияли на исход ТГСК, что позволило рассчитать весовые коэффициенты и связать показатели стоимости и клинические параметры. Это дает возможность рассчитать минимально допустимую стоимость ТГСК.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10290" ["VALUE"]=> array(2) { ["TEXT"]=> string(390) "<p>Институт гематологии и трансплантологии им. Р. М. Горбачевой и кафедра гематологии, трансфузиологии и трансплантологии Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(378) "

Институт гематологии и трансплантологии им. Р. М. Горбачевой и кафедра гематологии, трансфузиологии и трансплантологии Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(378) "

Институт гематологии и трансплантологии им. Р. М. Горбачевой и кафедра гематологии, трансфузиологии и трансплантологии Санкт-Петербургского государственного медицинского Университета им. И. П. Павлова

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10316" ["VALUE"]=> array(2) { ["TEXT"]=> string(36216) "<h3>Введение</h3> <p class="bodytext"> Главным основополагающим критерием выбора того или иного вида лечения в медицине должна являться эффективность его воздействия на возникшее заболевание. Руководствуясь этим принципом, следует подходить к лечению пациента, независимо от того, насколько дорогостоящим окажется самый эффективный при данном виде заболевания способ лечения. Однако, часто необоснованно высокая стоимость при однозначно не доказанной клинической эффективности того или иного вида лечения ставит под сомнение применение и дальнейшее развитие, а также государственное финансирование этих методов. </p> <p class="bodytext"> В соответствии с этим, в данной работе ставится задача найти обоснованные методы оценки стоимости лечения ТГСК. </p> <h3>Материал и методы исследования</h3> <p class="bodytext"> Исследование проводилось на группе из 209 пациентов, перенесших аутологичную ТГСК, аллогенную родственную и неродственную ТГСК с 1998 по 2005 год. Группа состояла из 91 (43,5%) пациента в возрасте от 1 до 66 лет, подвергшихся аллоТГСК, из  них  у 57 пациентов - от неродственного донора, у 34 пациентов от родственного донора, а 118 (56,5%) пациентов перенесли аутоТГСК.<br> <br> На основании клинических историй болезни проводили анализ эффективности лечения и анализ стоимости лечения вышеуказанных пациентов. Клиническую эффективность оценивали по результатам общей выживаемости за двухлетний период. Проводили оценку общей стоимости, а также различных составляющих стоимости лечения при аутологичной и аллогенной, родственной и неродственной ТГСК, оценку стоимости  аллоТГСК при миелоаблативных и немиелоаблативнных режимах кондиционирования; отдельно определяли стоимость осложненной ТГСК, и ТГСК протекавшей с/без осложнений.<strong> </strong>В работе сделана попытка выявить статистически обоснованные клинические и стоимостные показатели, влияющие на эффективность применения ТГСК. Полученные результаты были проанализированы с применением методов параметрической и непараметрической статистики, проведен регрессионный анализ полученных данных [1-3]. </p> <h3>Результаты исследования</h3> <p class="bodytext"> В результате анализа данных было предложено выражение общей стоимости ТГСК. Выражение общей стоимости ТГСК выглядит следующим образом: </p> <p> <img width="570" alt="2008-1-ru-Bagge-Formula-1-72dpi-814px.jpg" src="/upload/medialibrary/0f4/2008_1_ru_bagge_formula_1_72dpi_814px.jpg" height="62" title="2008-1-ru-Bagge-Formula-1-72dpi-814px.jpg"><br> </p> <p class="bodytext"> C_обс – стоимость лабораторного обследования, которое проводится при нахождении пациента в клинике. Величина, зависящая от характера заболевания и продолжительности нахождения пациента в стационаре. </p> <p class="bodytext"> С_к/д – стоимость нахождения пациента в условиях стационара в течение 1-го к/д. Это величина - фиксированная и рассчитывается статистическими отделами стационаров. </p> <p class="bodytext"> N_сут –длительность нахождения пациента в стационаре. Эта величина, будет зависеть от тяжести заболевания и наличия осложнений. </p> <p class="bodytext"> С_трансф – стоимость трансфузиологического пособия в сутки. Эта величина, также зависит от тяжести заболевания и наличия осложнений требующих гемотрансфузий. </p> <p class="bodytext"> С_конд – стоимость режима кондиционирования.  </p> <p class="bodytext"> С_конд – величина - фиксированная. </p> <p class="bodytext"> С_препар – стоимость  медикаментов в сутки. Зависит от тяжести течения заболевания. </p> <p class="bodytext"> С_инфуз – стоимость заготовки и инфузии КМ или ПСК. Величина фиксированная. </p> <p class="bodytext"> С_{поиск донора}– стоимость следует учитывать только при неродственной аллогенной ТГСК, соответствует стоимости поиска в международном регистре доноров. </p> <p class="bodytext"> Перед построением модели, которая может быть представлена как функция от клинических, стоимостных и других параметров, целесообразно выполнить разведочный статистический анализ. Целью данного анализа было выявление статистически достоверного влияния на исход заболевания следующих характеристик: пол пациента, диагноз, вид ТГСК, пол донора, использование в качестве трансплантата КМ или ПСКК, наличие рецидива или прогрессии, наличие осложнений в общем, и в частности - инфекционных, требующих гемотрансфузий, режима кондиционирования, возраста при ТГСК, наличия РТПХ. В зависимости от характера клинических характеристик были использованы методы анализа непрерывных и категориальных переменных. </p> <p class="bodytext"> На первом этапе был проведен анализ неслучайного различия центральных тенденций непрерывных переменных выражения (1). В табл. 1  приведены непрерывные параметры, которые выявили значимое различие в группах, сформированных по значению статуса пациента. </p> <p> <img width="614" alt="2008-1-ru-Bagge-Fig1.jpg" src="/upload/medialibrary/ba8/2008_1_ru_bagge_fig1.jpg" height="151" title="2008-1-ru-Bagge-Fig1.jpg"><br> </p> <p class="bodytext"> Далее были проанализированы клинические непрерывные и категориальные параметры влияющие на эффективность ТГСК. Статистически значимое влияние на исход ТГСК оказывали: </p> <p class="bodytext"> • вид ТГСК – аутологичная или аллогенная (р=0,002),<br> • наличие рецидива или прогрессии (р=0,048),<br> • наличие трансфузиологических осложнений (р=0,003),<br> • вид режима кондиционирования – миело или немиелоаблативный (р=0,023). </p> <p class="bodytext"> Выполненный разведочный анализ позволяет сформировать группу непрерывных и категориальных переменных, которые могут быть использованы в качестве предикторов при построении регрессионной модели статуса пациента в зависимости от клинических и стоимостных параметров. </p> <p class="bodytext"> Построение регрессионной модели с зависимой переменной, имеющей вид дихотомической категориальной переменной и независимыми переменными, представленными, приводит к необходимости использовать логистическую регрессию. Логистическая регрессия связывает вероятность наступления события (одного из событий переменной исход заболевания) с независимыми переменными (предикторами), влияние которых на независимую переменную выявлено в предыдущем разделе. Поскольку зависимая переменная оценивается вероятностной мерой, а независимые переменные включают категориальные и непрерывные параметры, необходимо выполнить функциональное преобразование независимых переменных к интервалу 0 – 1. Указанное функциональное преобразование выполняется функцией (2). </p> <p> <img width="215" alt="2008-1-ru-Bagge-Formula-2-72dpi-307px.jpg" src="/upload/medialibrary/682/2008_1_ru_bagge_formula_2_72dpi_307px.jpg" height="95" title="2008-1-ru-Bagge-Formula-2-72dpi-307px.jpg"><br> </p> <p class="bodytext"> которая называется логистической, с параметром <em>Z</em>.  </p> <p class="bodytext"> Параметр Z=<em>B</em>₁<em>X</em>₁+<em>B</em>₂<em>X</em>₂+<em>B</em>₃<em>X</em>₃+<em>B</em>₄<em>X</em>₄+<em>B</em><em>₅X</em><em>₅</em> связывает независимые переменные (предикторы). </p> <p class="bodytext"> Процедура построения логистической регрессии включает, как и обычная регрессия, три основные этапа:<br> • Получение модели логистической регрессии,<br> • Оценка значимостей полученных весовых коэффициентов уравнения (<em>B</em>₁, <em>B</em>₂, <em>B</em>₃, <em>B</em>₅),<br> • Определение устойчивости модели. </p> <p class="bodytext"> С помощью статистического пакета SPSS, используя пошаговые варианты логистической регрессии на включение и исключение параметров из модели и применение критерия Вальда была получена модель со следующими параметрами (Табл. 2). </p> <p> <img width="602" alt="2008-1-ru-Bagge-Table-2-72dpi-1003px-unsharp.jpg" src="/upload/medialibrary/cde/2008_1_ru_bagge_table_2_72dpi_1003px_unsharp.jpg" height="288" title="2008-1-ru-Bagge-Table-2-72dpi-1003px-unsharp.jpg"><br> </p> <p class="bodytext"> В соответствии с выражением (2) параметр </p> <p> <img width="650" alt="2008-1-ru-Bagge-Formula-3-72dpi-928px.jpg" src="/upload/medialibrary/f74/2008_1_ru_bagge_formula_3_72dpi_928px.jpg" height="61" title="2008-1-ru-Bagge-Formula-3-72dpi-928px.jpg"><br> </p> <p class="bodytext"> В выражение (3) входят: </p> <p class="bodytext"> <em>X</em>₁ – общая стоимость трансфузиологического пособия </p> <p class="bodytext"> <em>X</em>₂ - стоимость трансфузиологического пособия в сутки. </p> <p class="bodytext"> <em>X</em>₃ – стоимость медикаментов. </p> <p class="bodytext"> <em>X</em>₄– режим кондиционирования </p> <p class="bodytext"> <em>   X</em>₄=0 при немиелоаблативном режиме кондиционирования, </p> <p class="bodytext"> <em>   X</em>₄=1 при миелоаблативном режиме кондиционирования, </p> <p class="bodytext"> <em>X</em>₅ – рецидив перед ТГСК </p> <p class="bodytext"> <em>   X</em>₅=0 при отсутствии рецидива перед ТГСК, </p> <p class="bodytext"> <em>   X</em>₅=1 при наличии рецидива. </p> <p class="bodytext"> В связи с тем, что общая стоимость трансфузиологического пособия получена путем умножения стоимости трансфузиологического пособия в сутки на количество койко-дней, X₁=X₂*N_сут. Тогда выражение (3) принимает вид: </p> <p> <img width="694" alt="2008-1-ru-Bagge-Formula-4-72dpi-991px.jpg" src="/upload/medialibrary/b44/2008_1_ru_bagge_formula_4_72dpi_991px.jpg" height="63" title="2008-1-ru-Bagge-Formula-4-72dpi-991px.jpg"><br> </p> <p class="bodytext"> Как видно из табл. 2, модель обладает неслучайными параметрами, значимости которых p&lt;=0,05. </p> <p class="bodytext"> Качество прогноза статуса пациента может быть оценено с помощью таблицы классификации предсказания (см. табл. 3) </p> <p> <img width="473" alt="2008-1-ru-Bagge-Table-3-72dpi-788px.jpg" src="/upload/medialibrary/007/2008_1_ru_bagge_table_3_72dpi_788px.jpg" height="199" title="2008-1-ru-Bagge-Table-3-72dpi-788px.jpg"><br> </p> <p class="bodytext"> Значения табл. 3. характеризуют мощность теста (вероятность предсказания состояния «Жив» при наблюдаемом состоянии «Жив») и специфичность теста (вероятность предсказания «Умер» при  наблюдаемом состоянии «Умер»). Как видно из табл. 3 мощность  прогноза составляет 93,5%, а специфичность - 63,6%. При этом вероятность правильного прогноза составляет 81,1%. </p> <p class="bodytext"> Устойчивость полученной модели необходимо проверить на другой выборке, однако таких данных нет, поэтому прикладная статистика рекомендует выполнить повторный анализ, используя для построения модели только часть данных, другую часть использовать для проверки валидности построенной модели. Так поступили и в этом случае. </p> <p class="bodytext"> Весь массив данных был случайным образом с использованием распределения Бернулли разделен на две части. В первую (отобранные наблюдения) помещено примерно 70% данных, а во вторую (неотобранные наблюдения) - остальные. Первая выборка была использована в процедуре логистической регрессии для построения модели, а вторая – для проверки ее валидности. Модель была получена с такими же параметрами, как описано выше, а устойчивость ее подтверждена с помощью таблицы классификации (табл. 4), построенной раздельно для двух выборок. </p> <p> <img width="610" alt="2008-1-ru-Bagge-Table-4-72dpi-1016px.jpg" src="/upload/medialibrary/fce/2008_1_ru_bagge_table_4_72dpi_1016px.jpg" height="272" title="2008-1-ru-Bagge-Table-4-72dpi-1016px.jpg"><br> </p> <p class="bodytext"> Как видно из табл. 4, мощность и специфичность в выборках «отобранные значения» и «неотобранные значения» имеют различные величины. Эти различия обусловлены случайными вариациями. Отсутствие неслучайности различий может быть оценено с помощью теста Фишера, который в данном случае: </p> <p class="bodytext">   Для наблюдения «Жив» дает вероятность p = 0,1594, </p> <p class="bodytext">   Для наблюдения «Умер» дает вероятность p = 0,7081. </p> <p class="bodytext"> Обе вероятности говорят об отсутствии различий в столбцах классификационной таблицы, т.е. об отсутствии различия в диагносте двух выборок, первой, по которой строилась модель и второй, по которой она проверялась. </p> <p class="bodytext"> Выполненный в предыдущих разделах анализ выявил параметры зависящие от исхода заболевания и не зависящие от него. </p> <p class="bodytext"> Если параметры не связаны со статусом пациента, для их характеристики следует воспользоваться центральными тенденциями, полученными в результате общего анализа исследуемых предикторов представленных в выражении (1). Ввиду ненормальности распределений рассматриваемых случайных величин такой центральной тенденцией может выступить медиана. </p> <p class="bodytext"> Значения параметров, связанных со статусом, следует получить из регрессионной модели. Логистическая функция (2) принимает значение 0,5 при <em>Z</em>=0. Это значение соответствует ситуации, когда статус пациента определяется с вероятностью 0,5. Для получения более определенного прогноза должно выполняться условие Z&gt;0 или Z&lt;0 в зависимости от искомого значения статуса. </p> <p class="bodytext"> Примем Z=0 как значение для поиска минимальных затрат на ТГСК. Тогда из выражения (4) получим: </p> <p> <img width="676" alt="2008-1-ru-Bagge-Formula-5-72dpi-969px-corr.jpg" src="/upload/medialibrary/d46/2008_1_ru_bagge_formula_5_72dpi_969px_corr.jpg" height="65" title="2008-1-ru-Bagge-Formula-5-72dpi-969px-corr.jpg"><br> </p> <p class="bodytext"> В левой части уравнения находятся стоимостные параметры, а в правой клинические. </p> <p class="bodytext"> Для различных вариантов терапии (k), которые задаются правой частью уравнения (5) можно вычислить весовые значения, задаваемые уравнением: </p> <p class="bodytext"> <em>k</em>= 2,159*<em>X</em>₄+2,059*<em>X</em>₅. </p> <p class="bodytext"> Расчетные значения<em> </em><em>k</em> приведены в таблице 5. </p> <p> <img width="478" alt="2008-1-ru-Bagge-Table-5-72dpi-797px.jpg" src="/upload/medialibrary/e7e/2008_1_ru_bagge_table_5_72dpi_797px.jpg" height="263" title="2008-1-ru-Bagge-Table-5-72dpi-797px.jpg"><br> </p> <p class="bodytext"> Используя данные табл. 5 значений <em>к</em> и задав медиану для X₂ или X_3, можно вычислить минимальные значения стоимостей, зависящих от статуса, при которых больные будут живы с вероятностью 0,5 (т.е. 50%) </p> <p class="bodytext"> Возможны два варианта вычисления: </p> <p class="bodytext"> 1. Задается медиана X₂ (медиана стоимости трансфузиологического пособия в сутки при известных клинических параметрах), а второй параметр вычисляется как </p> <p> <img width="337" alt="2008-1-ru-Bagge-Calculation-1-72dpi-481px.jpg" src="/upload/medialibrary/8b6/2008_1_ru_bagge_calculation_1_72dpi_481px.jpg" height="99" title="2008-1-ru-Bagge-Calculation-1-72dpi-481px.jpg"><br> </p> <p class="bodytext"> 2. Задается медиана X₃ (т.е. медиана общей стоимости препаратов), а второй параметр вычисляется как </p> <p> <img width="261" alt="2008-1-ru-Bagge-Calculation-2-72dpi-373px.jpg" src="/upload/medialibrary/c17/2008_1_ru_bagge_calculation_2_72dpi_373px.jpg" height="97" title="2008-1-ru-Bagge-Calculation-2-72dpi-373px.jpg"><br> </p> <p class="bodytext">Таким образом, была получена модель расчета минимально допустимой стоимости предикторов имевших неслучайное воздействие на исход проведение ТГСК при котором вероятность наступления положительного исхода равна 50%. Подсчет минимальной общей стоимости ТГСК, при которой возможно достижение 50% выживаемости, становится возможным при подстановке полученных данных в выражение (1). </p> <h3>Обсуждение</h3> <p class="bodytext">Трансплантация гемопоэтических стволовых клеток относится к высокотехнологичным методам лечения. Это подразумевает необходимость значительных финансовых затрат, связанных с ее проведением в соответствии с требованиями международных стандартов (good medical practice-GMP, EBMT). </p> <p class="bodytext">Стоимость алло-ТГСК по литературным данным может составлять от 100 000 до 250 000 долларов США [4-9]; расхождения в стоимости связаны с особенностями   проведения ТГСК в различных странах с учетом их экономических факторов, стоимости оплаты труда, стоимости медикаментов и т.п. В работе M. van Agthoven et al. (2002) [<a href="1-1-bagge-etal-2008may28.html?&amp;L=1#c302" title="Внутренняя ссылка открывается в текущем окне" class="internal-link">10</a>] прослежены результаты алло-ТГСК у больных острыми лейкозаи (ОМЛ и ОЛЛ) за 2 года. У выживших пациентов стоимость аллоТКМ от HLA-совместимого родственного донора составила 103 509 евро, аллоТПСКК – 105 906 евро. Стоимость алло-ТГСК от неродственного донора была равна 173 587 евро, причем 1/3 этой суммы приходится на поиск донора. </p> <p class="bodytext">По данным зарубежных авторов, наибольшую долю общих госпитальных затрат при ТГСК составляют расходы на лекарственные препараты (38,9%); </p> <p class="bodytext">33,7% общих госпитальных затрат – расходы на пребывание больного в стационаре;<br />7,5% - трансфузиологическое пособие; <br />5,8% - лабораторно-диагностические исследования;<br />5,6% - микробиологические исследования;<br />1,4% - радиология; <br />1,9% составляют другие расходы [11]. <br /><br />В нашей работе представленные составляющие стоимости были проанализированы на предмет статистически достоверного влияния на летальность после ТГСК и включены в предложенную модель прогностическую модель оценки стоимости, при которой возможно достижение 50% выживаемости. </p> <p class="bodytext">Несмотря на важность рассматриваемого вопроса, а также лимитирующее воздействие высокой стоимости ТГСК на широкое внедрение этого метода в некоторых странах, в настоящий момент не существует метода анализа достоверно обосновывающего стоимость его стоимость, тем более не существует способов прогнозировать влияние затраченных денег на исход заболевания. </p> <p class="bodytext">В связи с вышеизложенным, представленный способ статистически обоснованной оценки стоимости ТГСК, позволяющий связать имеющиеся клинические параметры, влияющие на стоимость лечения, а также прогнозировать минимально возможную стоимость ТГСК, при которой достигается 50%-ный положительный эффект, может быть предложен для оценки необходимого финансирования данного вида лечения.</p> <h3>Литература</h3> <p class="bodytext">1. Дубно П.Ю. Обработка статистической информации с помощью SPSS. - М.: ООО «Издательство АСТ»: «НТ Пресс», 2004, 221 с. </p> <p class="bodytext">2. Наследов А.Д. Компьютерный анализ данных в психологии и социальных науках. – СПб.: Питер, 2005, 416 с. </p> <p class="bodytext">3. Флетчер Р., Флетчер С., Вагнер Э. Клиническая эпидемиология. Основы доказательной медицины. (перевод с англ.). Москва: Медиа-Сфера. 1998. – 352 с.</p> <p class="bodytext">4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol., 1984, 7 (3): 273-278. </p> <p class="bodytext">5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol., 1996, 14(5): 1413-1420. </p> <p class="bodytext">6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J., 1991, 104 (916): 303-305. </p> <p class="bodytext">7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission. Bone Marrow Transplant., 1992, 10(4):323-329. </p> <p class="bodytext">8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic transplantation. Bone Marrow Transplant., 1998, 21 (Suppl.3): S92-S98. </p> <p class="bodytext">9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a chidren’s hospital. Bone Marrow Transplant., 1998, 21:195-203.</p> <p class="bodytext">10. van Agthoven M., Groot M.T., Verdonck L.F. et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant., 2002, 30(4):243-251.11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med., 1989, 321(12): 807-812.  </p> <p class="bodytext"> 11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(32592) "

Введение

Главным основополагающим критерием выбора того или иного вида лечения в медицине должна являться эффективность его воздействия на возникшее заболевание. Руководствуясь этим принципом, следует подходить к лечению пациента, независимо от того, насколько дорогостоящим окажется самый эффективный при данном виде заболевания способ лечения. Однако, часто необоснованно высокая стоимость при однозначно не доказанной клинической эффективности того или иного вида лечения ставит под сомнение применение и дальнейшее развитие, а также государственное финансирование этих методов.

В соответствии с этим, в данной работе ставится задача найти обоснованные методы оценки стоимости лечения ТГСК.

Материал и методы исследования

Исследование проводилось на группе из 209 пациентов, перенесших аутологичную ТГСК, аллогенную родственную и неродственную ТГСК с 1998 по 2005 год. Группа состояла из 91 (43,5%) пациента в возрасте от 1 до 66 лет, подвергшихся аллоТГСК, из  них  у 57 пациентов - от неродственного донора, у 34 пациентов от родственного донора, а 118 (56,5%) пациентов перенесли аутоТГСК.

На основании клинических историй болезни проводили анализ эффективности лечения и анализ стоимости лечения вышеуказанных пациентов. Клиническую эффективность оценивали по результатам общей выживаемости за двухлетний период. Проводили оценку общей стоимости, а также различных составляющих стоимости лечения при аутологичной и аллогенной, родственной и неродственной ТГСК, оценку стоимости  аллоТГСК при миелоаблативных и немиелоаблативнных режимах кондиционирования; отдельно определяли стоимость осложненной ТГСК, и ТГСК протекавшей с/без осложнений. В работе сделана попытка выявить статистически обоснованные клинические и стоимостные показатели, влияющие на эффективность применения ТГСК. Полученные результаты были проанализированы с применением методов параметрической и непараметрической статистики, проведен регрессионный анализ полученных данных [1-3].

Результаты исследования

В результате анализа данных было предложено выражение общей стоимости ТГСК. Выражение общей стоимости ТГСК выглядит следующим образом:

C_обс – стоимость лабораторного обследования, которое проводится при нахождении пациента в клинике. Величина, зависящая от характера заболевания и продолжительности нахождения пациента в стационаре.

С_к/д – стоимость нахождения пациента в условиях стационара в течение 1-го к/д. Это величина - фиксированная и рассчитывается статистическими отделами стационаров.

N_сут – длительность нахождения пациента в стационаре. Эта величина, будет зависеть от тяжести заболевания и наличия осложнений.

С_трансф – стоимость трансфузиологического пособия в сутки. Эта величина, также зависит от тяжести заболевания и наличия осложнений требующих гемотрансфузий.

С_конд – стоимость режима кондиционирования. 

С_конд – величина - фиксированная.

С_препар – стоимость  медикаментов в сутки. Зависит от тяжести течения заболевания.

С_инфуз – стоимость заготовки и инфузии КМ или ПСК. Величина фиксированная.

С_{поиск донора} – стоимость следует учитывать только при неродственной аллогенной ТГСК, соответствует стоимости поиска в международном регистре доноров.

Перед построением модели, которая может быть представлена как функция от клинических, стоимостных и других параметров, целесообразно выполнить разведочный статистический анализ. Целью данного анализа было выявление статистически достоверного влияния на исход заболевания следующих характеристик: пол пациента, диагноз, вид ТГСК, пол донора, использование в качестве трансплантата КМ или ПСКК, наличие рецидива или прогрессии, наличие осложнений в общем, и в частности - инфекционных, требующих гемотрансфузий, режима кондиционирования, возраста при ТГСК, наличия РТПХ. В зависимости от характера клинических характеристик были использованы методы анализа непрерывных и категориальных переменных.

На первом этапе был проведен анализ неслучайного различия центральных тенденций непрерывных переменных выражения (1). В табл. 1  приведены непрерывные параметры, которые выявили значимое различие в группах, сформированных по значению статуса пациента.

Далее были проанализированы клинические непрерывные и категориальные параметры влияющие на эффективность ТГСК. Статистически значимое влияние на исход ТГСК оказывали:

• вид ТГСК – аутологичная или аллогенная (р=0,002),
• наличие рецидива или прогрессии (р=0,048),
• наличие трансфузиологических осложнений (р=0,003),
• вид режима кондиционирования – миело или немиелоаблативный (р=0,023).

Выполненный разведочный анализ позволяет сформировать группу непрерывных и категориальных переменных, которые могут быть использованы в качестве предикторов при построении регрессионной модели статуса пациента в зависимости от клинических и стоимостных параметров.

Построение регрессионной модели с зависимой переменной, имеющей вид дихотомической категориальной переменной и независимыми переменными, представленными, приводит к необходимости использовать логистическую регрессию. Логистическая регрессия связывает вероятность наступления события (одного из событий переменной исход заболевания) с независимыми переменными (предикторами), влияние которых на независимую переменную выявлено в предыдущем разделе. Поскольку зависимая переменная оценивается вероятностной мерой, а независимые переменные включают категориальные и непрерывные параметры, необходимо выполнить функциональное преобразование независимых переменных к интервалу 0 – 1. Указанное функциональное преобразование выполняется функцией (2).

которая называется логистической, с параметром Z. 

Параметр Z=B₁X₁+B₂X₂+B₃X₃+B₄X₄+B₅X₅ связывает независимые переменные (предикторы).

Процедура построения логистической регрессии включает, как и обычная регрессия, три основные этапа:
• Получение модели логистической регрессии,
• Оценка значимостей полученных весовых коэффициентов уравнения (B₁, B₂, B₃, B₅),
• Определение устойчивости модели.

С помощью статистического пакета SPSS, используя пошаговые варианты логистической регрессии на включение и исключение параметров из модели и применение критерия Вальда была получена модель со следующими параметрами (Табл. 2).

В соответствии с выражением (2) параметр

В выражение (3) входят:

X₁ – общая стоимость трансфузиологического пособия

X₂ - стоимость трансфузиологического пособия в сутки.

X₃ – стоимость медикаментов.

X₄ – режим кондиционирования

   X₄=0 при немиелоаблативном режиме кондиционирования,

   X₄=1 при миелоаблативном режиме кондиционирования,

X₅ – рецидив перед ТГСК

   X₅=0 при отсутствии рецидива перед ТГСК,

   X₅=1 при наличии рецидива.

В связи с тем, что общая стоимость трансфузиологического пособия получена путем умножения стоимости трансфузиологического пособия в сутки на количество койко-дней, X₁=X₂*N_сут. Тогда выражение (3) принимает вид:

Как видно из табл. 2, модель обладает неслучайными параметрами, значимости которых p<=0,05.

Качество прогноза статуса пациента может быть оценено с помощью таблицы классификации предсказания (см. табл. 3)

Значения табл. 3. характеризуют мощность теста (вероятность предсказания состояния «Жив» при наблюдаемом состоянии «Жив») и специфичность теста (вероятность предсказания «Умер» при  наблюдаемом состоянии «Умер»). Как видно из табл. 3 мощность  прогноза составляет 93,5%, а специфичность - 63,6%. При этом вероятность правильного прогноза составляет 81,1%.

Устойчивость полученной модели необходимо проверить на другой выборке, однако таких данных нет, поэтому прикладная статистика рекомендует выполнить повторный анализ, используя для построения модели только часть данных, другую часть использовать для проверки валидности построенной модели. Так поступили и в этом случае.

Весь массив данных был случайным образом с использованием распределения Бернулли разделен на две части. В первую (отобранные наблюдения) помещено примерно 70% данных, а во вторую (неотобранные наблюдения) - остальные. Первая выборка была использована в процедуре логистической регрессии для построения модели, а вторая – для проверки ее валидности. Модель была получена с такими же параметрами, как описано выше, а устойчивость ее подтверждена с помощью таблицы классификации (табл. 4), построенной раздельно для двух выборок.

Как видно из табл. 4, мощность и специфичность в выборках «отобранные значения» и «неотобранные значения» имеют различные величины. Эти различия обусловлены случайными вариациями. Отсутствие неслучайности различий может быть оценено с помощью теста Фишера, который в данном случае:

  Для наблюдения «Жив» дает вероятность p = 0,1594,

  Для наблюдения «Умер» дает вероятность p = 0,7081.

Обе вероятности говорят об отсутствии различий в столбцах классификационной таблицы, т.е. об отсутствии различия в диагносте двух выборок, первой, по которой строилась модель и второй, по которой она проверялась.

Выполненный в предыдущих разделах анализ выявил параметры зависящие от исхода заболевания и не зависящие от него.

Если параметры не связаны со статусом пациента, для их характеристики следует воспользоваться центральными тенденциями, полученными в результате общего анализа исследуемых предикторов представленных в выражении (1). Ввиду ненормальности распределений рассматриваемых случайных величин такой центральной тенденцией может выступить медиана.

Значения параметров, связанных со статусом, следует получить из регрессионной модели. Логистическая функция (2) принимает значение 0,5 при Z=0. Это значение соответствует ситуации, когда статус пациента определяется с вероятностью 0,5. Для получения более определенного прогноза должно выполняться условие Z>0 или Z<0 в зависимости от искомого значения статуса.

Примем Z=0 как значение для поиска минимальных затрат на ТГСК. Тогда из выражения (4) получим:

В левой части уравнения находятся стоимостные параметры, а в правой клинические.

Для различных вариантов терапии (k), которые задаются правой частью уравнения (5) можно вычислить весовые значения, задаваемые уравнением:

k= 2,159*X₄+2,059*X₅.

Расчетные значения k приведены в таблице 5.

Используя данные табл. 5 значений к и задав медиану для X₂ или X_3, можно вычислить минимальные значения стоимостей, зависящих от статуса, при которых больные будут живы с вероятностью 0,5 (т.е. 50%)

Возможны два варианта вычисления:

1. Задается медиана X₂ (медиана стоимости трансфузиологического пособия в сутки при известных клинических параметрах), а второй параметр вычисляется как

2. Задается медиана X₃ (т.е. медиана общей стоимости препаратов), а второй параметр вычисляется как

Таким образом, была получена модель расчета минимально допустимой стоимости предикторов имевших неслучайное воздействие на исход проведение ТГСК при котором вероятность наступления положительного исхода равна 50%. Подсчет минимальной общей стоимости ТГСК, при которой возможно достижение 50% выживаемости, становится возможным при подстановке полученных данных в выражение (1).

Обсуждение

Трансплантация гемопоэтических стволовых клеток относится к высокотехнологичным методам лечения. Это подразумевает необходимость значительных финансовых затрат, связанных с ее проведением в соответствии с требованиями международных стандартов (good medical practice-GMP, EBMT).

Стоимость алло-ТГСК по литературным данным может составлять от 100 000 до 250 000 долларов США [4-9]; расхождения в стоимости связаны с особенностями   проведения ТГСК в различных странах с учетом их экономических факторов, стоимости оплаты труда, стоимости медикаментов и т.п. В работе M. van Agthoven et al. (2002) [10] прослежены результаты алло-ТГСК у больных острыми лейкозаи (ОМЛ и ОЛЛ) за 2 года. У выживших пациентов стоимость аллоТКМ от HLA-совместимого родственного донора составила 103 509 евро, аллоТПСКК – 105 906 евро. Стоимость алло-ТГСК от неродственного донора была равна 173 587 евро, причем 1/3 этой суммы приходится на поиск донора.

По данным зарубежных авторов, наибольшую долю общих госпитальных затрат при ТГСК составляют расходы на лекарственные препараты (38,9%);

33,7% общих госпитальных затрат – расходы на пребывание больного в стационаре;
7,5% - трансфузиологическое пособие;
5,8% - лабораторно-диагностические исследования;
5,6% - микробиологические исследования;
1,4% - радиология;
1,9% составляют другие расходы [11].

В нашей работе представленные составляющие стоимости были проанализированы на предмет статистически достоверного влияния на летальность после ТГСК и включены в предложенную модель прогностическую модель оценки стоимости, при которой возможно достижение 50% выживаемости.

Несмотря на важность рассматриваемого вопроса, а также лимитирующее воздействие высокой стоимости ТГСК на широкое внедрение этого метода в некоторых странах, в настоящий момент не существует метода анализа достоверно обосновывающего стоимость его стоимость, тем более не существует способов прогнозировать влияние затраченных денег на исход заболевания.

В связи с вышеизложенным, представленный способ статистически обоснованной оценки стоимости ТГСК, позволяющий связать имеющиеся клинические параметры, влияющие на стоимость лечения, а также прогнозировать минимально возможную стоимость ТГСК, при которой достигается 50%-ный положительный эффект, может быть предложен для оценки необходимого финансирования данного вида лечения.

Литература

1. Дубно П.Ю. Обработка статистической информации с помощью SPSS. - М.: ООО «Издательство АСТ»: «НТ Пресс», 2004, 221 с.

2. Наследов А.Д. Компьютерный анализ данных в психологии и социальных науках. – СПб.: Питер, 2005, 416 с.

3. Флетчер Р., Флетчер С., Вагнер Э. Клиническая эпидемиология. Основы доказательной медицины. (перевод с англ.). Москва: Медиа-Сфера. 1998. – 352 с.

4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol., 1984, 7 (3): 273-278.

5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol., 1996, 14(5): 1413-1420.

6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J., 1991, 104 (916): 303-305.

7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission. Bone Marrow Transplant., 1992, 10(4):323-329.

8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic transplantation. Bone Marrow Transplant., 1998, 21 (Suppl.3): S92-S98.

9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a chidren’s hospital. Bone Marrow Transplant., 1998, 21:195-203.

10. van Agthoven M., Groot M.T., Verdonck L.F. et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant., 2002, 30(4):243-251.11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med., 1989, 321(12): 807-812. 

11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812.

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Введение

Главным основополагающим критерием выбора того или иного вида лечения в медицине должна являться эффективность его воздействия на возникшее заболевание. Руководствуясь этим принципом, следует подходить к лечению пациента, независимо от того, насколько дорогостоящим окажется самый эффективный при данном виде заболевания способ лечения. Однако, часто необоснованно высокая стоимость при однозначно не доказанной клинической эффективности того или иного вида лечения ставит под сомнение применение и дальнейшее развитие, а также государственное финансирование этих методов.

В соответствии с этим, в данной работе ставится задача найти обоснованные методы оценки стоимости лечения ТГСК.

Материал и методы исследования

Исследование проводилось на группе из 209 пациентов, перенесших аутологичную ТГСК, аллогенную родственную и неродственную ТГСК с 1998 по 2005 год. Группа состояла из 91 (43,5%) пациента в возрасте от 1 до 66 лет, подвергшихся аллоТГСК, из  них  у 57 пациентов - от неродственного донора, у 34 пациентов от родственного донора, а 118 (56,5%) пациентов перенесли аутоТГСК.

На основании клинических историй болезни проводили анализ эффективности лечения и анализ стоимости лечения вышеуказанных пациентов. Клиническую эффективность оценивали по результатам общей выживаемости за двухлетний период. Проводили оценку общей стоимости, а также различных составляющих стоимости лечения при аутологичной и аллогенной, родственной и неродственной ТГСК, оценку стоимости  аллоТГСК при миелоаблативных и немиелоаблативнных режимах кондиционирования; отдельно определяли стоимость осложненной ТГСК, и ТГСК протекавшей с/без осложнений. В работе сделана попытка выявить статистически обоснованные клинические и стоимостные показатели, влияющие на эффективность применения ТГСК. Полученные результаты были проанализированы с применением методов параметрической и непараметрической статистики, проведен регрессионный анализ полученных данных [1-3].

Результаты исследования

В результате анализа данных было предложено выражение общей стоимости ТГСК. Выражение общей стоимости ТГСК выглядит следующим образом:

C_обс – стоимость лабораторного обследования, которое проводится при нахождении пациента в клинике. Величина, зависящая от характера заболевания и продолжительности нахождения пациента в стационаре.

С_к/д – стоимость нахождения пациента в условиях стационара в течение 1-го к/д. Это величина - фиксированная и рассчитывается статистическими отделами стационаров.

N_сут – длительность нахождения пациента в стационаре. Эта величина, будет зависеть от тяжести заболевания и наличия осложнений.

С_трансф – стоимость трансфузиологического пособия в сутки. Эта величина, также зависит от тяжести заболевания и наличия осложнений требующих гемотрансфузий.

С_конд – стоимость режима кондиционирования. 

С_конд – величина - фиксированная.

С_препар – стоимость  медикаментов в сутки. Зависит от тяжести течения заболевания.

С_инфуз – стоимость заготовки и инфузии КМ или ПСК. Величина фиксированная.

С_{поиск донора} – стоимость следует учитывать только при неродственной аллогенной ТГСК, соответствует стоимости поиска в международном регистре доноров.

Перед построением модели, которая может быть представлена как функция от клинических, стоимостных и других параметров, целесообразно выполнить разведочный статистический анализ. Целью данного анализа было выявление статистически достоверного влияния на исход заболевания следующих характеристик: пол пациента, диагноз, вид ТГСК, пол донора, использование в качестве трансплантата КМ или ПСКК, наличие рецидива или прогрессии, наличие осложнений в общем, и в частности - инфекционных, требующих гемотрансфузий, режима кондиционирования, возраста при ТГСК, наличия РТПХ. В зависимости от характера клинических характеристик были использованы методы анализа непрерывных и категориальных переменных.

На первом этапе был проведен анализ неслучайного различия центральных тенденций непрерывных переменных выражения (1). В табл. 1  приведены непрерывные параметры, которые выявили значимое различие в группах, сформированных по значению статуса пациента.

Далее были проанализированы клинические непрерывные и категориальные параметры влияющие на эффективность ТГСК. Статистически значимое влияние на исход ТГСК оказывали:

• вид ТГСК – аутологичная или аллогенная (р=0,002),
• наличие рецидива или прогрессии (р=0,048),
• наличие трансфузиологических осложнений (р=0,003),
• вид режима кондиционирования – миело или немиелоаблативный (р=0,023).

Выполненный разведочный анализ позволяет сформировать группу непрерывных и категориальных переменных, которые могут быть использованы в качестве предикторов при построении регрессионной модели статуса пациента в зависимости от клинических и стоимостных параметров.

Построение регрессионной модели с зависимой переменной, имеющей вид дихотомической категориальной переменной и независимыми переменными, представленными, приводит к необходимости использовать логистическую регрессию. Логистическая регрессия связывает вероятность наступления события (одного из событий переменной исход заболевания) с независимыми переменными (предикторами), влияние которых на независимую переменную выявлено в предыдущем разделе. Поскольку зависимая переменная оценивается вероятностной мерой, а независимые переменные включают категориальные и непрерывные параметры, необходимо выполнить функциональное преобразование независимых переменных к интервалу 0 – 1. Указанное функциональное преобразование выполняется функцией (2).

которая называется логистической, с параметром Z. 

Параметр Z=B₁X₁+B₂X₂+B₃X₃+B₄X₄+B₅X₅ связывает независимые переменные (предикторы).

Процедура построения логистической регрессии включает, как и обычная регрессия, три основные этапа:
• Получение модели логистической регрессии,
• Оценка значимостей полученных весовых коэффициентов уравнения (B₁, B₂, B₃, B₅),
• Определение устойчивости модели.

С помощью статистического пакета SPSS, используя пошаговые варианты логистической регрессии на включение и исключение параметров из модели и применение критерия Вальда была получена модель со следующими параметрами (Табл. 2).

В соответствии с выражением (2) параметр

В выражение (3) входят:

X₁ – общая стоимость трансфузиологического пособия

X₂ - стоимость трансфузиологического пособия в сутки.

X₃ – стоимость медикаментов.

X₄ – режим кондиционирования

   X₄=0 при немиелоаблативном режиме кондиционирования,

   X₄=1 при миелоаблативном режиме кондиционирования,

X₅ – рецидив перед ТГСК

   X₅=0 при отсутствии рецидива перед ТГСК,

   X₅=1 при наличии рецидива.

В связи с тем, что общая стоимость трансфузиологического пособия получена путем умножения стоимости трансфузиологического пособия в сутки на количество койко-дней, X₁=X₂*N_сут. Тогда выражение (3) принимает вид:

Как видно из табл. 2, модель обладает неслучайными параметрами, значимости которых p<=0,05.

Качество прогноза статуса пациента может быть оценено с помощью таблицы классификации предсказания (см. табл. 3)

Значения табл. 3. характеризуют мощность теста (вероятность предсказания состояния «Жив» при наблюдаемом состоянии «Жив») и специфичность теста (вероятность предсказания «Умер» при  наблюдаемом состоянии «Умер»). Как видно из табл. 3 мощность  прогноза составляет 93,5%, а специфичность - 63,6%. При этом вероятность правильного прогноза составляет 81,1%.

Устойчивость полученной модели необходимо проверить на другой выборке, однако таких данных нет, поэтому прикладная статистика рекомендует выполнить повторный анализ, используя для построения модели только часть данных, другую часть использовать для проверки валидности построенной модели. Так поступили и в этом случае.

Весь массив данных был случайным образом с использованием распределения Бернулли разделен на две части. В первую (отобранные наблюдения) помещено примерно 70% данных, а во вторую (неотобранные наблюдения) - остальные. Первая выборка была использована в процедуре логистической регрессии для построения модели, а вторая – для проверки ее валидности. Модель была получена с такими же параметрами, как описано выше, а устойчивость ее подтверждена с помощью таблицы классификации (табл. 4), построенной раздельно для двух выборок.

Как видно из табл. 4, мощность и специфичность в выборках «отобранные значения» и «неотобранные значения» имеют различные величины. Эти различия обусловлены случайными вариациями. Отсутствие неслучайности различий может быть оценено с помощью теста Фишера, который в данном случае:

  Для наблюдения «Жив» дает вероятность p = 0,1594,

  Для наблюдения «Умер» дает вероятность p = 0,7081.

Обе вероятности говорят об отсутствии различий в столбцах классификационной таблицы, т.е. об отсутствии различия в диагносте двух выборок, первой, по которой строилась модель и второй, по которой она проверялась.

Выполненный в предыдущих разделах анализ выявил параметры зависящие от исхода заболевания и не зависящие от него.

Если параметры не связаны со статусом пациента, для их характеристики следует воспользоваться центральными тенденциями, полученными в результате общего анализа исследуемых предикторов представленных в выражении (1). Ввиду ненормальности распределений рассматриваемых случайных величин такой центральной тенденцией может выступить медиана.

Значения параметров, связанных со статусом, следует получить из регрессионной модели. Логистическая функция (2) принимает значение 0,5 при Z=0. Это значение соответствует ситуации, когда статус пациента определяется с вероятностью 0,5. Для получения более определенного прогноза должно выполняться условие Z>0 или Z<0 в зависимости от искомого значения статуса.

Примем Z=0 как значение для поиска минимальных затрат на ТГСК. Тогда из выражения (4) получим:

В левой части уравнения находятся стоимостные параметры, а в правой клинические.

Для различных вариантов терапии (k), которые задаются правой частью уравнения (5) можно вычислить весовые значения, задаваемые уравнением:

k= 2,159*X₄+2,059*X₅.

Расчетные значения k приведены в таблице 5.

Используя данные табл. 5 значений к и задав медиану для X₂ или X_3, можно вычислить минимальные значения стоимостей, зависящих от статуса, при которых больные будут живы с вероятностью 0,5 (т.е. 50%)

Возможны два варианта вычисления:

1. Задается медиана X₂ (медиана стоимости трансфузиологического пособия в сутки при известных клинических параметрах), а второй параметр вычисляется как

2. Задается медиана X₃ (т.е. медиана общей стоимости препаратов), а второй параметр вычисляется как

Таким образом, была получена модель расчета минимально допустимой стоимости предикторов имевших неслучайное воздействие на исход проведение ТГСК при котором вероятность наступления положительного исхода равна 50%. Подсчет минимальной общей стоимости ТГСК, при которой возможно достижение 50% выживаемости, становится возможным при подстановке полученных данных в выражение (1).

Обсуждение

Трансплантация гемопоэтических стволовых клеток относится к высокотехнологичным методам лечения. Это подразумевает необходимость значительных финансовых затрат, связанных с ее проведением в соответствии с требованиями международных стандартов (good medical practice-GMP, EBMT).

Стоимость алло-ТГСК по литературным данным может составлять от 100 000 до 250 000 долларов США [4-9]; расхождения в стоимости связаны с особенностями   проведения ТГСК в различных странах с учетом их экономических факторов, стоимости оплаты труда, стоимости медикаментов и т.п. В работе M. van Agthoven et al. (2002) [10] прослежены результаты алло-ТГСК у больных острыми лейкозаи (ОМЛ и ОЛЛ) за 2 года. У выживших пациентов стоимость аллоТКМ от HLA-совместимого родственного донора составила 103 509 евро, аллоТПСКК – 105 906 евро. Стоимость алло-ТГСК от неродственного донора была равна 173 587 евро, причем 1/3 этой суммы приходится на поиск донора.

По данным зарубежных авторов, наибольшую долю общих госпитальных затрат при ТГСК составляют расходы на лекарственные препараты (38,9%);

33,7% общих госпитальных затрат – расходы на пребывание больного в стационаре;
7,5% - трансфузиологическое пособие;
5,8% - лабораторно-диагностические исследования;
5,6% - микробиологические исследования;
1,4% - радиология;
1,9% составляют другие расходы [11].

В нашей работе представленные составляющие стоимости были проанализированы на предмет статистически достоверного влияния на летальность после ТГСК и включены в предложенную модель прогностическую модель оценки стоимости, при которой возможно достижение 50% выживаемости.

Несмотря на важность рассматриваемого вопроса, а также лимитирующее воздействие высокой стоимости ТГСК на широкое внедрение этого метода в некоторых странах, в настоящий момент не существует метода анализа достоверно обосновывающего стоимость его стоимость, тем более не существует способов прогнозировать влияние затраченных денег на исход заболевания.

В связи с вышеизложенным, представленный способ статистически обоснованной оценки стоимости ТГСК, позволяющий связать имеющиеся клинические параметры, влияющие на стоимость лечения, а также прогнозировать минимально возможную стоимость ТГСК, при которой достигается 50%-ный положительный эффект, может быть предложен для оценки необходимого финансирования данного вида лечения.

Литература

1. Дубно П.Ю. Обработка статистической информации с помощью SPSS. - М.: ООО «Издательство АСТ»: «НТ Пресс», 2004, 221 с.

2. Наследов А.Д. Компьютерный анализ данных в психологии и социальных науках. – СПб.: Питер, 2005, 416 с.

3. Флетчер Р., Флетчер С., Вагнер Э. Клиническая эпидемиология. Основы доказательной медицины. (перевод с англ.). Москва: Медиа-Сфера. 1998. – 352 с.

4. Armitage J.O., Klassen L.W., Burns C.P. et al. A comparison of bone marrow transplantation with maintenance chemotherapy for patients with acute nonlymphoblastic leukemia in first complete remission. Am. J. Clin. Oncol., 1984, 7 (3): 273-278.

5. Barr R., Furlong W., Henwood J. et al. Economic evaluation of allogeneic bone marrow transplantation: a rudimentary model to generate estimates for the timely formulation of clinical policy. J. Clin. Oncol., 1996, 14(5): 1413-1420.

6. Beard M.E., Inder A.B., Allen J.R. et al. The costs and benefits of bone marrow transplantation. N.Z. Med. J., 1991, 104 (916): 303-305.

7. Dufoir T., Saux M.C., Terraza B. et al. Comparative cost of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission. Bone Marrow Transplant., 1992, 10(4):323-329.

8. Faucher C., Fortanier C., Viens P. et al. Clinical and economic comparison of lenograstim-primed blood cells (BC) and bone marrow (BM) allogeneic transplantation. Bone Marrow Transplant., 1998, 21 (Suppl.3): S92-S98.

9. Kline R.M., Meiman M., Tarantino M.D. et al. A detailed analysis of charges for hematopoietic stem cell transplantation at a chidren’s hospital. Bone Marrow Transplant., 1998, 21:195-203.

10. van Agthoven M., Groot M.T., Verdonck L.F. et al. Cost analysis of HLA-identical sibling and voluntary unrelated allogeneic bone marrow and peripheral blood stem cell transplantation in adults with acute myelocytic leukaemia or acute lymphoblastic leukaemia. Bone Marrow Transplant., 2002, 30(4):243-251.11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med., 1989, 321(12): 807-812. 

11. Welch H.G., Larson E.B. Cost effectiveness of bone marrow transplantation in acute nonlymphocytic leukemia. N. Engl. J. Med. 1989,321(12):807-812.

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Introduction

The birth of every newborn human produces a precious byproduct. In the expelled placenta there is a sufficient amount of Cord Blood (CB), in which there is abundance of hematopoietic elements. In 1988 Elaine Gluckman showed that a Hematopoietic Stem Cell Transplantation (HSCT) can succeed by using CB as a source for the graft [33]. Gradually thousands of such transplantations began to be performed all over the world. Up until recently most transplantations with CB had been done in children; however the main progress in the field in the last 2 years has been achieved in adults with hematological malignancies. But even though HSCT is still the major indication for using CB, there is a growing interest in finding it as a source for non-hematopoietic stem cells (SC) for regenerative medicine, gene therapy vector, and other potential uses.

Collection of cord blood in the delivery room

CB's collection is done in the delivery room. The blood is drawn from the umbilical vein, before or after the expulsion of the placenta.

The main advantage of the collection process of CB is its simplicity. It poses no danger and causes no pain to the laboring mother or the newborn. Before the collection itself consent is given by the mother. Some centers also addend a short interview, and others use questionnaires for identification of high risk mothers [29].

Cryopreservation

After its collection CB undergoes cryopreservation. The most widely used method is the one reported by Rubinstein et al [89]. It is based on red blood cell depletion and volume reduction. At the end of the process the total volume of each unit is 25 milliliters.

Cord blood public banks

Before freezing, CB samples undergo several tests. Every unit is screened for infectious agents, and in some banks, for relevant inherited diseases. HLA typing is usually done for A, B in serology, and DR in DNA. Some diversity exists between banks with regard to the routine tests that each unit undergoes. Additional samples are maintained in small plastic segments attached to the frozen unit in case future tests are needed.

It is estimated that today there are about 250,000 CB units frozen in 35 banks in 21 countries [14]. CB banking is facing some challenges. The first is the scarcity of space, which is dealt with by volume reduction methods and selection of presumed optimal units, usually with higher volume. Another issue is the uncertainty regarding the period of time which units can be preserved without damage to the viability of the cells. The banks also face ethical issues. For example, if an adult disagrees with the usage of CB that his parents gave consent for donation for decades ago, what is the value of such consent? Another concern is the fate of the information that is stored in CB banks regarding donors' infectious status or the presence of genetic diseases. Is this sensitive data protected as it should be? The need for follow up is understandable, but it could also affect the diversity of ethnic pool of the donors. The ability to detect the donors might also put their families under pressure to donate more cells when the need for it might come.

The importance of public CB banking gained an official acknowledgment when the American congress decided to add $30 million for collection of an additional 150,000 units.

Apart from the above, one of the most controversial issues is private CB banking.

Private cord blood banks

This is an ever growing trend that emerged in the early 90s. These private firms offer storage of CB units against a future need for autologous or related allogeneic transplantations. Questions have been recently being raised  about whether overanxious parents are truly aware that there are no indications today for autologous cord blood transplantation (CBT). Are they informed about the slim chances for a family of ever needing a sibling CBT, and do they know about the lack of knowledge regarding the how long CB's hematopoietic SC preserve their viability while frozen?

The pace of collection in the private banks exceeds the one in the public banks. It is estimated that approximately 600,000 units are frozen privately. These facts raise questions about whether this limited source of hematopoietic SC should not be solely in public hands.

The unique properties of cord blood

Aspirates of bone marrow (BM), or the more recently used Peripheral Blood Stem Cell Collection (PBSC) product, have been traditionally used as sources for HSCT. CB has a few different qualities.

It had long been acknowledged that the more nucleated cells in a graft, the better the chances of engraftment. When taking CB into account as a hematopoietic SC source for transplantation, it is evident that it has fewer nucleated cells than other sources. Each aspirate of BM yields 750-1000 milliliters. This volume usually gives a nucleated cell dose of 2x10⁸/kg for an average weight adult. The product of PBSC yields similar number of SC. The volume of a typical CB unit is usually only 75-150 milliliters. The nucleated cells dose is only one tenth of the BM dose, usually no more than 2x10⁷/kg, for an adult.

Another relevant component of the graft that marks the difference between CB and BM is T cells. These are considered to have a deleterious effect regarding the immune response of the graft against the recipient. The total dose of T cells (CD3⁺ cells) in CB units is less than a fifth of the amount in BM grafts. When comparing it to mobilized peripheral blood grafts, CB units have less than 2% of T cell dose. But while less hematopoietic SC in CB is a setback regarding HSCT, the scarceness of T cells is an advantage, with respect to the risk of graft versus host disease (GVHD) [9, 12].

The low number of SC in CB graft is masked by an excellent proliferative response. When these cells are in a dormant state and cytokines are introduced into their environment, they expand much better than hematopoietic SC of BM. This trait enables CB to produce full hematopoietic recovery of BM in myeloablated recipients [64, 57].

The naïve nature of the immune system's cells in CB is a different issue.

The lymphocytes in CB grafts have a more tolerant nature [73, 82, 83, 88, 22, 32]. Other components of the system, such as dendritic and Natural Killer cells also have different properties, when compared to BM or adult peripheral blood [56, 45, 94, 17, 59, 23]. Because of this, CB allows greater human leukocyte antigen (HLA) disparities in transplantations, with less rejection and lower rates of GVHD.

Cord blood transplantation, clinical experience

Reports on a series of CBT started to appear at the beginning of the end of the 1990s and at the beginning of the third millennium. These were based mostly on the American and the European registries, with some reports from Japanese and other institutes. Table 1 & 2 summarizes the largest clinical trials of CBT using unrelated donors [89, 34, 101, 68, 60, 49, 50, 85, 97, 62]. A few important concepts could be built upon results from these works. First was the notion that CB, with its limited nucleated cells dose, can produce full hematopoietic reconstitution after myeloablative conditioning. Secondly, the median time of myeloid recovery in CBT ranged from 22 to 33 days. This is a far longer period than the time in bone marrow transplantation (BMT) experience. When BM aplasia is prolonged, morbidity and mortality rates rise. The third notion was that despite the existence of a significant proportion of HLA disparity between donors and recipients, rejection and GVHD rates were surprisingly low.

So these trials proved that CB is a legitimate source for HSCT, with problematic engraftment kinetics, but less restriction to HLA matching when compared to BM.

Since each placenta contains a limited volume of blood, it follows that there is also a limited amount of nucleated cells per unit. The correlation between nucleated cell dose and transplantation outcomes was evaluated. A positive impact of cell dose on time to engraftment, and hence the overall survival, has been demonstrated in both pediatric and adult series. It is probably agreed that the minimal acceptable threshold of nucleated cells dose should be 1.5x10⁷ nucleated cells/kg, but an association between dose of 3.7x10⁷ nucleated cells/kg and more and faster time to neutrophil engraftment was suggested by the Eurocord [34, 3]. The New York Blood Group reported that 2.5x10⁷ nucleated cells/kg is the minimal threshold for transplantation [89].

Historically CD34⁺ cells counts were not part of the tests done routinely on CB units. But it is reasonable to assume that it might be so in the near future. Counting nucleated cells involves many cells that do not contribute to the engraftment potential. And indeed, Wagner et al has shown a correlation between CD34⁺ dose of 1.7x10⁵cell/kg and higher to rapid neutrophil engraftment and probability of engraftment [101].

Related donor transplants

Although the first CBT was done from a sibling donor, related donors transplants are used less frequently in this setup. For the cure of malignant diseases CB from a sibling could be used if there is a perfect timing of a birth in the family, or a if a CB unit had been cryopreserved earlier, either by chance or by intention. In non-malignant disease there is usually more time. Families that are aware of CB as a source for transplantation might act on time when births are due.

Several reports of large series of trials have been published. These series have demonstrated that CB is a valid therapeutic option as a source for pediatric transplantation for malignant and non-malignant diseases. The probability for survival at 1 year was 0.63 (95% CI: 0.57-0.69) in the Eurocord study, and 0.61 (95% CI: 0.81-0.49) at 2 years in the ICBTR study [89, 35].

The largest of the series is a joint European and American work that compared 113 related donor CBT in children with 2052 cases of related donor BMT. Neutrophils engraftment in the CB group occurred at a median time of 26 days, compared to 18 in the BM group. Probability of myeloid recovery at day 60 was 0.89 and 0.98 in the CB and BM respectively. Children who received CB had a significantly lower risk of both AGVHD and CGVHD than those who were transplanted from BM (relative risk 0.41; p=0.001 and relative risk 0.35; p=0.02, respectively). Overall survival at 3 years was 0.64 for the CB and 0.66 for the BM group. This study demonstrated the role of related donor CBT for malignant diseases in children [86]. Related donor CBT for non malignant diseases will be discussed in the non malignant section.

Comparison to bone marrow

No randomized trials had been conducted to compare CB with BM grafts. Few retrospective reports have been published. As for children, it was shown by Eapen that 503 cases of matched CBT had better 5 DFS than 116 matched unrelated donor (8/8) BMT. Even the 5/6 matched CBT had comparable results with the BM group. An important factor was the cell dose. The group that received more than 3x10⁷ nucleated cell/kg had better DFS and OS [28]. It was Rocha and Gluckman who assessed leukemia-free survival at 5 years after CBT or BMT in children. 503 children received CB – either matched or mismatched. The outcome of these transplantations was compared to BMT of 282 children. Allele-matched bone-marrow transplants had similar outcomes to transplants of umbilical cord blood mismatched for either one or two antigens. Higher survival rates were demonstrated after transplants of HLA-matched umbilical cord blood [87].

Recent publications have managed to evoke hopes that even in adults CBT (matched, or 1-2 HLA antigens mismatched) is as good as matched unrelated donor BMT. The reports of Laughlin, Rocha and Takahashi in late 2004 compared a large series of adult patients who received unrelated CB or BM. Outcomes of CBT were similar, and in certain aspects superior, to unrelated donor mismatched BMT. Laughlin found that patients receiving mismatched CB had similar treatment-related mortality, treatment failure, relapse and overall mortality rates, to those received mismatched BM. Rocha compared matched unrelated donor of BM with CB. He found no differences in treatment-related mortality rates, relapse and leukemia-free survival rates between them. These results may refine the accepted approach for unrelated donor search. Many believe that a search for a BM donor and a CB unit should generally be started simultaneously and CB (matched or mismatched in up to 2 HLA antigens) should be preferred if matched BM donor can not be found within a reasonable period of time [85, 51, 97]. In late 2006 Takahashi et al published the first report of adult transplantation with CB as a first option for non related donor graft. The Japanese group transplanted 100 adults with hematological malignancies with CB, if they had no matched related donor. Results of the CBT were compared to matched related BM or peripheral SC transplantations. The outcome was similar in all groups. Whether this interesting approach is feasible in all cases of patients with no matched related donor, relies upon further reports from other ethnic groups [98].

CBT for non malignant diseases

HSCT can offer the only true chance for cure in many non-malignant diseases. CB offers some unique advantages in the area of transplantations for non malignant diseases. Many of these patients are children. This makes nucleated cells doses satisfactory in most of the cases. Moreover, rareness of GVHD tempts the preference of CB, especially in an unrelated donor setup. As opposed to HSCT for malignant disease, there is no presumed benefit from the Graft Versus Leukemia effect of GVHD. On the other hand, CB is a less attractive option for transplantation for bone marrow failure syndromes. There are high rates of graft rejection in HSCT in these diseases. When adding the negative impact of CB's tendency for delayed engraftment, it is regarded by some as a problematic solution for such patients. This was demonstrated in the work of Rocha et al. In a related donor setting, and definitely with unrelated donors, for bone marrow failure syndrome patients, it was clear that engraftment, and therefore event free survival (EFS) rates are not acceptable. The probability of myeloid engraftment at day 60 was not more than 67% for patients that were given related donor grafts, and it was 36% in unrelated donor-CBT. Only 33% of the Fanconi anemia patients engrafted [1]. Better results were reported by the European group when they summarized unrelated CBT for Fanconi patients. Although only 12 of the 93 cases were HLA identical; 60% of the patients engrafted by day 60. A positive impact of Fludarabine based regimens, cell dose, and CMV negative recipients was seen [36].

Some limited experience was gained by us with a few bone marrow failure syndromes, namely Fanconi anemia. We observed high rates of event free survival (EFS), especially in children who received a matched family donor transplant [37].

In one case we used a novel strategy of pre-implantation genetic diagnosis for one of the patients. This method, which is based on CBT, could pave the way for many malignant and non-malignant diseases [11].

Although the role of HSCT for Thalassemia in the era of newer iron chelating agents is yet to be determined, this strategy is still being practiced widely in an attempt to cure this hemoglobinopathy. Locatelli et al reported results of related CBT in 44 children with hemoglobinopathies (Thalassemia and Sickle Cell Disease), and showed that this procedure is feasible. High rates of engraftment (89% at day 60) and EFS (79% for Thalassemia and 90% for Sickle Cell Disease) were achieved [61].

As for CBT in inborn errors of metabolism, Staba et al reported impressive results in children with Hurler syndrome who were given unrelated donors CB grafts. Even though 19 of the 20 patients received mismatched grafts, high rates of engraftment were reported (at 2.4 years follow-up, 85%). This was probably due to the relatively high nucleated cells doses (median of 10.5x10⁷ nucleated cells/kg). The disease itself was cured, as could be seen in all 17 patients who were alive, and had normal peripheral-blood α-L-Iduronidase activity [95]. Recently a report of a case of a child who was cured of Wolman disease by a CBT was published [96].

CBT for the cure of Sickle Cell Anemia was reported recently by a French group. Importantly the authors noticed that after a 6 year follow up the group of patients that received a CB graft did not develop the main contributing factor for the morbidity, GVHD [10].

Investigational approaches in cord blood

Most patients needing HSCT are adults. For these heavier patients CB is a problematic solution because of the relatively low cell dose. Various strategies are being attempted in order to lower the toxicity of the conditioning regimen. This could be achieved either by lowering its intensity, or by hastening engraftment.

Reduced intensity conditioning

The practice of HSCT with reduced intensity conditioning (RIC) has emerged in the adult population. These older patients usually have pre-existing morbidities.

By reducing the intensity of the preparative regimen it has been shown that treatment-related morbidity and mortality rates could be lowered. The concept behind this is based on the assumption that in certain cases the immunological impact of the graft is more important than the ablative power of the conditioning regimen.

Experience with transplantations using RIC, though follow up time is still short, have shown encouraging results. Patients who benefit the most from RIC are those with diseases of a more indolent nature.

Few studies of RIC-CBT in adult and pediatric patients have been published. The major conclusion that could be drawn from these series is that RIC is feasible in CBT. Graft rejection happened mainly in cases in which the accumulative chemotherapy dose experienced by the recipients prior to the transplantation itself was low. Though survival rates are low, it must be emphasized that most studies included mainly high risk, heavily treated patients. GVHD rates correlated with unrelated donor BMT. Another encouraging finding is the lower than expected rates of treatment-related mortality at 100 days post-transplantation. Because of the small number of patients, and diversity of methods, conclusions regarding the optimal RIC conditioning regimen, or the GVHD prophylaxis, can not be drawn at this point. Even if it is definitely too early to recruit patients for RIC-CBT outside clinical trials for selected patients, these protocols could offer an alternative for selected patients [69, 27, 19, 20, 13, 6, 4, 104].

Engraftment hastening

The idea of shortening the period from transplantation to myeloid recovery is at the basis of many strategies. Some have shown preliminary encouraging results in the laboratory, in animal models, and even in clinical trials.

Transplantations with double cord blood units

Many recipients receive more than one partially matched CB units where the cell dose in each is not sufficient. In many cases the sum of these units provides an adequate number of SC. It has been shown in animal models that two CB units provide high rates of engraftment [71]. Some studies have used this strategy for high risk adult patients who received two mismatched CB units. Many believe that this strategy could pave the way for lowering treatment-related mortality rates in CBT. In most of these trials two encouraging facts were observed: stable mixed chimerism, and no mutual rejection of mismatched units [7, 8, 25, 39, 5]. Brunstein et al have shown that by using a non-myeloablative regimen for CBT in adults, the OS of the group that received 2 units was higher than the patients who received 1 unit. In this study 92% of the patients achieved neutrophil recovery, at a median time of 12 days [16]. Interestingly, sustained hematopoiesis after double CBT is usually derived from a single donor. The relative percent viability, the infused number of NC and CD34⁺ cell doses, and the donor–recipient HLA-disparity are not helpful in predicting which of the two CB units will predominate. Although early data suggested that the dominant unit had a higher median infused CD3⁺ cell dose, this observation has not persisted with investigation of a larger cohort of patients. Order of infusion, location of HLA mismatch, ABO blood group and/or sex mismatch also did not have a predictive effect on engraftment.

Double CBT can potentially produce a better graft versus leukemia effect. This was demonstrated in a study of the University of Minnesota. They compared leukemia patients who received 2 units of CB to those who received a single unit. The group who received the double CBT had a lower risk for relapse. It is still not known if the relatively high degree of HLA mismatch in this setting is responsible. It might also be a consequence of non-HLA disparity, such as KIR mismatch, between the CB units and the recipient, or between themselves [100].

Double unit transplantation has become a major breakthrough in the field of CB during the last 2 years. Several 2 arms protocols for using double units are on their way. Whether these expectations are justified depends on preliminary results of these trials.

Co transplantation with a Haploidentical donor

Relaying on the assumption that almost every patient has a donor, namely a parent that has a similar HLA type of one of his haplotypes, Magro et al have succeeded in transplanting CB together with a Haploidentical graft. They succeeded in inducing a rapid engraftment via a BM transplant. By administering only a small dose of Haploidentical SC, the Spanish team managed to induce a temporary engraftment only. These cells were rejected later, due to their low dose and significant HLA disparity, allowing engraftment of the CB graft. 69% of these high risk patients survived at 4 years [65].

Intra-osseous transplantation

One of the obstacles to a short period of engraftment is the possibility that the homing process is influenced by anatomical barriers. It has been suggested that intra BM injection of the graft could induce a rapid engraftment. This has been shown to be feasible, and has improved engraftment kinetics in BMT in adults [41]. Time will tell if intra osseous transplantation could shorten the way for CB's SC into the BM, and therefore improve time to engraftment, as has been shown in animal models [103, 102]. 

Ex vivo expansion of hematopoietic stem cells

In vitro studies had shown that SC proliferate with the addition of cytokines. But uncontrolled expansion is not biologically satisfactory, since maturation and differentiation of SC occur in these conditions. The SC proliferate and become committed to specific hematopoietic cell lines. Such cells lack what is known as "long term population ability." The optimal composition of the cytokine-rich media of the ex vivo expansion process is an important challenge for researchers to face. It has been demonstrated by Shpall et al that co transplantation of ex vivo expanded and non-manipulated grafts are feasible. But in spite of this, improvements in engraftment kinetics, are yet to be achieved [15, 80, 47, 91, 92, 44, 75].

Different attitudes have been taken in order to refine the expansion process, namely: co-culturing with different cells as feeder layers [105, 21], selection of SC for the expansion [30], and multiplying the proliferative potential by performing a two step harvesting technique [66, 81]. None of these strategies have yet been introduced into clinical trials.

A somewhat more promising field is interference with the differentiation of expanded SC. Reports have been published recently regarding ex vivo expansion with copper chelator, Tetraethylenepentamine (TEPA), which enhances the long term populating ability of the CB cells. Following large scale experiments, this appealing approach has been introduced into the clinic in phase I trials. Preliminary encouraging results of this trial with no significant toxicity were presented recently [76-78, 40, 93]. A Phase II multi center study has just started and the first 3 adult patients with hematological malignancies have already been recruited [26]. The same concept was behind the experiment held by Nolta et al, when they co-cultured primitive CB's SC (CD34⁺ CD38^-) together with a feeder layer of immortalized murine stromal cell-line AFT024. This method has yielded high rates of myeloid and lymphoid engraftment in a NOD/SCID mouse xenograft model [74]. Other molecules that play major roles in the differentiation of hematopoietic cells, and might be used in the future for ex vivo expansion of CB are Gfi-1 and some of the Notch ligand protein family [52, 53, 42]. Novel methods have been studied recently with the use of epigenetic factors. Silencing of genes could be a consequence of methylation of their promoters or deacetylation of histones. By trying to inhibit these processes, reactivation of some genes could augment the hematopoietic SC's self renewal potential. Recent publications have shown some success in the in vitro repopulating potential of CB when using histone deacetylase inhibitors, such as Valproic acid [7, 24]. This strategy is  the basis of a clinical study which has recruited the first patients (personal communications).

Cord Blood, Umbilical cord, and Mesenchymal Stem Cells

As their unique qualities are revealed, the interest in mesenchymal stem cells (MSCs) is growing continuously. These cells are non-hematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues, but possibly also to other tissue lineages. They have an in vitro expansion ability while their growth and differentiation potential is maintained. Currently it is expected that they could be used for tissue repair and regenerative medicine. MSCs have shown that they can modulate immune response both in vitro and in vivo. Preliminary studies are on their way for using MSCs as an anti GVHD prophylaxis. It was doubted that these cells could also play a roll in treating GVHD. It has also been postulated that these cells could be used for other immune mediated diseases. MSCs are used as a growing medium for ex vivo expansion of other cells [67, 84]. Le Blanc et al showed that MSCs could be transfused in parallel to HSC grafts and demonstrated fast engraftment [54]. Finally, MSCs are considered to be candidates as a vector for gene therapy.

Until recently only BM and adipose tissue were considered as a source for MSC. In the last few years it had been shown that CB contains MSC [55]. MSC from other sources has been demonstrated to have suppressive effect on T cells [58]. Few studies have focused on the different properties of MSC originating from CB. Their tendency to differentiate into specific tissue, their genomic expression, and proliferative response, are all different from BM or adipose tissue MSC [18, 46].

When considering the expulsion of the placenta at the end of delivery as a waste of a precious source of SCs, it is not only the CB itself that should be regarded as such. The Wharton jelly in the umbilical cord has also been found to be a source for MSCs [31, 90].

Cord blood uses in other fields

Gene transfer is an exciting new field in which CB could serve as a vector for correcting inborn genetic errors, or replace infected hematopoietic SC, such as in the case of HIV. Its availability, proliferative response, and engraftment potential, make it an appealing candidate for these uses [43]. Clinical trials of gene transfer to Adenosine Deaminase deficient Severe Combined Immunodeficiency children relied on BM and CB as a hematopoietic SC source. This method faced some obstacles that continue to prevent it from curing these patients [48, 2].

Another – to date only investigational – field is the potential non-hematopoietic use of hematopoietic SC. In recent years much interest has been focused on the ability of hematopoietic SC to differentiate into (or as some claim, to fuse with) cells of other tissues. It was demonstrated that cells with pluripotent differentiation potential could be found in CB [79, 72, 38]. CB has been suggested to have a role in improving performance of rats who were subjected to brain infarct [99]. CB is also considered by some to be a source of SC for regeneration of ischemic heart tissue by differentiation processes or neoangiogenesis [63]. It is too early to define whether SC's plasticity might have clinical benefits in repairing injured tissues, but this application is at the center of great interest and controversy.

Discussion

CB has become a legitimate source, not only for HSC for transplantations, but also for other uses. The experience gained in the last twenty years of work with CBT has shown us its advantages, as well as its setbacks.

Unlike BM donations, CB's collection is easier and poses no danger to the donor. In CB banks there is a greater proportion of ethnic minorities than in BM registries. It also has greater availability in an unrelated donor HSCT due to its shorter donor search time. Lesser risk for transmission of infectious agents in the transplantation process is another benefit of CB. There is no doubt that fewer HLA restrictions in unrelated transplantations is its main advantage. This fact allows successful transplantations with acceptable rates of graft failure and GVHD.

On the other hand, there is a slim potential for disease transmission, namely genetic, in CBT setup. In CBT there is almost no option for a second transplantation, or any boost of cells. A troubling disadvantage of CB is its low number of hematopoietic SC in each unit. This has proven to be a crucial point that has a direct relationship to relatively high rates of treatment-related mortality rates in CBT. This point is further emphasized within the setting of adult transplantations.

From the data collected in several series of CBT for both malignant and non malignant diseases it appears that CB can be used as a SC source in several settings.

The most urgent need for SC is transplantation for malignant diseases from unrelated donors. It is an acceptable approach to search first for BM donor. If a 5/6 or better HLA match can not be found, or progressive disease status does not allow completion of the search, then a CBT of 4/6 HLA match or better should be performed. This of course depends on a minimal cell dose of 2x10⁷ nucleated cells/kg per CB unit. Cell dose has greater relevancy in adult transplantation setup. Skepticism about the possibility of CBT in heavier patients might fade as newer strategies could overcome SC scarceness of nucleated cells in CB. At this stage the most appealing strategy is the double unit CBT. By receiving 2 CB units many adults could be transplanted with a reasonable time to engraftment. Time will tell if other methods could offer a solution for a better outcome in CBT for adults.

Impressive progress is constantly being achieved in the field of CBT. CB is still considered a second best choice for HSCT, but as newer reports are being published it is not so obvious whether it could not be preferred over BM. Interesting data in children showed that a perfect match (6/6) of CB could be the best choice. If larger studies can confirm this, we might see CB becoming the first option for transplantation in certain conditions.

For non malignant disease CB is a very good option, especially for the smaller patients. Caution should be practiced when using CB for bone marrow failure syndrome, though again it seems that larger units and better preparative regimens may overcome the tendency for graft failure.

Future uses of CB may not be just for HSCT. Time will tell if the fields of gene therapy and non hematopoietic injured tissues repair also benefit from the use of CB cells.

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Introduction

The birth of every newborn human produces a precious byproduct. In the expelled placenta there is a sufficient amount of Cord Blood (CB), in which there is abundance of hematopoietic elements. In 1988 Elaine Gluckman showed that a Hematopoietic Stem Cell Transplantation (HSCT) can succeed by using CB as a source for the graft [33]. Gradually thousands of such transplantations began to be performed all over the world. Up until recently most transplantations with CB had been done in children; however the main progress in the field in the last 2 years has been achieved in adults with hematological malignancies. But even though HSCT is still the major indication for using CB, there is a growing interest in finding it as a source for non-hematopoietic stem cells (SC) for regenerative medicine, gene therapy vector, and other potential uses.

Collection of cord blood in the delivery room

CB's collection is done in the delivery room. The blood is drawn from the umbilical vein, before or after the expulsion of the placenta.

The main advantage of the collection process of CB is its simplicity. It poses no danger and causes no pain to the laboring mother or the newborn. Before the collection itself consent is given by the mother. Some centers also addend a short interview, and others use questionnaires for identification of high risk mothers [29].

Cryopreservation

After its collection CB undergoes cryopreservation. The most widely used method is the one reported by Rubinstein et al [89]. It is based on red blood cell depletion and volume reduction. At the end of the process the total volume of each unit is 25 milliliters.

Cord blood public banks

Before freezing, CB samples undergo several tests. Every unit is screened for infectious agents, and in some banks, for relevant inherited diseases. HLA typing is usually done for A, B in serology, and DR in DNA. Some diversity exists between banks with regard to the routine tests that each unit undergoes. Additional samples are maintained in small plastic segments attached to the frozen unit in case future tests are needed.

It is estimated that today there are about 250,000 CB units frozen in 35 banks in 21 countries [14]. CB banking is facing some challenges. The first is the scarcity of space, which is dealt with by volume reduction methods and selection of presumed optimal units, usually with higher volume. Another issue is the uncertainty regarding the period of time which units can be preserved without damage to the viability of the cells. The banks also face ethical issues. For example, if an adult disagrees with the usage of CB that his parents gave consent for donation for decades ago, what is the value of such consent? Another concern is the fate of the information that is stored in CB banks regarding donors' infectious status or the presence of genetic diseases. Is this sensitive data protected as it should be? The need for follow up is understandable, but it could also affect the diversity of ethnic pool of the donors. The ability to detect the donors might also put their families under pressure to donate more cells when the need for it might come.

The importance of public CB banking gained an official acknowledgment when the American congress decided to add $30 million for collection of an additional 150,000 units.

Apart from the above, one of the most controversial issues is private CB banking.

Private cord blood banks

This is an ever growing trend that emerged in the early 90s. These private firms offer storage of CB units against a future need for autologous or related allogeneic transplantations. Questions have been recently being raised  about whether overanxious parents are truly aware that there are no indications today for autologous cord blood transplantation (CBT). Are they informed about the slim chances for a family of ever needing a sibling CBT, and do they know about the lack of knowledge regarding the how long CB's hematopoietic SC preserve their viability while frozen?

The pace of collection in the private banks exceeds the one in the public banks. It is estimated that approximately 600,000 units are frozen privately. These facts raise questions about whether this limited source of hematopoietic SC should not be solely in public hands.

The unique properties of cord blood

Aspirates of bone marrow (BM), or the more recently used Peripheral Blood Stem Cell Collection (PBSC) product, have been traditionally used as sources for HSCT. CB has a few different qualities.

It had long been acknowledged that the more nucleated cells in a graft, the better the chances of engraftment. When taking CB into account as a hematopoietic SC source for transplantation, it is evident that it has fewer nucleated cells than other sources. Each aspirate of BM yields 750-1000 milliliters. This volume usually gives a nucleated cell dose of 2x10⁸/kg for an average weight adult. The product of PBSC yields similar number of SC. The volume of a typical CB unit is usually only 75-150 milliliters. The nucleated cells dose is only one tenth of the BM dose, usually no more than 2x10⁷/kg, for an adult.

Another relevant component of the graft that marks the difference between CB and BM is T cells. These are considered to have a deleterious effect regarding the immune response of the graft against the recipient. The total dose of T cells (CD3⁺ cells) in CB units is less than a fifth of the amount in BM grafts. When comparing it to mobilized peripheral blood grafts, CB units have less than 2% of T cell dose. But while less hematopoietic SC in CB is a setback regarding HSCT, the scarceness of T cells is an advantage, with respect to the risk of graft versus host disease (GVHD) [9, 12].

The low number of SC in CB graft is masked by an excellent proliferative response. When these cells are in a dormant state and cytokines are introduced into their environment, they expand much better than hematopoietic SC of BM. This trait enables CB to produce full hematopoietic recovery of BM in myeloablated recipients [64, 57].

The naïve nature of the immune system's cells in CB is a different issue.

The lymphocytes in CB grafts have a more tolerant nature [73, 82, 83, 88, 22, 32]. Other components of the system, such as dendritic and Natural Killer cells also have different properties, when compared to BM or adult peripheral blood [56, 45, 94, 17, 59, 23]. Because of this, CB allows greater human leukocyte antigen (HLA) disparities in transplantations, with less rejection and lower rates of GVHD.

Cord blood transplantation, clinical experience

Reports on a series of CBT started to appear at the beginning of the end of the 1990s and at the beginning of the third millennium. These were based mostly on the American and the European registries, with some reports from Japanese and other institutes. Table 1 & 2 summarizes the largest clinical trials of CBT using unrelated donors [89, 34, 101, 68, 60, 49, 50, 85, 97, 62]. A few important concepts could be built upon results from these works. First was the notion that CB, with its limited nucleated cells dose, can produce full hematopoietic reconstitution after myeloablative conditioning. Secondly, the median time of myeloid recovery in CBT ranged from 22 to 33 days. This is a far longer period than the time in bone marrow transplantation (BMT) experience. When BM aplasia is prolonged, morbidity and mortality rates rise. The third notion was that despite the existence of a significant proportion of HLA disparity between donors and recipients, rejection and GVHD rates were surprisingly low.

So these trials proved that CB is a legitimate source for HSCT, with problematic engraftment kinetics, but less restriction to HLA matching when compared to BM.

Since each placenta contains a limited volume of blood, it follows that there is also a limited amount of nucleated cells per unit. The correlation between nucleated cell dose and transplantation outcomes was evaluated. A positive impact of cell dose on time to engraftment, and hence the overall survival, has been demonstrated in both pediatric and adult series. It is probably agreed that the minimal acceptable threshold of nucleated cells dose should be 1.5x10⁷ nucleated cells/kg, but an association between dose of 3.7x10⁷ nucleated cells/kg and more and faster time to neutrophil engraftment was suggested by the Eurocord [34, 3]. The New York Blood Group reported that 2.5x10⁷ nucleated cells/kg is the minimal threshold for transplantation [89].

Historically CD34⁺ cells counts were not part of the tests done routinely on CB units. But it is reasonable to assume that it might be so in the near future. Counting nucleated cells involves many cells that do not contribute to the engraftment potential. And indeed, Wagner et al has shown a correlation between CD34⁺ dose of 1.7x10⁵cell/kg and higher to rapid neutrophil engraftment and probability of engraftment [101].

Related donor transplants

Although the first CBT was done from a sibling donor, related donors transplants are used less frequently in this setup. For the cure of malignant diseases CB from a sibling could be used if there is a perfect timing of a birth in the family, or a if a CB unit had been cryopreserved earlier, either by chance or by intention. In non-malignant disease there is usually more time. Families that are aware of CB as a source for transplantation might act on time when births are due.

Several reports of large series of trials have been published. These series have demonstrated that CB is a valid therapeutic option as a source for pediatric transplantation for malignant and non-malignant diseases. The probability for survival at 1 year was 0.63 (95% CI: 0.57-0.69) in the Eurocord study, and 0.61 (95% CI: 0.81-0.49) at 2 years in the ICBTR study [89, 35].

The largest of the series is a joint European and American work that compared 113 related donor CBT in children with 2052 cases of related donor BMT. Neutrophils engraftment in the CB group occurred at a median time of 26 days, compared to 18 in the BM group. Probability of myeloid recovery at day 60 was 0.89 and 0.98 in the CB and BM respectively. Children who received CB had a significantly lower risk of both AGVHD and CGVHD than those who were transplanted from BM (relative risk 0.41; p=0.001 and relative risk 0.35; p=0.02, respectively). Overall survival at 3 years was 0.64 for the CB and 0.66 for the BM group. This study demonstrated the role of related donor CBT for malignant diseases in children [86]. Related donor CBT for non malignant diseases will be discussed in the non malignant section.

Comparison to bone marrow

No randomized trials had been conducted to compare CB with BM grafts. Few retrospective reports have been published. As for children, it was shown by Eapen that 503 cases of matched CBT had better 5 DFS than 116 matched unrelated donor (8/8) BMT. Even the 5/6 matched CBT had comparable results with the BM group. An important factor was the cell dose. The group that received more than 3x10⁷ nucleated cell/kg had better DFS and OS [28]. It was Rocha and Gluckman who assessed leukemia-free survival at 5 years after CBT or BMT in children. 503 children received CB – either matched or mismatched. The outcome of these transplantations was compared to BMT of 282 children. Allele-matched bone-marrow transplants had similar outcomes to transplants of umbilical cord blood mismatched for either one or two antigens. Higher survival rates were demonstrated after transplants of HLA-matched umbilical cord blood [87].

Recent publications have managed to evoke hopes that even in adults CBT (matched, or 1-2 HLA antigens mismatched) is as good as matched unrelated donor BMT. The reports of Laughlin, Rocha and Takahashi in late 2004 compared a large series of adult patients who received unrelated CB or BM. Outcomes of CBT were similar, and in certain aspects superior, to unrelated donor mismatched BMT. Laughlin found that patients receiving mismatched CB had similar treatment-related mortality, treatment failure, relapse and overall mortality rates, to those received mismatched BM. Rocha compared matched unrelated donor of BM with CB. He found no differences in treatment-related mortality rates, relapse and leukemia-free survival rates between them. These results may refine the accepted approach for unrelated donor search. Many believe that a search for a BM donor and a CB unit should generally be started simultaneously and CB (matched or mismatched in up to 2 HLA antigens) should be preferred if matched BM donor can not be found within a reasonable period of time [85, 51, 97]. In late 2006 Takahashi et al published the first report of adult transplantation with CB as a first option for non related donor graft. The Japanese group transplanted 100 adults with hematological malignancies with CB, if they had no matched related donor. Results of the CBT were compared to matched related BM or peripheral SC transplantations. The outcome was similar in all groups. Whether this interesting approach is feasible in all cases of patients with no matched related donor, relies upon further reports from other ethnic groups [98].

CBT for non malignant diseases

HSCT can offer the only true chance for cure in many non-malignant diseases. CB offers some unique advantages in the area of transplantations for non malignant diseases. Many of these patients are children. This makes nucleated cells doses satisfactory in most of the cases. Moreover, rareness of GVHD tempts the preference of CB, especially in an unrelated donor setup. As opposed to HSCT for malignant disease, there is no presumed benefit from the Graft Versus Leukemia effect of GVHD. On the other hand, CB is a less attractive option for transplantation for bone marrow failure syndromes. There are high rates of graft rejection in HSCT in these diseases. When adding the negative impact of CB's tendency for delayed engraftment, it is regarded by some as a problematic solution for such patients. This was demonstrated in the work of Rocha et al. In a related donor setting, and definitely with unrelated donors, for bone marrow failure syndrome patients, it was clear that engraftment, and therefore event free survival (EFS) rates are not acceptable. The probability of myeloid engraftment at day 60 was not more than 67% for patients that were given related donor grafts, and it was 36% in unrelated donor-CBT. Only 33% of the Fanconi anemia patients engrafted [1]. Better results were reported by the European group when they summarized unrelated CBT for Fanconi patients. Although only 12 of the 93 cases were HLA identical; 60% of the patients engrafted by day 60. A positive impact of Fludarabine based regimens, cell dose, and CMV negative recipients was seen [36].

Some limited experience was gained by us with a few bone marrow failure syndromes, namely Fanconi anemia. We observed high rates of event free survival (EFS), especially in children who received a matched family donor transplant [37].

In one case we used a novel strategy of pre-implantation genetic diagnosis for one of the patients. This method, which is based on CBT, could pave the way for many malignant and non-malignant diseases [11].

Although the role of HSCT for Thalassemia in the era of newer iron chelating agents is yet to be determined, this strategy is still being practiced widely in an attempt to cure this hemoglobinopathy. Locatelli et al reported results of related CBT in 44 children with hemoglobinopathies (Thalassemia and Sickle Cell Disease), and showed that this procedure is feasible. High rates of engraftment (89% at day 60) and EFS (79% for Thalassemia and 90% for Sickle Cell Disease) were achieved [61].

As for CBT in inborn errors of metabolism, Staba et al reported impressive results in children with Hurler syndrome who were given unrelated donors CB grafts. Even though 19 of the 20 patients received mismatched grafts, high rates of engraftment were reported (at 2.4 years follow-up, 85%). This was probably due to the relatively high nucleated cells doses (median of 10.5x10⁷ nucleated cells/kg). The disease itself was cured, as could be seen in all 17 patients who were alive, and had normal peripheral-blood α-L-Iduronidase activity [95]. Recently a report of a case of a child who was cured of Wolman disease by a CBT was published [96].

CBT for the cure of Sickle Cell Anemia was reported recently by a French group. Importantly the authors noticed that after a 6 year follow up the group of patients that received a CB graft did not develop the main contributing factor for the morbidity, GVHD [10].

Investigational approaches in cord blood

Most patients needing HSCT are adults. For these heavier patients CB is a problematic solution because of the relatively low cell dose. Various strategies are being attempted in order to lower the toxicity of the conditioning regimen. This could be achieved either by lowering its intensity, or by hastening engraftment.

Reduced intensity conditioning

The practice of HSCT with reduced intensity conditioning (RIC) has emerged in the adult population. These older patients usually have pre-existing morbidities.

By reducing the intensity of the preparative regimen it has been shown that treatment-related morbidity and mortality rates could be lowered. The concept behind this is based on the assumption that in certain cases the immunological impact of the graft is more important than the ablative power of the conditioning regimen.

Experience with transplantations using RIC, though follow up time is still short, have shown encouraging results. Patients who benefit the most from RIC are those with diseases of a more indolent nature.

Few studies of RIC-CBT in adult and pediatric patients have been published. The major conclusion that could be drawn from these series is that RIC is feasible in CBT. Graft rejection happened mainly in cases in which the accumulative chemotherapy dose experienced by the recipients prior to the transplantation itself was low. Though survival rates are low, it must be emphasized that most studies included mainly high risk, heavily treated patients. GVHD rates correlated with unrelated donor BMT. Another encouraging finding is the lower than expected rates of treatment-related mortality at 100 days post-transplantation. Because of the small number of patients, and diversity of methods, conclusions regarding the optimal RIC conditioning regimen, or the GVHD prophylaxis, can not be drawn at this point. Even if it is definitely too early to recruit patients for RIC-CBT outside clinical trials for selected patients, these protocols could offer an alternative for selected patients [69, 27, 19, 20, 13, 6, 4, 104].

Engraftment hastening

The idea of shortening the period from transplantation to myeloid recovery is at the basis of many strategies. Some have shown preliminary encouraging results in the laboratory, in animal models, and even in clinical trials.

Transplantations with double cord blood units

Many recipients receive more than one partially matched CB units where the cell dose in each is not sufficient. In many cases the sum of these units provides an adequate number of SC. It has been shown in animal models that two CB units provide high rates of engraftment [71]. Some studies have used this strategy for high risk adult patients who received two mismatched CB units. Many believe that this strategy could pave the way for lowering treatment-related mortality rates in CBT. In most of these trials two encouraging facts were observed: stable mixed chimerism, and no mutual rejection of mismatched units [7, 8, 25, 39, 5]. Brunstein et al have shown that by using a non-myeloablative regimen for CBT in adults, the OS of the group that received 2 units was higher than the patients who received 1 unit. In this study 92% of the patients achieved neutrophil recovery, at a median time of 12 days [16]. Interestingly, sustained hematopoiesis after double CBT is usually derived from a single donor. The relative percent viability, the infused number of NC and CD34⁺ cell doses, and the donor–recipient HLA-disparity are not helpful in predicting which of the two CB units will predominate. Although early data suggested that the dominant unit had a higher median infused CD3⁺ cell dose, this observation has not persisted with investigation of a larger cohort of patients. Order of infusion, location of HLA mismatch, ABO blood group and/or sex mismatch also did not have a predictive effect on engraftment.

Double CBT can potentially produce a better graft versus leukemia effect. This was demonstrated in a study of the University of Minnesota. They compared leukemia patients who received 2 units of CB to those who received a single unit. The group who received the double CBT had a lower risk for relapse. It is still not known if the relatively high degree of HLA mismatch in this setting is responsible. It might also be a consequence of non-HLA disparity, such as KIR mismatch, between the CB units and the recipient, or between themselves [100].

Double unit transplantation has become a major breakthrough in the field of CB during the last 2 years. Several 2 arms protocols for using double units are on their way. Whether these expectations are justified depends on preliminary results of these trials.

Co transplantation with a Haploidentical donor

Relaying on the assumption that almost every patient has a donor, namely a parent that has a similar HLA type of one of his haplotypes, Magro et al have succeeded in transplanting CB together with a Haploidentical graft. They succeeded in inducing a rapid engraftment via a BM transplant. By administering only a small dose of Haploidentical SC, the Spanish team managed to induce a temporary engraftment only. These cells were rejected later, due to their low dose and significant HLA disparity, allowing engraftment of the CB graft. 69% of these high risk patients survived at 4 years [65].

Intra-osseous transplantation

One of the obstacles to a short period of engraftment is the possibility that the homing process is influenced by anatomical barriers. It has been suggested that intra BM injection of the graft could induce a rapid engraftment. This has been shown to be feasible, and has improved engraftment kinetics in BMT in adults [41]. Time will tell if intra osseous transplantation could shorten the way for CB's SC into the BM, and therefore improve time to engraftment, as has been shown in animal models [103, 102]. 

Ex vivo expansion of hematopoietic stem cells

In vitro studies had shown that SC proliferate with the addition of cytokines. But uncontrolled expansion is not biologically satisfactory, since maturation and differentiation of SC occur in these conditions. The SC proliferate and become committed to specific hematopoietic cell lines. Such cells lack what is known as "long term population ability." The optimal composition of the cytokine-rich media of the ex vivo expansion process is an important challenge for researchers to face. It has been demonstrated by Shpall et al that co transplantation of ex vivo expanded and non-manipulated grafts are feasible. But in spite of this, improvements in engraftment kinetics, are yet to be achieved [15, 80, 47, 91, 92, 44, 75].

Different attitudes have been taken in order to refine the expansion process, namely: co-culturing with different cells as feeder layers [105, 21], selection of SC for the expansion [30], and multiplying the proliferative potential by performing a two step harvesting technique [66, 81]. None of these strategies have yet been introduced into clinical trials.

A somewhat more promising field is interference with the differentiation of expanded SC. Reports have been published recently regarding ex vivo expansion with copper chelator, Tetraethylenepentamine (TEPA), which enhances the long term populating ability of the CB cells. Following large scale experiments, this appealing approach has been introduced into the clinic in phase I trials. Preliminary encouraging results of this trial with no significant toxicity were presented recently [76-78, 40, 93]. A Phase II multi center study has just started and the first 3 adult patients with hematological malignancies have already been recruited [26]. The same concept was behind the experiment held by Nolta et al, when they co-cultured primitive CB's SC (CD34⁺ CD38^-) together with a feeder layer of immortalized murine stromal cell-line AFT024. This method has yielded high rates of myeloid and lymphoid engraftment in a NOD/SCID mouse xenograft model [74]. Other molecules that play major roles in the differentiation of hematopoietic cells, and might be used in the future for ex vivo expansion of CB are Gfi-1 and some of the Notch ligand protein family [52, 53, 42]. Novel methods have been studied recently with the use of epigenetic factors. Silencing of genes could be a consequence of methylation of their promoters or deacetylation of histones. By trying to inhibit these processes, reactivation of some genes could augment the hematopoietic SC's self renewal potential. Recent publications have shown some success in the in vitro repopulating potential of CB when using histone deacetylase inhibitors, such as Valproic acid [7, 24]. This strategy is  the basis of a clinical study which has recruited the first patients (personal communications).

Cord Blood, Umbilical cord, and Mesenchymal Stem Cells

As their unique qualities are revealed, the interest in mesenchymal stem cells (MSCs) is growing continuously. These cells are non-hematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues, but possibly also to other tissue lineages. They have an in vitro expansion ability while their growth and differentiation potential is maintained. Currently it is expected that they could be used for tissue repair and regenerative medicine. MSCs have shown that they can modulate immune response both in vitro and in vivo. Preliminary studies are on their way for using MSCs as an anti GVHD prophylaxis. It was doubted that these cells could also play a roll in treating GVHD. It has also been postulated that these cells could be used for other immune mediated diseases. MSCs are used as a growing medium for ex vivo expansion of other cells [67, 84]. Le Blanc et al showed that MSCs could be transfused in parallel to HSC grafts and demonstrated fast engraftment [54]. Finally, MSCs are considered to be candidates as a vector for gene therapy.

Until recently only BM and adipose tissue were considered as a source for MSC. In the last few years it had been shown that CB contains MSC [55]. MSC from other sources has been demonstrated to have suppressive effect on T cells [58]. Few studies have focused on the different properties of MSC originating from CB. Their tendency to differentiate into specific tissue, their genomic expression, and proliferative response, are all different from BM or adipose tissue MSC [18, 46].

When considering the expulsion of the placenta at the end of delivery as a waste of a precious source of SCs, it is not only the CB itself that should be regarded as such. The Wharton jelly in the umbilical cord has also been found to be a source for MSCs [31, 90].

Cord blood uses in other fields

Gene transfer is an exciting new field in which CB could serve as a vector for correcting inborn genetic errors, or replace infected hematopoietic SC, such as in the case of HIV. Its availability, proliferative response, and engraftment potential, make it an appealing candidate for these uses [43]. Clinical trials of gene transfer to Adenosine Deaminase deficient Severe Combined Immunodeficiency children relied on BM and CB as a hematopoietic SC source. This method faced some obstacles that continue to prevent it from curing these patients [48, 2].

Another – to date only investigational – field is the potential non-hematopoietic use of hematopoietic SC. In recent years much interest has been focused on the ability of hematopoietic SC to differentiate into (or as some claim, to fuse with) cells of other tissues. It was demonstrated that cells with pluripotent differentiation potential could be found in CB [79, 72, 38]. CB has been suggested to have a role in improving performance of rats who were subjected to brain infarct [99]. CB is also considered by some to be a source of SC for regeneration of ischemic heart tissue by differentiation processes or neoangiogenesis [63]. It is too early to define whether SC's plasticity might have clinical benefits in repairing injured tissues, but this application is at the center of great interest and controversy.

Discussion

CB has become a legitimate source, not only for HSC for transplantations, but also for other uses. The experience gained in the last twenty years of work with CBT has shown us its advantages, as well as its setbacks.

Unlike BM donations, CB's collection is easier and poses no danger to the donor. In CB banks there is a greater proportion of ethnic minorities than in BM registries. It also has greater availability in an unrelated donor HSCT due to its shorter donor search time. Lesser risk for transmission of infectious agents in the transplantation process is another benefit of CB. There is no doubt that fewer HLA restrictions in unrelated transplantations is its main advantage. This fact allows successful transplantations with acceptable rates of graft failure and GVHD.

On the other hand, there is a slim potential for disease transmission, namely genetic, in CBT setup. In CBT there is almost no option for a second transplantation, or any boost of cells. A troubling disadvantage of CB is its low number of hematopoietic SC in each unit. This has proven to be a crucial point that has a direct relationship to relatively high rates of treatment-related mortality rates in CBT. This point is further emphasized within the setting of adult transplantations.

From the data collected in several series of CBT for both malignant and non malignant diseases it appears that CB can be used as a SC source in several settings.

The most urgent need for SC is transplantation for malignant diseases from unrelated donors. It is an acceptable approach to search first for BM donor. If a 5/6 or better HLA match can not be found, or progressive disease status does not allow completion of the search, then a CBT of 4/6 HLA match or better should be performed. This of course depends on a minimal cell dose of 2x10⁷ nucleated cells/kg per CB unit. Cell dose has greater relevancy in adult transplantation setup. Skepticism about the possibility of CBT in heavier patients might fade as newer strategies could overcome SC scarceness of nucleated cells in CB. At this stage the most appealing strategy is the double unit CBT. By receiving 2 CB units many adults could be transplanted with a reasonable time to engraftment. Time will tell if other methods could offer a solution for a better outcome in CBT for adults.

Impressive progress is constantly being achieved in the field of CBT. CB is still considered a second best choice for HSCT, but as newer reports are being published it is not so obvious whether it could not be preferred over BM. Interesting data in children showed that a perfect match (6/6) of CB could be the best choice. If larger studies can confirm this, we might see CB becoming the first option for transplantation in certain conditions.

For non malignant disease CB is a very good option, especially for the smaller patients. Caution should be practiced when using CB for bone marrow failure syndrome, though again it seems that larger units and better preparative regimens may overcome the tendency for graft failure.

Future uses of CB may not be just for HSCT. Time will tell if the fields of gene therapy and non hematopoietic injured tissues repair also benefit from the use of CB cells.

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["PROPERTY_VALUE_ID"]=> string(5) "10537" ["VALUE"]=> array(2) { ["TEXT"]=> string(116) "<p class="Autor">Гэл Гольдштейн, Амос Торен, Арнон Наглер<p/>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(94) "

Гэл Гольдштейн, Амос Торен, Арнон Наглер

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10538" ["VALUE"]=> array(2) { ["TEXT"]=> string(4975) "<p class="bodytext">Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных. </p> <p class="bodytext">Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга. </p> <p class="bodytext">Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4909) "

Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных.

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга.

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10526" ["VALUE"]=> string(28) "10.3205/ctt2008-05-27-001-en" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(28) "10.3205/ctt2008-05-27-001-en" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10550" ["VALUE"]=> array(2) { ["TEXT"]=> string(154) "<p class="Autor">Gal Goldstein¹, Amos Toren¹, Arnon Nagler²</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(96) "

Gal Goldstein¹, Amos Toren¹, Arnon Nagler²

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10551" ["VALUE"]=> array(2) { ["TEXT"]=> string(345) "<p class="bodytext">¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;<br>²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(293) "

¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples.

Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects.

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Gal Goldstein¹, Amos Toren¹, Arnon Nagler²

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Gal Goldstein¹, Amos Toren¹, Arnon Nagler²

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10552" ["VALUE"]=> array(2) { ["TEXT"]=> string(2916) "<p class="bodytext">The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates. </p> <p class="bodytext">Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples. </p> <p class="bodytext">Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2838) "

The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples.

Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects.

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The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples.

Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects.

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¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных. </p> <p class="bodytext">Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга. </p> <p class="bodytext">Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4909) "

Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных.

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга.

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).

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Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных.

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга.

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).

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Multiple myeloma (MM)

MM is malignant growth of plasma cells, which are terminally differentiated B lymphocytes ¹⁷. The disease is characterized by production of monoclonal immunoglobulin, by anemia, and by destruction of bone. The malignant myeloma cells are usually located in the bone marrow (BM). 

Despite some advances in treatment in recent years, MM still is a persistently fatal disease with a median patient survival time of three to four years from the time of diagnosis. In addition to the dismal prognosis, patients also experience substantial morbidity during the course of the disease. MM therefore continues to be a serious health problem. Standard front-line therapy for patients with MM includes the chemotherapeutic agents melphalan and prednisone, drugs that have been used for this purpose for more than 40 years. Recently, immunomodulatory drugs with putative effect against formation of new blood vessels (e.g., thalidomide), as well as botezomib, a member of an entirely new class of drugs: so-called protesome inhibitors, have shown effects in subsets of patients with MM¹⁸. However, there is an urgent need for better therapy that is targeted at the weak points of MM.

Our understanding of the molecular etiology of MM has increased enormously over the past ten years^5;19. Approximately 50% of patients have translocations affecting the immunoglobulin heavy chain locus on chromosome 14. The translocation partner varies, but close to the breakpoint in the partner chromosome, there is a (putative) oncogene that is placed under transcriptional control of an enhancer normally controlling the immunoglobuline heavy chain gene. The ch14 translocations are believed to be early events in the development of MM, and are also present with roughly the same frequency in the premalignant condition “monoclonal gammopathy of undetermined significance”(MGUS) as in overt MM. (There is only a one percent chance per year of progressing from MGUS to MM, so the majority of MGUS cases never develop into MM.) The other 50% of MM cases do not have ch14 translocations, and the early and crucial genetic aberrations in this group of patients are still unknown, but overall, these cases tend to have hyperdiploidy with trisomy of a several recurrent chromosomes. A common theme in all patients with MM is the expression of various isoforms of the cell cycle regulatory protein cyclin-D⁵.

Myeloma cells usually do not grow for longer periods in vitro, despite addition of rich growth medium and growth factors. It is generally believed that the cells are dependent on currently unknown factors in the microenvironment of the bone marrow for growth and for protection against apoptosis. At the same time the malignant cells exert a profound influence on the same microenvironment. In overt myeloma there is increased bone marrow angiogenesis⁴⁰ and – in most cases – perturbed bone homeostasis^2;3. It has been known for more than three decades that myeloma cells stimulate osteoclasts, the bone-resorbing cells²⁸. A simultaneous reduction in bone formation, leading to an unbalanced bone metabolism with ensuing erosion of bone substance⁴ was also observed many years ago. Factors produced by myeloma cells and either secreted or presented on the cell surface, are believed to be responsible for the perturbed microenvironment, and many candidate factors have been proposed as being responsible for increased bone resorption, with variable experimental documentation.

Role of HGF in the pathogenesis of MM: a mediator of autocrine loops

In 1996 we showed for the first time that myeloma cells express the receptor for HGF, c-Met, and at the same time often produce the ligand HGF⁷. This simultaneous expression of a cytokine and its receptor in the same cell was suggestive of an autocrine stimulatory loop, and we were able to demonstrate that c-Met was indeed activated in the myeloma cell line JJN-3 in an autocrine fashion⁸. Autocrine HGF-driven growth loops have also been demonstrated in other MM cell lines²⁵. Later we showed that high levels of HGF in the serum of a patient with MM at the time of diagnosis was an adverse prognostic sign, a finding that has been confirmed by others^26;32. Recently, we and others have demonstrated that HGF stimulates growth and survival of myeloma cells, and that HGF uses the myeloma marker protein syndecan-1 (CD138) as a co-receptor^13;31. It has also been shown that myeloma cells express HGF activator, an enzyme converting pre-HGF into the active form of the growth factor³⁹. Pre-HGF can also be converted to HGF by urokinase plasminogen activator (uPA)²⁹. This enzyme is also produced by MM cells²⁰. HGF could also be involved in the migration of myeloma cells to the bone marrow⁴¹. HGF is important in promoting adherence of MM cells to fibronectin, a matrix protein in the bone marrow environment²³. Such adhesion is beneficial to the MM cells in the sense that it increases cell proliferation. HGF is also a potent angiogenic factor, and there is a positive correlation between HGF levels in serum and bone marrow angiogenesis in patients with MM, suggesting HGF's role in the excessive angiogenesis seen in these patients¹. In an abstract presented to the 2006 ASH meeting, D. Hose and colleagues presented data showing that among 89 proangiogic genes only HGF was significantly overexpressed in MM cells compared to normal bone marrow plasma cells²⁴.

HGF expression is characteristic of malignant plasma cells and distinguishes MM from other closely related diseases

The first comprehensive gene array study of MM by Zhan et al., comparing gene expression in MM cells with that in normal plasma cells, showed that HGF was the only secreted growth factor on the list of the 70 genes that were the most up-regulated of more than 5000 examined genes⁴⁴. Interestingly, HGF was not only expressed in overt MM, but also in BM plasma cells from a majority of patients with MGUS, indicating that initiation of HGF expression is an early event in the transformation of healthy cells into malignant MM cells (Erming Tian and John D. Shaughnessy Jr., personal communication). A recently published gene array study by Chng et al. showed that expression of HGF together with IL-6, a potent growth factor for MM cells, was characteristic for a subgroup of patients with hyperdiploid MM¹⁰. In another study, using comparative genomic hybridization (aCGH) analysis, recurrent gene copy number alterations were identified, and 47 areas of recurrent gene amplifications were found⁹. HGF was located within a small recurrent amplification that included a total of four genes, and HGF was found to be the only one of those genes with an oncogene-like expression pattern. This amplification was present in more than 40% of patients, and the finding indicates that gene aberrations leading to HGF expression are part of the oncogenic development leading to MM.

In order to identify the gene expression that is important for the specific clinical manifestations of MM, a logical approach would be to compare the gene expression profile of MM cells with that of cells from closely related diseases. This was done with gene array analysis of purified malignant cells from patients with chronic lymphocytic leukemia, Waldenstom macroglobulinemia and MM.¹¹ Again, HGF stood out as one of the genes that characterized MM as opposed to the two other diseases. Interestingly, the HGF receptor c-Met was also on this list of MM-related genes.

Disturbance of key regulators of bone homeostasis in patients with MM

Skeletal tissue in healthy people is constantly undergoing a balanced remodeling process, where osteoclasts resorb bone and are followed by osteoblasts forming bone. Central to this regulation are specific factors that act directly on osteoclasts and are downstream mediators for many of the systemic bone-active factors. It has become clear that osteoblasts play a crucial role in the direct regulation of osteoclast activity. Osteoblasts express the cell surface protein RANKL, which is necessary for osteoclast differentiation⁴³. Furthermore, the osteoblasts express a soluble decoy receptor for RANKL, osteoprotegerin (OPG)³⁵. The balance between the two osteoblast products, RANKL and OPG, seems to be critical for the regulation of bone homeostasis.

We have found that multiple myeloma patients have reduced levels of soluble OPG in bone marrow plasma compared to healthy controls³³ and others have found that there is also an increased expression of RANKL in the MM bone marrow³⁰. OPG contains a heparin binding site and may bind to heparan sulfates on cells in the bone marrow. We have shown that MM cells bind OPG, presumably via the heparan sulfate-containing protein Syndecan-1⁶. Moreover, we found that this binding led to internalization and degradation of OPG by the myeloma cells³⁷, thereby providing one possible explanation for the reduced OPG levels in the bone marrow of multiple myeloma patients.

Inhibition of bone formation is important for skeletal destruction in patients with MM

In patients with MM, the balanced process of bone remodeling is upset, leading to degradation of bone and to skeletal morbidity. Intensive research has been conducted to try to unravel the mechanism causing this bone disease. For several decades, the research focus was on factors leading to untimely activation of osteoclasts, although it had long beenrealized that perturbationin osteoblast function might be equally important⁴. In a mouse model of MM with severe bone disease, osteoblasts were virtually non-existent²². Lately, the focus has moved from osteoclasts to osteoblasts, and several papers have contributed to our understanding of osteoblast inhibition^34;38. Searching for a correlation between gene expression in purified primary MM cells and level of bone disease in the patients, Tian and colleagues identified DKK1, an inhibitor of Wnt signaling, as a prime suspect for the destruction of bone in MM patients³⁸. They found that DKK1 inhibited the differentiation of osteoblast precursors into mature bone-forming osteoblasts. Later studies seem to confirm that DKK1 is linked to excessive bone disease and that it works by inhibiting the formation of osteoblasts^16;42. Interestingly, genes that encode known osteoclast-regulating factors, such as RANKL, RANK, OPG, MIP1, PTHrP, and IL-1, did not show a significant relationto the presence of bone disease²⁷. This is not a proof against these factors as important for bone destruction in MM, but argues against MM cells as the source of them. Similarly, osteoclast-activating factors were conspicuously absent from the list of gene expression that was characteristic for MM cells; as opposed to cells from chronic lymphocytic leukemia and Waldenstom macroglobulinemia¹¹. Bone disease is not a common clinical trait of the latter two diseases, and one would expect the genes that are responsible for this hallmark of MM to be present on the list of genes that define the specific cancer phenotype of MM. Like HGF and c-Met, DKK1 was high up on this list, further supporting the role of DKK1 in promoting the bone disease that is linked to MM.

HGF inhibits bone morphogenetic protein-induced differentiation of mesenchymal stem cells into bone-forming osteoblasts

Since HGF is one of the genes distinguishing malignant plasma cells from healthy plasma cells, and also defines malignant plasma cells as opposed to other closely related malignant cells, it was logical to see whether HGF played a role in bone homeostasis. It had been previously published that HGF induces bone resorption by osteoclasts, but only in the presence of osteoblasts¹⁵. This indirect effect on osteoclasts could be partly through HGF-induced production of IL-11, an osteoclast-stimulating cytokine²¹. Bone morphogenetic proteins (BMP) promote differentiation of osteoblast precursors from mesenchymal stem cells (MSCs) and further maturation into bone forming osteoblasts. Experiments by our group showed that HGF inhibited BMP-induced expression of alkaline phosphatase in human MSCs and in the murine myoid cell line C2C12³⁶. HGF also prevented BMP-induced mineralization by human MSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. Interestingly, HGF promoted proliferation of human MSCs, whereas BMP halted the proliferation. Again, HGF was a key regulator, keeping the cells in a proliferative, undifferentiating state despite the presence of BMP. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation as to how HGF inhibits BMP signaling. These findings support a role of HGF similar to that of DKK1. By preventing MSCs from becoming mature osteoblasts, the osteoblast precursors are arrested in an intermediate stage of differentiation, where they express RANKL, an osteoclast-stimulating protein. Therefore, instead of contributing to bone repair, these cells promote the bone-destruction process: bone homeostasis is no longer balanced. Was there any clinical evidence that HGF really played this role as an osteoblast inhibitor in patients? Yes, the in vitro data were supported by the observation of a significant negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase, in sera from 34 patients with myeloma³⁶.

Targeting HGF hepatocyte growth factor and its receptor c-Met in multiple myeloma

Since expression of HGF seems to be an early oncogenic event in the development of MM, and due to HGF’s many effects on disease manifestations, it might be an attractive target in treatment of MM. A host of new pharmacological inhibitors of c-Met are in the pipelines of the pharmaceutical industry. Possible HGF inhibitors include small molecular drugs and antibodies, as well as naturally occurring splice variants of HGF with antagonistic or partially antagonistic effects on c-Met. NK4 belongs to the latter group: a variant of HGF that lacks part of the full molecule¹². This molecule was shown to block growth of MM cell line cells in a mouse model, an effect that was believed to be a combination of direct anti-proliferative effect of the drug on MM cells, as well as an indirect, anti-angiogenic effect on formation of new blood vessels¹⁴. PHA-665752, a novel pharmacological inhibitor of c-Met from Pfizer belongs to the group of small molecular inhibitors. This molecule prevented HGF-driven autocrine loops in an MM cell line, as well as in freshly isolated MM cells from myeloma patients²⁵. No in vivo data on effects on MM cells of small-molecule inhibitors of c-Met have been published yet, and no clinical trial with c-Met inhibitors has been started so far. However, the data from such studies are sure to be met with great anticipation.

References

1.   Andersen NF, Standal T, Nielsen JL et al. Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. Br.J.Haematol. 2005;128:210-217.

2.   Bataille R, Chappard D, Basle M. Excessive bone resorption in human plasmacytomas: direct induction by tumour cells in vivo. Br.J.Haematol. 1995;90:721-724.

3.   Bataille R, Chappard D, Klein B. Mechanisms of bone lesions in multiple myeloma. Hematol.Oncol.Clin.North Am. 1992;6:285-295.

4.   Bataille R, Chappard D, Marcelli C et al. Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease. J.Clin.Oncol. 1989;7:1909-1914.

5.   Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J.Clin.Oncol. 2005;23:6333-6338.

6.   Borset M, Hjertner O, Yaccoby S, Epstein J, Sanderson RD. Syndecan-1 is targeted to the uropods of polarized myeloma cells where it promotes adhesion and sequesters heparin-binding proteins. Blood 2000;96:2528-2536.

7.   Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A. Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 1996;88:3998-4004.

8.   Borset M, Lien E, Espevik T et al. Concomitant expression of hepatocyte growth factor/scatter factor and the receptor c-MET in human myeloma cell lines. J.Biol.Chem. 1996;271:24655-24661.

9.   Carrasco DR, Tonon G, Huang Y et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006;9:313-325.

10.   Chng WJ, Kumar S, Vanwier S et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 2007;67:2982-2989.

11.   Chng WJ, Schop RF, Price-Troska T et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006;108:2755-2763.

12.   Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett. 1997;420:1-6.

13.   Derksen PW, Keehnen RM, Evers LM et al. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood 2002;99:1405-1410.

14.   Du W, Hattori Y, Yamada T et al. NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells in vivo; molecular targeting of angiogenic growth factor. Blood 2006

15.   Grano M, Galimi F, Zambonin G et al. Hepatocyte growth factor is a coupling factor for osteoclasts and osteoblasts in vitro. Proc Natl Acad Sci USA 1996;93:7644-7648.

16.   Haaber J, Abildgaard N, Knudsen LM et al. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br.J.Haematol. 2007

17.   Hallek, M., Bergsagel, P. L., and Anderson, K. C. Multiple myeloma: Increasing evidence for a multistep transformation process. Blood 91, 3-21. 1998.

18.   Hayden PJ, Mitsiades CS, Anderson KC, Richardson PG. Novel therapies in myeloma. Curr.Opin.Hematol. 2007;14:609-615.

19.   Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607-618.

20.   Hjertner O, Qvigstad G, Hjorth-Hansen H et al. Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells. Br.J.Haematol. 2000;109:815-822.

21.   Hjertner O, Torgersen ML, Seidel C et al. Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease. Blood 1999;94:3883-3888.

22.   Hjorth-Hansen H, Seifert MF, Borset M et al. Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. J.Bone Miner.Res. 1999;14:256-263.

23.   Holt RU, Baykov V, Ro TB et al. Human myeloma cells adhere to fibronectin in response to hepatocyte growth factor. Haematologica 2005;90:479-488.

24.   Hose D, Devos J, Heib C et al. Angiogenesis in multiple myeloma (MM): Angiogenic switch or reflexion of plasma cell number? A gene expression based survey in primary myeloma cells and the bone marrow microenvironment. Blood 2006;108:972A-973A.

25.   Hov H, Holt RU, Ro TB et al. A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin.Cancer Res. 2004;10:6686-6694.

26.   Iwasaki T, Hamano T, Ogata A et al. Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma. Br.J.Haematol. 2002;116:796-802.

27.   Lu CM. DKK1 in multiple myeloma. N.Engl.J.Med. 2004;350:1464-1466.

28.   Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the Secretion of an Osteoclast Stimulating Factor in Myeloma. N.Engl.J.Med. 1974;291:1041-1046.

29.   Naldini L, Vigna E, Bardelli A et al. Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. J.Biol.Chem. 1995;270:603-611.

30.   Pearse RN, Sordillo EM, Yaccoby S et al. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc.Natl.Acad.Sci.U.S.A 2001;98:11581-11586.

31.   Seidel C, Borset M, Hjertner O et al. High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity. Blood 2000;96:3139-3146.

32.   Seidel C, Borset M, Turesson I et al. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. The Nordic Myeloma Study Group. Blood 1998;91:806-812.

33.   Seidel C, Hjertner O, Abildgaard N et al. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood 2001;98:2269-2271.

34.   Silvestris F, Cafforio P, Tucci M, Grinello D, Dammacco F. Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease. Br.J.Haematol. 2003;122:39-52.

35.   Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-319.

36.   Standal T, Abildgaard N, Fagerli UM et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood 2006

37.   Standal T, Seidel C, Hjertner O et al. Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 2002;100:3002-3007.

38.   Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N.Engl.J.Med. 2003;349:2483-2494.

39.   Tjin EP, Derksen PW, Kataoka H, Spaargaren M, Pals ST. Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator. Blood 2004;104:2172-2175.

40.   Vacca A, Ribatti D, Roncali L et al. Bone-Marrow Angiogenesis and Progression in Multiple Myeloma. Br.J.Haematol. 1994;87:503-508.

41.   Vande B, I, Asosingh K, Allegaert V et al. Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor. Leukemia 2004;18:976-982.

42.   Yaccoby S, Ling W, Zhan F et al. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106-2111.

43.   Yasuda H, Shima N, Nakagawa N et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc.Natl.Acad.Sci.U.S.A 1998;95:3597-3602.

44.   Zhan F, Hardin J, Kordsmeier B et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002;99:1745-1757.

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Multiple myeloma (MM)

MM is malignant growth of plasma cells, which are terminally differentiated B lymphocytes ¹⁷. The disease is characterized by production of monoclonal immunoglobulin, by anemia, and by destruction of bone. The malignant myeloma cells are usually located in the bone marrow (BM). 

Despite some advances in treatment in recent years, MM still is a persistently fatal disease with a median patient survival time of three to four years from the time of diagnosis. In addition to the dismal prognosis, patients also experience substantial morbidity during the course of the disease. MM therefore continues to be a serious health problem. Standard front-line therapy for patients with MM includes the chemotherapeutic agents melphalan and prednisone, drugs that have been used for this purpose for more than 40 years. Recently, immunomodulatory drugs with putative effect against formation of new blood vessels (e.g., thalidomide), as well as botezomib, a member of an entirely new class of drugs: so-called protesome inhibitors, have shown effects in subsets of patients with MM¹⁸. However, there is an urgent need for better therapy that is targeted at the weak points of MM.

Our understanding of the molecular etiology of MM has increased enormously over the past ten years^5;19. Approximately 50% of patients have translocations affecting the immunoglobulin heavy chain locus on chromosome 14. The translocation partner varies, but close to the breakpoint in the partner chromosome, there is a (putative) oncogene that is placed under transcriptional control of an enhancer normally controlling the immunoglobuline heavy chain gene. The ch14 translocations are believed to be early events in the development of MM, and are also present with roughly the same frequency in the premalignant condition “monoclonal gammopathy of undetermined significance”(MGUS) as in overt MM. (There is only a one percent chance per year of progressing from MGUS to MM, so the majority of MGUS cases never develop into MM.) The other 50% of MM cases do not have ch14 translocations, and the early and crucial genetic aberrations in this group of patients are still unknown, but overall, these cases tend to have hyperdiploidy with trisomy of a several recurrent chromosomes. A common theme in all patients with MM is the expression of various isoforms of the cell cycle regulatory protein cyclin-D⁵.

Myeloma cells usually do not grow for longer periods in vitro, despite addition of rich growth medium and growth factors. It is generally believed that the cells are dependent on currently unknown factors in the microenvironment of the bone marrow for growth and for protection against apoptosis. At the same time the malignant cells exert a profound influence on the same microenvironment. In overt myeloma there is increased bone marrow angiogenesis⁴⁰ and – in most cases – perturbed bone homeostasis^2;3. It has been known for more than three decades that myeloma cells stimulate osteoclasts, the bone-resorbing cells²⁸. A simultaneous reduction in bone formation, leading to an unbalanced bone metabolism with ensuing erosion of bone substance⁴ was also observed many years ago. Factors produced by myeloma cells and either secreted or presented on the cell surface, are believed to be responsible for the perturbed microenvironment, and many candidate factors have been proposed as being responsible for increased bone resorption, with variable experimental documentation.

Role of HGF in the pathogenesis of MM: a mediator of autocrine loops

In 1996 we showed for the first time that myeloma cells express the receptor for HGF, c-Met, and at the same time often produce the ligand HGF⁷. This simultaneous expression of a cytokine and its receptor in the same cell was suggestive of an autocrine stimulatory loop, and we were able to demonstrate that c-Met was indeed activated in the myeloma cell line JJN-3 in an autocrine fashion⁸. Autocrine HGF-driven growth loops have also been demonstrated in other MM cell lines²⁵. Later we showed that high levels of HGF in the serum of a patient with MM at the time of diagnosis was an adverse prognostic sign, a finding that has been confirmed by others^26;32. Recently, we and others have demonstrated that HGF stimulates growth and survival of myeloma cells, and that HGF uses the myeloma marker protein syndecan-1 (CD138) as a co-receptor^13;31. It has also been shown that myeloma cells express HGF activator, an enzyme converting pre-HGF into the active form of the growth factor³⁹. Pre-HGF can also be converted to HGF by urokinase plasminogen activator (uPA)²⁹. This enzyme is also produced by MM cells²⁰. HGF could also be involved in the migration of myeloma cells to the bone marrow⁴¹. HGF is important in promoting adherence of MM cells to fibronectin, a matrix protein in the bone marrow environment²³. Such adhesion is beneficial to the MM cells in the sense that it increases cell proliferation. HGF is also a potent angiogenic factor, and there is a positive correlation between HGF levels in serum and bone marrow angiogenesis in patients with MM, suggesting HGF's role in the excessive angiogenesis seen in these patients¹. In an abstract presented to the 2006 ASH meeting, D. Hose and colleagues presented data showing that among 89 proangiogic genes only HGF was significantly overexpressed in MM cells compared to normal bone marrow plasma cells²⁴.

HGF expression is characteristic of malignant plasma cells and distinguishes MM from other closely related diseases

The first comprehensive gene array study of MM by Zhan et al., comparing gene expression in MM cells with that in normal plasma cells, showed that HGF was the only secreted growth factor on the list of the 70 genes that were the most up-regulated of more than 5000 examined genes⁴⁴. Interestingly, HGF was not only expressed in overt MM, but also in BM plasma cells from a majority of patients with MGUS, indicating that initiation of HGF expression is an early event in the transformation of healthy cells into malignant MM cells (Erming Tian and John D. Shaughnessy Jr., personal communication). A recently published gene array study by Chng et al. showed that expression of HGF together with IL-6, a potent growth factor for MM cells, was characteristic for a subgroup of patients with hyperdiploid MM¹⁰. In another study, using comparative genomic hybridization (aCGH) analysis, recurrent gene copy number alterations were identified, and 47 areas of recurrent gene amplifications were found⁹. HGF was located within a small recurrent amplification that included a total of four genes, and HGF was found to be the only one of those genes with an oncogene-like expression pattern. This amplification was present in more than 40% of patients, and the finding indicates that gene aberrations leading to HGF expression are part of the oncogenic development leading to MM.

In order to identify the gene expression that is important for the specific clinical manifestations of MM, a logical approach would be to compare the gene expression profile of MM cells with that of cells from closely related diseases. This was done with gene array analysis of purified malignant cells from patients with chronic lymphocytic leukemia, Waldenstom macroglobulinemia and MM.¹¹ Again, HGF stood out as one of the genes that characterized MM as opposed to the two other diseases. Interestingly, the HGF receptor c-Met was also on this list of MM-related genes.

Disturbance of key regulators of bone homeostasis in patients with MM

Skeletal tissue in healthy people is constantly undergoing a balanced remodeling process, where osteoclasts resorb bone and are followed by osteoblasts forming bone. Central to this regulation are specific factors that act directly on osteoclasts and are downstream mediators for many of the systemic bone-active factors. It has become clear that osteoblasts play a crucial role in the direct regulation of osteoclast activity. Osteoblasts express the cell surface protein RANKL, which is necessary for osteoclast differentiation⁴³. Furthermore, the osteoblasts express a soluble decoy receptor for RANKL, osteoprotegerin (OPG)³⁵. The balance between the two osteoblast products, RANKL and OPG, seems to be critical for the regulation of bone homeostasis.

We have found that multiple myeloma patients have reduced levels of soluble OPG in bone marrow plasma compared to healthy controls³³ and others have found that there is also an increased expression of RANKL in the MM bone marrow³⁰. OPG contains a heparin binding site and may bind to heparan sulfates on cells in the bone marrow. We have shown that MM cells bind OPG, presumably via the heparan sulfate-containing protein Syndecan-1⁶. Moreover, we found that this binding led to internalization and degradation of OPG by the myeloma cells³⁷, thereby providing one possible explanation for the reduced OPG levels in the bone marrow of multiple myeloma patients.

Inhibition of bone formation is important for skeletal destruction in patients with MM

In patients with MM, the balanced process of bone remodeling is upset, leading to degradation of bone and to skeletal morbidity. Intensive research has been conducted to try to unravel the mechanism causing this bone disease. For several decades, the research focus was on factors leading to untimely activation of osteoclasts, although it had long beenrealized that perturbationin osteoblast function might be equally important⁴. In a mouse model of MM with severe bone disease, osteoblasts were virtually non-existent²². Lately, the focus has moved from osteoclasts to osteoblasts, and several papers have contributed to our understanding of osteoblast inhibition^34;38. Searching for a correlation between gene expression in purified primary MM cells and level of bone disease in the patients, Tian and colleagues identified DKK1, an inhibitor of Wnt signaling, as a prime suspect for the destruction of bone in MM patients³⁸. They found that DKK1 inhibited the differentiation of osteoblast precursors into mature bone-forming osteoblasts. Later studies seem to confirm that DKK1 is linked to excessive bone disease and that it works by inhibiting the formation of osteoblasts^16;42. Interestingly, genes that encode known osteoclast-regulating factors, such as RANKL, RANK, OPG, MIP1, PTHrP, and IL-1, did not show a significant relationto the presence of bone disease²⁷. This is not a proof against these factors as important for bone destruction in MM, but argues against MM cells as the source of them. Similarly, osteoclast-activating factors were conspicuously absent from the list of gene expression that was characteristic for MM cells; as opposed to cells from chronic lymphocytic leukemia and Waldenstom macroglobulinemia¹¹. Bone disease is not a common clinical trait of the latter two diseases, and one would expect the genes that are responsible for this hallmark of MM to be present on the list of genes that define the specific cancer phenotype of MM. Like HGF and c-Met, DKK1 was high up on this list, further supporting the role of DKK1 in promoting the bone disease that is linked to MM.

HGF inhibits bone morphogenetic protein-induced differentiation of mesenchymal stem cells into bone-forming osteoblasts

Since HGF is one of the genes distinguishing malignant plasma cells from healthy plasma cells, and also defines malignant plasma cells as opposed to other closely related malignant cells, it was logical to see whether HGF played a role in bone homeostasis. It had been previously published that HGF induces bone resorption by osteoclasts, but only in the presence of osteoblasts¹⁵. This indirect effect on osteoclasts could be partly through HGF-induced production of IL-11, an osteoclast-stimulating cytokine²¹. Bone morphogenetic proteins (BMP) promote differentiation of osteoblast precursors from mesenchymal stem cells (MSCs) and further maturation into bone forming osteoblasts. Experiments by our group showed that HGF inhibited BMP-induced expression of alkaline phosphatase in human MSCs and in the murine myoid cell line C2C12³⁶. HGF also prevented BMP-induced mineralization by human MSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. Interestingly, HGF promoted proliferation of human MSCs, whereas BMP halted the proliferation. Again, HGF was a key regulator, keeping the cells in a proliferative, undifferentiating state despite the presence of BMP. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation as to how HGF inhibits BMP signaling. These findings support a role of HGF similar to that of DKK1. By preventing MSCs from becoming mature osteoblasts, the osteoblast precursors are arrested in an intermediate stage of differentiation, where they express RANKL, an osteoclast-stimulating protein. Therefore, instead of contributing to bone repair, these cells promote the bone-destruction process: bone homeostasis is no longer balanced. Was there any clinical evidence that HGF really played this role as an osteoblast inhibitor in patients? Yes, the in vitro data were supported by the observation of a significant negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase, in sera from 34 patients with myeloma³⁶.

Targeting HGF hepatocyte growth factor and its receptor c-Met in multiple myeloma

Since expression of HGF seems to be an early oncogenic event in the development of MM, and due to HGF’s many effects on disease manifestations, it might be an attractive target in treatment of MM. A host of new pharmacological inhibitors of c-Met are in the pipelines of the pharmaceutical industry. Possible HGF inhibitors include small molecular drugs and antibodies, as well as naturally occurring splice variants of HGF with antagonistic or partially antagonistic effects on c-Met. NK4 belongs to the latter group: a variant of HGF that lacks part of the full molecule¹². This molecule was shown to block growth of MM cell line cells in a mouse model, an effect that was believed to be a combination of direct anti-proliferative effect of the drug on MM cells, as well as an indirect, anti-angiogenic effect on formation of new blood vessels¹⁴. PHA-665752, a novel pharmacological inhibitor of c-Met from Pfizer belongs to the group of small molecular inhibitors. This molecule prevented HGF-driven autocrine loops in an MM cell line, as well as in freshly isolated MM cells from myeloma patients²⁵. No in vivo data on effects on MM cells of small-molecule inhibitors of c-Met have been published yet, and no clinical trial with c-Met inhibitors has been started so far. However, the data from such studies are sure to be met with great anticipation.

References

1.   Andersen NF, Standal T, Nielsen JL et al. Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. Br.J.Haematol. 2005;128:210-217.

2.   Bataille R, Chappard D, Basle M. Excessive bone resorption in human plasmacytomas: direct induction by tumour cells in vivo. Br.J.Haematol. 1995;90:721-724.

3.   Bataille R, Chappard D, Klein B. Mechanisms of bone lesions in multiple myeloma. Hematol.Oncol.Clin.North Am. 1992;6:285-295.

4.   Bataille R, Chappard D, Marcelli C et al. Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease. J.Clin.Oncol. 1989;7:1909-1914.

5.   Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J.Clin.Oncol. 2005;23:6333-6338.

6.   Borset M, Hjertner O, Yaccoby S, Epstein J, Sanderson RD. Syndecan-1 is targeted to the uropods of polarized myeloma cells where it promotes adhesion and sequesters heparin-binding proteins. Blood 2000;96:2528-2536.

7.   Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A. Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 1996;88:3998-4004.

8.   Borset M, Lien E, Espevik T et al. Concomitant expression of hepatocyte growth factor/scatter factor and the receptor c-MET in human myeloma cell lines. J.Biol.Chem. 1996;271:24655-24661.

9.   Carrasco DR, Tonon G, Huang Y et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006;9:313-325.

10.   Chng WJ, Kumar S, Vanwier S et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 2007;67:2982-2989.

11.   Chng WJ, Schop RF, Price-Troska T et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006;108:2755-2763.

12.   Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett. 1997;420:1-6.

13.   Derksen PW, Keehnen RM, Evers LM et al. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood 2002;99:1405-1410.

14.   Du W, Hattori Y, Yamada T et al. NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells in vivo; molecular targeting of angiogenic growth factor. Blood 2006

15.   Grano M, Galimi F, Zambonin G et al. Hepatocyte growth factor is a coupling factor for osteoclasts and osteoblasts in vitro. Proc Natl Acad Sci USA 1996;93:7644-7648.

16.   Haaber J, Abildgaard N, Knudsen LM et al. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br.J.Haematol. 2007

17.   Hallek, M., Bergsagel, P. L., and Anderson, K. C. Multiple myeloma: Increasing evidence for a multistep transformation process. Blood 91, 3-21. 1998.

18.   Hayden PJ, Mitsiades CS, Anderson KC, Richardson PG. Novel therapies in myeloma. Curr.Opin.Hematol. 2007;14:609-615.

19.   Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607-618.

20.   Hjertner O, Qvigstad G, Hjorth-Hansen H et al. Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells. Br.J.Haematol. 2000;109:815-822.

21.   Hjertner O, Torgersen ML, Seidel C et al. Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease. Blood 1999;94:3883-3888.

22.   Hjorth-Hansen H, Seifert MF, Borset M et al. Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. J.Bone Miner.Res. 1999;14:256-263.

23.   Holt RU, Baykov V, Ro TB et al. Human myeloma cells adhere to fibronectin in response to hepatocyte growth factor. Haematologica 2005;90:479-488.

24.   Hose D, Devos J, Heib C et al. Angiogenesis in multiple myeloma (MM): Angiogenic switch or reflexion of plasma cell number? A gene expression based survey in primary myeloma cells and the bone marrow microenvironment. Blood 2006;108:972A-973A.

25.   Hov H, Holt RU, Ro TB et al. A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin.Cancer Res. 2004;10:6686-6694.

26.   Iwasaki T, Hamano T, Ogata A et al. Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma. Br.J.Haematol. 2002;116:796-802.

27.   Lu CM. DKK1 in multiple myeloma. N.Engl.J.Med. 2004;350:1464-1466.

28.   Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the Secretion of an Osteoclast Stimulating Factor in Myeloma. N.Engl.J.Med. 1974;291:1041-1046.

29.   Naldini L, Vigna E, Bardelli A et al. Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. J.Biol.Chem. 1995;270:603-611.

30.   Pearse RN, Sordillo EM, Yaccoby S et al. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc.Natl.Acad.Sci.U.S.A 2001;98:11581-11586.

31.   Seidel C, Borset M, Hjertner O et al. High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity. Blood 2000;96:3139-3146.

32.   Seidel C, Borset M, Turesson I et al. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. The Nordic Myeloma Study Group. Blood 1998;91:806-812.

33.   Seidel C, Hjertner O, Abildgaard N et al. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood 2001;98:2269-2271.

34.   Silvestris F, Cafforio P, Tucci M, Grinello D, Dammacco F. Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease. Br.J.Haematol. 2003;122:39-52.

35.   Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-319.

36.   Standal T, Abildgaard N, Fagerli UM et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood 2006

37.   Standal T, Seidel C, Hjertner O et al. Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 2002;100:3002-3007.

38.   Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N.Engl.J.Med. 2003;349:2483-2494.

39.   Tjin EP, Derksen PW, Kataoka H, Spaargaren M, Pals ST. Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator. Blood 2004;104:2172-2175.

40.   Vacca A, Ribatti D, Roncali L et al. Bone-Marrow Angiogenesis and Progression in Multiple Myeloma. Br.J.Haematol. 1994;87:503-508.

41.   Vande B, I, Asosingh K, Allegaert V et al. Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor. Leukemia 2004;18:976-982.

42.   Yaccoby S, Ling W, Zhan F et al. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106-2111.

43.   Yasuda H, Shima N, Nakagawa N et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc.Natl.Acad.Sci.U.S.A 1998;95:3597-3602.

44.   Zhan F, Hardin J, Kordsmeier B et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002;99:1745-1757.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(70) "rol-faktora-rosta-gepatotsitov-hgf-v-patogeneze-mnozhestvennoy-mielomy" ["~CODE"]=> string(70) "rol-faktora-rosta-gepatotsitov-hgf-v-patogeneze-mnozhestvennoy-mielomy" ["EXTERNAL_ID"]=> string(3) "769" ["~EXTERNAL_ID"]=> string(3) "769" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["ELEMENT_META_KEYWORDS"]=> string(253) "миеломная болезнь онкогематология фактор роста гепатоцитов RANK RANKL остеопротегерин (ОПГ) канцерогенез костная резорбция остеогенез обзор" ["ELEMENT_META_DESCRIPTION"]=> string(199) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломыHepatocyte growth factor (HGF) in the pathogenesis of multiple myeloma" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(10157) "<p class="bodytext">Множественная миелома (<strong>ММ</strong>)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. </p> <p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. </p> <p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). 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Борсет, Т. Стандал, А. Вааге, А. Сундан</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(91) "

М. Борсет, Т. Стандал, А. Вааге, А. Сундан

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10407" ["VALUE"]=> array(2) { ["TEXT"]=> string(10157) "<p class="bodytext">Множественная миелома (<strong>ММ</strong>)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. </p> <p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. </p> <p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(9747) "

Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов.

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ.

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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Magne Børset^1,2, Therese Standal¹, Anders Waage^1,3 and Anders Sundan¹

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¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; ³ Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.

Corresponding author:
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

Telephone: + 47 72573038,
Fax: + 47 73598801,
E-mail: magne.borset@ntnu.no

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HGF is emerging as a cytokine with an important role in the pathophysiology of multiple myeloma. Originally identified and described as a growth factor for hepatocytes, HGF was later found to have mitogenic, motogenic, or morphogenic effects on several cell types through its interaction with the tyrosine kinase receptor c-Met. This cytokine–receptor pair is implicated in the development and promotion of several types of cancer. The expression of both HGF and c-Met by myeloma cells is one of the traits distinguishing these cells from healthy plasma cells, and seems to be an early step in tumor development. HGF and c-Met have an effect on proliferation, migration, and adhesion of myeloma cells; and research suggests that myeloma cell-produced HGF is an important factor in angiogenesis and bone destruction seen in the majority of patients with multiple myeloma.

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Magne Børset^1,2, Therese Standal¹, Anders Waage^1,3 and Anders Sundan¹

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HGF is emerging as a cytokine with an important role in the pathophysiology of multiple myeloma. Originally identified and described as a growth factor for hepatocytes, HGF was later found to have mitogenic, motogenic, or morphogenic effects on several cell types through its interaction with the tyrosine kinase receptor c-Met. This cytokine–receptor pair is implicated in the development and promotion of several types of cancer. The expression of both HGF and c-Met by myeloma cells is one of the traits distinguishing these cells from healthy plasma cells, and seems to be an early step in tumor development. HGF and c-Met have an effect on proliferation, migration, and adhesion of myeloma cells; and research suggests that myeloma cell-produced HGF is an important factor in angiogenesis and bone destruction seen in the majority of patients with multiple myeloma.

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HGF is emerging as a cytokine with an important role in the pathophysiology of multiple myeloma. Originally identified and described as a growth factor for hepatocytes, HGF was later found to have mitogenic, motogenic, or morphogenic effects on several cell types through its interaction with the tyrosine kinase receptor c-Met. This cytokine–receptor pair is implicated in the development and promotion of several types of cancer. The expression of both HGF and c-Met by myeloma cells is one of the traits distinguishing these cells from healthy plasma cells, and seems to be an early step in tumor development. HGF and c-Met have an effect on proliferation, migration, and adhesion of myeloma cells; and research suggests that myeloma cell-produced HGF is an important factor in angiogenesis and bone destruction seen in the majority of patients with multiple myeloma.

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¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; ³ Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.

Corresponding author:
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

Telephone: + 47 72573038,
Fax: + 47 73598801,
E-mail: magne.borset@ntnu.no

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¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; ³ Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.

Corresponding author:
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

Telephone: + 47 72573038,
Fax: + 47 73598801,
E-mail: magne.borset@ntnu.no

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М. Борсет, Т. Стандал, А. Вааге, А. Сундан

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М. Борсет, Т. Стандал, А. Вааге, А. Сундан

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"Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(10) { [0]=> string(77) "миеломная болезнь" [1]=> string(74) "онкогематология" [2]=> string(90) "фактор роста гепатоцитов" [3]=> string(48) "RANK" [4]=> string(49) "RANKL" [5]=> string(83) "остеопротегерин (ОПГ)" [6]=> string(68) "канцерогенез" [7]=> string(77) "костная резорбция" [8]=> string(64) "остеогенез" [9]=> string(54) "обзор" } ["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(5) "10407" ["VALUE"]=> array(2) { ["TEXT"]=> string(10157) "<p class="bodytext">Множественная миелома (<strong>ММ</strong>)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. </p> <p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. </p> <p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(9747) "

Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов.

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ.

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов.

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ.

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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Cell therapy in medicine

The idea of utilizing cells for therapeutic purposes is by no means new. The Swiss physician Paul Niehans propagated, as early as 1931, different cell types as tools for rejuvenation and cure against diseases, a therapy he called ‘Zellulartherapie’, which has also been called ‘Frischzelltherapie’ [51]. Niehans treated a patient with tetany with injections of the parathyroid glands of an ox and the patient recovered. He also successfully treated Pope Pious XII. However, the use of animal cells was hampered by considerable side effects and this form of therapy subsequently was banned in Germany [76].

The best-known and most successful example of cell therapy is bone marrow transplantation. Lorenz showed in 1949 that lethally irradiated mice could be rescued by bone marrow cell infusion [43]. A first patient report of intravenous infusion followed by transient engraftment was published in 1957 [68] and in 1968-9 the first matched sibling transplantations were reported [20].  Bone marrow transplantation (BMT) is now established as the first successful cell therapy as a routine procedure for the treatment of formerly incurable leukemias and the pioneer of this therapy, E. Donnall Thomas, received the Nobel Price in Physiology in 1990 [49].

The concept of cell therapy

The initial intention of BMT was to replace the lethally injured and ablated organ with a new one to rescue the patient. However, it was recognized later that the infused bone marrow also has anti-leukemic properties, a phenomenon called graft-versus leukemia effect [32]. This represents a fundamental advantage of cell therapy over pharmaceutical approaches. Furthermore, cells are able to react in vivo depending on the different circumstances under normal and pathophysiological conditions, systemically through secretion of growth factors, cytokines or chemokines as well as through paracrine and local actions at the site of injury. Additionally, cells are able to integrate into tissues, either as differentiated parenchymal cells or as undifferentiated stromal cells, thereby affecting the organ of engraftment in the long run. These versatile properties make the development of cellular therapies promising and attractive.

Multipotent marrow stromal cells (MSCs)

Friedenstein showed that fibroblast like cells could be generated and propagated in vitro from bone marrow and called these cells ‘marrow stromal cells’ [19]. Due to their differentiation into osteocytes, chondrocytes and adipocytes they have also been called ‘mesenchymal stem cells’. These cells support hematopoietic stem cells (HSCs) by growth factor and cytokine secretion and differentiate into bone, cartilage and fat. MSCs have now been recognized as the second stem cell population in the bone marrow, next to HSCs, but can also be generated from almost any organ [10]. They are now defined by plastic adherence, positivity for the surface markers CD73, CD90 and CD105 and absence of CD45, CD34, HLA-DR [15].

Extensive in vitro and in vivo studies have shown that MSCs exhibit a potential to differentiate into various cell types (Graph 1). Lineage analyses of cloned MSCs showed that their natural differentiation pathway (‘default pathway’) is the osteogenic lineage and different clones exhibit different lineage potential in vitro [52]. Differentiation of MSCs into different cell types in vitro can be induced through culture conditions and addition of endogenous substances like steroids, growths factors or PPARs or by demethylation agents like 5-azacytidine [45]. MSCs are not a homogeneous population of cells, in vitro cultures are phenotypically different in size and shape, and can be generated from most organs [79]. MSCs are readily generated from bone marrow aspirations, can be expanded in culture on a large scale without the addition of xenogenic additives like fetal calf serum [37] and are susceptible to transduction with viral vectors which makes them ideal vehicles for cell therapy.

MSCs have been originally derived from the bone marrow by a protocol from Friedenstein, however, with subsequent variation in culture conditions different cell populations with similar but not identical properties like MSCs have been described by various groups. It is currently not entirely clear how these different ‘brands’ of MSCs are related in vivo or if they are derived from a “basic” MSC and how culture conditions, e.g. the addition of growth factors like EGF, a low oxygen environment, low serum conditions and seeding density influence propagation and differentiation potential after several passages in vitro. Verfaillie’s group generated multipotent adult progenitor cells (MAPCs) from the bone marrow under low density and low serum conditions and could show that they have embryonic stem cell like properties when injected into blastocysts [28]. So-called marrow-isolated adult multilineage inducible cells (MIAMI) were generated under low-oxygen tension on fibronectin from bone marrow cells [9]. Lange et al described a population of bone marrow-derived adult stem cells, separated on a Percoll gradient with low density, that showed an extraordinary high proliferative potential and a conserved phenotype characteristic of MSCs [38]. MSCs not only have been derived from bone marrow but from almost any organ [10].

Unrestricted somatic stem cells (USSCs) have been cultured from human cord blood [31]. The authors state that USSCs have a wider differentiation potential and differ in immunophenotype and in their mRNA expression profile. Not all groups have been successful in generating stem cell like cells from cord blood [46]. In contrast to Mareschi, Lee et al. found a mesenchymal stem cell like population derived from cord blood cells with classical characteristics of MSCs as well as differentiation into neuroglial- and hepatocyte-like cells under appropriate induction conditions. Adipose tissue contains MSCs that are easy to obtain from lipoaspirates [81]. Because they are easy to culture and readily available from different sources, MSCs continue to be a popular research subject with steadily increasing numbers of publications and applications.

Mechanisms of action of MSCs used in cell therapy and regenerative medicine

1. Replacement of injured cells by MSCs through differentiation and integration into organ parenchyma

Cellular differentiation is not an irreversible process. Pathologists know the phenomenon of differentiation of one cell type into another due to prolonged exposure to un-physiological stimuli in epithelia, e.g. gastric reflux causes the squamous epithelium of the esophagus to differentiate into gastric mucosa, and have termed it ‘metaplasia’. In the kidney, tubular cells de-differentiate after ischemic injury, re-express embryonic and developmental markers like Pax-2, and start dividing to repopulate the denuded tubular parts, thereby regenerating a sublethally injured tubule [75, 25].

In the late 1990s researchers described so far unknown and unexpected differentiation of HSCs into a number of cell types, e.g. liver and muscle [17, 55]. These results were surprising because a long held dogma stated that adult stem cells are lineage restricted and can only differentiate into tissue from their lineage and that differentiation is terminal [39]. This so called transdifferentiation was immediately recognized as a new and promising way of regeneration of injured tissue and proposed as a mechanism of action for cell therapy. However, initial enthusiasm led researchers to overlook some problems associated with early studies. These studies utilized crude cell preparations, e.g. whole bone marrow, and therefore it was not clear, which cell type was responsible for the observed phenomenon. Furthermore, transdifferentiation was very rare and only some dispersed single cells could be detected after a meticulous search, calling into question the therapeutic value of this approach. Krause et al in a very carefully conducted study showed, that a prospectively isolated HSCs are indeed the cell type responsible for tissue contribution and differentiation into most organ cells, but the contribution was below 0.1% [33].

Some time later two groups described fusion of cells in vitro and it was discussed, that this could be a potential explanation for the phenomena described in the early stem cell studies [67, 78]. Indeed, some groups attributed cell fusion as the main mechanism for organ regeneration in certain disease models [47, 72, 74].

Meticulous studies by Wagers and Balsam showed that transdifferentiation is an extremely rare event under steady state and ischemic conditions and HSCs do not contribute much to tissue turnover [73, 5].

The lessons learned from these studies with HSCs are:

• Transdifferentiation or plasticity is a real phenomenon but exceedingly rare in most disease models.

• Replacement of damaged tissue is therefore not a major mechanism for tissue regeneration.

• Under steady state conditions tissue replacement is rare and in  disease conditions it is dependent on the model and kinetics used to study transdifferentiation.

Based on initial observations with whole bone marrow and the fact that MSCs can be differentiated into a large number of differentiated cells in vitro and in vivo, e.g. neurons [57], cardiomyocytes [45], myocytes [11], endothelial cells [54, 41], pulmonary cells [53] and liver cells [34-36], it was hypothesized that differentiation of MSCs into organ parenchymal cells is a major mechanism of tissue protection and regeneration after injury. However, MCSs exhibited tissue repair capacity despite low or transient engraftment in vivo, e.g. in the treatment of osteogenesis imperfecta it was less than 1% [22], and therefore differentiation into target tissues is most likely only a minor mechanisms of tissue protection and regeneration. The fact that tissue protection is observed without evidence of long-term engraftment also argues against differentiation as a main mechanism of action [27].

2. Paracrine mechanisms

MSCs produce a number of cytokines, growth factors and adhesion molecules that have been shown to be involved in tissue homeostasis and regeneration [13]. Furthermore, transcriptome analysis by serial analysis of gene expression (SAGE) revealed a large number of transcripts for proteins involved in wound repair, immunological regulation, neural factors as well as angiogenesis [70, 56] implying a role for these factors in MSC mediated tissue regeneration. These factors stimulate cell proliferation (growth factors like IGF [24]) and are anti-apoptotic [7]. The advantage of administering MSCs rather than growth factors directly lies in the fact that MSCs act on a local level and are able to interact with damaged tissue, which means they probably respond to cytokines like TNF-a secreted by damaged tissue with more or less secretion of a number of growth factors or modulatory cytokines and thereby influence the local environment directly and better than any systemically administered growth factors [41, 62]. In the kidney, MSCs regenerate renal function after acute kidney injury mainly by secreting epidermal growth factor (EGF), insulin-like growth factor (IGF-1), VEGF and by changing the cytokine expression profile of the injured kidney towards a more favorable anti-inflammatory state with higher IL-10 levels [60, 69]. In the heart, MSCs stimulate angiogenesis by secretion of VEGF [1, 29]. Endogenous cell proliferation in the brain is stimulated by MSCs through paracrine mechanisms after injury mediated by different factors [44, 8].

3. Vasculo- and angiogenesis

Blood supply is the most critical factor for tissue survival and most injury mechanisms involve the vasculature in one way or another. Ischemic injury is the most common mechanism of tissue damage for every organ system and fast restoration of regular blood supply is critical for tissue survival. The microvascular bed can be damaged in many ways, but endothelial dysfunction or apoptosis are major factors. MSCs express a number of angiogenic and vasculogenic factors and proteins that have been shown to increase endothelial cell survival and proliferation [2, 23]. In vivo studies have shown that vasculo- and angiogenesis by MSCs is either mediated directly by integration into vascular structures or through paracrine mechanisms stimulating angiogenesis, e.g. secretion of VEGF, angiopoietin or other growth factors [2, 3, 65, 64, 77]. MSCs can be genetically engineered, using different strategies like bcl-2, Akt or erythropoietin expression, to enhance endogenous angiogenic activity [16, 21].

4. Immunomodulation

MSCs exhibit low immunogenity due to low or absent MHC-II expression, low MHC-I expression and negativity for costimulatory molecules CD80, CD86 and CD40. Therefore infusion of MSCs do not trigger a direct rejection reaction, although several groups have shown that MSCs are not neutral towards the immune system and antibodies can be measured as well as T cell activation but not proliferation [30, 58]. A large body of data shows immunomodulatory properties of MSCs in vitro on different cell types such as T-cells, B-cells and NK cells [18]. MSCs suppress T-cell proliferation in vitro, interfere with dendritic cell differentiation, inhibit B-cell proliferation and suppress the proliferation and cytokine production of natural killer cells [50]. The in vivo relevance of these in vitro finding has been demonstrated in humans with acute graft versus host (GvHD) and Crohn’s disease [61, 66]. In animal models MSCs have been shown to modify experimental autoimmune encephalitis, a model of multiple sclerosis, and prolonged skin graft survival in baboons [6, 71]. There are conflicting data about effects of MSCs in organ transplantation models. Inoue reported that MSCs were ineffective at prolonging allograft survival and tended to promote rejection [26]. In a different model cardiac allograft survival was prolonged [80]. MSCs also favored tumour survival in animal models [14].

While the currently known immunomodulatory effects of MSCs show promise for the treatment of a number of diseases, data have to be interpreted carefully dependent on the animal model or in vitro strategy. Culture conditions and numerous other factors not least the model that is studied play important roles and have to be considered carefully to avoid preliminary conclusions.

5. Other applications for MSCs

MSCs are ideally suited as cellular delivery systems in tumor treatment. They can be engineered to express the interferon-beta (IFN-beta) gene and deliver therapeutic doses of IFN-beta directly into the tumor through infiltration thereby suppressing tumor growth and metastasis [63]. In metabolic diseases and enzyme defects, either allogeneic or genetically engineered MSCs are able to function as enzyme replacement therapy [48] by providing necessary concentrations of an enzyme that is lacking due to a genetic defect. MSCs are rapidly transducable with different viral vectors and are thereby ideal vehicles for therapeutic genes [59]. Other important applications include adjunct infusion to enhance hematopoietic engraftment [4] and as a source for engineered tissue such as cartilage and bone in tissue engineering [12].

Conclusions

In the ongoing story of stem cell treatment for patients MSCs have been so far the most promising development and have rapidly advanced from bench to bedside with several products already in late stage trials. Although little is known about MSCs in vivo, they have been characterized extensively in vitro and clinical studies have been finished and new ones are on their way. The mechanisms of action of MSCs are currently investigated in detail and there is still a large number of questions to be addressed until the full therapeutic benefit of these cells can be utilized but the field is rapidly advancing and is giving a shining example for the whole stem cell community. 

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61. Ringden O, M Uzunel, et al. "Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.&ququot; Transplantation. 2006;81(10):1390-7.

62. Segers VF, I Van Riet, et al. "Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms." Am J Physiol Heart Circ Physiol. 2006;290(4):H1370-7.

63. Studeny M, Marini FC, et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst. 2004;96(21):1593-603.

64. Tang J, Q Xie, et al. "Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion." Eur J Cardiothorac Surg. 2006;30(2):353-61.

65. Tang YL, Q Zhao, et al. "Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction." Ann Thorac Surg. 2005;80(1):229-36;discussion 236-7.

66. Taupin P. "OTI-010 Osiris Therapeutics/JCR Pharmaceuticals." Curr Opin Investig Drugs. 2006;7(5):473-81.

67. Terada N, T Hamazaki, et al. "Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion." Nature. 2002;416(6880):542-5.

68. Thomas ED, HL Lochte, Jr, et al. "Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy." N Engl J Med. 1957;257:4-91-6.

69. Togel F, Z Hu, et al. "Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms." Am J Physiol Renal Physiol. 2005;289(1):F31-42.

70. Tremain N, J Korkko, et al. "MicroSAGE analysis of 2,353 expressed genes in a single cell-derived colony of undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages." Stem Cells. 2001;19(5):408-18.

71. Uccelli A, E Zappia, et al. "Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection." Expert Opin Biol Ther. 2006;6(1):17-22.

72. Vassilopoulos G, PR Wang, et al. "Transplanted bone marrow regenerates liver by cell fusion." Nature. 2003;422(6934):901-4.

73. Wagers AJ, RI Sherwood, et al. "Little evidence for developmental plasticity of adult hematopoietic stem cells." Science. 2002;297(5590):2256-9.

74. Wang X, H Willenbring, et al. "Cell fusion is the principal source of bone-marrow-derived hepatocytes." Nature. 2003;422(6934):897-901.

75. Witzgall R, D Brown, et al. "Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells." J Clin Invest. 1994;93(5):2175-88.

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77. Wu Y, L Chen, et al. "Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis." Stem Cells. 2007;25(10):2648-59.

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80. Zhou HP, DH Yi, et al. "Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft." Transplant Proc. 2006;38(9):3046-51.

81. Zuk PA, Zhu M, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279-95.

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Cell therapy in medicine

The idea of utilizing cells for therapeutic purposes is by no means new. The Swiss physician Paul Niehans propagated, as early as 1931, different cell types as tools for rejuvenation and cure against diseases, a therapy he called ‘Zellulartherapie’, which has also been called ‘Frischzelltherapie’ [51]. Niehans treated a patient with tetany with injections of the parathyroid glands of an ox and the patient recovered. He also successfully treated Pope Pious XII. However, the use of animal cells was hampered by considerable side effects and this form of therapy subsequently was banned in Germany [76].

The best-known and most successful example of cell therapy is bone marrow transplantation. Lorenz showed in 1949 that lethally irradiated mice could be rescued by bone marrow cell infusion [43]. A first patient report of intravenous infusion followed by transient engraftment was published in 1957 [68] and in 1968-9 the first matched sibling transplantations were reported [20].  Bone marrow transplantation (BMT) is now established as the first successful cell therapy as a routine procedure for the treatment of formerly incurable leukemias and the pioneer of this therapy, E. Donnall Thomas, received the Nobel Price in Physiology in 1990 [49].

The concept of cell therapy

The initial intention of BMT was to replace the lethally injured and ablated organ with a new one to rescue the patient. However, it was recognized later that the infused bone marrow also has anti-leukemic properties, a phenomenon called graft-versus leukemia effect [32]. This represents a fundamental advantage of cell therapy over pharmaceutical approaches. Furthermore, cells are able to react in vivo depending on the different circumstances under normal and pathophysiological conditions, systemically through secretion of growth factors, cytokines or chemokines as well as through paracrine and local actions at the site of injury. Additionally, cells are able to integrate into tissues, either as differentiated parenchymal cells or as undifferentiated stromal cells, thereby affecting the organ of engraftment in the long run. These versatile properties make the development of cellular therapies promising and attractive.

Multipotent marrow stromal cells (MSCs)

Friedenstein showed that fibroblast like cells could be generated and propagated in vitro from bone marrow and called these cells ‘marrow stromal cells’ [19]. Due to their differentiation into osteocytes, chondrocytes and adipocytes they have also been called ‘mesenchymal stem cells’. These cells support hematopoietic stem cells (HSCs) by growth factor and cytokine secretion and differentiate into bone, cartilage and fat. MSCs have now been recognized as the second stem cell population in the bone marrow, next to HSCs, but can also be generated from almost any organ [10]. They are now defined by plastic adherence, positivity for the surface markers CD73, CD90 and CD105 and absence of CD45, CD34, HLA-DR [15].

Extensive in vitro and in vivo studies have shown that MSCs exhibit a potential to differentiate into various cell types (Graph 1). Lineage analyses of cloned MSCs showed that their natural differentiation pathway (‘default pathway’) is the osteogenic lineage and different clones exhibit different lineage potential in vitro [52]. Differentiation of MSCs into different cell types in vitro can be induced through culture conditions and addition of endogenous substances like steroids, growths factors or PPARs or by demethylation agents like 5-azacytidine [45]. MSCs are not a homogeneous population of cells, in vitro cultures are phenotypically different in size and shape, and can be generated from most organs [79]. MSCs are readily generated from bone marrow aspirations, can be expanded in culture on a large scale without the addition of xenogenic additives like fetal calf serum [37] and are susceptible to transduction with viral vectors which makes them ideal vehicles for cell therapy.

MSCs have been originally derived from the bone marrow by a protocol from Friedenstein, however, with subsequent variation in culture conditions different cell populations with similar but not identical properties like MSCs have been described by various groups. It is currently not entirely clear how these different ‘brands’ of MSCs are related in vivo or if they are derived from a “basic” MSC and how culture conditions, e.g. the addition of growth factors like EGF, a low oxygen environment, low serum conditions and seeding density influence propagation and differentiation potential after several passages in vitro. Verfaillie’s group generated multipotent adult progenitor cells (MAPCs) from the bone marrow under low density and low serum conditions and could show that they have embryonic stem cell like properties when injected into blastocysts [28]. So-called marrow-isolated adult multilineage inducible cells (MIAMI) were generated under low-oxygen tension on fibronectin from bone marrow cells [9]. Lange et al described a population of bone marrow-derived adult stem cells, separated on a Percoll gradient with low density, that showed an extraordinary high proliferative potential and a conserved phenotype characteristic of MSCs [38]. MSCs not only have been derived from bone marrow but from almost any organ [10].

Unrestricted somatic stem cells (USSCs) have been cultured from human cord blood [31]. The authors state that USSCs have a wider differentiation potential and differ in immunophenotype and in their mRNA expression profile. Not all groups have been successful in generating stem cell like cells from cord blood [46]. In contrast to Mareschi, Lee et al. found a mesenchymal stem cell like population derived from cord blood cells with classical characteristics of MSCs as well as differentiation into neuroglial- and hepatocyte-like cells under appropriate induction conditions. Adipose tissue contains MSCs that are easy to obtain from lipoaspirates [81]. Because they are easy to culture and readily available from different sources, MSCs continue to be a popular research subject with steadily increasing numbers of publications and applications.

Mechanisms of action of MSCs used in cell therapy and regenerative medicine

1. Replacement of injured cells by MSCs through differentiation and integration into organ parenchyma

Cellular differentiation is not an irreversible process. Pathologists know the phenomenon of differentiation of one cell type into another due to prolonged exposure to un-physiological stimuli in epithelia, e.g. gastric reflux causes the squamous epithelium of the esophagus to differentiate into gastric mucosa, and have termed it ‘metaplasia’. In the kidney, tubular cells de-differentiate after ischemic injury, re-express embryonic and developmental markers like Pax-2, and start dividing to repopulate the denuded tubular parts, thereby regenerating a sublethally injured tubule [75, 25].

In the late 1990s researchers described so far unknown and unexpected differentiation of HSCs into a number of cell types, e.g. liver and muscle [17, 55]. These results were surprising because a long held dogma stated that adult stem cells are lineage restricted and can only differentiate into tissue from their lineage and that differentiation is terminal [39]. This so called transdifferentiation was immediately recognized as a new and promising way of regeneration of injured tissue and proposed as a mechanism of action for cell therapy. However, initial enthusiasm led researchers to overlook some problems associated with early studies. These studies utilized crude cell preparations, e.g. whole bone marrow, and therefore it was not clear, which cell type was responsible for the observed phenomenon. Furthermore, transdifferentiation was very rare and only some dispersed single cells could be detected after a meticulous search, calling into question the therapeutic value of this approach. Krause et al in a very carefully conducted study showed, that a prospectively isolated HSCs are indeed the cell type responsible for tissue contribution and differentiation into most organ cells, but the contribution was below 0.1% [33].

Some time later two groups described fusion of cells in vitro and it was discussed, that this could be a potential explanation for the phenomena described in the early stem cell studies [67, 78]. Indeed, some groups attributed cell fusion as the main mechanism for organ regeneration in certain disease models [47, 72, 74].

Meticulous studies by Wagers and Balsam showed that transdifferentiation is an extremely rare event under steady state and ischemic conditions and HSCs do not contribute much to tissue turnover [73, 5].

The lessons learned from these studies with HSCs are:

• Transdifferentiation or plasticity is a real phenomenon but exceedingly rare in most disease models.

• Replacement of damaged tissue is therefore not a major mechanism for tissue regeneration.

• Under steady state conditions tissue replacement is rare and in  disease conditions it is dependent on the model and kinetics used to study transdifferentiation.

Based on initial observations with whole bone marrow and the fact that MSCs can be differentiated into a large number of differentiated cells in vitro and in vivo, e.g. neurons [57], cardiomyocytes [45], myocytes [11], endothelial cells [54, 41], pulmonary cells [53] and liver cells [34-36], it was hypothesized that differentiation of MSCs into organ parenchymal cells is a major mechanism of tissue protection and regeneration after injury. However, MCSs exhibited tissue repair capacity despite low or transient engraftment in vivo, e.g. in the treatment of osteogenesis imperfecta it was less than 1% [22], and therefore differentiation into target tissues is most likely only a minor mechanisms of tissue protection and regeneration. The fact that tissue protection is observed without evidence of long-term engraftment also argues against differentiation as a main mechanism of action [27].

2. Paracrine mechanisms

MSCs produce a number of cytokines, growth factors and adhesion molecules that have been shown to be involved in tissue homeostasis and regeneration [13]. Furthermore, transcriptome analysis by serial analysis of gene expression (SAGE) revealed a large number of transcripts for proteins involved in wound repair, immunological regulation, neural factors as well as angiogenesis [70, 56] implying a role for these factors in MSC mediated tissue regeneration. These factors stimulate cell proliferation (growth factors like IGF [24]) and are anti-apoptotic [7]. The advantage of administering MSCs rather than growth factors directly lies in the fact that MSCs act on a local level and are able to interact with damaged tissue, which means they probably respond to cytokines like TNF-a secreted by damaged tissue with more or less secretion of a number of growth factors or modulatory cytokines and thereby influence the local environment directly and better than any systemically administered growth factors [41, 62]. In the kidney, MSCs regenerate renal function after acute kidney injury mainly by secreting epidermal growth factor (EGF), insulin-like growth factor (IGF-1), VEGF and by changing the cytokine expression profile of the injured kidney towards a more favorable anti-inflammatory state with higher IL-10 levels [60, 69]. In the heart, MSCs stimulate angiogenesis by secretion of VEGF [1, 29]. Endogenous cell proliferation in the brain is stimulated by MSCs through paracrine mechanisms after injury mediated by different factors [44, 8].

3. Vasculo- and angiogenesis

Blood supply is the most critical factor for tissue survival and most injury mechanisms involve the vasculature in one way or another. Ischemic injury is the most common mechanism of tissue damage for every organ system and fast restoration of regular blood supply is critical for tissue survival. The microvascular bed can be damaged in many ways, but endothelial dysfunction or apoptosis are major factors. MSCs express a number of angiogenic and vasculogenic factors and proteins that have been shown to increase endothelial cell survival and proliferation [2, 23]. In vivo studies have shown that vasculo- and angiogenesis by MSCs is either mediated directly by integration into vascular structures or through paracrine mechanisms stimulating angiogenesis, e.g. secretion of VEGF, angiopoietin or other growth factors [2, 3, 65, 64, 77]. MSCs can be genetically engineered, using different strategies like bcl-2, Akt or erythropoietin expression, to enhance endogenous angiogenic activity [16, 21].

4. Immunomodulation

MSCs exhibit low immunogenity due to low or absent MHC-II expression, low MHC-I expression and negativity for costimulatory molecules CD80, CD86 and CD40. Therefore infusion of MSCs do not trigger a direct rejection reaction, although several groups have shown that MSCs are not neutral towards the immune system and antibodies can be measured as well as T cell activation but not proliferation [30, 58]. A large body of data shows immunomodulatory properties of MSCs in vitro on different cell types such as T-cells, B-cells and NK cells [18]. MSCs suppress T-cell proliferation in vitro, interfere with dendritic cell differentiation, inhibit B-cell proliferation and suppress the proliferation and cytokine production of natural killer cells [50]. The in vivo relevance of these in vitro finding has been demonstrated in humans with acute graft versus host (GvHD) and Crohn’s disease [61, 66]. In animal models MSCs have been shown to modify experimental autoimmune encephalitis, a model of multiple sclerosis, and prolonged skin graft survival in baboons [6, 71]. There are conflicting data about effects of MSCs in organ transplantation models. Inoue reported that MSCs were ineffective at prolonging allograft survival and tended to promote rejection [26]. In a different model cardiac allograft survival was prolonged [80]. MSCs also favored tumour survival in animal models [14].

While the currently known immunomodulatory effects of MSCs show promise for the treatment of a number of diseases, data have to be interpreted carefully dependent on the animal model or in vitro strategy. Culture conditions and numerous other factors not least the model that is studied play important roles and have to be considered carefully to avoid preliminary conclusions.

5. Other applications for MSCs

MSCs are ideally suited as cellular delivery systems in tumor treatment. They can be engineered to express the interferon-beta (IFN-beta) gene and deliver therapeutic doses of IFN-beta directly into the tumor through infiltration thereby suppressing tumor growth and metastasis [63]. In metabolic diseases and enzyme defects, either allogeneic or genetically engineered MSCs are able to function as enzyme replacement therapy [48] by providing necessary concentrations of an enzyme that is lacking due to a genetic defect. MSCs are rapidly transducable with different viral vectors and are thereby ideal vehicles for therapeutic genes [59]. Other important applications include adjunct infusion to enhance hematopoietic engraftment [4] and as a source for engineered tissue such as cartilage and bone in tissue engineering [12].

Conclusions

In the ongoing story of stem cell treatment for patients MSCs have been so far the most promising development and have rapidly advanced from bench to bedside with several products already in late stage trials. Although little is known about MSCs in vivo, they have been characterized extensively in vitro and clinical studies have been finished and new ones are on their way. The mechanisms of action of MSCs are currently investigated in detail and there is still a large number of questions to be addressed until the full therapeutic benefit of these cells can be utilized but the field is rapidly advancing and is giving a shining example for the whole stem cell community. 

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Тегель Ф., Вестенфельдер Кр.

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Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК.

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Florian Tögel, Christof Westenfelder

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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA

Correspondence:
University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA

E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu

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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript.

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Florian Tögel, Christof Westenfelder

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Florian Tögel, Christof Westenfelder

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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript.

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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript.

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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA

Correspondence:
University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA

E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu

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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA

Correspondence:
University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA

E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu

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Тегель Ф., Вестенфельдер Кр.

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Тегель Ф., Вестенфельдер Кр.

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["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10633" ["VALUE"]=> array(2) { ["TEXT"]=> string(2292) "<p class="bodytext">Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2270) "

Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2270) "

Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК.

" } } } }