ISSN 1866-8836
Клеточная терапия и трансплантация
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М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области<br> трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.<br> Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.<br> Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. 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Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(179) "Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)" ["TYPE"]=> string(4) "TEXT" } ["~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) "20173" ["VALUE"]=> array(2) { ["TEXT"]=> string(4161) "<p style="text-align: justify;"> Дорогие коллеги и читатели,<br> Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области<br> трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.<br> Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.<br> Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.<br> Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4109) "

Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.

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["PROPERTY_VALUE_ID"]=> string(5) "20175" ["VALUE"]=> array(2) { ["TEXT"]=> string(2344) "<p style="text-align: justify;"> Dear Colleagues and Readers,<br> This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.<br> I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.<br> I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.<br> We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2298) "

Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20174" ["VALUE"]=> array(2) { ["TEXT"]=> string(82) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Therapy and Transplantation" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(82) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Therapy and Transplantation" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(82) "Professor Boris V.Afanasyev, Editor-in-Chief, Cellular Therapy and Transplantation" } ["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" 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Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.<br> I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.<br> I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.<br> We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2298) "

Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.

" ["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(2298) "

Dear Colleagues and Readers,
This issue of CTT Journal is produced before the XII International R. Gorbacheva Memorial Symposium Hematopoietic Stem Cell Transplantation. Gene and Cellular Therapy (St. Petersburg, 20-22 September, 2018). Thus this issue of CTT Journal contains several articles which reflect the important areas of clinical research in the field of hematopoietic stem cell transplantation which were not covered by the main scientific program of the Symposium. Therefore, I would like to express my deep gratitude to the authors who have positively responded to our invitation and contributed with their studies to this issue of CTT which will be published just before the Symposium.
I would like to highlight the novel educational trend in the journal, which addresses the current controversies in the field of stem cell transplantation. A concise, but conceptual article Transplants for acute myeloid leukemia in 1st remission: statisticians, magicians and the rest of us was published by Prof. Robert P. Gale in CTT No.4 (2017) has drawn a significant attention of Journal’s audience. The author’s opinion about role and ability of modern statistics to assess risk factors when deciding allogeneic hematopoietic stem cell transplantation (allo-HCT) has initiated an interesting discussion concerning the role, optimal timing and risk factors of allo-HCT in first remission of acute myeloblastic leukemia.
I hope that this article by R. Gale, a reply by Dr. Ivan S. Moiseev (CTT v.7, No.1), and concluding remarks by Prof. Axel R. Zander published in the this CTT issue have drawn attention to the complex problem of clinical risk evaluation, either from medical, scientific, and ethical points of view. I appreciate the valuable input of the authors to spotlight an important issue of a clinical medicine. I hope that the practice of discussing thematic controversies will continue in the upcoming issues to ensure that the readers receive the up-todate views of opinion leaders.
We hope that the number of contributors to our journal will grow with time, since its visibility and readership are steadily increasing at the platforms of SCOPUS, eLibrary, Research-Gate, and other popular journal databases.

" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20176" ["VALUE"]=> string(17) "Editorial article" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(17) "Editorial article" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(17) "Editorial article" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20172" ["VALUE"]=> array(2) { ["TEXT"]=> string(179) "Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(179) "Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)" ["TYPE"]=> string(4) "TEXT" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(187) "Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)" } ["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) "20173" ["VALUE"]=> array(2) { ["TEXT"]=> string(4161) "<p style="text-align: justify;"> Дорогие коллеги и читатели,<br> Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области<br> трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.<br> Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.<br> Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.<br> Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4109) "

Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.

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Дорогие коллеги и читатели,
Этот выпуск журнала CTT выходит незадолго до XII Международного Симпозиума памяти Р. М. Горбачевой «Трансплантация гемопоэтических стволовых клеток. Генная и клеточная терапия» (Санкт-Петербург, 20-22 сентября 2018 г.). Таким образом, данный выпуск журнала СТТ содержит несколько статей, которые касаются важных областей клинических исследований в области
трансплантации гемопоэтических стволовых клеток, которые не вошли в основную научную программу Симпозиума. Поэтому я хотел бы выразить глубокую благодарность авторам, которые отозвались на нашу просьбу и прислали данные своих исследований в СТТ, где они будут опубликованы перед Симпозиумом.
Я хотел бы указать и на новые образовательные тенденции в нашем журнале, касающиеся современных противоречий в области трансплантации стволовых клеток. Краткая, но концептуальная статья «Трансплантация при остром миелобластном лейкозе в 1-й ремиссии: статистики, волшебники и прочие» была опубликована профессором Робертом П. Гэйлом в СТТ №4 (2017) и привлекла существенное внимание читательской аудитории журнала. Мнение автора о роли и способности современной статистики в оценке факторов риска при решении вопроса об аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) вызвало интересную дискуссию, касающуюся роли, оптимальных сроков и факторов риска при алло-ТГСК в 1-й ремиссии острого миелобластного лейкоза.
Я надеюсь, что эта статья Р. Гэйла, ответ д-ра И. С. Моисеева (CTТ т.7, №1) и заключительные замечания профессора Акселя Р. Цандера, опубликованные в этом номере СТТ, привлекли внимание к сложной проблеме оценки клинического риска, как с медицинской, так и с научной и этической точек зрения. Я признателен авторам за ценный вклад в освещении этого важного вопроса клинической медицины. Надеюсь, что практика обсуждения тематических проблем будет продолжаться в последующих выпусках журнала для того, чтобы читатели знакомились с современными взглядами ведущих специалистов.
Мы надеемся, что количество авторов в нашем журнале будет со временем возрастать, поскольку его роль и читательская аудитория постоянно растут на платформах SCOPUS, eLibrary, ResearchGate и других популярных баз журнальных данных.

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Introduction

Over last years, a number of effective protocols has been developed for treatment of oncohematological diseases (leukemias and lymphomas) based on application of cytoreductive chemo- or radiation therapy. These treatment protocols, along with novel targeted drugs, bring about long-term remissions in these patients. However, quality of life in these patients is often disturbed, due to serious complications affecting different organs and systems. Dental complications, such as infectious and atrophy of oral mucosa and teeth occur quite often when treating oncological patients, especially children after chemo- or radiation treatment of leukemias and other malignancies [1, 2, 3, 4]. Treatment protocols in oncohematology usually include several rounds of cytoreductive therapy. Cytotoxic drugs or radiation treatment affect sensitive cells, both malignant and normal ones. Due to heavy insult to hematopoietic system, the leukocyte numbers begin to drop since day 5-6 after starting cytotoxic therapy cycle and recovers only at 2-3 weeks when the next round of therapy could be performed.
Quite intensive cytoreductive therapy, the so-called conditioning treatment, is administered before hematopoieticstem cell transplantation (HSCT) which causes a very deep suppression of hematopoiesis with entire depletion of granulocytes and most lymphoid cell population in peripheral blood, bone marrow and lymphoid organs. Their recovery occurs within weeks and months [5]. Along with blood cells, the cytoreductive treatment causes massive death of epithelial stem cells in oral cavity, intestines, lungs, urogenital tract etc. The therapy-induced epithelial damage manifests by early mucosites, colitis and other organ-specific syndromes. Intensive death of normal cells due to cytoreductive treatment followed by HSCT is, therefore, connected with repeated rounds of chemo-and radiation therapy which lead to maximal cytoreduction in epithelial organs as well.
The most common oral complications and main guidelines for managing dental disorders in the patients undergoing chemo/radiation therapy in children are well described in appropriate recommendations issued by American Academy of Pediatric Dentistry [6]. One should be noted that, by the time of HSCT, the patients already have marked immune deficiency cuased by previous courses of cytostatic therapy. Such immunocompromising condtions require all preventive dental programs to be performed before starting intensive anticancer treatment with following HSCT. If it is not possible, some provisional dental procedures are performed that should be continued upon stabilization of hematological and immune state of the patient. Over the period of post-transplant cytopenia, immune deficiency and concomitant oral complications, only local treatment is performed which is aimed for cytoprotection and accelerated healing of oral mucosae.
Hence, the aim of this review article was the discussion of epidemiology, pathogenesis, prevention and treatment of oral complications following intensive cytostatic therapy and hematopoietic stem cell transplantation. Disorders of oral mucosa represent several pathogenetic phases, from early toxic mucositis to late immune-induced atrophy of mucosal structures and salivary glands. Their treatment requires special approaches at every time period post-transplant.

Conditioning- and time-dependent features of oral complications in HSCT-procedure

Classical protocol for hematopoietic stem cell transplantation (HSCT) includes intensive chemo and/or radiation therapy (either myeloablative, or reduced conditioning regimens) delivered over limited terms (several days), thus causing a subsequent prolonged immune suppression. Such temporary immune deficiency is determined by several cytotoxic factors, i.e.:
1) High-dose cytoreductive therapy;
2) Long-term recovery of myelo- and lymphopoiesis posttransplant;
3) Antibacterial and antiviral treatment;
4) Acute graft-versus-host disease (aGVHD);
5) Long-term immunosuppressive therapy
(Cyclosporin etc.);
6) Chronic GVHD
Time course of bacterial and viral complications observed after intensive chemotherapy and hematopoietic stem cell transplantation is well presented in appropriate reviews [7,8]. The dental and mucosal complications are dependent on distinct time periods of conditioning therapy and subsequent transplantation [6]:
Phase I: Dental care before conditioning therapy
At this stage, oral complications are determined by the patient’s age, his/her general condition and oral health. In cases of hematological malignancies, the risk of posttransplant disorders depends on extent of local oral pathology, total intensity of previous cytoreductive therapy. Oral pathology at the pre-transplant stage may include oral infections, gingival leukemic infiltration, ulcers, bleeding, temporo-mandibular dysfunction.
Most principles of dental care before HSCT are similar to those applied to children suffering with malignancies. The two main differences are as follows: 1) in HSCT, the patient receives entire course of chemo- or radiation therapy several days before transplant; 2) HSCT is accompanied by a longterm immune suppression. Therefore, any elective dental care should be postponed until the immune restoration, i.e., at least 100 days after HSCT and even later, in cases of severe chronic GVHD or other complications. Vice versa, all urgent dental treatment should be completed before development of immune suppression in the patient.
Phase II: Neutropenic period following HSCT
The major oral complications at this time period, from the patient admission to HSCT clinic, and up to day +30 post-transplant, are caused by the cytostatic treatment and supporting therapy. They include oral mucositis, xerostomia, local pain, hemorrhages, taste anomalies, neurotoxicity (toothache, muscle tremor, temporo-mandibular pain, head ache etc.) may be registered, associated with common oral infections.
Oral mucositis develops within 7 to 10 days after starting of intensive treatment, and its symptoms are traceable for ca. 2 weeks after its completion. The patients should be observed thoroughly, and their oral condition should be traced. Optimal oral care is of crucial importance at this stage. Any kind of dental treatment should be avoided, due to severe immune suppression in the patient over this time period. Urgent dental interventions should be performed in close co-ordination with attending oncohematologists.
Phase III: Engraftment and recovery of hematopoiesis
Severity of the oral symptoms decreases by 3 to 4 weeks posttransplant, with domination of fungal invasion and herpes simplex infection. The infections are often combined with acute graft-versus-host disease, which may present sufficient problems after allogeneic HSCT. Differential histopathological features of oral infections and aGVHD should be considered. I.e., sometimes, one may observe xerostomia, hemorrhages, neurotoxicity, temporo-mandibular dysfunction, granulomas, papillomas etc. Examination of oral cavity and teeth as well as invasive stomatological procedures, e.g., tooth cleaning and soft tissue curettage should be agreed with transplantation team, due to continuous immune suppression in the patients. They should be encouraged to optimize their dental hygiene and avoid caryogenic diet, also being alert for xerostomia (“dry mouth”) and oral GVHD signs. For unclear reasons, oral cavity in transplanted patients shows increased temperature sensitivity for 2 to 4 months after HSCT. Local application of neutral fluoride or desensitizing tooth pastes may alleviate these symptoms.
Phase IV: Long-term restoration of immunity after systemic cytotoxic treatment
At later terms (over 100 days post-transplant), most oral complications are caused by chronic effects of preceding cytostatic therapy, including dysfunction of salivary glands, chronic GVHD affecting oral mucosa, as well as late viral infections. Oral squamous cell carcinoma may develop in oral cavity, like as other secondary malignancies. Relapse of the disease may be associated with xerostomia and injuries of oral cavity. However, late bacterial infections are less common, despite common neutropenia or severe chronic GVHD in the patients. Occasional dental examination with X-ray studies could be performed. Invasive dental care should be avoided in immunocompromised patients. Orthodontic care should be consulted with attending doctor and relatives of the patient, concerning risks and benefits of such treatment.
Phase V: Long-term survival following HSCT
Problems with development of orofacial, skeletal structures or teeth have similar origin for any complications observed in children who survived treatment of malignant diseases. In children, delayed growth of jaws and skull bones is observed months and years after intensive chemo-and radiotherapy. Such problems, generally, manifest in children under 6 years old and occur due to osteoblast suppression caused by prolonged cytostatic therapy. Long-term effects of the anticancer treatment may also include dental agenesis, microdontia, altered size and form of teeth, hypoplastic enamel, malformations of pulp cavity and dental roots as well as underdevelopment of jaws. Severity of such anomalies will depend on the patients’ age at the time of cytotoxic treatment. The patients may suffer of permanent dysfunction of salivary glands or xerostomia. Moreover, relapses of primary malignancies, or secondary cancer may also develop several years later.
Hence, the cancer survivors, especially younger patients, need routine dental examination and optimal oral care. The attending dentist should perform regular careful inspection of teeth, gingivae, tongue and oral mucosae, as well as adjacent areas. X ray studies and accessory cytological diagnostics should be performed in order to detect any head and neck malignancy. Dental treatment in such cohort needs a multidisciplinary approach with cooperation of different dental specialists in order to administer optimal treatment for any distinct case. Steady contact and consulting with attending oncologists is required, especially in case of relapse or immune deficiency suspected in the patient.
Most pathological changes of oral mucosae and epithelium (mucositis, gVHD, infections, later chronic complications) are accompanied by inflammation of mucosae and salivary glands. Role and pathogenetic mechanisms of inflammatory events are discussed, e.g., by Havermann et al. [9].
According to Fabuel et al. [10], the most common early oral complications in HSCT patients are as follows:
1. Acute mucositis caused by direct toxic action upon progenitor epithelial and bone cells of oral cavity. WHO classification distinguishes 5 grades of mucositis, from mild erythema to severe ulceration of oral mucosa. This pathology is associated with xerostomia, viscous saliva, intensive pain syndrome when eating, drinking or swallowing. Oral mucositis becomes clinically sound soon after HSCT reaching its maximum 5 to 7 days post-transplant and fades away gradually, within 2-3 weeks after HSCT. Focal necrosis of mucosae and labial skin is observed. In addition, caries new caries lesions may occur. For practical purposes, three stages of posttransplant oral mucositis are distinguished, depending on severity of mucositis, local pains and feeding difficulties [11].
2. Infectious complications mostly manifest as stomatitis caused by pathogenic bacteria, viruses or fungi.
3. Oral bleedings may occur in the patients due to suppression of hematopoiesis and thrombocytopenia, as well as primary disorder (e.g., acute leukemia).
4. Acute graft-versus-host disease (aGVHD) is observed within 100 days post-HSCT being a pathological immune reaction induced by the donor autoaggressive lymphocytes against some recipient antigens. aGVHD proceeds as a systemic inflammatory response involving cytokine activation. aGVHD affects mostly epithelial cell populations, including oral epithelium, thus representing a leading factor of severe complications and mortality among HSCT patients. Oral aGVHD presents as xerostomia, erythema, lichenoids, papular lesions, atrophy, and ulceration of mucosal surfaces.

Stepwise development of oral histopathology after conditioning therapy and hematopoietic transplantation

The first step of cytotoxic lesion, oral mucositis (OM) is a serious complication which depends on the total dose of chemotherapy and types of cytostatic drugs. E.g., Chaudhry et al. [12] have performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and their occurrence at various conditioning regimens. Grade of OM was analyzed based on the standard WHO Criteria for Adverse Events scales. Severe mucositis was defined as grades 2-3-4. A total of 624 studies were taken for analysis. In general, 73% experienced any signs of OM, whereas severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% after reduced-intensity-conditioning. In comparing graft-versus-host disease (GVHD) prophylaxis, the non-methotrexate regimens caused OM in 55.4%, thus being lower than among patients who received methotrexate (83.4%).
Primary insult to oral mucosa induced by intensive cytostatic treatment was described as early as in 1988 [13]. The workers analyzed early oral changes after HSCT. These changes included altered mucosal color (white and red) with subsequent atrophy, ulceration, accompanied by more viscous saliva, hyposecretion of salivary glands, causing xerostomia. This pathology determines subjective complaints of oral pain and dryness. The histological and clinical changes were most evident at ventral tongue, buccal and labial mucosa, and marginal gingival beginning just after conditioning treatment, peaking at 2 weeks after HSCT with following gradual mucosal repair. This complex pathology occurs due to conditioning chemoradiotherapy, immunosuppression after HSCT, occasional traumas posttransplant immunosuppressive chemotherapy, as well as due to activationg infections (mostly viral activation) local trauma, oral infections (especially those caused by HSV), and possibly acute GVHD. The viral and GVHD mechanisms should be considered in cases of worsening oral lesions at 3 weeks or later post-transplant.
These pathological findings were supported by several other studies [14]. A group of 54 children with oncohematological disorders were subjected to allo-HSCT, with 62% exhibiting clinical oral side effects upon treatment. These lesions were observed over first 2 weeks after conditioning therapy, transplantation, and until engraftment of the donor marrow having been ascribed to preceding chemo- and radiotherapy. Oral ulcers were seen in 34% of the cases. Administration of methotrexate for GVHD prophylaxis seemed to cause more common oral ulcerations rather than cyclosporin. HSV reactivation was observed in 35% of the children who were seropositive prior to BMT. Oral candidiasis was also a common finding (15% of the patients).

Early infections and inflammatory conditions of oral cavity following HSCT

Clinical infections of teeth and oral mucosa are widely spread in general population. E.g., colonization with Streptococcus mutans and parodonthogenic bacteria is revealed in gingival mucosa and dental plaque since pre-school age, becoming more common in later life [15]. The long-term immune deficiency after cytostatic chemo- and radiation therapy is widely known to promote a more active growth of odontogenic microflora. Incidence of oral HSCT complications was summarized using databases of the USA transplantation centers from 2004 to 2010 [16]. Over this time period, HSCT was performed in 101462 patients. Gingivitis or periodontitis was diagnosed in only 0.22% of the cases. Such low incidence, when compared to general population, may be connected with optimal dental care and full mouth debridement carried out before HSCT. Meanwhile, this study shows that gingival and periodontal problems in HSCT patients implies higher treatment costs, longer hospitalization period, and increased risks of infectious complications. E.g., septicemia, bacterial infections and mycoses in the patients with periodontitis were observed significantly more often than in cases without gingival problems before HSCT.
Several studies from 90’s support a defnite role of human herpesvirus type 6 (HHV6) in oral pathology occurring after HSCT [17]. This study was performed using a golden standard, the virus isolation, in 15 allogeneic and 11 autologous marrow transplantation patients. HHV6 type B was isolated posttransplant from peripheral blood mononuclears of 12 of 26 patients. Interestingly, 11 of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA both before and after transplantation. In sum, 23 of 26 patients showed evidence of active HHV-6 infection either by the virus isolation, salivary shedding, or increased antibody titers. Active human cytomegalovirus infection was associated with HHV-6 isolation, as also confirmed in later studies. However, no association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression in this study. The initial results of HHV6 studies were confirmed by Cone et al. [18].

Oral immune pathology in chronic GVHD

Histological changes observed at later stages post-HSCT, the s.c. chronic GVHD, seems to be of mostly autoimmune origin, due to cytotoxic damage of vascular structures and mucosal epithelium induced by donor effector cells. In cases of chronic GVHD, the changes in oral mucosa developing 12 months or later after transplantation comprise erythema of mucous membranes, tongue atrophy and also lichenoid changes in the buccal mucosa [14]. The study by Motta to al. [19] was performed in 12 patients undergoing allo-HSCT. The paired oral cGVHD biopsies obtained before and 1 month after treatment with topical dexamethasone (n=8), or tacrolimus (n=4) were subjected to immunohistochemistry of main immune markers (CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3) as compared to bioptates from aGVHD, oral lichen planus, and normal tissues. The oral bioptates in cGVHD were characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating immune cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+, and FoxP3+ cells, exceeding the levels of normal tissues thus presuming a largely T-cell-driven inflammation with macrophage participation. Topical dexamethasone or tacrolimus reduced the mentioned cell pathology in oral cGVHD, while reducing the number of CD4+ and CD103+ cells.
Clinical signs of chronic oral GVHD develop at later terms post-transplant (>100 days after HSCT), being observed in 50-80% of total cases. The cGVHD symptoms include erythema, atrophy of the tongue surfaces, lichenoid changes of buccal mucosae accompanied by ulcers and increased oral cancer risk [10]. Salivary gland dysfunction causes xerostomia, clinical pattern of parotitis, excess of mucous substances and lower saliva production. These symptoms may persist, at least, for 1 year after HSCT.
The cGVHD, like as acute GVHD, develops by immune mechanisms. It affects different organs and tissues including oral cavity. Clinical pattern of oral cGVHD, generally, is similar to the Sjogren disease, a well-known autoimmune disorder [20].
So far, there are no validated cGVHD biomarkers correlating with clinical except of relatively unspecific parameters, e.g., altered albumin or high complement levels [21]. Increased albumin, Na+ , Cl− concentrations, changes of lactoferrin an protease inhibitors may be observed in oral fluid of the cGVHD patients [22].

Treatment of early post-transplant oral disorders (mucositis and aGVHD)

Oral mucositis, being a very common complication of intensive chemotherapy followed by HSCT occurring in ca.70-80% of the cases, thus needing novel management strategies which include both preventive measures and therapeutic approaches. Pathophysiology of acute oral includes complex interactions between the products of tissue damage, reactive oxygen species, local microbiota and host immune system, which determines the grade of inflammatory response in oral mucosa and salivary glands. Genetic factors plays a major role in the development of this toxicity [23]. Although only few therapeutic agents are available, several promising drugs are under clinical trials.
Palifermin (keratinocyte growth factor) is the only pharmacological drug approved by the European Medicines Agency and the US Food and Drug Administration (FDA) for mucositis. Palifermin is administered intravenously prior to the initiation of chemotherapy and for an additional 3 days beginning since the day of HSCT [24].
Pathogenetic treatment also includes a number of anti-inflammatory drugs, either cytokine-based therapy, or non-steroid anti-inflammatory drugs, pentoxifylline etc. [23]. Biological cell-containing preparations are also tried to this purpose. Recently, Piccin et al. [25] has reported a lymphoma patient with severe oral and esophageal mucositis developed after high-dose chemotherapy, auto-HSCT, severe sepsis, viral infection and neutropenia. Platelet gel from cord blood was topically administered daily to the oral cavity. After 8 consecutive days, full recovery of mucositis was seen without any side effects. Therefore, controlled studies are required to compare efficacy of autologous and allogeneic platelet gels in severe mucositis.
A study in pediatric patients has also shown some efficiency of low-level laser therapy (LLT) in oral mucositis [26]. The authors have developed a specialized oral care protocol that included LLT for pediatric HSCT patients. Data from OM-related morbidity were collected from 51 HSCT pediatric patients treated daily with LLT, followed by standard oral care protocols. All the patients, even at younger ages, tolerated the LLT therapy well. The maximum OM degree was WHO II. Patients after autologous and HLA-haploidentical transplants showed less severe OM, and better clinical outcomes are reported with LLT which could be included into the specialized oral care in this cohort of children.

Novel treatments of mucosal aGVHD

Oral immune-like syndromes are sometimes observed in acute GVHD after HSCT. E.g., Ion et al. [27] has studied twenty-one such GVHD cases of which 5 demonstrated only oral features; the remaining 16 had variable involvement of skin (n=14), liver (n=7), and gut (n=5). The median time for onset of oral aGVHD was 35 days (11 to 159 days). The sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21) tongue (18 of 21 dorsum in 8), labial mucosa (16 of 21, palatal mucosa (15 of 21; hard palate in 7), and floor of mouth (7 of 21). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for additional support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and nonkeratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing.
Previous successful experience with blood platelet gels was based on regenerative effects upon diabetic or surgical wounds, due to local release of growth factors such as fibroblast – derived growth factor, platelet-derived growth factor etc. [28]. Their study was aimed for assessing efficacy and safety of allogeneic platelet gel for treating ulcers in the skin or oral aGVHD. Platelet-rich fibrin was obtained by automated process (Vivostat system, Vivostat A/S). Six patients with multiple lesions involving dermis (Grade I, n=2), subcutaneous (Grade II, n=4), or oral mucosa related to GVHD were administered the gel as local therapy. After the second gel application, the pain faded away, and granulation tissue was observed in four cases with Grade II lesions. After a median of eight PLT gel applications (range, -10), five of six patients showed a complete response, without any side effects documented.
Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. Induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), was suggested to potentiate intestinal crypt proliferation and mucosal repair [29]. A pilot study included 20 patients with steroid refractory intestinal GVHD who were given oral lithium carbonate against a group treated with glucocorticoids. As a result, 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients.

Therapy of chronic oral GVHD

Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy with minimal side effects which alleviates cGVHD in most patients. Its curative effects are explained by immunomodulatory action upon T-regulatory lymphocytes. Recent data suggest that favorable effects of extracorporeal photopheresis (UVA irradiation) upon cGVHD may be also caused by inactivation and apoptosis of peripheral blood neutrophils [30]. Meanwhile, chronic GVHD is often refractory to systemic therapies. Some workers draw attention to intraoral narrow-band ultraviolet B (NB-UVB) irradiation in oral cGVHD delivered as a course of 24 phototherapy sessions, at a single dose of >50 mJ/cm [31]. Median symptom scores (0-10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. In sum, 7/11 patients had improvement and 2/11 worsened. Hence, NB-UVB may be considered a treatment option in refractory oral cGVHD, however, requiring clinical trials with appropriate control groups.
A supplementary topical treatment of oral cGVHD is proposed by means the glucocorticoid inhalers [32]. The authors compared different formulations showing pharmacological superiority of Budesonide for topical application in oral cGVHD. Marked local anti-inflammatory effects of Budesonide are based on its very low absorption through mucosal surfaces, thus increasing the potential role in oral cGVHD management. Moreover, its viscous formulation increases mucosal contact time and provides greater pharmacological effect in mucosal inflammation [33].
Second-line treatment in refractory cGVHD may include low doses of alemtuzumab plus low doses of rituximab as suggested by Gutiérrez-Aguirre et al. [34]. The authors have observed 15 patients who received one cycle of subcutaneous alemtuzumab (10 mg/day/3 days), and intravenous rituximab 100 mg on D+4, +11, +18 and +25 post-transplant (the protocol is under clinical trial). The therapeutic response was measured on Days +30, +90 and +365 of the protocol. The main site involved was the oral mucosa (86.7%). The overall response to the treatment was 100% at Day +30 evaluation, i.e., 10 patients had partial remission and 5, complete remission. At D+90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. Adverse effects were mainly infections in 67% of patients; these were usually quickly solved.

Specific cautions for drug therapy following HSCT

First of all, one should take into account those anticancer drugs that carry the highest risk for mucositis, i.e., methotrexate, cyclophosphamide, cisplatin, and fluorouracil (Villa, Sonis, 2015).
Risk of mucositis is dose-dependent and increases with higher intensity of chemo- and/or radiation therapy. One should be cautious when administering some drugs to such patients, as follows [10]:
– General anesthetics;
– Non-steroid anti-inflammatory drugs (NSAIDs) since these drugs may augment cyclosporine and tacrolimus nephrotoxicity, and they may increase bleeding and aggravate peptic ulcers in the corticosteroid-treated patients;
– Aspirin dosage should be adjusted since it increases bleeding risks;
– Antibiotics (erythromycin, clarithromycin, tetracycline, aminoglycosides, chinolones), as well as azol antifungal azoles (ketonazol, fluconazole and itroconazol), like as NSAIDs could aaalter cyclosporine lebels in blood serum thus causing more expressed immunosuppression.
– Usage of Sirolimus, and probably, of other mTOR inhibitors for the GVHD prophylaxis, may cause acute ulcerative stomatitis affecting the non-keratinized mucosa, mainly, with tongue involvement, at median onset time of 55 days after HCST [35]. Topical corticosteroid treatment is successful in these cases.

Potential diagnostic markers

Dozens of salivary components may reflect different diseases of periodont and oral cavity, including inflammatory mediators, reactive oxidative products, cellular enzymes, tissue-breakdown products etc. [36]. Over last decade, a number of reviews have been dedicated to potential clinical significance of salivary markers for diagnostics of different somatic and infectious disorders. E.g., salivary diagnostics of cancer proteins in oral fluid is now an evolving field of diagnostics as reported by Kaur et al. [37]. However, most of current studies are directed to novel applications of salivary using the "omics" approach, studying genomic, transcriptomic, proteomic, microbiomic, and metabolomic parameters, thus bringing the solution to a big data analysis [38]. Meanwhile, a search may be focused on single specific markers showing distinct pathological disorders of oral cavity or in the entire host organism.

DNA markers

Salivary biomarkers for infectious diseases were extensively studied earlier [39]. The issue is that the infectious agents were detected by different laboratory tests (by specific antibodies, antigens or nucleic acid markers) in salivary samples. These include a large range of Herpes viruses, Hepatitis viruses, HIV, Human Papillomavirus (HPV), Influenza virus, and Poliovirus.
Moreover, hundreds of bacterial species could be found in saliva, at the oral mucosa, dental plaques and tongue surface including Escherichia coli, Mycobacterium tuberculosis, Helicobacter pylori, Treponema pallidum and a wide range of streptococcal species. Concerning fungal presentation in oral rinses, Candida species were the most frequently cultured fungi (in 75% of samples), followed by Cladosporium (65%), Aureobasidium, Saccharomycetales (50% for both), Aspergillus (35%), Fusarium (30%), and Cryptococcus (20%). [40].
Post-cytostatic immune deficiency is regularly associated with viral infections. In this view, the levels of herpesvirus type VI (HHVVI) in saliva were suggested to be a probable severity marker of chemotherapy-induced oral damage [41]. However, excessive HHV6 activation was not confirmed at later terms post-HSCT, in chronic GVHD patients [42]. The authors tested for HHV6 peripheral blood, different oral fluids from cGVHD patients and oral tissue samples from healthy blood donors. HHV6 was detected by nested polymerase chain reaction. The virus was detected in whole saliva in 13 cGVHD patients (68%) and in 19 blood donors (67%) but not in gingival crevicular fluid or parotid gland saliva. Only two oral tissue samples of cGVHD patients of 12 were positive for HHV6. In sum, these data do not support the importance of HHV6 in oral lesions of cGVHD.
Over 40 years, it has been well known that oral cavity and intestinal microbiota contain similar bacterial species as shown, e.g., by Hamilton et al. [43]. Large numbers of similar organisms (>106/m1) were recovered by microbiological cultures from oral samples and jejunal aspirate of 16 subjects, in five of whom the same organisms were present in similar relative proportions in the saliva, e.g., Fusobacteria, whereas in other cases jejunal organisms differed from those in saliva. In eight of them, jejunal flora showed a typical 'faecal' pattern usually associated with small bowel bacterial overgrowth but, in three, the jejunal floral was somewhat similar to that of saliva.
Nowadays, with development of high-throughput NGS and 16S RNA sequencing, these ratios are studied in more details [44]. Human microbiota from three different compartments, i.e., saliva, feces, and cancer tissue (CT), of patients with colorectal cancer (CRC) vs. 10 healthy controls (saliva and feces). Taxonomic analysis based on 16S rRNA gene, revealed the presence of three main bacterial phyla, which includes about 80% of sequence reads: Firmicutes, Bacteroidetes, and Proteobacteria. Differences in bacterial composition, F. nucleatum abundance in healthy controls vs. colon cancer patients, and the association of F. nucleatum with clinical parameters were observed. Hence, Fusobacterium species are part of the both oral and intestinal microbiota, especially of colon tissue. Metagenomic analyses have shown that F. nucleatum detection in saliva may be predictive for development of colorectal cancer (Nosho et al., 2016).
The leukocytes shed to saliva may be also used even for detection of specific mutations in the patients with myeloproliferative diseases. E.g., Strati et al. [45] have performed a comparative study of JAK2V617F mutation in blood and saliva taken from the patients with primary myelofibrosis. Analysis of results from 167 patients has shown that the concordance between JAK2V617F detection in blood and saliva was 96%, with a sensitivity of 100% and a specificity of 90%. This biological material seems to have, at least, as sensitive as blood analysis for this mutation.

Protein markers

Like as DNA markers, immune protein molecules, like specific immunoglobulins , may be measured in saliva and salivary gland secretions in order to detect some latent and activable viruses [46].
Searching novel markers of acute GVHD is an important issue. E.g., one may check such potential salivary biomarkers as S100 protein family members (S100A8, S100A9, and S100A7) performed by Chiusolo et al. [47]. By means of HPLC, the authors have shown S100A8 in 14 of 23 cases of GVHD in allo-HSCT patients as compared with 2 GVHDfree parients and in none case of control group ( (P<0.001). Similar trend was registered for S100A9 protein. Multiple analysis of salivary proteome allows to detect some candidate proteins specific to acute GVHD as shown by Souza et al. [48] who carried out a preliminary study of salivary proteins using PAGE gel electrophoresis, liquid chromatograpy, and modern mass spectrometry. The most relevant proteins recognized exclusively in GVHD patients were: CSF2RB, protocadherin Fat 2 precursor, protein capicua homolog isoform CIC-S, MUC16 and RGPD8_HUMAN RANBP2. Their physiological role in this complication is not clear and needs further studies.
Diagnostic and prognostic markers of acute or chronic chronic GVHD are currently searched by means of proteomic analysis performed with mass-spectrometry or other methods of protein analysis. For example, saliva collected from oral cavity of allo-HSCT patients with chronic oral GVHD and cGVHD-free cases using isobaric Tags for quantification labeling, followed by tandem mass spectrometry. The method allowed identify up to 249 salivary proteins. Of them, 82 proteins were differently expressed in oral cGVHD patients compared to GVHD-free patients. Of these proteins, most played role in immunity, proteolytic functions, or as cytoskeleton components. Salivary IL-1 receptor antagonist and Cystatin B proved to exhibit decreased expression in oral chronic GVHD (P<0.003), thus, probably, being of some diagnostic significance [49].

Conclusions

1. Intensive chemotherapy and radiation treatment of the oncohematological patients followed by hematopoietic stem cell transplantation (HSCT) brings about early inflammation and acute necrosis of oral mucosa and gingivae, atrophy of salivary glands
2. Immune deficiency is evident at all post-transplant phases and later, at the stage of immunesuppressive therapy. At early terms, it is complicated by infections, at later phase, by autoimmune affection of oral mucosae. Over next years, a risk of secondary cancers is increased.
3. Bacterial and fungal infections of oral cavity and gastrointestinal tract are especially common at early terms, whereas viral activation (including secondary tumors) is detected at later terms after HSCT. The diagnosis of infections in immunocompromised patients represents an important task for the dentist that should be resolved in close contact with attending physician.
4. Late oral pathology after HSCT in children is presented, mainly, by developmental anomalies of dental system in young patients.
5. Chronic graft-versus-host disease (cGVHD) is accompanied by the Sjogren-like problems with oral mucosa and salivary glands.
6. There is no effective etiological treatment for acute mucositis, oral GVHD, both acute and chronic clinical forms. Appropriate pathogenetic therapy is aimed for release of painful symptoms and anti-inflammatory treatment. Some new promising drugs are still used as experimental therapy.
6. By the present time, there are no recognized salivary markers for early diagnostic and prediction of severe damage of oral mucosa expected after intensive cytostatic therapy, as well as GVHD following allogeneic transplantation. However, some promising salivary tests are to be studied, to detect infections of oral cavity, local and systemic malignancies.

Conflict of interest

No conflict of interest reported.

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Introduction

Over last years, a number of effective protocols has been developed for treatment of oncohematological diseases (leukemias and lymphomas) based on application of cytoreductive chemo- or radiation therapy. These treatment protocols, along with novel targeted drugs, bring about long-term remissions in these patients. However, quality of life in these patients is often disturbed, due to serious complications affecting different organs and systems. Dental complications, such as infectious and atrophy of oral mucosa and teeth occur quite often when treating oncological patients, especially children after chemo- or radiation treatment of leukemias and other malignancies [1, 2, 3, 4]. Treatment protocols in oncohematology usually include several rounds of cytoreductive therapy. Cytotoxic drugs or radiation treatment affect sensitive cells, both malignant and normal ones. Due to heavy insult to hematopoietic system, the leukocyte numbers begin to drop since day 5-6 after starting cytotoxic therapy cycle and recovers only at 2-3 weeks when the next round of therapy could be performed.
Quite intensive cytoreductive therapy, the so-called conditioning treatment, is administered before hematopoieticstem cell transplantation (HSCT) which causes a very deep suppression of hematopoiesis with entire depletion of granulocytes and most lymphoid cell population in peripheral blood, bone marrow and lymphoid organs. Their recovery occurs within weeks and months [5]. Along with blood cells, the cytoreductive treatment causes massive death of epithelial stem cells in oral cavity, intestines, lungs, urogenital tract etc. The therapy-induced epithelial damage manifests by early mucosites, colitis and other organ-specific syndromes. Intensive death of normal cells due to cytoreductive treatment followed by HSCT is, therefore, connected with repeated rounds of chemo-and radiation therapy which lead to maximal cytoreduction in epithelial organs as well.
The most common oral complications and main guidelines for managing dental disorders in the patients undergoing chemo/radiation therapy in children are well described in appropriate recommendations issued by American Academy of Pediatric Dentistry [6]. One should be noted that, by the time of HSCT, the patients already have marked immune deficiency cuased by previous courses of cytostatic therapy. Such immunocompromising condtions require all preventive dental programs to be performed before starting intensive anticancer treatment with following HSCT. If it is not possible, some provisional dental procedures are performed that should be continued upon stabilization of hematological and immune state of the patient. Over the period of post-transplant cytopenia, immune deficiency and concomitant oral complications, only local treatment is performed which is aimed for cytoprotection and accelerated healing of oral mucosae.
Hence, the aim of this review article was the discussion of epidemiology, pathogenesis, prevention and treatment of oral complications following intensive cytostatic therapy and hematopoietic stem cell transplantation. Disorders of oral mucosa represent several pathogenetic phases, from early toxic mucositis to late immune-induced atrophy of mucosal structures and salivary glands. Their treatment requires special approaches at every time period post-transplant.

Conditioning- and time-dependent features of oral complications in HSCT-procedure

Classical protocol for hematopoietic stem cell transplantation (HSCT) includes intensive chemo and/or radiation therapy (either myeloablative, or reduced conditioning regimens) delivered over limited terms (several days), thus causing a subsequent prolonged immune suppression. Such temporary immune deficiency is determined by several cytotoxic factors, i.e.:
1) High-dose cytoreductive therapy;
2) Long-term recovery of myelo- and lymphopoiesis posttransplant;
3) Antibacterial and antiviral treatment;
4) Acute graft-versus-host disease (aGVHD);
5) Long-term immunosuppressive therapy
(Cyclosporin etc.);
6) Chronic GVHD
Time course of bacterial and viral complications observed after intensive chemotherapy and hematopoietic stem cell transplantation is well presented in appropriate reviews [7,8]. The dental and mucosal complications are dependent on distinct time periods of conditioning therapy and subsequent transplantation [6]:
Phase I: Dental care before conditioning therapy
At this stage, oral complications are determined by the patient’s age, his/her general condition and oral health. In cases of hematological malignancies, the risk of posttransplant disorders depends on extent of local oral pathology, total intensity of previous cytoreductive therapy. Oral pathology at the pre-transplant stage may include oral infections, gingival leukemic infiltration, ulcers, bleeding, temporo-mandibular dysfunction.
Most principles of dental care before HSCT are similar to those applied to children suffering with malignancies. The two main differences are as follows: 1) in HSCT, the patient receives entire course of chemo- or radiation therapy several days before transplant; 2) HSCT is accompanied by a longterm immune suppression. Therefore, any elective dental care should be postponed until the immune restoration, i.e., at least 100 days after HSCT and even later, in cases of severe chronic GVHD or other complications. Vice versa, all urgent dental treatment should be completed before development of immune suppression in the patient.
Phase II: Neutropenic period following HSCT
The major oral complications at this time period, from the patient admission to HSCT clinic, and up to day +30 post-transplant, are caused by the cytostatic treatment and supporting therapy. They include oral mucositis, xerostomia, local pain, hemorrhages, taste anomalies, neurotoxicity (toothache, muscle tremor, temporo-mandibular pain, head ache etc.) may be registered, associated with common oral infections.
Oral mucositis develops within 7 to 10 days after starting of intensive treatment, and its symptoms are traceable for ca. 2 weeks after its completion. The patients should be observed thoroughly, and their oral condition should be traced. Optimal oral care is of crucial importance at this stage. Any kind of dental treatment should be avoided, due to severe immune suppression in the patient over this time period. Urgent dental interventions should be performed in close co-ordination with attending oncohematologists.
Phase III: Engraftment and recovery of hematopoiesis
Severity of the oral symptoms decreases by 3 to 4 weeks posttransplant, with domination of fungal invasion and herpes simplex infection. The infections are often combined with acute graft-versus-host disease, which may present sufficient problems after allogeneic HSCT. Differential histopathological features of oral infections and aGVHD should be considered. I.e., sometimes, one may observe xerostomia, hemorrhages, neurotoxicity, temporo-mandibular dysfunction, granulomas, papillomas etc. Examination of oral cavity and teeth as well as invasive stomatological procedures, e.g., tooth cleaning and soft tissue curettage should be agreed with transplantation team, due to continuous immune suppression in the patients. They should be encouraged to optimize their dental hygiene and avoid caryogenic diet, also being alert for xerostomia (“dry mouth”) and oral GVHD signs. For unclear reasons, oral cavity in transplanted patients shows increased temperature sensitivity for 2 to 4 months after HSCT. Local application of neutral fluoride or desensitizing tooth pastes may alleviate these symptoms.
Phase IV: Long-term restoration of immunity after systemic cytotoxic treatment
At later terms (over 100 days post-transplant), most oral complications are caused by chronic effects of preceding cytostatic therapy, including dysfunction of salivary glands, chronic GVHD affecting oral mucosa, as well as late viral infections. Oral squamous cell carcinoma may develop in oral cavity, like as other secondary malignancies. Relapse of the disease may be associated with xerostomia and injuries of oral cavity. However, late bacterial infections are less common, despite common neutropenia or severe chronic GVHD in the patients. Occasional dental examination with X-ray studies could be performed. Invasive dental care should be avoided in immunocompromised patients. Orthodontic care should be consulted with attending doctor and relatives of the patient, concerning risks and benefits of such treatment.
Phase V: Long-term survival following HSCT
Problems with development of orofacial, skeletal structures or teeth have similar origin for any complications observed in children who survived treatment of malignant diseases. In children, delayed growth of jaws and skull bones is observed months and years after intensive chemo-and radiotherapy. Such problems, generally, manifest in children under 6 years old and occur due to osteoblast suppression caused by prolonged cytostatic therapy. Long-term effects of the anticancer treatment may also include dental agenesis, microdontia, altered size and form of teeth, hypoplastic enamel, malformations of pulp cavity and dental roots as well as underdevelopment of jaws. Severity of such anomalies will depend on the patients’ age at the time of cytotoxic treatment. The patients may suffer of permanent dysfunction of salivary glands or xerostomia. Moreover, relapses of primary malignancies, or secondary cancer may also develop several years later.
Hence, the cancer survivors, especially younger patients, need routine dental examination and optimal oral care. The attending dentist should perform regular careful inspection of teeth, gingivae, tongue and oral mucosae, as well as adjacent areas. X ray studies and accessory cytological diagnostics should be performed in order to detect any head and neck malignancy. Dental treatment in such cohort needs a multidisciplinary approach with cooperation of different dental specialists in order to administer optimal treatment for any distinct case. Steady contact and consulting with attending oncologists is required, especially in case of relapse or immune deficiency suspected in the patient.
Most pathological changes of oral mucosae and epithelium (mucositis, gVHD, infections, later chronic complications) are accompanied by inflammation of mucosae and salivary glands. Role and pathogenetic mechanisms of inflammatory events are discussed, e.g., by Havermann et al. [9].
According to Fabuel et al. [10], the most common early oral complications in HSCT patients are as follows:
1. Acute mucositis caused by direct toxic action upon progenitor epithelial and bone cells of oral cavity. WHO classification distinguishes 5 grades of mucositis, from mild erythema to severe ulceration of oral mucosa. This pathology is associated with xerostomia, viscous saliva, intensive pain syndrome when eating, drinking or swallowing. Oral mucositis becomes clinically sound soon after HSCT reaching its maximum 5 to 7 days post-transplant and fades away gradually, within 2-3 weeks after HSCT. Focal necrosis of mucosae and labial skin is observed. In addition, caries new caries lesions may occur. For practical purposes, three stages of posttransplant oral mucositis are distinguished, depending on severity of mucositis, local pains and feeding difficulties [11].
2. Infectious complications mostly manifest as stomatitis caused by pathogenic bacteria, viruses or fungi.
3. Oral bleedings may occur in the patients due to suppression of hematopoiesis and thrombocytopenia, as well as primary disorder (e.g., acute leukemia).
4. Acute graft-versus-host disease (aGVHD) is observed within 100 days post-HSCT being a pathological immune reaction induced by the donor autoaggressive lymphocytes against some recipient antigens. aGVHD proceeds as a systemic inflammatory response involving cytokine activation. aGVHD affects mostly epithelial cell populations, including oral epithelium, thus representing a leading factor of severe complications and mortality among HSCT patients. Oral aGVHD presents as xerostomia, erythema, lichenoids, papular lesions, atrophy, and ulceration of mucosal surfaces.

Stepwise development of oral histopathology after conditioning therapy and hematopoietic transplantation

The first step of cytotoxic lesion, oral mucositis (OM) is a serious complication which depends on the total dose of chemotherapy and types of cytostatic drugs. E.g., Chaudhry et al. [12] have performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and their occurrence at various conditioning regimens. Grade of OM was analyzed based on the standard WHO Criteria for Adverse Events scales. Severe mucositis was defined as grades 2-3-4. A total of 624 studies were taken for analysis. In general, 73% experienced any signs of OM, whereas severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% after reduced-intensity-conditioning. In comparing graft-versus-host disease (GVHD) prophylaxis, the non-methotrexate regimens caused OM in 55.4%, thus being lower than among patients who received methotrexate (83.4%).
Primary insult to oral mucosa induced by intensive cytostatic treatment was described as early as in 1988 [13]. The workers analyzed early oral changes after HSCT. These changes included altered mucosal color (white and red) with subsequent atrophy, ulceration, accompanied by more viscous saliva, hyposecretion of salivary glands, causing xerostomia. This pathology determines subjective complaints of oral pain and dryness. The histological and clinical changes were most evident at ventral tongue, buccal and labial mucosa, and marginal gingival beginning just after conditioning treatment, peaking at 2 weeks after HSCT with following gradual mucosal repair. This complex pathology occurs due to conditioning chemoradiotherapy, immunosuppression after HSCT, occasional traumas posttransplant immunosuppressive chemotherapy, as well as due to activationg infections (mostly viral activation) local trauma, oral infections (especially those caused by HSV), and possibly acute GVHD. The viral and GVHD mechanisms should be considered in cases of worsening oral lesions at 3 weeks or later post-transplant.
These pathological findings were supported by several other studies [14]. A group of 54 children with oncohematological disorders were subjected to allo-HSCT, with 62% exhibiting clinical oral side effects upon treatment. These lesions were observed over first 2 weeks after conditioning therapy, transplantation, and until engraftment of the donor marrow having been ascribed to preceding chemo- and radiotherapy. Oral ulcers were seen in 34% of the cases. Administration of methotrexate for GVHD prophylaxis seemed to cause more common oral ulcerations rather than cyclosporin. HSV reactivation was observed in 35% of the children who were seropositive prior to BMT. Oral candidiasis was also a common finding (15% of the patients).

Early infections and inflammatory conditions of oral cavity following HSCT

Clinical infections of teeth and oral mucosa are widely spread in general population. E.g., colonization with Streptococcus mutans and parodonthogenic bacteria is revealed in gingival mucosa and dental plaque since pre-school age, becoming more common in later life [15]. The long-term immune deficiency after cytostatic chemo- and radiation therapy is widely known to promote a more active growth of odontogenic microflora. Incidence of oral HSCT complications was summarized using databases of the USA transplantation centers from 2004 to 2010 [16]. Over this time period, HSCT was performed in 101462 patients. Gingivitis or periodontitis was diagnosed in only 0.22% of the cases. Such low incidence, when compared to general population, may be connected with optimal dental care and full mouth debridement carried out before HSCT. Meanwhile, this study shows that gingival and periodontal problems in HSCT patients implies higher treatment costs, longer hospitalization period, and increased risks of infectious complications. E.g., septicemia, bacterial infections and mycoses in the patients with periodontitis were observed significantly more often than in cases without gingival problems before HSCT.
Several studies from 90’s support a defnite role of human herpesvirus type 6 (HHV6) in oral pathology occurring after HSCT [17]. This study was performed using a golden standard, the virus isolation, in 15 allogeneic and 11 autologous marrow transplantation patients. HHV6 type B was isolated posttransplant from peripheral blood mononuclears of 12 of 26 patients. Interestingly, 11 of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA both before and after transplantation. In sum, 23 of 26 patients showed evidence of active HHV-6 infection either by the virus isolation, salivary shedding, or increased antibody titers. Active human cytomegalovirus infection was associated with HHV-6 isolation, as also confirmed in later studies. However, no association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression in this study. The initial results of HHV6 studies were confirmed by Cone et al. [18].

Oral immune pathology in chronic GVHD

Histological changes observed at later stages post-HSCT, the s.c. chronic GVHD, seems to be of mostly autoimmune origin, due to cytotoxic damage of vascular structures and mucosal epithelium induced by donor effector cells. In cases of chronic GVHD, the changes in oral mucosa developing 12 months or later after transplantation comprise erythema of mucous membranes, tongue atrophy and also lichenoid changes in the buccal mucosa [14]. The study by Motta to al. [19] was performed in 12 patients undergoing allo-HSCT. The paired oral cGVHD biopsies obtained before and 1 month after treatment with topical dexamethasone (n=8), or tacrolimus (n=4) were subjected to immunohistochemistry of main immune markers (CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3) as compared to bioptates from aGVHD, oral lichen planus, and normal tissues. The oral bioptates in cGVHD were characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating immune cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+, and FoxP3+ cells, exceeding the levels of normal tissues thus presuming a largely T-cell-driven inflammation with macrophage participation. Topical dexamethasone or tacrolimus reduced the mentioned cell pathology in oral cGVHD, while reducing the number of CD4+ and CD103+ cells.
Clinical signs of chronic oral GVHD develop at later terms post-transplant (>100 days after HSCT), being observed in 50-80% of total cases. The cGVHD symptoms include erythema, atrophy of the tongue surfaces, lichenoid changes of buccal mucosae accompanied by ulcers and increased oral cancer risk [10]. Salivary gland dysfunction causes xerostomia, clinical pattern of parotitis, excess of mucous substances and lower saliva production. These symptoms may persist, at least, for 1 year after HSCT.
The cGVHD, like as acute GVHD, develops by immune mechanisms. It affects different organs and tissues including oral cavity. Clinical pattern of oral cGVHD, generally, is similar to the Sjogren disease, a well-known autoimmune disorder [20].
So far, there are no validated cGVHD biomarkers correlating with clinical except of relatively unspecific parameters, e.g., altered albumin or high complement levels [21]. Increased albumin, Na+ , Cl− concentrations, changes of lactoferrin an protease inhibitors may be observed in oral fluid of the cGVHD patients [22].

Treatment of early post-transplant oral disorders (mucositis and aGVHD)

Oral mucositis, being a very common complication of intensive chemotherapy followed by HSCT occurring in ca.70-80% of the cases, thus needing novel management strategies which include both preventive measures and therapeutic approaches. Pathophysiology of acute oral includes complex interactions between the products of tissue damage, reactive oxygen species, local microbiota and host immune system, which determines the grade of inflammatory response in oral mucosa and salivary glands. Genetic factors plays a major role in the development of this toxicity [23]. Although only few therapeutic agents are available, several promising drugs are under clinical trials.
Palifermin (keratinocyte growth factor) is the only pharmacological drug approved by the European Medicines Agency and the US Food and Drug Administration (FDA) for mucositis. Palifermin is administered intravenously prior to the initiation of chemotherapy and for an additional 3 days beginning since the day of HSCT [24].
Pathogenetic treatment also includes a number of anti-inflammatory drugs, either cytokine-based therapy, or non-steroid anti-inflammatory drugs, pentoxifylline etc. [23]. Biological cell-containing preparations are also tried to this purpose. Recently, Piccin et al. [25] has reported a lymphoma patient with severe oral and esophageal mucositis developed after high-dose chemotherapy, auto-HSCT, severe sepsis, viral infection and neutropenia. Platelet gel from cord blood was topically administered daily to the oral cavity. After 8 consecutive days, full recovery of mucositis was seen without any side effects. Therefore, controlled studies are required to compare efficacy of autologous and allogeneic platelet gels in severe mucositis.
A study in pediatric patients has also shown some efficiency of low-level laser therapy (LLT) in oral mucositis [26]. The authors have developed a specialized oral care protocol that included LLT for pediatric HSCT patients. Data from OM-related morbidity were collected from 51 HSCT pediatric patients treated daily with LLT, followed by standard oral care protocols. All the patients, even at younger ages, tolerated the LLT therapy well. The maximum OM degree was WHO II. Patients after autologous and HLA-haploidentical transplants showed less severe OM, and better clinical outcomes are reported with LLT which could be included into the specialized oral care in this cohort of children.

Novel treatments of mucosal aGVHD

Oral immune-like syndromes are sometimes observed in acute GVHD after HSCT. E.g., Ion et al. [27] has studied twenty-one such GVHD cases of which 5 demonstrated only oral features; the remaining 16 had variable involvement of skin (n=14), liver (n=7), and gut (n=5). The median time for onset of oral aGVHD was 35 days (11 to 159 days). The sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21) tongue (18 of 21 dorsum in 8), labial mucosa (16 of 21, palatal mucosa (15 of 21; hard palate in 7), and floor of mouth (7 of 21). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for additional support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and nonkeratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing.
Previous successful experience with blood platelet gels was based on regenerative effects upon diabetic or surgical wounds, due to local release of growth factors such as fibroblast – derived growth factor, platelet-derived growth factor etc. [28]. Their study was aimed for assessing efficacy and safety of allogeneic platelet gel for treating ulcers in the skin or oral aGVHD. Platelet-rich fibrin was obtained by automated process (Vivostat system, Vivostat A/S). Six patients with multiple lesions involving dermis (Grade I, n=2), subcutaneous (Grade II, n=4), or oral mucosa related to GVHD were administered the gel as local therapy. After the second gel application, the pain faded away, and granulation tissue was observed in four cases with Grade II lesions. After a median of eight PLT gel applications (range, -10), five of six patients showed a complete response, without any side effects documented.
Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. Induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), was suggested to potentiate intestinal crypt proliferation and mucosal repair [29]. A pilot study included 20 patients with steroid refractory intestinal GVHD who were given oral lithium carbonate against a group treated with glucocorticoids. As a result, 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients.

Therapy of chronic oral GVHD

Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy with minimal side effects which alleviates cGVHD in most patients. Its curative effects are explained by immunomodulatory action upon T-regulatory lymphocytes. Recent data suggest that favorable effects of extracorporeal photopheresis (UVA irradiation) upon cGVHD may be also caused by inactivation and apoptosis of peripheral blood neutrophils [30]. Meanwhile, chronic GVHD is often refractory to systemic therapies. Some workers draw attention to intraoral narrow-band ultraviolet B (NB-UVB) irradiation in oral cGVHD delivered as a course of 24 phototherapy sessions, at a single dose of >50 mJ/cm [31]. Median symptom scores (0-10) for sensitivity, pain, and dryness at baseline/end of therapy were 7.5, 3, 1, and 3, 1, 2, respectively. In sum, 7/11 patients had improvement and 2/11 worsened. Hence, NB-UVB may be considered a treatment option in refractory oral cGVHD, however, requiring clinical trials with appropriate control groups.
A supplementary topical treatment of oral cGVHD is proposed by means the glucocorticoid inhalers [32]. The authors compared different formulations showing pharmacological superiority of Budesonide for topical application in oral cGVHD. Marked local anti-inflammatory effects of Budesonide are based on its very low absorption through mucosal surfaces, thus increasing the potential role in oral cGVHD management. Moreover, its viscous formulation increases mucosal contact time and provides greater pharmacological effect in mucosal inflammation [33].
Second-line treatment in refractory cGVHD may include low doses of alemtuzumab plus low doses of rituximab as suggested by Gutiérrez-Aguirre et al. [34]. The authors have observed 15 patients who received one cycle of subcutaneous alemtuzumab (10 mg/day/3 days), and intravenous rituximab 100 mg on D+4, +11, +18 and +25 post-transplant (the protocol is under clinical trial). The therapeutic response was measured on Days +30, +90 and +365 of the protocol. The main site involved was the oral mucosa (86.7%). The overall response to the treatment was 100% at Day +30 evaluation, i.e., 10 patients had partial remission and 5, complete remission. At D+90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. Adverse effects were mainly infections in 67% of patients; these were usually quickly solved.

Specific cautions for drug therapy following HSCT

First of all, one should take into account those anticancer drugs that carry the highest risk for mucositis, i.e., methotrexate, cyclophosphamide, cisplatin, and fluorouracil (Villa, Sonis, 2015).
Risk of mucositis is dose-dependent and increases with higher intensity of chemo- and/or radiation therapy. One should be cautious when administering some drugs to such patients, as follows [10]:
– General anesthetics;
– Non-steroid anti-inflammatory drugs (NSAIDs) since these drugs may augment cyclosporine and tacrolimus nephrotoxicity, and they may increase bleeding and aggravate peptic ulcers in the corticosteroid-treated patients;
– Aspirin dosage should be adjusted since it increases bleeding risks;
– Antibiotics (erythromycin, clarithromycin, tetracycline, aminoglycosides, chinolones), as well as azol antifungal azoles (ketonazol, fluconazole and itroconazol), like as NSAIDs could aaalter cyclosporine lebels in blood serum thus causing more expressed immunosuppression.
– Usage of Sirolimus, and probably, of other mTOR inhibitors for the GVHD prophylaxis, may cause acute ulcerative stomatitis affecting the non-keratinized mucosa, mainly, with tongue involvement, at median onset time of 55 days after HCST [35]. Topical corticosteroid treatment is successful in these cases.

Potential diagnostic markers

Dozens of salivary components may reflect different diseases of periodont and oral cavity, including inflammatory mediators, reactive oxidative products, cellular enzymes, tissue-breakdown products etc. [36]. Over last decade, a number of reviews have been dedicated to potential clinical significance of salivary markers for diagnostics of different somatic and infectious disorders. E.g., salivary diagnostics of cancer proteins in oral fluid is now an evolving field of diagnostics as reported by Kaur et al. [37]. However, most of current studies are directed to novel applications of salivary using the "omics" approach, studying genomic, transcriptomic, proteomic, microbiomic, and metabolomic parameters, thus bringing the solution to a big data analysis [38]. Meanwhile, a search may be focused on single specific markers showing distinct pathological disorders of oral cavity or in the entire host organism.

DNA markers

Salivary biomarkers for infectious diseases were extensively studied earlier [39]. The issue is that the infectious agents were detected by different laboratory tests (by specific antibodies, antigens or nucleic acid markers) in salivary samples. These include a large range of Herpes viruses, Hepatitis viruses, HIV, Human Papillomavirus (HPV), Influenza virus, and Poliovirus.
Moreover, hundreds of bacterial species could be found in saliva, at the oral mucosa, dental plaques and tongue surface including Escherichia coli, Mycobacterium tuberculosis, Helicobacter pylori, Treponema pallidum and a wide range of streptococcal species. Concerning fungal presentation in oral rinses, Candida species were the most frequently cultured fungi (in 75% of samples), followed by Cladosporium (65%), Aureobasidium, Saccharomycetales (50% for both), Aspergillus (35%), Fusarium (30%), and Cryptococcus (20%). [40].
Post-cytostatic immune deficiency is regularly associated with viral infections. In this view, the levels of herpesvirus type VI (HHVVI) in saliva were suggested to be a probable severity marker of chemotherapy-induced oral damage [41]. However, excessive HHV6 activation was not confirmed at later terms post-HSCT, in chronic GVHD patients [42]. The authors tested for HHV6 peripheral blood, different oral fluids from cGVHD patients and oral tissue samples from healthy blood donors. HHV6 was detected by nested polymerase chain reaction. The virus was detected in whole saliva in 13 cGVHD patients (68%) and in 19 blood donors (67%) but not in gingival crevicular fluid or parotid gland saliva. Only two oral tissue samples of cGVHD patients of 12 were positive for HHV6. In sum, these data do not support the importance of HHV6 in oral lesions of cGVHD.
Over 40 years, it has been well known that oral cavity and intestinal microbiota contain similar bacterial species as shown, e.g., by Hamilton et al. [43]. Large numbers of similar organisms (>106/m1) were recovered by microbiological cultures from oral samples and jejunal aspirate of 16 subjects, in five of whom the same organisms were present in similar relative proportions in the saliva, e.g., Fusobacteria, whereas in other cases jejunal organisms differed from those in saliva. In eight of them, jejunal flora showed a typical 'faecal' pattern usually associated with small bowel bacterial overgrowth but, in three, the jejunal floral was somewhat similar to that of saliva.
Nowadays, with development of high-throughput NGS and 16S RNA sequencing, these ratios are studied in more details [44]. Human microbiota from three different compartments, i.e., saliva, feces, and cancer tissue (CT), of patients with colorectal cancer (CRC) vs. 10 healthy controls (saliva and feces). Taxonomic analysis based on 16S rRNA gene, revealed the presence of three main bacterial phyla, which includes about 80% of sequence reads: Firmicutes, Bacteroidetes, and Proteobacteria. Differences in bacterial composition, F. nucleatum abundance in healthy controls vs. colon cancer patients, and the association of F. nucleatum with clinical parameters were observed. Hence, Fusobacterium species are part of the both oral and intestinal microbiota, especially of colon tissue. Metagenomic analyses have shown that F. nucleatum detection in saliva may be predictive for development of colorectal cancer (Nosho et al., 2016).
The leukocytes shed to saliva may be also used even for detection of specific mutations in the patients with myeloproliferative diseases. E.g., Strati et al. [45] have performed a comparative study of JAK2V617F mutation in blood and saliva taken from the patients with primary myelofibrosis. Analysis of results from 167 patients has shown that the concordance between JAK2V617F detection in blood and saliva was 96%, with a sensitivity of 100% and a specificity of 90%. This biological material seems to have, at least, as sensitive as blood analysis for this mutation.

Protein markers

Like as DNA markers, immune protein molecules, like specific immunoglobulins , may be measured in saliva and salivary gland secretions in order to detect some latent and activable viruses [46].
Searching novel markers of acute GVHD is an important issue. E.g., one may check such potential salivary biomarkers as S100 protein family members (S100A8, S100A9, and S100A7) performed by Chiusolo et al. [47]. By means of HPLC, the authors have shown S100A8 in 14 of 23 cases of GVHD in allo-HSCT patients as compared with 2 GVHDfree parients and in none case of control group ( (P<0.001). Similar trend was registered for S100A9 protein. Multiple analysis of salivary proteome allows to detect some candidate proteins specific to acute GVHD as shown by Souza et al. [48] who carried out a preliminary study of salivary proteins using PAGE gel electrophoresis, liquid chromatograpy, and modern mass spectrometry. The most relevant proteins recognized exclusively in GVHD patients were: CSF2RB, protocadherin Fat 2 precursor, protein capicua homolog isoform CIC-S, MUC16 and RGPD8_HUMAN RANBP2. Their physiological role in this complication is not clear and needs further studies.
Diagnostic and prognostic markers of acute or chronic chronic GVHD are currently searched by means of proteomic analysis performed with mass-spectrometry or other methods of protein analysis. For example, saliva collected from oral cavity of allo-HSCT patients with chronic oral GVHD and cGVHD-free cases using isobaric Tags for quantification labeling, followed by tandem mass spectrometry. The method allowed identify up to 249 salivary proteins. Of them, 82 proteins were differently expressed in oral cGVHD patients compared to GVHD-free patients. Of these proteins, most played role in immunity, proteolytic functions, or as cytoskeleton components. Salivary IL-1 receptor antagonist and Cystatin B proved to exhibit decreased expression in oral chronic GVHD (P<0.003), thus, probably, being of some diagnostic significance [49].

Conclusions

1. Intensive chemotherapy and radiation treatment of the oncohematological patients followed by hematopoietic stem cell transplantation (HSCT) brings about early inflammation and acute necrosis of oral mucosa and gingivae, atrophy of salivary glands
2. Immune deficiency is evident at all post-transplant phases and later, at the stage of immunesuppressive therapy. At early terms, it is complicated by infections, at later phase, by autoimmune affection of oral mucosae. Over next years, a risk of secondary cancers is increased.
3. Bacterial and fungal infections of oral cavity and gastrointestinal tract are especially common at early terms, whereas viral activation (including secondary tumors) is detected at later terms after HSCT. The diagnosis of infections in immunocompromised patients represents an important task for the dentist that should be resolved in close contact with attending physician.
4. Late oral pathology after HSCT in children is presented, mainly, by developmental anomalies of dental system in young patients.
5. Chronic graft-versus-host disease (cGVHD) is accompanied by the Sjogren-like problems with oral mucosa and salivary glands.
6. There is no effective etiological treatment for acute mucositis, oral GVHD, both acute and chronic clinical forms. Appropriate pathogenetic therapy is aimed for release of painful symptoms and anti-inflammatory treatment. Some new promising drugs are still used as experimental therapy.
6. By the present time, there are no recognized salivary markers for early diagnostic and prediction of severe damage of oral mucosa expected after intensive cytostatic therapy, as well as GVHD following allogeneic transplantation. However, some promising salivary tests are to be studied, to detect infections of oral cavity, local and systemic malignancies.

Conflict of interest

No conflict of interest reported.

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Чухловин1" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20178" ["VALUE"]=> array(2) { ["TEXT"]=> string(407) "<sup>1</sup>Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup>Центральный научно-исследовательский институт стоматологии, Москва, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(371) "1Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия
2Центральный научно-исследовательский институт стоматологии, Москва, Россия
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Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.

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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20182" ["VALUE"]=> array(2) { ["TEXT"]=> string(211) "<sup>1</sup>The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia<br> <sup>2</sup>Central Research Institute of Stomatology, Moscow, Russia<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(175) "1The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
2Central Research Institute of Stomatology, Moscow, 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) "20183" ["VALUE"]=> array(2) { ["TEXT"]=> string(3049) "<p style="text-align: justify;"> The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.<br> There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2977) "

The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.

Keywords

Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.

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The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.

Keywords

Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.

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The review article deals with early and late oral and dental problems occurring after intensive anticancer chemoand radiotherapy and hematopoietic stem cell transplantation (HSCT). High-dose cytoreductive therapy may be accompanied by long-term cytopenia followed by slow recovery of myelo- and lymphopoiesis; complications of immunosuppressive treatment due to graft-versus-host disease (GVHD). I.e., post-transplant immune pathology is accompanied by high risk of dental infections thus requiring prophylactic caries treatment, and antiseptic regimens in cytopenic period. The therapy-associated affection of oral epithelial cells leads to early mucositis and aggravates acute graft-versus-host disease. Autoimmune-like complications (atrophy of oral epithelium and salivary glands, dry mouth syndrome) are frequently observed within several months after allogeneic HSCT. In pediatric patients, massive chemotherapy and radiation treatment is followed by stunted root growth, lagging primary dentition, hypoplasia of tooth enamel etc. In adults, cytostatic chemotherapy causes more intensive oral infections. Differential protocols are proposed for children and adults in order to perform prophylaxis and treatment of dental pathology in the patients undergoing auto- and allo-HSCT. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.

Keywords

Hematopoietic stem cell transplantation, immunosuppressive treatment, oral epithelium, immune-mediated disorders, dental infections, treatment, prophylaxis.

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Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.

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Данная обзорная статья описывает ранние и поздние стоматологические осложнения, возникающие после интенсивной антибластомной химио- и радиотерапии и трансплантации гемопоэтических стволовых клеток (ТГСК). Высокодозная циторедуктивная терапия может сопровождаться долгосрочными цитопениями с медленным восстановлением миело и лимфопоэза, осложнениями иммуносупрессивного лечения в связи с «болезнью трансплантат против хозяина» (РТПХ). Таким образом, эта иммунная патология сопряжена с высоким риском стоматологических инфекций, что требует профилактического лечения кариеса и антисептической обработки в периоде цитопении. Связанное с терапией повреждение эпителия ротовой полости ведет к развитию раннего мукозита и отягощает течение острой реакции «трансплантат против хозяина». Аутоиммуно подобные осложнения (атрофия эпителия полости рта и слюнных желез, синдром «сухого рта») часто отмечаются в течение нескольких месяцев после аллогенной ТГСК. У пациентов детского возраста массивная химио- и лучевая терапия дают осложнения в виде задержки развития корней зубов, задержка прорезывания зубов, гипоплазия зубной эмали и др. У взрослых цитостатическая химиотерапия ведет к более интенсивной патологии пародонта. Предложены дифференциальные протоколы для детей и взрослых с целью профилактики и лечения зубной патологии у пациентов после ауто- или алло-ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, иммуносупрессивное лечение, эпителий полости рта, иммуно-опосредованные заболевания, инфекции зубов, лечение, профилактика.

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Introduction

Modern chemotherapy protocols and optimal radiotherapy allow to achieve stable remission in ~80% newly diagnosed Hodgkin’s lymphoma (HL) patients [1]. However, a proportion of HL patients has chemoresistant disease or relapse after initial objective response [1, 2]. Further strategy with HL patients includes salvage treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), and/or antibody-drug conjugate brentuximab vedotin [3, 4]. The patients with failure of second-line treatment have poor prognosis and limited therapeutic options [5]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated for the patients with relapsed and refractory (R/R) disease, being able to improve long-term survival and control of the disease [5]. Although allo-HSCT is a potentially curative approach in these patients, a substantial fraction of patients develops relapses and disease progression in posttransplant period, showing strong dependence on the disease status at the time of transplantation [5]. The dysfunction of immune surveillance mechanisms with alteration of PD-1 ligand (PDL-1)-to-PD-1 signaling is considered a defining feature of classical Hodgkin’s lymphoma [6]. nivolumab, a PD-1-blocking antibody, is an immune checkpoint inhibitor, showing high efficiency in patients with relapsed/refractory HL patients after ASCT and brentuximab vedotin treatment with benign toxicity profile. The most specific complications include autoimmune disorders such as pneumonitis, autoimmune hepatitis, hypothyroidism and other disorders [5]. Retrospective data demonstrated that nivolumab treatment for post-allo-HSCT may cause graft-versus-host disease (GVHD) manifestation and aggravation [7, 8, 9]. By contrary, some reports show no signs of GVHD after initiation of anti-PD-1 therapy [10]. Moreover, earlier observations show that, in HL patients after allo-HSCT, nivolumab may lead to profound clinical benefit even if applied at low doses [11]. With respect to previous reports we present retrospective results on seven HL patients relapsing after allo-HSCT subjected to nivolumab administered at different dosing regimens. In all the patients, nivolumab showed clinical efficiency with objective response and considerable toxicity, i.e., immune adverse effects, irrespective of nivolumab dosage, with no cases of GVHD manifestation.

Patients and methods

Our single-center study included seven patients (3 men and 4 women) with relapsed/refractory HL who underwent allo- HSCT. Their median age was 29 years (21 to 43 years old). Baseline characteristics of the patients are shown in Table 1. When entering the study, all the patients signed an informed consent for the use of their medical data for research purposes. The median number of prior therapeutic lines was 9 (8 to 9) including autologous stem cell transplantation (performed in 5/7 patients), and allo-HSCT. Matched HLA-related siblings were used for 3 patients. Four patients had unrelated donors: three of them were HLA-identical and one with 9/10-locus mismatch. Peripheral blood stem cells were transplanted in four patients, and bone marrow, in rest of the cases. Six patients received reduced intensity conditioning (RIC): fludarabine 30 mg/m2/bendamustine 130 mg/m2 per day for 3 days (FluBe) regimen was used in 3 patients, Flu/2 Gy TBI, in 2 patients, and Flu/8 mg/kg busulfan was used in 1 case. In 5/7 patients, the post-transplant cyclophosphamide based regimen was used for GVHD prophylaxis, i.e., cyclophosphamide 50 mg/kg on day +3 and +4 after alloHSCT (PTC) in 2 patients, PTC in combination with tacrolimus started on day + 5 (PTC-Tx) in 1 patient, PTC-Tx with addition of mycophenolate mofetil (MMF) in 2 patients, methotrexate/tacrolimus in 1 case, and antithymocyte globulin/methotrexate/ MMF/cyclosporine A in 1 patient. Objective response determined as CR or PR before allo-HSCT was documented in four patients (3 CR, 1 PR), two patients received transplant during the disease progression. Acute GVHD was reported in 6 patients, with no severe (grade III-IV) cases, and 3 patients had a limited chronic skin GVHD. Median time between the allo-HSCT and disease relapse/progression was 3.3 months (1.5-10). As salvage therapy after allo-HSCT, all patients have received the treatment with brentuximab vedotin, six of them received treatment with bendamustine. Five patients received donor lymphocyte infusions before nivolumab initiation. Median time from allo-HSCT to first injection of nivolumab was 26.7 months (range 7-42.4). One patient has received nivolumab before allo-HSCT, but treatment was discontinued due to grade 4 adverse event (bacterial meningitis). Transplantation modalities and complications are shown in Table 2. By the moment of nivolumab initiation, six patients had disease progression, one patient had stabilization of disease, 6/7 of patients presented with extranodal disease and 3/7 with B-symptoms. None of the patients had signs of GVHD at the moment of treatment initiation. Nivolumab was given as monotherapy at the dose of 3 mg/kg of body weight intravenously every two weeks for two patients. Due to concerns regarding the manifestation of GVHD and immune-related adverse events, the dose were reduced to 1 mg/kg and to the dose of 0.5 mg/kg i.v. every two weeks for 1 patient and for 4 patients, respectively. A median number of nivolumab injections was 7 (1 to 20). The treatment efficacy was assessed by total body PET/CT scan [12] every 3 months after nivolumab initiation or earlier in the event of treatment discontinuation. Toxicities were graded retrospectively according to the National Cancer Institute Common Toxicity Criteria for AEs (version 4.03).

Results

Treatment efficiency

Response to the nivolumab-based therapy was evaluated at a median follow-up time of 14.5 (3.3-22.5) months. Objective response was noted in all the patients at either nivolumab dosage. Complete metabolic response was observed in two patients (28.6%) treated with, respectively, 0.5 and 1 mg/kg of the drug. The rest of this group exhibited partial clinical responses. The maximal response and tumor mass reduction at the best response are shown in Fig. 1. and Fig. 2. The specific B symptoms of lymphoma reported before the therapy were resolved in two of three patients. The objective response was observed after a median of 6 (1-6) nivolumab injections. Four patients (57%) have experienced the disease progression at a median of 6.7 months (5 to 8.5). Two of these patients were re-treated with the same dose of nivolumab, thus allowing to achieve an objective response (CR) in one patient. After monotherapy with nivolumab, three patients underwent further treatment, with addition of bendamustine or other cytostatic agents. At the time of this report, three patients (42.9%) still receive the nivolumab monotherapy. Clinical outcomes are presented in Table 3 and Fig. 3.

28-35_Lepik Table 1. Baseline charasteristics of the patients.png

Toxicity

All the patients were alive at the time of report and were subject to the safety analysis. During nivolumab treatment, 3/7 (42.9%) of the patients experienced grade 3-4 adverse events (AEs), which included two cases of aseptic meningitis (28.6%) and one case of аutoimmune hepatitis, autoimmune hypophysitis. This adverse events manifested after median of 2 (1-2) infusions of the drug. Due to severe adverse events, the nivolumab treatment was discontinued, and patients received short courses of glucocorticoids (1 mg/kg methylprednisolone) with complete resolution of the event. There was no correlation with nivolumab dosing regimen, since severe AEs were observed in patients with different drug dosage (0.5, 1, or 3 mg/kg of body weight). There were no cases of GVHD onset. Notably, the patient who had discontinued nivolumab before allo-HSCT had no adverse events in post-transplant setting. Two patients who discontinued nivolumab treatment due to AE’s, received retreatment after the disease relapse. In one patient with meningitis and hypophisitis, no AE recurrence was revealed later, in another case, a recurrence of autoimmune hepatitis was noted after 2 infusions during the first retreatment. The therapy was again discontinued, and the patient received glucocorticoids followed by complete resolution of hepatitis. The second retreatment was performed with addition of low-dose glucocorticoids in both patients, without AE signs observed.

Discussion

Allo-HSCT is a potentially curative treatment strategy for relapsed and refractory HL patients. Despite novel therapeutic modalities in HL, allogeneic HSCT is remaining an important option. Transplant-related mortality continues to decline owing to lower intensity preparative regimens [13], improved GVHD prophylaxis [5] and novel treatment modalities [4]. At the same time, HL relapse continues to present a significant problem [5]. Therapeutic options are limited in this severely pre-treated group of patients. Common treatment modalities in patients with relapse after allo-HSCT include brentuximab vedotin [14], donor lymphocyte infusions [15] and chemotherapy regimens, such as bendamustine [16] and drug combinations [17-19] with modest results.Therefore, improved post allo-HSCT treatment strategies are needed. Based on biological features of HL, and described mechanisms of graft-versus-lymphoma (GVL) effect, the enhancement of GVL with PD-1 blockade was proposed and demonstrated with several murine models [20, 21] with no GVHD aggravation, and confirmed by early clinical observations [22, 23]. Two retrospective studies [7, 9] of nivolumab salvage treatment in HL relapse after allo-HSCT demonstrate profound activity of this drug (ORR 77%-95%, CR 42%-50%), but also significant toxicity, with high rate of GVHD manifestation (30%-50%) including steroid-refractory and lethal cases of GVHD. The authors conclude that administration of anti-PD-1 after allo-HSCT should be done with extreme caution. This multicenter retrospective studies included mixed population of patients with different types of conditioning regimens and GVHD prophylaxis. Therefore, a strong need for prospective studies with standardized preparative regimens is required.
28-35_Lepik Table 2. Transplantation modalities and complications.png
Another aspect addressed in our retrospective analysis is the dosing regimen for nivolumab. Most data regarding efficiency of nivolumab after allo-HSCT were obtained at a standard dose of 3 mg/kg every two weeks [7, 9]. Meanwhile, its pharmacokinetic studies reveal that the PD-1 peripheral receptor occupancy was saturated at doses as low as 0.3 mg/kg. There are also reports of efficient treatment with lower doses of the drug (0.5 mg/kg) in post allo-HSCT setting [11]. Thus, there is rationale for testing different doses of nivolumab in patients after allo-HSCT.
Here we present a retrospective analysis of 7 patients with HL relapse after allo-HSCT treated with nivolumab at different dosing regimens (0,5-3 mg/kg). All the patients were severely pre-treated with previous therapy (a median of 9 infusions). Most of the patients included into the study (5/7) received the posttransplant cyclophosphamide (PTC)-based GVHD prophylaxis. We demonstrate high efficiency of treatment with 100% ORR in all assessed patients and 28.6% CR rate, irrespective of the nivolumab dosing regimen. Despite high initial response rates, 4 of 7 patients (57%) have experienced disease progression at the median of 6.7 months. Importantly, nivolumab retreatment in two patients was followed by CR achievement in one patient, and clinical improvement in both cases. After median follow up of 14.5 (3.3 to 22.5) months, all the patients are alive with good quality of life.
We did not observe any GVHD onset or exacerbation in our group of patients, possibly due to use of PTC based GVHD prophylaxis regimen and long median time of treatment initiation after alloSCT (26.7 mo), 3/7 patients were experienced grade 3-4 immune AE including aseptic meningitis, hypophysitis and hepatitis. Whether the hepatic involvement was due the autoimmune hepatitis or GVHD is not completely clear, as clinical and histologic differences between GVHD and anti-PD-1 toxicity are not strictly defined. We consider our case of hepatic toxicity as hepatitis associated with anti-PD-1 drug treatment, because it presented with asymptomatic, profound increase in transaminases, while bilirubin level was within reference ranges during the entire observation period, which corresponds to common hepatic AEs induced by PD-1/PD-L1 inhibitors presenting as asymptomatic increase of AST and ALT, and total bilirubin in rare instances [24].

28-35_Lepik Figures 1-3.png

28-35_Lepik Table 3. Clinical outcomes following treatment with different doses of Nivolumab.png

Despite severity of the observed immune AE’s, they regressed shortly after nivolumab discontinuation and initiation of glucocorticoid therapy. Therefore, anti-PD-1 antibodies after allo-HSCT should be administered with caution, and careful monitoring of patient is needed, especially during the first month of anti-PD-1 treatment. Previous reports of treatment with ipilimumab [25, 26] and lower doses of anti-PD-1 antibodies [11], suggested a dose-dependent or context-dependent risk of developing toxicity after the apoptosis checkpoint blockade. During our analysis we did not observed the dependence of the toxicity and effect from nivolumab dosage. Complete metabolic response observed in two patients with 0.5 and 1 mg/kg dosing regimen, and severe AEs was experienced in patients with 0.5, 1, 3 mg/kg. The results obtained with anti-PD therapy of Hodgkin’s disease should be compared with efficiency of Brentuximab, an immunotoxic drug targeted for CD30 antigen on tumor cells [27]. It proved to be highly efficient in resistant/relapsed cases of HD being currently under extensive trials [28-30]. Its combined effects with anti-PD drugs deserve further studies.

Conclusion

Our retrospective analysis of nivolumab treatment at different single dosages concerned post-allo-HSCT patients who developed HL relapse. We have confirmed clinical efficacy of nivolumab, however, with induction of severe-grade 3-4 immune AEs in three patients subjected to different dosing regimens (0.5, 1, 3 mg/kg), but without any documented GVHD cases. The prospective studies are warranted, aiming for establishment of optimal dosing regimens, as well as potential effects of conditioning and GVHD prophylaxis upon the risks and benefits of nivolumab treatment after allo-HSCT.

Conflict of interest

The authors report no conflicts of interest.

References

1. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 ;327(21):1478-1484.
2. Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386-2395.
3. Rancea M, Monsef I, von Tresckow B, Engert A, Skoetz N. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma, Cochrane Database Syst Rev. 2013; (6):CD009411
4. Zinzani PL, Viviani S, Anastasia A., Vitolo U., Luminari S, Zaja F, Corradini P, Spina M, Brusamolino E, Gianni A, Santoro A, Botto B, Derenzini E, Pellegrini C, Argnani L. Brentuximab Vedotin in relapsed/refractory Hodgkin’s lymphoma: The Italian experience and results of its use in daily clinical practice outside clinical trials. Haematologica. 2013; 98: 1232-1236.
5. Martínez C, Gayoso J, Canals C, Finel H, Peggs K, Dominietto A, Castagna L, Afanasyev B, Robinson S, Blaise D, Corradini P, Itälä-Remes M, Bermúdez A, Forcade E, Russo D, Potter M, McQuaker G, Yakoub-Agha I, Scheid C, Bloor A, Montoto S, Dreger P, Sureda A. Post-transplantation cyclophosphamide-based haploidentical transplantation as alternative to matched sibling or unrelated donor transplantation for Hodgkin lymphoma: A registry study of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation. J Clin Oncol. 2017;35(30):3425-3432.
6. Roemer MGM, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, Connelly CF, Sun HH, Daadi SE, Freeman GJ, Armand P, Chapuy B, de Jong D, Hoppe RT, Neuberg DS, Rodig SJ, Shipp MA. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34(23):2690-2697.
7. Herbaux C, Gauthier J, Brice P, Drumez E, Ysebaert L, Doyen H, Fornecker L, Bouabdallah K, Manson G, Ghesquières H, Tabrizi R, Hermet E, Lazarovici J, Thiebaut-Bertrand A, Chauchet A, Demarquette H, Boyle E, Houot R, Yakoub-Agha I, Morschhauser F. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin’s lymphoma. Blood. 2017; 129(18):2471-2478.
8. El Cheikh J, Massoud R, Abudalle I, Haffar B, Mahfouz R, Kharfan-Dabaja MA, Jisr T, Mougharbel A, Ibrahim A, Bazarbachi A. Nivolumab salvage therapy before or after allogeneic stem cell transplantation in Hodgkin lymphoma. Bone Marrow Transplant. 2017; 52(7):1074-1077.
9. Haverkos BM, Abbott D, Hamadani M, Armand P, Flowers ME, Merryman R, Kamdar M, Kanate AS, Saad A, Mehta A, Ganguly S, Fenske TS, Hari P, Lowsky R, Andritsos L, Jagasia M, Bashey A, Brown S, Bachanova V, Stephens D, Mineishi S, Nakamura R, Chen YB, Blazar BR, Gutman J, Devine SM. PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate
but frequent GVHD. Blood. 2017;130(2):221-228.
10. Villasboas JC, Ansell SM, Witzig TE. Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective. Oncotarget. 2016; 7: 13260–13264.
11. Onizuka M, Kojima M, Matsui K, Machida S, Toyosaki M, Aoyama Y, Kawai H, Amaki J, Hara R, Ichiki A, Ogawa Y, Kawada H, Nakamura N, Ando K. Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Int J Hematol. 2017; 106(1):141-145.
12. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano Classification. J Clin Oncol. 2014; 32(27):3059-3068.
13. Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014; 124(14):2306-2312.
14. Carlo-Stella C, Ricci F, Dalto S, Mazza R, Malagola M, Patriarca F, Viviani S, Russo D, Giordano L, Castagna L, Corradini P, Santoro A. Brentuximab vedotin in patients with Hodgkin lymphoma and a failed allogeneic stem cell transplantation: results from a named patient program at four Italian centers. Oncologist. 2015;20(3):323–328.
15. Anderlini P, Saliba R, Acholonu S, Okoroji GJ, Ledesma C, Andersson BS, Jones R, Popat UR, Hosing CM, Nieto Y, Qazilbash MH, Ueno NT, Giralt SA, de Lima MJ, Champlin RE. Donor leukocyte infusions in recurrent Hodgkin lymphoma following allogeneic stem cell transplant: 10-year experience at the MD Anderson Cancer Center. Leuk Lymphoma. 2012;53(6):1239-1241.
16. Anastasia A, Carlo-Stella C, Corradini P, Salvi F, Rusconi C, Pulsoni A, Hohaus S, Pregno P, Viviani S, Brusamolino E, Luminari S, Giordano L, Santoro A. Bendamustine for Hodgkin lymphoma patients failing autologous or autologous and allogeneic stem cell transplantation: a retrospective study of the Fondazione Italiana Linfomi. Br. J. Haematol. 2014;166(1):140–142.
17. Theurich S, Malcher J, Wennhold K, Shimabukuro-Vornhagen A, Chemnitz J, Holtick U, Krause A, Kobe C, Kahraman D, Engert A, Scheid C, Chakupurakal G, Hallek M, von Bergwelt-Baildon M. Brentuximab vedotin combined with donor lymphocyte infusions for early relapse of Hodgkin lymphoma after allogeneic stem-cell transplantation induces tumor-specific immunity and sustained clinical remission. J Clin Oncol. 2013;31(5):e59-63. DOI: 10.1200/JCO.2012.43.6832
18. Tsirigotis P, Danylesko I, Gkirkas K., Shem-Tov N, Yerushalmi R, Stamouli M, Avigdor A, Spyridonidis A, Gauthier J, Goldstein G, Apostolidis J, Mohty M, Shimoni A, Nagler A. Brentuximab vedotin in combination with or without donor lymphocyte infusion for patients with Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51(10):1313–1317.
19. Sala E, Crocchiolo R, Gandolfi S, Bruno-Ventre M, Bramanti S, Peccatori J, Sarina B, Corti C, Ciceri F, Santoro A, Marktel S, Castagna L. Bendamustine combined with donor lymphocytes infusion in Hodgkin’s lymphoma relapsing after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 2014;20(9):1444–1447.
20. Koestner W, Hapke M, Herbst J., Klein C, Welte K, Fruehauf J, Flatley A, Vignali DA, Hardtke-Wolenski M, Jaeckel E, Blazar BR, Sauer MG. PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graftversus- host disease after delayed adoptive transfer of T-cell receptor gene engineered allogeneic CD8+ T cells. Blood. 2011;117(3):1030-1041.
21. Michonneau D, Sagoo P, Breart B, Garcia Z, Celli S, Bousso P. The PD-1 axis enforces an anatomical segregation of CTL activity that creates tumor niches after allogeneic hematopoietic stem cell transplantation. Immunity. 2016;44(1):143-154.
22. Angenendt L, Schliemann C, Lutz M, Rebber E, Schulze AB, Weckesser M, Stegger L, Schäfers M, Groth C, Kessler T, Lenz G, Stelljes M, Berdel WE. Nivolumab in a patient with refractory Hodgkin's lymphoma after allogeneic stem cell transplantation. Bone Marrow Ttransplant. 2016;51(3):443-445.
23. Yared JA, Hardy N, Singh Z, Hajj S, Badros AZ, Kocoglu M, Yanovich S, Sausville EA, Ujjani C, Ruehle K, Goecke C, Landau M, Rapoport AP. Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51(6):850- 852.
24. Zhang X, Ran Y, Wang K, Zhu Y, Li J. Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. Drug Design, Development and Therapy. 2016; 10:3153-3161.
25. Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L, Lowy I, Solomon SR, Morris LE, Holland HK, Mason JR, Alyea EP, Soiffer RJ, Ball ED. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581-1588.
26. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, Rodig SJ, Hirakawa M, Severgnini M, Hodi FS, Wu CJ, Ho VT, Cutler C, Koreth J, Alyea EP, Antin JH, Armand P, Streicher H, Ball ED, Ritz J, Bashey A, Soiffer RJ. Ipilimumab for patients with relapse after allogeneic transplantation. New Engl J Med. 2016;375(2):143-153.
27. King RL, Howard MT, Bagg A. Hodgkin Lymphoma: Pathology, pathogenesis, and a plethora of potential prognostic predictors. Anat Pathol. 2014;21:12–25.
28. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II Study of Brentuximab Vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.
29. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, Armand P, Fanale M, Ratanatharathorn V, Kuruvilla J, Cohen JB, Collins G, Savage KJ, Trneny M, Kato K, Farsaci B, Parker SM, Rodig S, Roemer MG, Ligon AH, Engert A. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294.
30. Afanasyev BV, Moiseev IS, Alekseev SM, Mikhailova NB, Kondakova EV, Ilyin NV, Belyaеv AM. Multicenter prospective escalation-de-escalation PET-guided clinical study in classical type Hodgkin disease in the North-East of Russian Federation (RNWOHG-HD1): rationale and design. Cell Ther Transplant. 2017; 6(4): 76-81.

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Introduction

Modern chemotherapy protocols and optimal radiotherapy allow to achieve stable remission in ~80% newly diagnosed Hodgkin’s lymphoma (HL) patients [1]. However, a proportion of HL patients has chemoresistant disease or relapse after initial objective response [1, 2]. Further strategy with HL patients includes salvage treatment with high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), and/or antibody-drug conjugate brentuximab vedotin [3, 4]. The patients with failure of second-line treatment have poor prognosis and limited therapeutic options [5]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated for the patients with relapsed and refractory (R/R) disease, being able to improve long-term survival and control of the disease [5]. Although allo-HSCT is a potentially curative approach in these patients, a substantial fraction of patients develops relapses and disease progression in posttransplant period, showing strong dependence on the disease status at the time of transplantation [5]. The dysfunction of immune surveillance mechanisms with alteration of PD-1 ligand (PDL-1)-to-PD-1 signaling is considered a defining feature of classical Hodgkin’s lymphoma [6]. nivolumab, a PD-1-blocking antibody, is an immune checkpoint inhibitor, showing high efficiency in patients with relapsed/refractory HL patients after ASCT and brentuximab vedotin treatment with benign toxicity profile. The most specific complications include autoimmune disorders such as pneumonitis, autoimmune hepatitis, hypothyroidism and other disorders [5]. Retrospective data demonstrated that nivolumab treatment for post-allo-HSCT may cause graft-versus-host disease (GVHD) manifestation and aggravation [7, 8, 9]. By contrary, some reports show no signs of GVHD after initiation of anti-PD-1 therapy [10]. Moreover, earlier observations show that, in HL patients after allo-HSCT, nivolumab may lead to profound clinical benefit even if applied at low doses [11]. With respect to previous reports we present retrospective results on seven HL patients relapsing after allo-HSCT subjected to nivolumab administered at different dosing regimens. In all the patients, nivolumab showed clinical efficiency with objective response and considerable toxicity, i.e., immune adverse effects, irrespective of nivolumab dosage, with no cases of GVHD manifestation.

Patients and methods

Our single-center study included seven patients (3 men and 4 women) with relapsed/refractory HL who underwent allo- HSCT. Their median age was 29 years (21 to 43 years old). Baseline characteristics of the patients are shown in Table 1. When entering the study, all the patients signed an informed consent for the use of their medical data for research purposes. The median number of prior therapeutic lines was 9 (8 to 9) including autologous stem cell transplantation (performed in 5/7 patients), and allo-HSCT. Matched HLA-related siblings were used for 3 patients. Four patients had unrelated donors: three of them were HLA-identical and one with 9/10-locus mismatch. Peripheral blood stem cells were transplanted in four patients, and bone marrow, in rest of the cases. Six patients received reduced intensity conditioning (RIC): fludarabine 30 mg/m2/bendamustine 130 mg/m2 per day for 3 days (FluBe) regimen was used in 3 patients, Flu/2 Gy TBI, in 2 patients, and Flu/8 mg/kg busulfan was used in 1 case. In 5/7 patients, the post-transplant cyclophosphamide based regimen was used for GVHD prophylaxis, i.e., cyclophosphamide 50 mg/kg on day +3 and +4 after alloHSCT (PTC) in 2 patients, PTC in combination with tacrolimus started on day + 5 (PTC-Tx) in 1 patient, PTC-Tx with addition of mycophenolate mofetil (MMF) in 2 patients, methotrexate/tacrolimus in 1 case, and antithymocyte globulin/methotrexate/ MMF/cyclosporine A in 1 patient. Objective response determined as CR or PR before allo-HSCT was documented in four patients (3 CR, 1 PR), two patients received transplant during the disease progression. Acute GVHD was reported in 6 patients, with no severe (grade III-IV) cases, and 3 patients had a limited chronic skin GVHD. Median time between the allo-HSCT and disease relapse/progression was 3.3 months (1.5-10). As salvage therapy after allo-HSCT, all patients have received the treatment with brentuximab vedotin, six of them received treatment with bendamustine. Five patients received donor lymphocyte infusions before nivolumab initiation. Median time from allo-HSCT to first injection of nivolumab was 26.7 months (range 7-42.4). One patient has received nivolumab before allo-HSCT, but treatment was discontinued due to grade 4 adverse event (bacterial meningitis). Transplantation modalities and complications are shown in Table 2. By the moment of nivolumab initiation, six patients had disease progression, one patient had stabilization of disease, 6/7 of patients presented with extranodal disease and 3/7 with B-symptoms. None of the patients had signs of GVHD at the moment of treatment initiation. Nivolumab was given as monotherapy at the dose of 3 mg/kg of body weight intravenously every two weeks for two patients. Due to concerns regarding the manifestation of GVHD and immune-related adverse events, the dose were reduced to 1 mg/kg and to the dose of 0.5 mg/kg i.v. every two weeks for 1 patient and for 4 patients, respectively. A median number of nivolumab injections was 7 (1 to 20). The treatment efficacy was assessed by total body PET/CT scan [12] every 3 months after nivolumab initiation or earlier in the event of treatment discontinuation. Toxicities were graded retrospectively according to the National Cancer Institute Common Toxicity Criteria for AEs (version 4.03).

Results

Treatment efficiency

Response to the nivolumab-based therapy was evaluated at a median follow-up time of 14.5 (3.3-22.5) months. Objective response was noted in all the patients at either nivolumab dosage. Complete metabolic response was observed in two patients (28.6%) treated with, respectively, 0.5 and 1 mg/kg of the drug. The rest of this group exhibited partial clinical responses. The maximal response and tumor mass reduction at the best response are shown in Fig. 1. and Fig. 2. The specific B symptoms of lymphoma reported before the therapy were resolved in two of three patients. The objective response was observed after a median of 6 (1-6) nivolumab injections. Four patients (57%) have experienced the disease progression at a median of 6.7 months (5 to 8.5). Two of these patients were re-treated with the same dose of nivolumab, thus allowing to achieve an objective response (CR) in one patient. After monotherapy with nivolumab, three patients underwent further treatment, with addition of bendamustine or other cytostatic agents. At the time of this report, three patients (42.9%) still receive the nivolumab monotherapy. Clinical outcomes are presented in Table 3 and Fig. 3.

28-35_Lepik Table 1. Baseline charasteristics of the patients.png

Toxicity

All the patients were alive at the time of report and were subject to the safety analysis. During nivolumab treatment, 3/7 (42.9%) of the patients experienced grade 3-4 adverse events (AEs), which included two cases of aseptic meningitis (28.6%) and one case of аutoimmune hepatitis, autoimmune hypophysitis. This adverse events manifested after median of 2 (1-2) infusions of the drug. Due to severe adverse events, the nivolumab treatment was discontinued, and patients received short courses of glucocorticoids (1 mg/kg methylprednisolone) with complete resolution of the event. There was no correlation with nivolumab dosing regimen, since severe AEs were observed in patients with different drug dosage (0.5, 1, or 3 mg/kg of body weight). There were no cases of GVHD onset. Notably, the patient who had discontinued nivolumab before allo-HSCT had no adverse events in post-transplant setting. Two patients who discontinued nivolumab treatment due to AE’s, received retreatment after the disease relapse. In one patient with meningitis and hypophisitis, no AE recurrence was revealed later, in another case, a recurrence of autoimmune hepatitis was noted after 2 infusions during the first retreatment. The therapy was again discontinued, and the patient received glucocorticoids followed by complete resolution of hepatitis. The second retreatment was performed with addition of low-dose glucocorticoids in both patients, without AE signs observed.

Discussion

Allo-HSCT is a potentially curative treatment strategy for relapsed and refractory HL patients. Despite novel therapeutic modalities in HL, allogeneic HSCT is remaining an important option. Transplant-related mortality continues to decline owing to lower intensity preparative regimens [13], improved GVHD prophylaxis [5] and novel treatment modalities [4]. At the same time, HL relapse continues to present a significant problem [5]. Therapeutic options are limited in this severely pre-treated group of patients. Common treatment modalities in patients with relapse after allo-HSCT include brentuximab vedotin [14], donor lymphocyte infusions [15] and chemotherapy regimens, such as bendamustine [16] and drug combinations [17-19] with modest results.Therefore, improved post allo-HSCT treatment strategies are needed. Based on biological features of HL, and described mechanisms of graft-versus-lymphoma (GVL) effect, the enhancement of GVL with PD-1 blockade was proposed and demonstrated with several murine models [20, 21] with no GVHD aggravation, and confirmed by early clinical observations [22, 23]. Two retrospective studies [7, 9] of nivolumab salvage treatment in HL relapse after allo-HSCT demonstrate profound activity of this drug (ORR 77%-95%, CR 42%-50%), but also significant toxicity, with high rate of GVHD manifestation (30%-50%) including steroid-refractory and lethal cases of GVHD. The authors conclude that administration of anti-PD-1 after allo-HSCT should be done with extreme caution. This multicenter retrospective studies included mixed population of patients with different types of conditioning regimens and GVHD prophylaxis. Therefore, a strong need for prospective studies with standardized preparative regimens is required.
28-35_Lepik Table 2. Transplantation modalities and complications.png
Another aspect addressed in our retrospective analysis is the dosing regimen for nivolumab. Most data regarding efficiency of nivolumab after allo-HSCT were obtained at a standard dose of 3 mg/kg every two weeks [7, 9]. Meanwhile, its pharmacokinetic studies reveal that the PD-1 peripheral receptor occupancy was saturated at doses as low as 0.3 mg/kg. There are also reports of efficient treatment with lower doses of the drug (0.5 mg/kg) in post allo-HSCT setting [11]. Thus, there is rationale for testing different doses of nivolumab in patients after allo-HSCT.
Here we present a retrospective analysis of 7 patients with HL relapse after allo-HSCT treated with nivolumab at different dosing regimens (0,5-3 mg/kg). All the patients were severely pre-treated with previous therapy (a median of 9 infusions). Most of the patients included into the study (5/7) received the posttransplant cyclophosphamide (PTC)-based GVHD prophylaxis. We demonstrate high efficiency of treatment with 100% ORR in all assessed patients and 28.6% CR rate, irrespective of the nivolumab dosing regimen. Despite high initial response rates, 4 of 7 patients (57%) have experienced disease progression at the median of 6.7 months. Importantly, nivolumab retreatment in two patients was followed by CR achievement in one patient, and clinical improvement in both cases. After median follow up of 14.5 (3.3 to 22.5) months, all the patients are alive with good quality of life.
We did not observe any GVHD onset or exacerbation in our group of patients, possibly due to use of PTC based GVHD prophylaxis regimen and long median time of treatment initiation after alloSCT (26.7 mo), 3/7 patients were experienced grade 3-4 immune AE including aseptic meningitis, hypophysitis and hepatitis. Whether the hepatic involvement was due the autoimmune hepatitis or GVHD is not completely clear, as clinical and histologic differences between GVHD and anti-PD-1 toxicity are not strictly defined. We consider our case of hepatic toxicity as hepatitis associated with anti-PD-1 drug treatment, because it presented with asymptomatic, profound increase in transaminases, while bilirubin level was within reference ranges during the entire observation period, which corresponds to common hepatic AEs induced by PD-1/PD-L1 inhibitors presenting as asymptomatic increase of AST and ALT, and total bilirubin in rare instances [24].

28-35_Lepik Figures 1-3.png

28-35_Lepik Table 3. Clinical outcomes following treatment with different doses of Nivolumab.png

Despite severity of the observed immune AE’s, they regressed shortly after nivolumab discontinuation and initiation of glucocorticoid therapy. Therefore, anti-PD-1 antibodies after allo-HSCT should be administered with caution, and careful monitoring of patient is needed, especially during the first month of anti-PD-1 treatment. Previous reports of treatment with ipilimumab [25, 26] and lower doses of anti-PD-1 antibodies [11], suggested a dose-dependent or context-dependent risk of developing toxicity after the apoptosis checkpoint blockade. During our analysis we did not observed the dependence of the toxicity and effect from nivolumab dosage. Complete metabolic response observed in two patients with 0.5 and 1 mg/kg dosing regimen, and severe AEs was experienced in patients with 0.5, 1, 3 mg/kg. The results obtained with anti-PD therapy of Hodgkin’s disease should be compared with efficiency of Brentuximab, an immunotoxic drug targeted for CD30 antigen on tumor cells [27]. It proved to be highly efficient in resistant/relapsed cases of HD being currently under extensive trials [28-30]. Its combined effects with anti-PD drugs deserve further studies.

Conclusion

Our retrospective analysis of nivolumab treatment at different single dosages concerned post-allo-HSCT patients who developed HL relapse. We have confirmed clinical efficacy of nivolumab, however, with induction of severe-grade 3-4 immune AEs in three patients subjected to different dosing regimens (0.5, 1, 3 mg/kg), but without any documented GVHD cases. The prospective studies are warranted, aiming for establishment of optimal dosing regimens, as well as potential effects of conditioning and GVHD prophylaxis upon the risks and benefits of nivolumab treatment after allo-HSCT.

Conflict of interest

The authors report no conflicts of interest.

References

1. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 ;327(21):1478-1484.
2. Diehl V, Franklin J, Pfreundschuh M, Lathan B, Paulus U, Hasenclever D, Tesch H, Herrmann R, Dörken B, Müller-Hermelink HK, Dühmke E, Loeffler M; German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386-2395.
3. Rancea M, Monsef I, von Tresckow B, Engert A, Skoetz N. High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma, Cochrane Database Syst Rev. 2013; (6):CD009411
4. Zinzani PL, Viviani S, Anastasia A., Vitolo U., Luminari S, Zaja F, Corradini P, Spina M, Brusamolino E, Gianni A, Santoro A, Botto B, Derenzini E, Pellegrini C, Argnani L. Brentuximab Vedotin in relapsed/refractory Hodgkin’s lymphoma: The Italian experience and results of its use in daily clinical practice outside clinical trials. Haematologica. 2013; 98: 1232-1236.
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Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. 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Р. М. Горбачевой; кафедра гематологии, трансфузиологиии трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Российская Федерация" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(471) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологиии трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Российская Федерация" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20261" ["VALUE"]=> array(2) { ["TEXT"]=> string(3338) "<p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3272) "

Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.

Ключевые слова

Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.

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M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. P. Pavlov Medical University, Roentgen St. 12; 197022, St. Petersburg,Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(257) "R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. P. 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However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1806) "

Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.

Keywords

Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.

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Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.

Keywords

Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.

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Allogeneic hematopoietic cell transplantation (alloHSCT) is a potentially curative treatment for patients with relapsed and refractory Hodgkin lymphoma (HL) followed by long-term survival. However, relapse and progression of disease in the post-transplant period may occur in a substantial number of patients. nivolumab, an antibody blocking the programmed cell death receptor 1 (PD-1) has shown high efficiency in patients with HL in pre- and post-allo-HSCT setting. We have retrospectively assessed efficacy and toxicity of nivolumab as a single agent in seven HL patients relapsing after allo-HSCT using the drug at different doses (0.5 to 3 mg/kg body mass) administered every 2 weeks. We did not observe any cases of graft-versus-host disease (GVHD) after nivolumab initiation. An objective clinical response to the therapy was noted in all patients (100%), at any dosing regimen. Complete metabolic response, as detected by PET/CT, was observed in two patients (28.6%) treated at 0.5 and 1 mg/kg. Three patients of seven (42.9%) experienced grade 3-4 grade adverse events (AEs) from nivolumab, which included immune disorders. There was no correlation with nivolumab dosing regimen since severe AEs were documented in patients treated at 0.5, 1, or 3 mg/kg. All the patients are alive by the time of evaluation, 4/7 patients had the disease relapse at a median of 7 months (5 to 9) after initiation of the treatment. nivolumab may represent an efficient therapeutic tool in patients with HL relapse after allo-HSCT, however, followed by a considerable toxicity in some cases.

Keywords

Hodgkin’s lymphoma, allo-HSCT, relapse, immune checkpoints inhibitors, nivolumab, dosage.

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Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3272) "

Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.

Ключевые слова

Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.

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Аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) обладает потенциалом излечения пациентов с рецидивирующей и рефрактерной лимфомой Ходжкина (р/р ЛХ). Несмотря на это, рецидив и прогрессирование заболевания в посттрансплантационном периоде происходит у значимой части пациентов. Ниволумаб представляет собой препарат моноклональных антител, блокирующих рецептор программируемой гибели 1 (PD-1), который показал высокую эффективность у пациентов с р/р ЛХ перед и после алло-ТГСК. Мы ретроспективно оценили эффективность и токсичность терапии ниволумабом в монорежиме у 7 пациентов с рецидивами ЛХ после алло-ТГСК в различных режимах дозирования (0,5-3 мг/кг) с кратностью введения каждые 2 недели. В нашей группе не было отмечено случаев возникновения РТПХ на фоне лечения ниволумабом. Вне зависимости от режима дозирования, объективный ответ на терапию отмечен у всех пациентов (100%). Полный метаболический ответ наблюдался у двух пациентов (28.6%) с режимом дозирования 0.5 и 1 мг/кг. Во время лечения ниволумабом у 3/7 (42,9%) пациентов наблюдались иммунные нежелательные явления (НЯ) 3-4 степени тяжести. Тяжелые НЯ отмечались у пациентов с различными режимами дозирования (0,5; 1 или 3 мг/кг. Отмечался полный регресс НЯ на фоне терапии люкокортикостероидами. Все пациенты были живы на момент анализа. У 4/7 пациентов отмечался рецидив заболевания через 7 (5-9) месяцев после начала терапии ниволумабом. Таким образом, ниволумаб может быть эффективным терапевтическим подходом у пациентов с рецидивом ЛХ после алло-ТГСК, с риском проявления иммунной токсичности в ряде случаев.

Ключевые слова

Лимфома Ходжкина, аллогенная трансплантация гемопоэтических клеток, рецидив, ингибиторы контрольных точек, ниволумаб, дозировка.

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option in a number of high-risk oncohematological patients [1]. Availability of HLA-identical siblings or compatible unrelated donors is a common limiting factor for broader allo-HSCT practice, especially among ethnical minorities [2, 3, 4]. Sufficient growth of allo HSCT worldwide activities occurs because of lowering limitations by the stage of diseases, patients’ age and comorbidities, due to introduction of fludarabin-containing conditioning regimens (RICs), thus reducing intensity of cytostatic load and transplantation-associated mortality while retaining efficiency and of treatment, along with immunoadoptive effects [5, 6, 7]. Meanwhile, nearly all patients have a potential haploidentical family donor. However, early attempts of haplo-HSCT using a native graft without T cell purging using standard immunosuppression shedules resulted into unacceptable graft-versus-host disease (GVHD) rates whereas ex vivo T cell depletion for GVHD control was accomplished by high risk of non-engraftment and infectious complications causing high mortality [8, 9, 10, 11]. In Russia, approximately 80% of patients requiring allo-HSCT do not have a compatible sibling donor, whereas a chance to find an unrelated donor do not exceed 60-70%, requiring high financial costs, thus presenting the main obstacle for timely performance of allo-HSCT [3]. Search for alternative stem cell sources, such as umbilical blood cells, or haploidentical donor is quite challenging. To control HSCT risks and to prevent non-engraftment, the workers form Perugia (Italy) have used megadoses of CD34+ cells after their positive selection (a median of >10×106/ kg weight), with minimal T cell contamination (a median of 1×104/kg weight) combined with intensive conditioning regimen [11]. This study reported engraftment in 94 of 101 patients with good GVHD control. However, the rates of non-relapse-associated mortality proved to be very high (36.5%) which were largely determined by infections associated with slow immunological recovery. Event-free survival was satisfactory in the patients transplanted in remission, being, however, extremely poor for the patients treated in resistant or relapsing cases. Complexity of this transplantation approach and high costs of the method limited its approval by other transplantation centers. A group of Chinese workers has used a method avoiding ex vivo T cell depletion based on intensive pre-transplant treatment using myeloablative GIAC conditioning regimens (MAC) combined with anti-thymocyte gobulin as in vivo T cell depletion. The research team used a combined non-manipulated graft containing stimulated peripheral HCSs and bone marrow HSCs. 250 patients with acute leukemias were reported to achieve full donor chimerism, whereas acute and chronic GVHD frequencies were, respectively, 46% and 54%. Despite satisfactory relapse-free survival rates, the standard-risk patients often suffered with opportunistic infections, Transplant-related mortality rates for standard-risk and high-risk groups were, respectively, 19.5% и 29.5% for acute myeloid leukemia (AML), or 21% and 51% for acute lymphoblastic leukemia (ALL) [13]. Another approach to allo-HSCT was developed in Baltimore (USA) included usage of non-manipulated graft followed by post-transplant cyclophosphamide injection (PtCy) to control T cell reactivity after HSCT seems to overcome most obstacles historically connected with haplo-HSCT [14, 22]. Over last years, the haplo-HSCT methodology has experienced sufficient changes, i.e., novel conditioning protocols were developed with decreased toxicity and low dose intensity; the ex vivo T cell depletion options were designed, i.e., CD34+ cell selection, CD3+/CD19+ cell depletion, γ/β TCR chain depletion. The in vivo trials, suggest favorable effects from usage of anti-thymocyte globulins (ATG), cyclophosphamide at at high doses on D+3, D+4 after the haploidentical transplant. An immune response modification could be carried out as reduction of T cell reactivity by changing the Th1/Th2 balance, by means of hematopoiesis stimulation with G-CSF before myeloexfusion. Pharmacological prophylaxis of acute GVHD (aGVHD) is accomplished by new therapies, e.g., with rapamycin, the mTOR inhibitor [14, 15, 16]. Good efficiency of haploidentical HSCT is shown for the 1st and 2nd remissions of AML, with 5-year relapse-free survival of 82.5%, and 59.4%. Appropriate figures for ALL were 68.9% and 56.6% [15]. The results of relapsed and resistant clinical forms were unsatisfactory if using allo-HSCT, or hapolo-HSC, i.e., the 5-year overall survival in AML was 42.9% and 22.2% in ALL [15, 16, 17, 18]. The aim of our study was to assess efficiency of haplo-HSCT performed with non-manipulated grafts of children and adolescents with high-risk acute leukemias. In this respect an efficiency study of haploidentical GVHD was performed at our clinic in children and adolescents with high-risk ALL and AML, at maximal observation terms of 10 years.

Patients and methods

The study included 106 children and adolescents 0 to 18 years old (median age, 7 y.o.). with primary diagnosis of ALL in 63 cases (59.4%), and AML (43 patients, 41%), who underwent allo-HSCT from haploidentical donors within a time period of December 2006 to December 2016 года. The patients were followed up for a maximum of 10 years.
Haploidentical HSCT was performed in remission state for 43 patients (40.6%), i.e., 21 patients were transplanted in 1st remission, 13 patients, in 2nd remission, and nine children were treated in 3rd remission. Sixty-three relapsed/ therapy-resistant (R/R) patients with AL were transplanted (59.4% of total). Several MAC schedules were applied for conditioning treatment, i.e., GIAC protocol (39 cases, 36.8% of total) including busulfan (16 mg/kg body weight), cyclophosphamide (Cy) at a dose of 2000 mg/m2, cytosar (8000 mg/m2), lomustin (120 mg/kg). Other MACs were based on busulfan (12 mg/kg) and Fludarabin (150 mg/m2), being applied in 2 patients (2%), and a regimen based on Treosulfan (42 g/m2) was used in 6 cases (5.7%). The reduced-intensity conditioning regimens (RICs) based on melphalan (140 mg/m2) were applied in 40 recipients (37.7%), whereas RICs containing busulfan (8 mg/kg) were used in 18 patients (17%).
All the patients underwent aGHVD prophylaxis, i.e., antithymocyte globulin (ATGAM) was injected at 60 mg/kg weight in 39 cases (36.8%); whereas post-transplant cyclophosphamide (PtCy, 50 mg/kg) was injected on D+3 and D+4 in 67 recipients (63.2%). Basic immune suppressive therapy (IST) included Tacrolimus (0.03 mg/kg/d) for 47 patients (44.3%); cyclosporine A (3 mg/kg/d was used in 59 cases (55.7%). In addition to tacrolimus, an mTOR inhibitor at 1 mg/m2 was administered since D+3. Clinical parameters of the patients enrolled into the study, are summarized in Table 1.
Two methods were used for yielding the haploidentical donor grafts, i.e.:
1. A combined graft containing bone marrow and peripheral hematopoietic stem cells (PHSCs) obtained after G-CSF priming (5 mg/kg/d, for 4 days) then followed by positive selection of CD34+ клеток with a CliniMACS device (Miltenyi Biotec). This cell product was applied in 27 cases (25.5%).
2. Non-manipulated marrow graft primed with G-CSF (5 mg/kg/d for 3 days) was obtained and used in 79 patients (74.5%). The median cellularity as for transfused CD34+ cells comprised 5.9х106/kg weight for non-manipulated bone marrow (1.0 to 9х106/kg), and 5.9х106/kg for the combined graft (2.5 to 30.9х106/kg).

20-27_Paina Table 1. Characteristics of the patients subjected to haploidentical HSCT.png

For statistical evaluation, SPSS Statistics v.17 and Statistica 8.0 software was used. The patients in remission are censored for 01.01.2018. Overall survival was compared by means of log-rank test, comparative analysis of differential proportions was performed by the Fisher’s exact test. The difference levels of p<0.05 were considered significant.

Results

Hematopoiesis recovery

Stem cell engraftment after haplo-HSCT was documented in 80 total group of patients (75.7% of total). Median engraftment term was D+24 (D+14 to D+34). Primary non-engraftment was revealed in 26 patients (24.5%) due to chemoresistance and/or relapsed AL. The median recovery terms for granulocytes (>0.5x109/L) was D+19 (D+10 to D+34); for leukocytes (>1.0x109/L), D+17 (D+10 to D+34); for platelets reconstitution (>20x109/L), D+17 (D+10–D+41). Median recovery time for lymphocytes (>30x109/L) was D+29 (D+14 to D+50). Full donor chimerism was registered in 67 cases (83.8%) by day +30 posttransplant. Thirteen patients (16.2%) developed full chimerism by day +60 after HSCT.

Survival data

Ten-year overall survival (OS) in total group proved to be 33.3% after haplo-HSCT (Fig. 1). In particular, the ten-year OS in patients transplanted in 1st and 2nd remissions was 64.7% as compared to 18.1% for the patients transplanted beyond the remission. (р=0.01; Fig. 2). Overall survival for the patients who received G-CSF-primed, non-manipulated bone marrow and in those who got combined marrow/peripheral grafts was, respectively, 38% and 18.5% (р=0.03, Fig. 3). The AL type did not influence the 10-year survival, i.e., 36.5% vs 27.9% respectively, for ALL and AML subgroups. The OS values in ALL versus AML patients transplanted in 1st or 2nd remissions have shown comparable OS rates, respectively, 68.2% and 58.3%. We could not show any significant correlations between the 10-year survival and recovery kinetics of leukocytes, neutrophils and platelets post-transplant.

20-27_Paina Figure 1. Ten-year overall survival in children and adolescents.png

Figure 1. Ten-year overall survival in children and adolescents with acute leukemias after haplo-HSCT

20-27_Paina Figure 2. Ten-year overall survival in children and adolescents after haplo-HSCT performed in 1st and 2nd.png

Figure 2. Ten-year overall survival in children and adolescents after haplo-HSCT performed in 1st and 2nd remission (р=0.01)

20-27_Paina Figure 3. Ten-year overall survival in children and adolescents.png

Figure 3. Ten-year overall survival in children and adolescents after haplo-HSCT for the groups receiving a G-CSF-primed nonmanipulated bone marrow (blue graph), or a combined hematopoietic graft (green graph). The difference is significant at р=0.03

20-27_Paina Table 2. Comparative indexes of the 10-year overall survival and recovery of granulocytes, platelets and lymphocytes.png

Comparative OS values are presented in Table 2. The 10-year OS did not statistically differ between the groups receiving different conditioning regimens. It could be explained by small numbers of cases and inability to tolerate the full-dose conditioning regimens in resistant AL cases. Hence, OS rates among patients who received MAC regimens comprised 36.2% as compared to 30.5% for the RIC group. The OS values upon more detailed evaluation and subgroup division were as follows: MAC, 28.6%; MAC+PtCy treatment, 40%; RIC, 16.7%, and RIC+PtCy, 38.1% (р>0.05).

Posttransplant complications

Acute graft-versus-host disease (GVHD) is a major immunological disorder developing early after allo-HSCT. Of 80 patients who achieved engraftment, aGVHD grade II was observed in 21 cases (26.3%); severe GVHD (grade III to IV) was diagnosed in 15 patients (18.6%). Leukemia relapses were registered in 51 of 106 patients (48.1%), with a mediane of D+91 after haplo-HSCT (D+17 to D+1101). Occurrence of relapses post haplo-HSCT, if performed in 1st or 2nd remission was 23.5%, with a median of D+88 (D+30 to D+301). The disease recurrence was more common in recipients with resistant or relapsing disease (56,9%, with a median development on D+81 post-transplant). The overall transplant-associated mortality was 21.6% in the studied group. Fatal infectious complications in the early post-transplant period were registered in 14 patients (13.2%). Acute GVHD caused death of 7 patients (8.8%), lethal toxic conditions, in 2 cases (1.9%). Meanwhile, the leukemia relapses proved to prevail in post-engraftment lethality among children and adolescents undergoing haplo-HSCT (39 patients, 48.8%). Posttransplant relapses among the patients transplanted in 1st and 2nd remissions resulted into lethal outcome in 6 cases (17.6%). Meanwhile, the AL recurrence with lethal outcome was registered in 33 cases (45.8%) among patients who received haploidentical grafts in resistant or relapsing disease upon engraftment.

Discussion

At the present time, HSCT from haploidentical donors is known to be an effective and safe treatment approach for the high-risk leukemia patients, requiring allo-HSCT for urgent reasons, especially in absence of a compatible donors, either related or unrelated ones. Fast preparation of a donor and HSC isolation, good chances for repeated graft harvest if required, as well as minimal financial costs comprise clear benefits of haplo-HSCT. However, some cautions exist, due to risks of posttransplant complications, such as acute GVHD and severe infections determined by marked immunosuppression and prolonged immune recovery after haplo-HSCT. Moreover, a specific graft-versus-leukemia (GvL) response after haplo-HSCT and persistence of this effect is still in question, being subject to different studies [20]. Application of RIC regimens as a platform for the post-transplant immunonadoptive therapy may provide an additional tool for enhancement of the GvL immune reaction without increasing the transplant-related mortality. Some promising data on the subject are published by a study team at the John Hopkins and Fred Hutchinson Cancer Research Center on the patients with high-risk acute leukemia who underwent reduced-intensity conditioning followed by haplo-HSCT and post-transplant cyclophosphamide injections on D+3 and D+4. According to this study, clinical engraftment was registered in 87% of the cases, with OS values of 41%. Clinically sound aGHVD (grade II-IV) was registered in <27%, with chronic GVHD documented in 15% of the cases. However, frequency of post-transplant relapses remained high (55%), with relatively low transplant-related mortality (18%) [20, 22]. Our own data on haplo-HSCT confirm the high rates of transplant engraftment (80%), while reaching full donor chimerism by day+30 in 84% of the cases. The rest of this group developed full chimerism by day +60 post-HSCT. Overall survival with a maximal observation term of 10 years was 33.3% for the total group. Frequency of clinical aGVHD in our study is also comparable to the previously reported data,i.e., prevalence of aGVHD grade II was 26.3%, aGVHD grade III-IV, 18.6%, which does not exceed the published values [20]. We have obtained encouraging results on the 10-year overall survival (64.7%) for the haplo-HSCT patients who received their graft during 1st and 2nd remissions. Absence of severe lethal infectious complications before D+100 seems to be connected with faster T cell reconstitution. Post-transplant relapses represent the main problem for these patients. High percentage of such dismal outcomes (48.1%) may be explained by the disease status at the time of haplo-HSCT. The majority of patients (72 cases, 68%) were transplanted beyond the registered remission. According to the data published by Italian workers, the relapse rates may reach 50% in such patient groups [7, 12].

Conclusion

Allo-HSCT of the non-manipulated primed bone marrow from a haploidentical donor proved to be an effective approach, in order to achieve clinical remission in children and adolescents with high-risk AL. At the present time, one may discuss relative benefits of different stem cell separation techniques for haplo-HSCT in childhood. Implementation of post-transplant cyclophosphamide (PtCy) proved to be an available and effective regimen improving clinical results of haplo-HSCT. State of the disease is the main factor influencing overall survival after haplo-HSCT. First or second remission of ALL or AML is the optimal time-point for haplo- HSCT. To improve the results of haplo-HSCT in Russia, the appropriate cooperative multicentric studies are required in this research area.

Conflict of interest

The authors report no conflicts of interest.

References

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2. Bashey A, Solomon SR. T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor. Bone Marrow Transplantation 2014; 49, 999–1008.
3. Alyanskyi AL, Kucher MA, Makarenko OA, Golovacheva AA, Kuzmich EV, Babenko EV, Estrina MA, Paina OV, Pevtcov DE, Zubarovskaya LS, Afanasyev BV. Actual issues of search for unrelated bone marrow donors in Russian Federation. Transfuziologiya. 2016; 3:21-28 (In Russian).
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18. Zecca M, Strocchio L, Pagliara D, Comoli P, Bertaina A, Giorgiani G, Perotti C, Corbella F, Brescia L, Locatelli F. HLA-haploidentical T-cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia. Biol Blood Marrow Transplant. 2014; 20(4):571-576.
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21. Wang Y, Chang Y-J, Xu L-P, Liu K-Y, Liu D-H, Zhang X-H, Chen H et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood 2014; 124:843-850.
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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option in a number of high-risk oncohematological patients [1]. Availability of HLA-identical siblings or compatible unrelated donors is a common limiting factor for broader allo-HSCT practice, especially among ethnical minorities [2, 3, 4]. Sufficient growth of allo HSCT worldwide activities occurs because of lowering limitations by the stage of diseases, patients’ age and comorbidities, due to introduction of fludarabin-containing conditioning regimens (RICs), thus reducing intensity of cytostatic load and transplantation-associated mortality while retaining efficiency and of treatment, along with immunoadoptive effects [5, 6, 7]. Meanwhile, nearly all patients have a potential haploidentical family donor. However, early attempts of haplo-HSCT using a native graft without T cell purging using standard immunosuppression shedules resulted into unacceptable graft-versus-host disease (GVHD) rates whereas ex vivo T cell depletion for GVHD control was accomplished by high risk of non-engraftment and infectious complications causing high mortality [8, 9, 10, 11]. In Russia, approximately 80% of patients requiring allo-HSCT do not have a compatible sibling donor, whereas a chance to find an unrelated donor do not exceed 60-70%, requiring high financial costs, thus presenting the main obstacle for timely performance of allo-HSCT [3]. Search for alternative stem cell sources, such as umbilical blood cells, or haploidentical donor is quite challenging. To control HSCT risks and to prevent non-engraftment, the workers form Perugia (Italy) have used megadoses of CD34+ cells after their positive selection (a median of >10×106/ kg weight), with minimal T cell contamination (a median of 1×104/kg weight) combined with intensive conditioning regimen [11]. This study reported engraftment in 94 of 101 patients with good GVHD control. However, the rates of non-relapse-associated mortality proved to be very high (36.5%) which were largely determined by infections associated with slow immunological recovery. Event-free survival was satisfactory in the patients transplanted in remission, being, however, extremely poor for the patients treated in resistant or relapsing cases. Complexity of this transplantation approach and high costs of the method limited its approval by other transplantation centers. A group of Chinese workers has used a method avoiding ex vivo T cell depletion based on intensive pre-transplant treatment using myeloablative GIAC conditioning regimens (MAC) combined with anti-thymocyte gobulin as in vivo T cell depletion. The research team used a combined non-manipulated graft containing stimulated peripheral HCSs and bone marrow HSCs. 250 patients with acute leukemias were reported to achieve full donor chimerism, whereas acute and chronic GVHD frequencies were, respectively, 46% and 54%. Despite satisfactory relapse-free survival rates, the standard-risk patients often suffered with opportunistic infections, Transplant-related mortality rates for standard-risk and high-risk groups were, respectively, 19.5% и 29.5% for acute myeloid leukemia (AML), or 21% and 51% for acute lymphoblastic leukemia (ALL) [13]. Another approach to allo-HSCT was developed in Baltimore (USA) included usage of non-manipulated graft followed by post-transplant cyclophosphamide injection (PtCy) to control T cell reactivity after HSCT seems to overcome most obstacles historically connected with haplo-HSCT [14, 22]. Over last years, the haplo-HSCT methodology has experienced sufficient changes, i.e., novel conditioning protocols were developed with decreased toxicity and low dose intensity; the ex vivo T cell depletion options were designed, i.e., CD34+ cell selection, CD3+/CD19+ cell depletion, γ/β TCR chain depletion. The in vivo trials, suggest favorable effects from usage of anti-thymocyte globulins (ATG), cyclophosphamide at at high doses on D+3, D+4 after the haploidentical transplant. An immune response modification could be carried out as reduction of T cell reactivity by changing the Th1/Th2 balance, by means of hematopoiesis stimulation with G-CSF before myeloexfusion. Pharmacological prophylaxis of acute GVHD (aGVHD) is accomplished by new therapies, e.g., with rapamycin, the mTOR inhibitor [14, 15, 16]. Good efficiency of haploidentical HSCT is shown for the 1st and 2nd remissions of AML, with 5-year relapse-free survival of 82.5%, and 59.4%. Appropriate figures for ALL were 68.9% and 56.6% [15]. The results of relapsed and resistant clinical forms were unsatisfactory if using allo-HSCT, or hapolo-HSC, i.e., the 5-year overall survival in AML was 42.9% and 22.2% in ALL [15, 16, 17, 18]. The aim of our study was to assess efficiency of haplo-HSCT performed with non-manipulated grafts of children and adolescents with high-risk acute leukemias. In this respect an efficiency study of haploidentical GVHD was performed at our clinic in children and adolescents with high-risk ALL and AML, at maximal observation terms of 10 years.

Patients and methods

The study included 106 children and adolescents 0 to 18 years old (median age, 7 y.o.). with primary diagnosis of ALL in 63 cases (59.4%), and AML (43 patients, 41%), who underwent allo-HSCT from haploidentical donors within a time period of December 2006 to December 2016 года. The patients were followed up for a maximum of 10 years.
Haploidentical HSCT was performed in remission state for 43 patients (40.6%), i.e., 21 patients were transplanted in 1st remission, 13 patients, in 2nd remission, and nine children were treated in 3rd remission. Sixty-three relapsed/ therapy-resistant (R/R) patients with AL were transplanted (59.4% of total). Several MAC schedules were applied for conditioning treatment, i.e., GIAC protocol (39 cases, 36.8% of total) including busulfan (16 mg/kg body weight), cyclophosphamide (Cy) at a dose of 2000 mg/m2, cytosar (8000 mg/m2), lomustin (120 mg/kg). Other MACs were based on busulfan (12 mg/kg) and Fludarabin (150 mg/m2), being applied in 2 patients (2%), and a regimen based on Treosulfan (42 g/m2) was used in 6 cases (5.7%). The reduced-intensity conditioning regimens (RICs) based on melphalan (140 mg/m2) were applied in 40 recipients (37.7%), whereas RICs containing busulfan (8 mg/kg) were used in 18 patients (17%).
All the patients underwent aGHVD prophylaxis, i.e., antithymocyte globulin (ATGAM) was injected at 60 mg/kg weight in 39 cases (36.8%); whereas post-transplant cyclophosphamide (PtCy, 50 mg/kg) was injected on D+3 and D+4 in 67 recipients (63.2%). Basic immune suppressive therapy (IST) included Tacrolimus (0.03 mg/kg/d) for 47 patients (44.3%); cyclosporine A (3 mg/kg/d was used in 59 cases (55.7%). In addition to tacrolimus, an mTOR inhibitor at 1 mg/m2 was administered since D+3. Clinical parameters of the patients enrolled into the study, are summarized in Table 1.
Two methods were used for yielding the haploidentical donor grafts, i.e.:
1. A combined graft containing bone marrow and peripheral hematopoietic stem cells (PHSCs) obtained after G-CSF priming (5 mg/kg/d, for 4 days) then followed by positive selection of CD34+ клеток with a CliniMACS device (Miltenyi Biotec). This cell product was applied in 27 cases (25.5%).
2. Non-manipulated marrow graft primed with G-CSF (5 mg/kg/d for 3 days) was obtained and used in 79 patients (74.5%). The median cellularity as for transfused CD34+ cells comprised 5.9х106/kg weight for non-manipulated bone marrow (1.0 to 9х106/kg), and 5.9х106/kg for the combined graft (2.5 to 30.9х106/kg).

20-27_Paina Table 1. Characteristics of the patients subjected to haploidentical HSCT.png

For statistical evaluation, SPSS Statistics v.17 and Statistica 8.0 software was used. The patients in remission are censored for 01.01.2018. Overall survival was compared by means of log-rank test, comparative analysis of differential proportions was performed by the Fisher’s exact test. The difference levels of p<0.05 were considered significant.

Results

Hematopoiesis recovery

Stem cell engraftment after haplo-HSCT was documented in 80 total group of patients (75.7% of total). Median engraftment term was D+24 (D+14 to D+34). Primary non-engraftment was revealed in 26 patients (24.5%) due to chemoresistance and/or relapsed AL. The median recovery terms for granulocytes (>0.5x109/L) was D+19 (D+10 to D+34); for leukocytes (>1.0x109/L), D+17 (D+10 to D+34); for platelets reconstitution (>20x109/L), D+17 (D+10–D+41). Median recovery time for lymphocytes (>30x109/L) was D+29 (D+14 to D+50). Full donor chimerism was registered in 67 cases (83.8%) by day +30 posttransplant. Thirteen patients (16.2%) developed full chimerism by day +60 after HSCT.

Survival data

Ten-year overall survival (OS) in total group proved to be 33.3% after haplo-HSCT (Fig. 1). In particular, the ten-year OS in patients transplanted in 1st and 2nd remissions was 64.7% as compared to 18.1% for the patients transplanted beyond the remission. (р=0.01; Fig. 2). Overall survival for the patients who received G-CSF-primed, non-manipulated bone marrow and in those who got combined marrow/peripheral grafts was, respectively, 38% and 18.5% (р=0.03, Fig. 3). The AL type did not influence the 10-year survival, i.e., 36.5% vs 27.9% respectively, for ALL and AML subgroups. The OS values in ALL versus AML patients transplanted in 1st or 2nd remissions have shown comparable OS rates, respectively, 68.2% and 58.3%. We could not show any significant correlations between the 10-year survival and recovery kinetics of leukocytes, neutrophils and platelets post-transplant.

20-27_Paina Figure 1. Ten-year overall survival in children and adolescents.png

Figure 1. Ten-year overall survival in children and adolescents with acute leukemias after haplo-HSCT

20-27_Paina Figure 2. Ten-year overall survival in children and adolescents after haplo-HSCT performed in 1st and 2nd.png

Figure 2. Ten-year overall survival in children and adolescents after haplo-HSCT performed in 1st and 2nd remission (р=0.01)

20-27_Paina Figure 3. Ten-year overall survival in children and adolescents.png

Figure 3. Ten-year overall survival in children and adolescents after haplo-HSCT for the groups receiving a G-CSF-primed nonmanipulated bone marrow (blue graph), or a combined hematopoietic graft (green graph). The difference is significant at р=0.03

20-27_Paina Table 2. Comparative indexes of the 10-year overall survival and recovery of granulocytes, platelets and lymphocytes.png

Comparative OS values are presented in Table 2. The 10-year OS did not statistically differ between the groups receiving different conditioning regimens. It could be explained by small numbers of cases and inability to tolerate the full-dose conditioning regimens in resistant AL cases. Hence, OS rates among patients who received MAC regimens comprised 36.2% as compared to 30.5% for the RIC group. The OS values upon more detailed evaluation and subgroup division were as follows: MAC, 28.6%; MAC+PtCy treatment, 40%; RIC, 16.7%, and RIC+PtCy, 38.1% (р>0.05).

Posttransplant complications

Acute graft-versus-host disease (GVHD) is a major immunological disorder developing early after allo-HSCT. Of 80 patients who achieved engraftment, aGVHD grade II was observed in 21 cases (26.3%); severe GVHD (grade III to IV) was diagnosed in 15 patients (18.6%). Leukemia relapses were registered in 51 of 106 patients (48.1%), with a mediane of D+91 after haplo-HSCT (D+17 to D+1101). Occurrence of relapses post haplo-HSCT, if performed in 1st or 2nd remission was 23.5%, with a median of D+88 (D+30 to D+301). The disease recurrence was more common in recipients with resistant or relapsing disease (56,9%, with a median development on D+81 post-transplant). The overall transplant-associated mortality was 21.6% in the studied group. Fatal infectious complications in the early post-transplant period were registered in 14 patients (13.2%). Acute GVHD caused death of 7 patients (8.8%), lethal toxic conditions, in 2 cases (1.9%). Meanwhile, the leukemia relapses proved to prevail in post-engraftment lethality among children and adolescents undergoing haplo-HSCT (39 patients, 48.8%). Posttransplant relapses among the patients transplanted in 1st and 2nd remissions resulted into lethal outcome in 6 cases (17.6%). Meanwhile, the AL recurrence with lethal outcome was registered in 33 cases (45.8%) among patients who received haploidentical grafts in resistant or relapsing disease upon engraftment.

Discussion

At the present time, HSCT from haploidentical donors is known to be an effective and safe treatment approach for the high-risk leukemia patients, requiring allo-HSCT for urgent reasons, especially in absence of a compatible donors, either related or unrelated ones. Fast preparation of a donor and HSC isolation, good chances for repeated graft harvest if required, as well as minimal financial costs comprise clear benefits of haplo-HSCT. However, some cautions exist, due to risks of posttransplant complications, such as acute GVHD and severe infections determined by marked immunosuppression and prolonged immune recovery after haplo-HSCT. Moreover, a specific graft-versus-leukemia (GvL) response after haplo-HSCT and persistence of this effect is still in question, being subject to different studies [20]. Application of RIC regimens as a platform for the post-transplant immunonadoptive therapy may provide an additional tool for enhancement of the GvL immune reaction without increasing the transplant-related mortality. Some promising data on the subject are published by a study team at the John Hopkins and Fred Hutchinson Cancer Research Center on the patients with high-risk acute leukemia who underwent reduced-intensity conditioning followed by haplo-HSCT and post-transplant cyclophosphamide injections on D+3 and D+4. According to this study, clinical engraftment was registered in 87% of the cases, with OS values of 41%. Clinically sound aGHVD (grade II-IV) was registered in <27%, with chronic GVHD documented in 15% of the cases. However, frequency of post-transplant relapses remained high (55%), with relatively low transplant-related mortality (18%) [20, 22]. Our own data on haplo-HSCT confirm the high rates of transplant engraftment (80%), while reaching full donor chimerism by day+30 in 84% of the cases. The rest of this group developed full chimerism by day +60 post-HSCT. Overall survival with a maximal observation term of 10 years was 33.3% for the total group. Frequency of clinical aGVHD in our study is also comparable to the previously reported data,i.e., prevalence of aGVHD grade II was 26.3%, aGVHD grade III-IV, 18.6%, which does not exceed the published values [20]. We have obtained encouraging results on the 10-year overall survival (64.7%) for the haplo-HSCT patients who received their graft during 1st and 2nd remissions. Absence of severe lethal infectious complications before D+100 seems to be connected with faster T cell reconstitution. Post-transplant relapses represent the main problem for these patients. High percentage of such dismal outcomes (48.1%) may be explained by the disease status at the time of haplo-HSCT. The majority of patients (72 cases, 68%) were transplanted beyond the registered remission. According to the data published by Italian workers, the relapse rates may reach 50% in such patient groups [7, 12].

Conclusion

Allo-HSCT of the non-manipulated primed bone marrow from a haploidentical donor proved to be an effective approach, in order to achieve clinical remission in children and adolescents with high-risk AL. At the present time, one may discuss relative benefits of different stem cell separation techniques for haplo-HSCT in childhood. Implementation of post-transplant cyclophosphamide (PtCy) proved to be an available and effective regimen improving clinical results of haplo-HSCT. State of the disease is the main factor influencing overall survival after haplo-HSCT. First or second remission of ALL or AML is the optimal time-point for haplo- HSCT. To improve the results of haplo-HSCT in Russia, the appropriate cooperative multicentric studies are required in this research area.

Conflict of interest

The authors report no conflicts of interest.

References

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За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ. </p> <h3 style="text-align: justify;">Цель</h3> <p style="text-align: justify;"> Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии. </p> <h3 style="text-align: justify;">Материалы и методы</h3> <p style="text-align: justify;"> 106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х10<sup>6</sup>/кг (медиана 5,9х10<sup>6</sup>/кг), клеточность КМ+ПСКК от 2,5 до 30,9х10<sup>6</sup>/ кг (медиана 5,9х10<sup>6</sup>/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p&lt;0,05. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (&gt;0,5x10<sup>6</sup>/л) Д+21 (Д+10 – Д+47), лейкоциты (&gt;1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (&gt;20x10<sup>6</sup>/л) Д+20 (Д+10 – Д+72), лимфоциты (&gt;30x10<sup>6</sup>/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек. </p> <h3 style="text-align: justify;">Выводы</h3> <p style="text-align: justify;"> Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина». </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_META_TITLE"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_META_KEYWORDS"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_META_DESCRIPTION"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_PICTURE_FILE_ALT"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_PICTURE_FILE_TITLE"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "desyatiletniy-opyt-primeneniya-allogennoy-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-ot-gap" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного донора неманипулированного трансплантата у детей и подростков с острыми лейкозами высокой группы риска" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(398) "Десятилетний опыт применения аллогенной трансплантации гемопоэтических стволовых клеток от гаплоидентичного 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Р. М. Горбачевой; Первый Санкт-Петербургский государственный медицинский университет им. академика И. П. Павлова Министерства здравоохранения России; Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(571) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; Первый Санкт-Петербургский государственный медицинский университет им. академика И. П. Павлова Министерства здравоохранения России; Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия" ["TYPE"]=> string(4) "TEXT" } ["~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) "20189" ["VALUE"]=> array(2) { ["TEXT"]=> string(7222) "<p style="text-align: justify;"> Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ. </p> <h3 style="text-align: justify;">Цель</h3> <p style="text-align: justify;"> Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии. </p> <h3 style="text-align: justify;">Материалы и методы</h3> <p style="text-align: justify;"> 106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х10<sup>6</sup>/кг (медиана 5,9х10<sup>6</sup>/кг), клеточность КМ+ПСКК от 2,5 до 30,9х10<sup>6</sup>/ кг (медиана 5,9х10<sup>6</sup>/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p&lt;0,05. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (&gt;0,5x10<sup>6</sup>/л) Д+21 (Д+10 – Д+47), лейкоциты (&gt;1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (&gt;20x10<sup>6</sup>/л) Д+20 (Д+10 – Д+72), лимфоциты (&gt;30x10<sup>6</sup>/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек. </p> <h3 style="text-align: justify;">Выводы</h3> <p style="text-align: justify;"> Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина». </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6876) "

Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.

Цель

Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.

Материалы и методы

106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.

Результаты

Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.

Выводы

Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.

Ключевые слова

Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».

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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State I. Pavlov Medical University; St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(241) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State I. 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During 10 years in R/G/Memorial Institute of children oncology,<br> hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients. </p> <h3 style="text-align: justify;">Materials and methods</h3> <p style="text-align: justify;"> 106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w. </p> <h3 style="text-align: justify;">Statistical analysis</h3> <p style="text-align: justify;"> SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike. </p> <h3 style="text-align: justify;">Conclusion</h3> <p style="text-align: justify;"> Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100. </p> <h3 style="text-align: justify;">Keywords</h3> <p style="text-align: justify;"> Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3258) "

Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.

Materials and methods

106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.

Statistical analysis

SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.

Conclusion

Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.

Keywords

Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.

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Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.

Materials and methods

106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.

Statistical analysis

SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.

Conclusion

Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.

Keywords

Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.

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Haploidentical transplantation (Haplo-HSCT) is an effective method for treating patients with high-risk acute leukemias (AL) who do not have HLA-matched related (MRD) and matched unrelated donors (MUD). During 10 years in R/G/Memorial Institute of children oncology,
hematology and transplantation more than 150 patients have Haplo-HSCT. More than 50% of patients were «salvage group» patients.

Materials and methods

106 patients with high-risk AL, median age 7 y.o. (range 0-18), acute lymphoblastic leukemia (ALL) – 63 (59.4%), acute myeloid leukemia (AML) – 43 (40.6%), received Haplo-HSCT from December 2006 till December 2016. Forty three patients (40.6%) recived Haplo-HSCT in complete remission (CR): CR1 21 patients (49%), CR2 – 13 patients (30%), CR3 – 9 patients (21%). Resistance disease or resistance relapse AL – 63 (59.4%) patients. Сonditioning regimens were as follows: MAC «GIAC» 39 patients (36.8%), MAC based on Busulfan 12mg/b.w. and Fludarabine 150 mg/mg(2) – 2 (2%), MAC reduced toxisity based on Treosulfan 42 g/m(2) – 6 (5.7%), RIC based on Melfalan 140 mg/m(2) – 40 (37.7%), RIC with Busulfan 8 mg/b.w. – 18 (17%). All patients received prophylaxis of acute graft versus host disease (aGVHD). Seroprophylaxis with ATG – ATGAM 60mg/b.w. – 39 (36.8%), posttransplant cyclophosphomide 50 mg/b.w. on D+3, D+4 – 67 (63.2%). Conventional immunosuppressive therapy: tacrolimus 47 patients (44.3%), CsA 59 patients (55.7%). Source of transplant – combined unmanipulated stimulated Haplo-bone marrow plus manipulated (positive selected CD34+) stimulated CD34+ cells – 27 patients (25.5%) and unmanipulated stimulated Haplo- bone marrow – 79 (74.5%). Stem cells dose of unmanipulated stimulated Haplo-bone marrow transplant CD34+x106/b.w. median 5.9x10(6)/b.w., stem cells dose of combined transplant median 5.9x10(6)/b.w. (range from 2.5 till 30.9х10(6)/b.w.

Statistical analysis

SPSS Statistics v.17. Overal survival (OS) was defined as time from study enrollment to death, with living patients censored on the date of the last follow-up. The Kaplan–Meier method was used to estimate OS rates, and the exact log-rank test was used to compare survival curves. Survival estimates are reported with standard errors determined by the method of Peto and Pike.

Conclusion

Haplo-HSCT in 1 and 2 remissions of AL allows to achieve 10-year OS in 64.7% of children, while the type of acute leukemia does not influence the outcome of haplo-HSCT. The acceptable frequency of development of aGVHD III0-IV0 – 18.6% allows to treat haplo-HSCT as therapy in 1 and 2 remissions of high risk group. The main complication of haplo-HSCT is relapse – 23.5% in the early posttransplant period to D + 100.

Keywords

Allogeneic hematopoietic stem cell transplantation, haploidentical, children, overall survival, relapse, graftversus- host disease.

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За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ. </p> <h3 style="text-align: justify;">Цель</h3> <p style="text-align: justify;"> Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии. </p> <h3 style="text-align: justify;">Материалы и методы</h3> <p style="text-align: justify;"> 106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х10<sup>6</sup>/кг (медиана 5,9х10<sup>6</sup>/кг), клеточность КМ+ПСКК от 2,5 до 30,9х10<sup>6</sup>/ кг (медиана 5,9х10<sup>6</sup>/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p&lt;0,05. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (&gt;0,5x10<sup>6</sup>/л) Д+21 (Д+10 – Д+47), лейкоциты (&gt;1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (&gt;20x10<sup>6</sup>/л) Д+20 (Д+10 – Д+72), лимфоциты (&gt;30x10<sup>6</sup>/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек. </p> <h3 style="text-align: justify;">Выводы</h3> <p style="text-align: justify;"> Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина». </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6876) "

Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.

Цель

Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.

Материалы и методы

106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.

Результаты

Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.

Выводы

Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.

Ключевые слова

Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».

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Гаплоидентичная трансплантация (гапло-ТГСК) эффективный метод лечения пациентов с острыми лейкозами высокой группы риска (ОЛ), не имеющих полностью совместимого по генам HLA-системы родственного донора и неродственного донора в Международном регистре. За десятилетний период в НИИ ДОГиТ им. Р. М. Горбачевой выполнено более 150 аллогенных трансплантаций от гаплоидентичного донора, превалирующая часть, как терапия «спасения» больным в первично-резистентном течении ОЛ и/или резистентном течением рецидива ОЛ.

Цель

Оценить эффективность гапло-ТГСК у больных с ОЛ высокой группы риска, выполненной в 1 и 2 ремиссии.

Материалы и методы

106 больных с ОЛ высокой группы риска, медиана возраста 7 лет (от 0 до 18 лет), ОЛЛ – 63 (59,4%), ОМЛ – 43 (40,6%), получивших гапло-ТГСК с декабря 2006 года по декабрь 2016 года. В ремиссии заболевания гапло-ТГСК выполнена у 43 больных (40,6%): в 1й ремиссии – 21 (49%), во 2й – 13 больных (30%), в 3й – 9 (21%). В резистентном течении болезни или рецидиве ОЛ – 63 (59,4%) пациента. МАК «GIAC» 39 человек (36,8%), МАК на основе Бусульфана 12мг/кг и Флюдарабина 150мг/м(2) – 2 (2%), МАК со сниженной токсичностью на основе Треосульфана 42 г/м2 – 6 (5,7%), РИК на основе Мелфалана 140мг/м(2) у 40 (37,7%), РИК с использованием Бусульфана 8мг/кг – 18 (17%). Все больные получили профилактику острой реакции «трансплантата против хозяина» (оРТПХ). Серопрофилактика АТГАМ 60мг/кг – 39 (36,8%), ПТЦф 50мг/кг Д+3, Д+4 – 67 (63,2%). Базовая ИСТ: такролимус 47 (44,3%), циклоспорин А в 59 (55,7%) случаях. Источник трансплантата ГСК праймированный КМ и ПСКК, в комбинации – 27 (25,5%) и гапло-КМ – 79 (74,5%). Клеточность трансплантата КМ по CD34+x106/кг от 1 до 9х106/кг (медиана 5,9х106/кг), клеточность КМ+ПСКК от 2,5 до 30,9х106/ кг (медиана 5,9х106/кг). Статистический анализ: SPSS Statistics v.17. Выживаемость и кумулятивная веро ятность анализированы по методу Каплана-Майера. Пациенты, живущие в ремиссии на момент анализа данных, цензурированы 01.01.2018 года. Сравнение ОВ выполнялось при помощи log-rang теста, сравнительный анализ разности долей – точного теста Fisher. Статистически значимыми считались различия при p<0,05.

Результаты

Приживление трансплантата после гало-ТГСК зафиксировано у 80 (75,7%) реципиентов. Медиана приживления составила Д+24 (Д+14 – Д+34). Первичное неприживление трансплантата зафиксировано у 26 (24,5%) пациентов по причине химиорезистентности и резистентного течения рецидива ОЛ. Медианы восстановления: гранулоциты (>0,5x106/л) Д+21 (Д+10 – Д+47), лейкоциты (>1,0 x109/л) Д+20 (Д+10 – Д+47), тромбоциты (>20x106/л) Д+20 (Д+10 – Д+72), лимфоциты (>30x106/л) Д+17 (Д+12 – Д+73). Полный донорский химеризм к 30-му дню определялся у 67 (83,8%) пациентов, к 60 дню – у 13 (16,2%). 10-летняя ОВ после гапло – ТГСК – 33,3%. Выживаемость в 1 и 2 ремиссиях составила 64,7% против 18,1% в группе трансплантированных вне ремиссии (р=0,01). Тип ОЛ не повлиял на ОВ 36,5% против 27,9% ОЛЛ и ОМЛ соответственно. Частота развития рецидивов после гапло-ТГСК, выполненной в 1 и 2 ремиссии составила 23,5%, с медианой наступления Д+88 (Д+30 – Д+301). Частота развития оРТПХ II0 – 21 (26,3%) человек, оРТПХ III0-IV0 – 15 (18,6%) человек.

Выводы

Гапло-ТГСК в 1 и 2 ремиссиях ОЛ, позволяет достигнуть 10-летней ОВ у 64,7% детей, при этом тип острого лейкоза не влияет на исход гапло-ТГСК. Приемлемая частота развития оРТПХ III0-IV0 – 18,6% позволяет рассматривать гапло-ТГСК, как терапию в 1 и 2 ремиссиях ОЛ высокой группы риска. Основным осложнением гапло-ТГСК является рецидив – 23,5% в ранний посттрансплантационный период до Д+100.

Ключевые слова

Аллогенная трансплантация гемопоэтических клеток, гаплоидентичная, дети, общая выживаемость, рецидивирование, реакция «трансплантат против хозяина».

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Introduction

Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, W. Dameshek (1967) has noticed that severe AA may transform into paroxysmal nocturnal hemoglobinuria (PNH), secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [1]. At the present time, this dependence is confirmed by numerous studies [2-15]. Moreover, recent data show high incidence up to 50% somatic mutations in patients with acquired AA, involving genes commonly mutated in myeloid malignancies [4]. Previously, most patients died within a year after primary diagnosis of SAA, until 1980’s when implementation of antithymocyte globulin (ATG) combined with cyclosporin A (CsA) proved to be an effective immunosuppressive therapy (IST). Therefore, secondary clonal disorders in AA have become more common, due to longer survival of the patients. From 10 to 30% of AA patients treated with IST were shown to develop secondary clonal diseases, i.e., MDS/AML or PNH, with a cumulative risk of 8 to 18% within next 10 years [2-6, 7, 8, 14]. The patients with secondary disorders have worse prognosis than de novo AML or MDS cases, with a median survival of <1 year [11, 12, 13]. Diagnosis of NSAA, shorter telomere length, splenectomy, two or more ATG courses is related to increase risk for subsequent clonal complications [2, 6, 9, 10, 15, 16]. By contrary, allogeneic bone marrow transplantation aimed for AA treatment causes a sufficiently reduced risk of such secondary disorders [11]. Therapeutic experience for these patients is limited, due to their rarity in common hematological practice. Clinical remissions achieved in such patients usually short and accompanied by high minimal residual disease levels. Moreover, these patients poorly tolerate chemotherapy; they develop longer cytopenia and often die from complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative method for these conditions. The aim of present study was to evaluate efficiency of allo-HSCT in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes.

Patients and methods

The retrospective study included 26 patients with MDS/AML, previously treated with IST due to acquired AA. The patients were observed in First St. Petersburg State I. Pavlov Medical University and Novosibirsk Institute of Clinical Immunology from July 1998 to June 2018. The survival assessment was completed at 15.06.2018. Acquired AA was diagnosed according to standard criteria (International Agranulocytosis and Aplastic Anemia Study Group, 1987). The AA severity grade was evaluated by common criteria [17, 18]. The degree of response corresponded to standard definitions [19]. Fanconi anemia and other inherited AA were not included into the study. Majority of patients (19/26), received as a combination of ATG and CsA, six patients received CsA as monotherapy. Splenectomy has been performed in other centers in seven cases. The patients were observed for a median of 6 years (range, 0.9 to 33) from the AA diagnosis. Sixteen patients were enrolled into the study group at the stage of clonal disorders. The median age at the time of AA diagnosis was 17 (range, 5 to 41) and 25 (range, 9 to 45) years at MDS/AML transformation, respectively. MDS transformation was diagnosed by characteristic morphological changes in bone marrow, increasing blast cell numbers, and typical chromosome aberrations (International Working Group on Morphology of Myelodysplastic Syndrome, 2008). Clinical MDS variant was determined according to the WHO classification (WHO classification of the myeloid neoplasms, 2016). AML was diagnosed when the ratio of blast cells in bone marrow exceeded 20%. The AML phenotype was determined by means of morphological, cytochemical, mmunophenotyping assays, as well as cytogenetic methods and molecular markers. Eight patients were treated with chemotherapy and/or hypomethylating treatment. All the patients provided informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. Eighteen patients received allo-HSCT, either from matched related donor (MRD) (n=6), matched unrelated donor (MUD) (n=9) or haploidentical donor (n=3). Most patients underwent the non-myeloablative conditioning regimen consisting of fludarabine 180 mg/m2 and busulfan 10 mg/kg (n=14). Graft-versus-host disease (GVHD) prophylaxis included the combination tacrolimus (Tx) and mycophenolate mofetil (MMF) (n=6), CsA/methotrexate combined therapy (n=6) and post-transplant cyclophosphamide (PtCy) at a dose of 50 mg/kg on D+3, D+4 (n=6). Engraftment criteria were absolute neutrophil counts of >0.5х109/L for 3 subsequent days and platelet numbers to >20х109/L in absence of preceding platelet transfusions for 7 days. The GvHD severity and grade were assessed according to Przepiorka D. et al., 1995 [20]. Clinical relapse was diagnosed upon hematological recurrence of MDS or AML signs. The overall survival parameters were evaluated by Kaplan-Meier approach, calculating the confidence interval values (CI 95%) using a log-rank test for evaluation of differences between the survival curves. Descriptive inter-group differences were evaluated with exact Fisher criterion for categorical characteristics, and Mann-Whitney U test (for 2 groups) and Kruskal-Wallis criterion (>2 groups). Univariate and multivariate survival analyses were carried out using the Cox proportional hazard model. All significant variables among those assessed in univariate analysis were considered for the multivariate model. The STATISTICA 10.0 (StatSoft Inc., USA) software was used.

Results

Clinical characteristics

A total of 26 patients were included, male/female 15/11, with median age of 25 years at the moment of MDS/AML diagnosis. More than a half of patients (n=14) had the history of non-severe AA (NSAA). Cytogenetic study was performed in twelve cases upon primary diagnostics, showing normal karyotype in all cases. The PNH clone was tested in 17 patients as a part of AA diagnostics, and a minor PNH clone was revealed in 7 cases. Moreover, three patients with partial AA remission showed signs of hemolytic PNH (resp., 4, 6 and 14 years after the debut), with subsequent PNH clone disappearance and evolution to MDS/AML, respectively, 10, 13 and 22 years later. In 7 out of 26 patients, even partial AA remission was achieved. The most common cytogenetic abnormality was monosomy 7. The demographic and clinical characteristics of the patients are presented in Table 1.

Treatment results

Eight patients with secondary AML who had no available compatible donors, received chemotherapy: «7+3» (n=3), low-dose cytarabine (n=2), FLAG (n=1) and high-dose cytarabine (n=2). MDS patients were treated with 5-azacytidine or low-dose cytarabine. All patients initially diagnosed with MDS developed AML within 24 months. All patients treated by chemotherapy/hypomethylating agents alone (n=8), died with median survival time of 6 (1 to 25) months since the malignant transformation. They all were scheduled for unrelated HSCT which, however, could not be timely performed. Among the patients subjected to allo-HSCT (n=18), eight patients are still alive, at a median follow-up time of 4.8 years (0.5 to 12 years). The 2-year overall survival (OS) in the chemotherapy alone group was 0 %, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024] as shown in Fig. 1.

Allo-HSCT for secondary MDS/AML

A total of 26 allo-HSCTs were perfo

rmed in 18 patients. Median age at the HSCT was 23 (11-44) years. The median time from MDS/AML diagnosis to HSCT was 7 (2 to 18) months. For the first HSCT, HLA-identical siblings were used for 6 patients (33%), a MUD in 9 (50 %) of cases, whereas haploidentical familial donor was used for three patients (17%). Repeated HSCT was in most cases performed from haploidentical donors (n=5). Before allo-HSCT, eight patients received hypomethylating agents (5-azacytidine, decitabine). Four of six patients achieved first complete remission after «7+3» chemotherapy. One patient was treated at low-dose cytarabine and 3 patients with myelodysplastic syndrome with multilineage dysplasia (MDS-MLD), received only supportive care. All the patients had multiple transfusions of RBC and platelets in their past history. The median of ferritin level at the time of HSCT was 1430 (205-10500) ng/mL.

36-44_Golubovskaya Table 1. Characteristics of the patients with AA transformed to MDS_AML.png


36-44_Golubovskaya Figures 1-2.png

Biological and clinical characteristics of transplanted patients and HSCT procedure are presented in Table 2. Successful engraftment was documented in 12 patients, with a median at D+16 (D+12 to D+25), platelet recovery, at D+17 (D+11 to D+20). Seven patients (39%) developed acute GVHD grade II-IV, resulted in death in 2 cases. All the HSCT survivors have clinical signs of moderate or severe chronic GVHD. Primary graft failure was registered in six patients (33%): 3 after haploidentical, 2 after unrelated and 2 after related HSCT. A secondary graft rejection was revealed in 2 patients after unrelated HSCT. Two patients developed relapse of MDS/AML. Seven patients with primary graft failure/graft rejection were subjected to repeated HSCT from haploidentical donor (n=5), related (n=1), or unrelated donors (n=1). However, the engraftment after repeated HSCT was not achieved in 5 cases, patients died in cytopenia from hemorrhagic and infectious complications. One patient after repeated MUD HSCT developed a fatal GVHD grade IV. Two patients developed the disease relapse (respectively, D+56 after related HSCT in 2 cases, and D+380 after unrelated HSCT). The causes of post-transplant mortality are presented in Table 3. Seven transplanted patients have got hypomethylating drugs at a mean of 6 courses (5-azacytidine, in 4 cases; decitabine in 3 patients) aiming to prevent relapses.

Analysis of prognostic factors

Assessment of prognostic significance for distinct biological and clinical parameters is presented in Table 4. According to further statistical evaluation, such factors as patient’s gender, age, conditioning regimen, GVHD prophylaxis, CMV status, ABO mismatch, numbers of CD34+ and mononuclear cells did not have a significant effect on overall survival (p>0,1). The use of peripheral blood as a source of graft was associated with higher overall survival (p=0.014). The overall post-transplant survival proved to be significantly dependent only on remission state at the time of HSCT (Fig. 2). HSCT timing seems to be important in patients with MDSMLD. Of the three patients only one survived, who received hematopoietic graft 2 months after the MDS diagnosis (monosomy 7, marrow dysplasia). Two deceased patients were transplanted much later, >1 year after the diagnosis, when the patients continued to receive replacement transfusions. High ferritin levels did not significantly impair survival. Of note, the transfusion load for these patients was quite significant (median RBC transfusions 23 units; platelets, 44 units by the time of HSCT).

Discussion

Treatment of the patients with secondary MDS/AML remains unresolved problem, and its results are worse to those in primary patients. Especially, one should consider high rates of severe cytopenia-associated complications after standard therapy of the patients with previously diagnosed AA, probably, due to reduced regenerative ability of bone marrow. In most patients, unstable clinical remission could be obtained after chemotherapy, with high levels of minimal residual disease. In some patients remission is not achieved, or they die from hemorrhagic and infectious complications after 1st induction course. Meanwhile, with increased life duration of IST-treated AA patients, the number of patients with secondary MDS/AML will increase. Therefore, novel algorithm is required for management of such patients.

36-44_Golubovskaya Table 2. Transplant and patients characteristics.png

36-44_Golubovskaya Table 3. Causes of death in the patients after allo-HSCT dependent on a donor type.png

36-44_Golubovskaya Table 4. Factors influencing overall survival values in HSCT (Cox regression method).png

In our study, all the non-transplanted patients have developed acute leukemia within 2 years since the MDS diagnosis. Overall 4-year survival of the patients subjected to HSCT was 40% (95% CI, 38-52) compared to zero survival among non-transplanted patients. For the patients being in remission state at the time of HSCT, the 4-year OS comprised 80 % (95% CI, 65-95), thus being in accordance with results presented by European Bone Marrow Transplantation Group [21]. Our study has confirmed that allogeneic HSCT is the only option able to cure the patient with secondary MDS/AML evolving after AA. The time interval from diagnosis of secondary disorder to HSCT is the critical factor for success, due to rapid transformation of MDS to AML, poor chemotherapy tolerance, and high risk of lethal outcome before HSCT. To provide HSCT within short terms for these patients, itis necessary to perform HLA typing of the patients at the stage of AA, in order to assess availability of potential donors (for NSAA patients as well), regular examination after IST, including cytogenetic studies of bone marrow, especially, in resistant and relapsing AA conditions. It was shown that the probability of arising pathological clones with chromosomal aberrations makes up to 40% in non-responders to IST, in 6% with partial response, and in 10% of patients well responding to the treatment. Risk for clonal disorders in the patients non-responding to IST, and in cases of preceding NSAA sufficiently exceeds appropriate hazards in the patients with partial response, full response to the therapy, and severe AA [8, 9, 10]. Our study, though performed in a small group, has detected a significantly increased OS in the patients subjected to allo-HSCT, as compared to the patients who received chemotherapy only (40% among transplanted patients versus 0 % in the non-transplanted cases), thus again stressing the role of remission state as the main factor of favorable prognosis in HSCT series. Prognostic significance of remission state was confirmed in our multifactorial analysis. However, one may suppose that, when increasing the number of patients, this factor will significantly influence the results as it was shown in other studies dealing with greater cohorts [21]. Moreover, we have noted a tendency towards better HSCT outcomes in the persons <21 years old, as well as when using the mobilized hematopoietic stem cells as a source of graft. The type of conditioning regimen also did not have significant impact on the HSCT results, but some studies declare benefits of myeloablative conditioning for treatment of secondary MDS [21, 23]. In our study, only 3 out of 16 patients were subjected to myeloablative conditioning, with engraftment in 2 of 3 cases. However, the most patients were admitted to the BMT Center after prolonged conservative therapy, and their comorbid state did not allow to performing myeloablative conditioning. Frequency of aGVHD in total was 27%, severe aGVHD (grade III-IV) was 19% and caused lethal outcome in two cases. Chronic GVHD of different grade was observed in all survivors; however, it did not result into severe disability. According to our data, primary graft failure is the most common cause for HSCT failure (33% of total group in our study). This is a significantly higher incidence compared with data reported by other authors [21, 23]. To our mind, heavy pre-treatment, multiple blood transfusions, as well as numerous courses of chemotherapy and demethylating treatment predisposing for infections, may cause this post-transplant complication. It is difficult to determine efficiency оf haploidentical HSCT in this study because of few clinical cases (n=3), however, primary non-engraftment seems to be the main problem in this HSCT option. Carrying out repeated HSCTs following primary non-engraftment allowed achieving hematopoietic recovery in two cases (25%), with one lethal outcome due to grade IV aGVHD. Therapy with hypomethylating drugs during the post-transplant period is used to prevent and treat relapses in the patients with high risk AML [24]. Our study has shown promising results of such strategy in cases of secondary MDS/AML as well.

Conclusions

Allogeneic hematopoietic stem cell transplantation is the only potentially curative method for treatment of MDS/AML occurring in the patients previously treated with immunosuppressive therapy for AA. Remission state at the time of HSCT is the main predictor for a successful transplantation. Using peripheral blood as a source of graft improves overall survival in patients with secondary MDS/AML from AA. Allo-HSCT is indicated as soon as possible in the case of registered evolution of AA to MDS/AML.

Conflict of interest

No conflicts of interests are reported.

References

1. Dameshek W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) and «hypoplastic» leukemia have in common? Blood 1967;30(2):251-254.
2. Tichelli A, Gratwohl A, Nissen C, Speck B. Late clonal complications in severe aplastic anemia. Leuk Lymphoma 1994;12 (3-4):167–175.
3. Ohara A, Kojima S, Hamajima N, Tsuchida M, Imashuku S, Ohta S, Sasaki H, Okamura J, Sugita K, Kigasawa H, Kiriyama Y, Akatsuka J, Tsukimoto I. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90(3):1009–1013.
4. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood. 2016;128(3):337-347.
5. Kojima S, Ohara A, Tsuchida M, Kudoh T. Hanada R, Okimoto Y, Kaneko T, Takano T, Ikuta K, Tsukimoto I. Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002;100(3):786-790.
6. Socie G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, McCann SR, Frickhofen N, Van't Veer-Korthof E, Gluckman E. European Bone Marrow Transplantation Severe Aplastic Anemia Working Party: Malignant tumors occurring after treatment of aplastic anemia. N Engl J Med. 1993;329(16):1152-1157.
7. Afable M, Tiu R, Maciejewski J. Clonal evolution in aplastic anemia. Hematology Am Soc Hematol Educ Program. 2011;2011:90-95.
8. Kulagin AD, Lisukov IA, Kozlov VA. Aplastic anemia: immune pathogenesis, clinical features, diagnostics, treatment. 2008; Novosibirsk: Nauka Publ. 236 p (In Russian).
9. Kulagin AD. Clinical, hematological and immunological criteria for long-term prognosis of acquired aplastic anemia. Doctor’sThesis: 1st St.Petersburg State I.Pavlov Medical University, St.Petersburg, 2015 (In Russian).
10. Kulagin A, Borisov V, Pronkina N, Kruchkova I, Lisukov I, Afanasyev B. Long-term outcomes of accelerated telomere shortening in acquired aplastic anemia. Blood. 2014;124(21):4396.
11. Golubovskaya IK, Ganapiev AA, Kulagin AD, Bondarenko SN, Stancheva NV, Vavilov VV, Lisukov IA, Afanasyev BV. Myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term survivors of aplastic anemia. Cell Ther Transplant. 2010; 3(3): 44.
12. Borthakur G, Estey A. Therapy-related acute myelogenous leukemia and myelodysplastic syndrome. Curr Oncol Rep. 2007;9(5):373-377.
13. Armand P, Kim H, DeAngelo DJ, Ho VT, Cutler CS, Stone RM, Ritz J, Alyea EP, Antin JH, Soiffer RJ. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant 2007; 13(6):655-664.
14. Kulagin A, Golubovskaya I, Ivanova M, Babenko E, Pronkina N, Kruchkova I, Lisukov I, Afanasyev B. Incidence and risk factors for hemolytic paroxysmal nocturnal hemoglobinuria (PNH) in aplastic anemia (AA) patients. Bone Marrow Transplant. 2014;49 (Suppl 1):S42–43.
15. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 2003;101(4):1236-1242.
16. Scheinberg P, Cooper JN, Sloand EM, Wu CO, Calado RT, Young NS. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA. 2010; 304(12):1358-1364.
17. Camitta B, Thomas E, Nathan DG, Santos G, Gordon- Smith EC, Gale RP, Rappeport JM, Storb R. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976;48(1):63-70.
18. Bacigalupo A, Hows J, Gluckman E. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol. 1988;70(2):177-182.
19. Camitta B. What is the definition of cure for aplastic anemia? Acta Haematol. 2000;103(1):16-18.
20. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15(6):825-828.
21. Kröger N, Iacobelli S, Franke GN, Platzbecker U, Uddin R, Hübel K, Scheid C, Weber T, Robin M, Stelljes M, Afanasyev B, Heim D, Deliliers GL, Onida F, Dreger P, Pini M, Guidi S, Volin L, Günther A, Bethge W, Poiré X, Kobbe G, van Os M, Brand R, de Witte T. Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized Phase III Study of the EBMT (RICMAC Trial). J Clin Oncol. 2017;35(19):2157-2164.
22. Hussein AA, Halkes CM, Socié G, Tichelli A, von dem Borne PA, Schaap MN, Foa R, Ganser A, Dufour C, Bacigalupo A, Locasciulli A, Aljurf M, Peters C, Robin M, van Biezen A, Volin L, De Witte T, Marsh J, Passweg JR, Kröger N. Outcome of allogeneic stem cell transplantation for patients transformed to myelodysplastic syndrome or leukemia from severe aplastic anemia: a report from the MDS Subcommittee of the Chronic Malignancies Working Party and the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2014;20(9):1448–1450.
23. Kim S, Le Rademacher J, Antin J, Anderlini P, Ayas M, Battiwalla M, Carreras J, Kurtzberg J, Nakamura R, Eapen M, Deeg HJ. Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation. Haematologica. 2014;99(12):1868-1875.
24. Mawad R, Lionberger J, Pagel J. Strategies to reduce relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Curr Hematol Malig Rep. 2013;8(2):132–140.

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Introduction

Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, W. Dameshek (1967) has noticed that severe AA may transform into paroxysmal nocturnal hemoglobinuria (PNH), secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [1]. At the present time, this dependence is confirmed by numerous studies [2-15]. Moreover, recent data show high incidence up to 50% somatic mutations in patients with acquired AA, involving genes commonly mutated in myeloid malignancies [4]. Previously, most patients died within a year after primary diagnosis of SAA, until 1980’s when implementation of antithymocyte globulin (ATG) combined with cyclosporin A (CsA) proved to be an effective immunosuppressive therapy (IST). Therefore, secondary clonal disorders in AA have become more common, due to longer survival of the patients. From 10 to 30% of AA patients treated with IST were shown to develop secondary clonal diseases, i.e., MDS/AML or PNH, with a cumulative risk of 8 to 18% within next 10 years [2-6, 7, 8, 14]. The patients with secondary disorders have worse prognosis than de novo AML or MDS cases, with a median survival of <1 year [11, 12, 13]. Diagnosis of NSAA, shorter telomere length, splenectomy, two or more ATG courses is related to increase risk for subsequent clonal complications [2, 6, 9, 10, 15, 16]. By contrary, allogeneic bone marrow transplantation aimed for AA treatment causes a sufficiently reduced risk of such secondary disorders [11]. Therapeutic experience for these patients is limited, due to their rarity in common hematological practice. Clinical remissions achieved in such patients usually short and accompanied by high minimal residual disease levels. Moreover, these patients poorly tolerate chemotherapy; they develop longer cytopenia and often die from complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative method for these conditions. The aim of present study was to evaluate efficiency of allo-HSCT in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes.

Patients and methods

The retrospective study included 26 patients with MDS/AML, previously treated with IST due to acquired AA. The patients were observed in First St. Petersburg State I. Pavlov Medical University and Novosibirsk Institute of Clinical Immunology from July 1998 to June 2018. The survival assessment was completed at 15.06.2018. Acquired AA was diagnosed according to standard criteria (International Agranulocytosis and Aplastic Anemia Study Group, 1987). The AA severity grade was evaluated by common criteria [17, 18]. The degree of response corresponded to standard definitions [19]. Fanconi anemia and other inherited AA were not included into the study. Majority of patients (19/26), received as a combination of ATG and CsA, six patients received CsA as monotherapy. Splenectomy has been performed in other centers in seven cases. The patients were observed for a median of 6 years (range, 0.9 to 33) from the AA diagnosis. Sixteen patients were enrolled into the study group at the stage of clonal disorders. The median age at the time of AA diagnosis was 17 (range, 5 to 41) and 25 (range, 9 to 45) years at MDS/AML transformation, respectively. MDS transformation was diagnosed by characteristic morphological changes in bone marrow, increasing blast cell numbers, and typical chromosome aberrations (International Working Group on Morphology of Myelodysplastic Syndrome, 2008). Clinical MDS variant was determined according to the WHO classification (WHO classification of the myeloid neoplasms, 2016). AML was diagnosed when the ratio of blast cells in bone marrow exceeded 20%. The AML phenotype was determined by means of morphological, cytochemical, mmunophenotyping assays, as well as cytogenetic methods and molecular markers. Eight patients were treated with chemotherapy and/or hypomethylating treatment. All the patients provided informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. Eighteen patients received allo-HSCT, either from matched related donor (MRD) (n=6), matched unrelated donor (MUD) (n=9) or haploidentical donor (n=3). Most patients underwent the non-myeloablative conditioning regimen consisting of fludarabine 180 mg/m2 and busulfan 10 mg/kg (n=14). Graft-versus-host disease (GVHD) prophylaxis included the combination tacrolimus (Tx) and mycophenolate mofetil (MMF) (n=6), CsA/methotrexate combined therapy (n=6) and post-transplant cyclophosphamide (PtCy) at a dose of 50 mg/kg on D+3, D+4 (n=6). Engraftment criteria were absolute neutrophil counts of >0.5х109/L for 3 subsequent days and platelet numbers to >20х109/L in absence of preceding platelet transfusions for 7 days. The GvHD severity and grade were assessed according to Przepiorka D. et al., 1995 [20]. Clinical relapse was diagnosed upon hematological recurrence of MDS or AML signs. The overall survival parameters were evaluated by Kaplan-Meier approach, calculating the confidence interval values (CI 95%) using a log-rank test for evaluation of differences between the survival curves. Descriptive inter-group differences were evaluated with exact Fisher criterion for categorical characteristics, and Mann-Whitney U test (for 2 groups) and Kruskal-Wallis criterion (>2 groups). Univariate and multivariate survival analyses were carried out using the Cox proportional hazard model. All significant variables among those assessed in univariate analysis were considered for the multivariate model. The STATISTICA 10.0 (StatSoft Inc., USA) software was used.

Results

Clinical characteristics

A total of 26 patients were included, male/female 15/11, with median age of 25 years at the moment of MDS/AML diagnosis. More than a half of patients (n=14) had the history of non-severe AA (NSAA). Cytogenetic study was performed in twelve cases upon primary diagnostics, showing normal karyotype in all cases. The PNH clone was tested in 17 patients as a part of AA diagnostics, and a minor PNH clone was revealed in 7 cases. Moreover, three patients with partial AA remission showed signs of hemolytic PNH (resp., 4, 6 and 14 years after the debut), with subsequent PNH clone disappearance and evolution to MDS/AML, respectively, 10, 13 and 22 years later. In 7 out of 26 patients, even partial AA remission was achieved. The most common cytogenetic abnormality was monosomy 7. The demographic and clinical characteristics of the patients are presented in Table 1.

Treatment results

Eight patients with secondary AML who had no available compatible donors, received chemotherapy: «7+3» (n=3), low-dose cytarabine (n=2), FLAG (n=1) and high-dose cytarabine (n=2). MDS patients were treated with 5-azacytidine or low-dose cytarabine. All patients initially diagnosed with MDS developed AML within 24 months. All patients treated by chemotherapy/hypomethylating agents alone (n=8), died with median survival time of 6 (1 to 25) months since the malignant transformation. They all were scheduled for unrelated HSCT which, however, could not be timely performed. Among the patients subjected to allo-HSCT (n=18), eight patients are still alive, at a median follow-up time of 4.8 years (0.5 to 12 years). The 2-year overall survival (OS) in the chemotherapy alone group was 0 %, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024] as shown in Fig. 1.

Allo-HSCT for secondary MDS/AML

A total of 26 allo-HSCTs were perfo

rmed in 18 patients. Median age at the HSCT was 23 (11-44) years. The median time from MDS/AML diagnosis to HSCT was 7 (2 to 18) months. For the first HSCT, HLA-identical siblings were used for 6 patients (33%), a MUD in 9 (50 %) of cases, whereas haploidentical familial donor was used for three patients (17%). Repeated HSCT was in most cases performed from haploidentical donors (n=5). Before allo-HSCT, eight patients received hypomethylating agents (5-azacytidine, decitabine). Four of six patients achieved first complete remission after «7+3» chemotherapy. One patient was treated at low-dose cytarabine and 3 patients with myelodysplastic syndrome with multilineage dysplasia (MDS-MLD), received only supportive care. All the patients had multiple transfusions of RBC and platelets in their past history. The median of ferritin level at the time of HSCT was 1430 (205-10500) ng/mL.

36-44_Golubovskaya Table 1. Characteristics of the patients with AA transformed to MDS_AML.png


36-44_Golubovskaya Figures 1-2.png

Biological and clinical characteristics of transplanted patients and HSCT procedure are presented in Table 2. Successful engraftment was documented in 12 patients, with a median at D+16 (D+12 to D+25), platelet recovery, at D+17 (D+11 to D+20). Seven patients (39%) developed acute GVHD grade II-IV, resulted in death in 2 cases. All the HSCT survivors have clinical signs of moderate or severe chronic GVHD. Primary graft failure was registered in six patients (33%): 3 after haploidentical, 2 after unrelated and 2 after related HSCT. A secondary graft rejection was revealed in 2 patients after unrelated HSCT. Two patients developed relapse of MDS/AML. Seven patients with primary graft failure/graft rejection were subjected to repeated HSCT from haploidentical donor (n=5), related (n=1), or unrelated donors (n=1). However, the engraftment after repeated HSCT was not achieved in 5 cases, patients died in cytopenia from hemorrhagic and infectious complications. One patient after repeated MUD HSCT developed a fatal GVHD grade IV. Two patients developed the disease relapse (respectively, D+56 after related HSCT in 2 cases, and D+380 after unrelated HSCT). The causes of post-transplant mortality are presented in Table 3. Seven transplanted patients have got hypomethylating drugs at a mean of 6 courses (5-azacytidine, in 4 cases; decitabine in 3 patients) aiming to prevent relapses.

Analysis of prognostic factors

Assessment of prognostic significance for distinct biological and clinical parameters is presented in Table 4. According to further statistical evaluation, such factors as patient’s gender, age, conditioning regimen, GVHD prophylaxis, CMV status, ABO mismatch, numbers of CD34+ and mononuclear cells did not have a significant effect on overall survival (p>0,1). The use of peripheral blood as a source of graft was associated with higher overall survival (p=0.014). The overall post-transplant survival proved to be significantly dependent only on remission state at the time of HSCT (Fig. 2). HSCT timing seems to be important in patients with MDSMLD. Of the three patients only one survived, who received hematopoietic graft 2 months after the MDS diagnosis (monosomy 7, marrow dysplasia). Two deceased patients were transplanted much later, >1 year after the diagnosis, when the patients continued to receive replacement transfusions. High ferritin levels did not significantly impair survival. Of note, the transfusion load for these patients was quite significant (median RBC transfusions 23 units; platelets, 44 units by the time of HSCT).

Discussion

Treatment of the patients with secondary MDS/AML remains unresolved problem, and its results are worse to those in primary patients. Especially, one should consider high rates of severe cytopenia-associated complications after standard therapy of the patients with previously diagnosed AA, probably, due to reduced regenerative ability of bone marrow. In most patients, unstable clinical remission could be obtained after chemotherapy, with high levels of minimal residual disease. In some patients remission is not achieved, or they die from hemorrhagic and infectious complications after 1st induction course. Meanwhile, with increased life duration of IST-treated AA patients, the number of patients with secondary MDS/AML will increase. Therefore, novel algorithm is required for management of such patients.

36-44_Golubovskaya Table 2. Transplant and patients characteristics.png

36-44_Golubovskaya Table 3. Causes of death in the patients after allo-HSCT dependent on a donor type.png

36-44_Golubovskaya Table 4. Factors influencing overall survival values in HSCT (Cox regression method).png

In our study, all the non-transplanted patients have developed acute leukemia within 2 years since the MDS diagnosis. Overall 4-year survival of the patients subjected to HSCT was 40% (95% CI, 38-52) compared to zero survival among non-transplanted patients. For the patients being in remission state at the time of HSCT, the 4-year OS comprised 80 % (95% CI, 65-95), thus being in accordance with results presented by European Bone Marrow Transplantation Group [21]. Our study has confirmed that allogeneic HSCT is the only option able to cure the patient with secondary MDS/AML evolving after AA. The time interval from diagnosis of secondary disorder to HSCT is the critical factor for success, due to rapid transformation of MDS to AML, poor chemotherapy tolerance, and high risk of lethal outcome before HSCT. To provide HSCT within short terms for these patients, itis necessary to perform HLA typing of the patients at the stage of AA, in order to assess availability of potential donors (for NSAA patients as well), regular examination after IST, including cytogenetic studies of bone marrow, especially, in resistant and relapsing AA conditions. It was shown that the probability of arising pathological clones with chromosomal aberrations makes up to 40% in non-responders to IST, in 6% with partial response, and in 10% of patients well responding to the treatment. Risk for clonal disorders in the patients non-responding to IST, and in cases of preceding NSAA sufficiently exceeds appropriate hazards in the patients with partial response, full response to the therapy, and severe AA [8, 9, 10]. Our study, though performed in a small group, has detected a significantly increased OS in the patients subjected to allo-HSCT, as compared to the patients who received chemotherapy only (40% among transplanted patients versus 0 % in the non-transplanted cases), thus again stressing the role of remission state as the main factor of favorable prognosis in HSCT series. Prognostic significance of remission state was confirmed in our multifactorial analysis. However, one may suppose that, when increasing the number of patients, this factor will significantly influence the results as it was shown in other studies dealing with greater cohorts [21]. Moreover, we have noted a tendency towards better HSCT outcomes in the persons <21 years old, as well as when using the mobilized hematopoietic stem cells as a source of graft. The type of conditioning regimen also did not have significant impact on the HSCT results, but some studies declare benefits of myeloablative conditioning for treatment of secondary MDS [21, 23]. In our study, only 3 out of 16 patients were subjected to myeloablative conditioning, with engraftment in 2 of 3 cases. However, the most patients were admitted to the BMT Center after prolonged conservative therapy, and their comorbid state did not allow to performing myeloablative conditioning. Frequency of aGVHD in total was 27%, severe aGVHD (grade III-IV) was 19% and caused lethal outcome in two cases. Chronic GVHD of different grade was observed in all survivors; however, it did not result into severe disability. According to our data, primary graft failure is the most common cause for HSCT failure (33% of total group in our study). This is a significantly higher incidence compared with data reported by other authors [21, 23]. To our mind, heavy pre-treatment, multiple blood transfusions, as well as numerous courses of chemotherapy and demethylating treatment predisposing for infections, may cause this post-transplant complication. It is difficult to determine efficiency оf haploidentical HSCT in this study because of few clinical cases (n=3), however, primary non-engraftment seems to be the main problem in this HSCT option. Carrying out repeated HSCTs following primary non-engraftment allowed achieving hematopoietic recovery in two cases (25%), with one lethal outcome due to grade IV aGVHD. Therapy with hypomethylating drugs during the post-transplant period is used to prevent and treat relapses in the patients with high risk AML [24]. Our study has shown promising results of such strategy in cases of secondary MDS/AML as well.

Conclusions

Allogeneic hematopoietic stem cell transplantation is the only potentially curative method for treatment of MDS/AML occurring in the patients previously treated with immunosuppressive therapy for AA. Remission state at the time of HSCT is the main predictor for a successful transplantation. Using peripheral blood as a source of graft improves overall survival in patients with secondary MDS/AML from AA. Allo-HSCT is indicated as soon as possible in the case of registered evolution of AA to MDS/AML.

Conflict of interest

No conflicts of interests are reported.

References

1. Dameshek W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) and «hypoplastic» leukemia have in common? Blood 1967;30(2):251-254.
2. Tichelli A, Gratwohl A, Nissen C, Speck B. Late clonal complications in severe aplastic anemia. Leuk Lymphoma 1994;12 (3-4):167–175.
3. Ohara A, Kojima S, Hamajima N, Tsuchida M, Imashuku S, Ohta S, Sasaki H, Okamura J, Sugita K, Kigasawa H, Kiriyama Y, Akatsuka J, Tsukimoto I. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90(3):1009–1013.
4. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood. 2016;128(3):337-347.
5. Kojima S, Ohara A, Tsuchida M, Kudoh T. Hanada R, Okimoto Y, Kaneko T, Takano T, Ikuta K, Tsukimoto I. Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002;100(3):786-790.
6. Socie G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, McCann SR, Frickhofen N, Van't Veer-Korthof E, Gluckman E. European Bone Marrow Transplantation Severe Aplastic Anemia Working Party: Malignant tumors occurring after treatment of aplastic anemia. N Engl J Med. 1993;329(16):1152-1157.
7. Afable M, Tiu R, Maciejewski J. Clonal evolution in aplastic anemia. Hematology Am Soc Hematol Educ Program. 2011;2011:90-95.
8. Kulagin AD, Lisukov IA, Kozlov VA. Aplastic anemia: immune pathogenesis, clinical features, diagnostics, treatment. 2008; Novosibirsk: Nauka Publ. 236 p (In Russian).
9. Kulagin AD. Clinical, hematological and immunological criteria for long-term prognosis of acquired aplastic anemia. Doctor’sThesis: 1st St.Petersburg State I.Pavlov Medical University, St.Petersburg, 2015 (In Russian).
10. Kulagin A, Borisov V, Pronkina N, Kruchkova I, Lisukov I, Afanasyev B. Long-term outcomes of accelerated telomere shortening in acquired aplastic anemia. Blood. 2014;124(21):4396.
11. Golubovskaya IK, Ganapiev AA, Kulagin AD, Bondarenko SN, Stancheva NV, Vavilov VV, Lisukov IA, Afanasyev BV. Myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term survivors of aplastic anemia. Cell Ther Transplant. 2010; 3(3): 44.
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Голубовская, Александр Д. Кулагин, Юлия В. Рудницкая, Елена В. Морозова, Анна А. Осипова, Варвара Н. Овечкина, Николай Ю. Цветков, Сергей Н. Бондаренко, *Борис И. Смирнов, Людмила С. Зубаровская, Инна В. Маркова, Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(421) "Ирина К. Голубовская, Александр Д. Кулагин, Юлия В. Рудницкая, Елена В. Морозова, Анна А. Осипова, Варвара Н. Овечкина, Николай Ю. Цветков, Сергей Н. Бондаренко, *Борис И. Смирнов, Людмила С. Зубаровская, Инна В. Маркова, Борис В. 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Р. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова *Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(584) "НИИ детской онкологии, гематологии и трансплантологии им. Р. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова *Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20209" ["VALUE"]=> array(2) { ["TEXT"]=> string(3868) "<p style="text-align: justify;"> Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3802) "

Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.

Ключевые слова

Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.

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Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(246) "Irina K. Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, 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) "20214" ["VALUE"]=> array(2) { ["TEXT"]=> string(289) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(289) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20215" ["VALUE"]=> array(2) { ["TEXT"]=> string(2022) "<p style="text-align: justify;"> Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1956) "

Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.

Keywords

Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.

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Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(246) "Irina K. Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(246) "Irina K. Golubovskaya, Alexander D. Kulagin, Yulia V. Rudnitskaya, Elena V. Morozova, Anna A.Osipova, Varvara N. Ovechkina, Nikolay Y. Tсvetkov, Sergey N.Bondarenko, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Inna V. Markova, Boris V. 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However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1956) "

Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.

Keywords

Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.

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Aplastic anemia (АА) is the most common clinical form of bone marrow failure which is still considered as a non-malignant disorder. However, development secondary myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) in long-term AA survivors is confirmed by numerous studies. Treatment of the patients with secondary MDS/AML remains unresolved problem. The aim of present study was to evaluate efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in secondary MDS/AML evolving from AA, and to determine the factors influencing clinical outcomes. The study included 26 patients with MDS/AML, previously treated with immunosuppressive treatment due to acquired AA. Median age was 25 (range, 9-45) years at the moment of MDS/AML diagnosis. Eight patients who had no available compatible donors, received chemotherapy alone, 18 patients received allo-HSCT (from matched related donor (n=6), matched unrelated donor (n=9), haploidentical donor (n=3)). Groups were comparable in pre-transplant characteristics of patients. The 2-year overall survival (OS) in the chemotherapy alone group was 0%, being 53.1% in HSCT group [(95% CI 41-65.2), p=0.024]. For the patients being in remission state at the time of allo-HSCT, the 4-year OS comprised 80% [(95% CI, 65-95), p=0.021] vs 27 % in non-remission group. The use of peripheral blood as a source of graft was associated with higher OS (p=0.014). Allo-HSCT remains the only potentially curative method for treatment of secondary MDS/AML from AA and should be performed as soon as possible in the case of registered evolution of AA to MDS/AML. Remission state at the time of allo-HSCT is the main predictor for a successful transplantation.

Keywords

Aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, hematopoietic stem cell transplantation.

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Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(289) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, Chair of Hematology, Transfusiology and Transplantology at The First St. Petersburg State I. Pavlov Medical University *St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(289) "R. 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Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3802) "

Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.

Ключевые слова

Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.

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Апластическая анемия (АА) наиболее частый встречаемый вариант костно-мозговой недостаточности, рассматриваемый как незлокачественное заболевание. Тем не менее, во многих исследованиях подтверждено развитие вторичного миелодиспластического синдрома и острого миелоидного лейкоза (МДС/ОМЛ) у долгоживущих пациентов с АА. Лечение пациентов с вторичным МДС/ОМЛ остается нерешенной проблемой. Целью данного исследования являлась оценка эффективности аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) при развитии вторичного МДС/ОМЛ из АА и выявление факторов, оказывающих влияние на клинические исходы лечения. В исследование было включено 26 пациентов с МДС/ОМЛ,ранее получавших иммуносупрессивную терапию в рамках лечения приобретенной АА. Медиана возраста на момент установления диагноза МДС/ОМЛ составила 25 лет (9-45). Восемь пациентов, не имевших доступного совместимого донора, получали только химиотерапию, 18 пациентов получили алло-ТГСК (от полностью совместимого родственного донора (n=6), полностью совместимого неродственного донора (n=9), гаплоидентичного донора (n=3). Двухлетняя общая выживаемость (ОВ) в группе пациентов, получавших только химиотерапию, составила 0 % с равнение с 53,1% ((95% ДИ 41-65,2), p=0,024) ОВ в группе пациентов после алло-ТГСК. Для пациентов, получивших ТГСК в ремиссии заболевания ОВ, составляла 80% ((95% ДИ, 65-95), p=0,021) против 27% ОВ среди пациентов, не достигших ремиссии к моменту алло-ТГСК. Использование периферической крови в качестве источника трансплантата было ассоциировано с более высокой ОВ (р=0,014). Алло-ТГСК остается единственным потенциально излечивающим методом лечения для пациентов с вторичным МДС/ОМЛ из АА, и должна по возможности выполняться в самые кратчайшие сроки после констатации перехода АА в МДС/ОМЛ. Ремиссионный статус на момент алло-ТГСК является главным предиктором успешной трансплантации.

Ключевые слова

Апластическая анемия, миелодиспластический синдром, острый миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток.

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Introduction

Hematopoietic stem cell transplantation (HSCT) is a rapidly developing method for the treatment of various malignant and non-malignant diseases [1]. However, it requires synchronization between donor preparation to donation, conditioning regimen, donation and graft-versus-host disease (GVHD) prophylaxis. Thus situations occur, like unexpected infection in a recipient or fulminate relapse of the underling disease, when there is a dilemma whether to transplant a patient with these unexpected conditions or postpone the transplant and administer appropriate treatment . It is well known that grafting in relapse is the worst predictive factor for long-term survival [2]. On the other hand, active infections at the start of the conditioning also impact the outcome adversely [3, 4]. Thus in the majority of cases like these the decision is made to postpone the HSCT, however this is not possible in certain situations with unrelated donors, and also when a related donor has started the stimulation with granulocyte-colony stimulating factor. In these case the graft is usually cryopreserved before infusion. The other situation leading to cryopreservation is the poor graft cellularity collected from a donor. It is well known that low number of CD3 and CD34-positive cells in the graft significantly affect the incidence of primary graft failure and poor graft function after HSCT, which are associated with significant non-relapse mortality [5, 6]. Unlike the related setting when CD34-selected boost could be collected after unrelated transplantation this might be difficult due to donor decision or logistics. Thus several centers prefer to receive and access the graft quality before the start of the conditioning, and then transfuse the cryopreserved graft. Despite the safe use of freezing stage during autologous HSCT procedure, there is a lack of large comparative studies evaluating the effects of graft cryopreservation on the outcome of allogeneic HSCT. Despite the evidence that engraftment of the cryopreserved bone marrow is comparable [7, 8], there are reports that the risk of graft failure is increased with frozen peripheral blood stem cell (PBSC) graft [9], or the risk of the GVHD might be altered after thawing [10, 11]. We conducted a single-institution pair-matched retrospective study to evaluate the impact of graft cryopreservation on the outcomes and toxicity of allogeneic stem cell transplantation.

Patients and Methods

Patients and transplantation procedures

162 patients transplanted in 2006-2017 at the I. Pavlov First St. Petersburg State Medical University were included into the study. All patients signed informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. 81 patients received the cryopreserved graft. The graft was stored with 10% DMSO at -180⁰C until the day of the transplant. The reasons for freezing were: infection before the start of the conditioning (38.3%), relapse of the underlying disease (32.2%), unavailability of a related donor at the time of HSCT (17.2%), availability of the cryopreserved graft after the first donation due to restriction of CD34 cell count (11.1%), pregnancy before the conditioning (1.2%). The study group (Cryo group) comprised predominantly adult patients with unrelated donors, leukemia as an underlying disease and reduced intensity conditioning. The study group was represented by high-risk disease with 42% of patients having DRI 3 or 4 and active disease in 40% of patients. The control group (native group) comprised 81 pairmatched patients. The criteria for matching were type of the donor, graft source (bone marrow or PBSC), diagnosis, stage of the disease at the time of the performed HSCT, intensity of the conditioning, age ±5 years, CD34 count ± 1x106/kg and graft versus host disease prophylaxis. The significance of the matching factors was in the order listed above. The resulting groups were well matched and were not significantly different in any of the patient- or transplantation-related factors (Table 1). Median follow up was 25 months, thus the two year outcomes were used in the study.

Transplantation procedures

Myeloablative conditioning (MAC) was performed with oral busulfan 16 mg/kg and cyclophosphamide 100-120 mg/kg. Reduced intensity conditioning (RIC) was performed with fludarabine 180 mg/m2 and busulfan 8-10 mg/kg. Patients were assigned to RIC if they were 40 years or older, had hematopoietic cell transplantation-specific comorbidity index (HCT-CI)≥2, exbited, at least, grade 3 hepatic toxicity during previous therapy, or uncontrolled infection at the start of the conditioning. Patients subjected to second HSCT also received RIC. GVHD prophylaxis in the post-transplantation cyclophosphamide (PTCy) group consisted of cyclophosphamide (50 mg/kg) administered at days +3, +4, tacrolimus 0.03 mg/kg and mycophenolate mofetil (MMF) 30-45 mg/kg from day +5. The classical GVHD prophylaxis included either tacrolimus with target concentrations of 5-15 ng/ml, or cyclosporine A with target concentrations of 150-350 ng/ml from day -1. As second agents in the prophylaxis regimen we used short-course methotrexate 10-15 mg/m2 at days +1, +3, +6 or mycophenolate mofetil (MMF) 30 mg/kg from day -1 to day +30.

Clinical definitions

Time to disease relapse, acute GVHD (aGVHD), moderate to severe chronic GVHD (cGVHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GVHD-relapse free survival (GRFS) were defined as the time from transplantation to the event. All these parameters were calculated for the two-year interval. Incidence of aGVHD was calculated at 125 days after HSCT, and the time frame for the other outcomes was two years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grades III-IV acute GVHD or systemic therapy-requiring chronic GVHD. The Consensus Conference criteria and NIH criteria were used for aGVHD and cGVHD grading, respectively [12,13]. Primary graft failure was defined as the complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraftment was calculated as time from HSCT to unsupported neutrophil count > 500/ul and white blood cell count >1000/ul for 3 consecutive days.
Toxicity was assessed with CTCAE ver. 4.03. Sepsis in the study was defined as systemic inflammatory reaction with microbiologically confirmed bacteremia. The risk of the disease was accessed with disease risk index (DRI) by Armand et al. [14].

45-53_Babenko Table 1. Characteristics of patients and transplantations..png

AML=acute myeloid leukeina; ALL=acute lymphoblastic leukemia; MDS=myelodysplastic syndrome; MPN=myeloprolipherative neoplasm; CML=chronic myeloid leukemia; AA=aplastic anemia; BM=bone marrow; PBSC=peripheral blood stem cells; RIC=reduced-intensity conditioning; MAC=myeloablative conditioning; PTCy=post-transplantation cyclophosphamide.

Statistical Analysis

Comparison between the groups was performed by Chisquare test. The comparison of the quantitative parameters between groups were preformed with log-normalized t-test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGVHD, cGVHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate analysis was not performed, because patients were matched by the majority of significant variables. The subgroup analysis was performed for OS. Heterogeneities between the hazard ratios in the subgroup analysis were tested for significance using the Cochran’s Q test, with df degrees of freedom. Incidence and severity of complications were compared using Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

Engraftment

There was a trend towards higher incidence of graft failure in the Cryo group (15.7% vs 6.3%, p=0.0588). When the graft source was analyzed separately, there was a significant increase in graft failure for BM (26% vs 0%, p=0.025), but no difference for peripheral blood (12% vs 9%, p=0.483). Among patients who engrafted there was no difference for the time of neutrophil engraftment (median 19 vs 18 days, p=0.345 in the Cryo and control groups, respectively), white blood cell recovery (18 vs 16 days, p=0.419) and platelet engraftment (17 vs 14 days, p=0.442).

45-53_Babenko Figure 1. Influence of graft cryopreservation on clinical outcomes of stem cell transplantation.png

Graft-versus-host disease, mortality and survival

No differences were observed in the incidence of acute GVHD grade II-IV (39%, 95%CI 28-50% vs 37%, 95%CI 26-48% in the Cryo and control groups, respectively, p=0.8865, Fig. 1A) and grade III-IV acute GVHD (25%, 95%CI 16-36% vs 19%, 95%CI 11-29% in the Cryo and control groups, respectively, p=0.4708). Incidence of grade I GVHD (14.8% vs 13,5%, p=0.873) as well as the incidence of steroid-refractory GVHD (9.9% vs 9.9%, p=1.0) were also not different. The incidence of moderate and severe chronic GVHD was also comparable in the study groups: Cryo group, 29% (95%CI 17-42%) vs Control group, 30% (95%CI 14-48%), p=0.3918, Fig. 1B. A significantly higher non-relapse mortality was observed for patients with cryopreserved graft: 45% (95%CI 34-56%) vs 28% (95% CI 18-39%), p=0.0145, Fig. 1C. However, the incidence of relapse was reduced the Cryo group: 21% (95% CI 12-30%) vs 34% (95% CI 23-45%), p=0.0481, Fig. 1D. This bidirectional differences resulted in absence of statistically significant impact of graft thawing on overall survival (37%, 95% CI 27-48% vs 44%, 95% CI 32-55% in the Cryo Figure 2. Subgroup analysis of overall survival and control groups, respectively, p=0.2384, Fig. 1E), EFS (35%, 95% CI 24-45% vs 40%, 95% CI 29-51%, respectively, p=0.38) and GFRS (19% ,95% CI 10-28% vs 25% , 95% CI 15-26, respectively, p=0.2041, Fig. 1F). The subgroup analysis of the OS outcome revealed no differences between cryopreserved and native graft irrespective of the conditioning intensity, graft source, age of the patients, underlying disease, status of the disease and type of donor (p>0.2, Fig. 2).

Complications of transplantation

In general, toxicity of HSCT was comparable between the groups (Fig. 3), but we observed a significant increase in the incidence of acute clinically significant renal toxicity (30% vs 10%, p=0.0046). The mean maximal creatinine observed after HSCT was 143±108 vs 114±65 μmol/l in the Cryo and control groups, respectively. Borderline differences were observed in the incidence of sepsis before engraftment (24% vs 13%, p=0.0681) and severe sepsis before engraftment (17% vs 8%, p=0.0981). Although relatively high incidence of VOD (15%) for predominantly RIC regimen was observed in the Cryo group, the difference was not statistically significant.


45-53_Babenko Figure 2. Subgroup analysis of overall survival.png
45-53_Babenko Figure 3. Complications of stem cell transplantation.png

Discussion

In this well-matched cohort of patients, we have shown that the survival of patients after HSCT with cryopreserved graft is not significantly compromised. Also we have not observed any differences in the incidence of acute and chronic GVHD. These results are comparable to the ones previously reported by Medd et al. [11], despite their cohort included predominantly matched related donors and PBSC only. Despite the comparable OS levels, we observed that NRM was significantly higher in the Cryo group, which was compensated by lower relapse risk. To our knowledge, this observation hadnot been previously reported in the literature. The increment in non-relapse mortality was primary driven by higher incidence of graft failures. This corresponds to the data previously reported by M. Lioznov et al. [9]. In our study we observed increased incidence in the BM, but not in PBSC group. However, the number of graft failures in our dataset is relatively low to draw a definitive conclusion. Since primary graft failure is a multifactorial event [6] with significant impact of anti-HLA antibodies [15], other antibody types [16], microenvironment abnormalities, particularly in MDS and MPN [17], and other potential factors, this difference in graft failure should be confirmed in large registry studies. Nonetheless, the current understanding of immune mechanisms behind graft failure might partially explain the increased Figure 3. Complications of stem cell transplantation incidence of this complication after freezing the graft. The release of specific antigens during thawing, particularly from granulocytes, might trigger both the antibody-mediated and T-cell-mediated rejection [18]. The other complication leading to non-relapse mortality was the tendency to higher incidence of sepsis. It is unlikely that the mechanisms behind this observation are related to the cryopreservation of the graft. It was rather due to difference between groups. For the majority of patients in the Cryo group, the reason for freezing the graft was an unexpected infection. This indicates that this group might have been more prone to infections. In allo HSCT recipients this is usually associated by iron overload [19], and the groups were not matched by this parameter. Also the Cryo group included patients in whom the remissions were reinduced before HSCT, using high-dose cytarabine with fludarabine. This mode of chemotherapy is usually associated with relatively high incidence of bloodstream infections [20], and recurrence of septic episodes after HSCT has previously been reported [21]. The finding about reduced risk of relapse in the study group also lacks logical explanation, since the incidence of acute and chronic GVHD was not different between the groups, and it is hard to speculate about the augmentation of graft-versus-leukemia affect. Despite the groups were matched by the disease type and stage, the abovementioned mechanism of re-induction close to the start of the conditioning might play a role. Although chemotherapy and conditioning were not sequential like in certain protocols for high-risk leukemia [22], the factor of timing is likely to play a role in the observed results.

Conclusion

Despite certain differences between the groups compared and non-randomized study design, we have demonstrated that cryopreservation of allogeneic graft is a viable option in case of complications that increase the risk of HSCT, however the benefit from postponing a transplant should be weighed against the possible risk of primary graft failure. The results of the study require confirmation in the muticenter setting or in the studies with international registry data.

Acknowledgements

The authors declare no conflict of interest.

References

1. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, Dufour C, Kröger N, Kuball J, Lankester A, Montoto S, Nagler A, Snowden JA, Styczynski J, Mohty M, and EMBT. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018 Mar 14. doi: 10.1038/s41409-018-0153-1.
2. Craddock C, Hoelzer D, Komanduri KV. Current status and future clinical directions in the prevention and treatment of relapse following hematopoietic transplantation for acute myeloid and lymphoblastic leukemia. Bone Marrow Transplant. 2018 May 31. doi: 10.1038/s41409-018-0203-8.
3. He GL, Chang YJ, Xu LP, Zhang XH, Wang Y, Liu KY, Huang XJ. Impact of pre-transplant pulmonary infection developed in horizontal laminar flow unit on the outcome of subsequent allogeneic hematopoietic stem cell transplantation. J Thorac Dis. 2016;8(8):2219-2225.
4. Yamamoto W, Fujii E, Matsumoto K, Yamamoto E, Aoki J, Tanaka M, Ishigatsubo Y, Kanamori H. Prognostic value of pretransplant serum C-reactive protein in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2016;103(4):444-452.
5. Ringdén O, Barrett AJ, Zhang MJ, Loberiza FR, Bolwell BJ, Cairo MS, Gale RP, Hale GA, Litzow MR, Martino R, Russell JA, Tiberghien P, Urbano-Ispizua A, Horowitz MM. Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses. Br J Haematol. 2003;121(6):874-885.
6. Mattsson J, Ringden O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(1 Suppl 1):165-170.
7. Lasky LC, Van Buren N, Weisdorf DJ, Filipovich A, McGlave P, Kersey JH, McCullough J, Ramsay NK, Blazar BR. Successful allogeneic cryopreserved marrow transplantation. Transfusion. 1989;29(2):182-184.
8. Stockschläder M, Hassan HT, Krog C Krüger W, Löliger C, Horstman M, Altnöder M, Clausen J, Grimm J, Kabisch H, Zander A. Long-term follow-up of leukaemia patients after related cryopreserved allogeneic bone marrow transplantation. Br J Haematol. 1997;96(2):382-386.
9. Lioznov M, Dellbrügger C, Sputtek A, Fehse B, Kröger N, Zander AR. Transportation and cryopreservation may impair haematopoietic stem cell function and engraftment of allogeneic PBSCs, but not BM. Bone Marrow Transplant. 2008 Jul;42(2):121-128.
10. Frey NV, Lazarus HM, Goldstein SC. Has allogeneic stem cell cryopreservation been given the 'cold shoulder'? An analysis of the pros and cons of using frozen versus fresh stem cell products in allogeneic stem cell transplantation. Bone Marrow Transplant. 2006; 38(6):399-405.
11. Medd P, Nagra S, Hollyman D, Craddock C, Malladi R. Cryopreservation of allogeneic PBSC from related and unrelated donors is associated with delayed platelet engraftment but has no impact on survival. Bone Marrow Transplant. 2013;48(2):243-248.
12. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–828.
13. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945–956.
14. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, Maziarz RT, Antin JH, Soiffer RJ, Weisdorf DJ, Rizzo JD, Horowitz MM, Saber W. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123(23):3664-3671.
15. Ciurea SO, Cao K, Fernadez-Vina M, Kongtim P, Malki MA, Fuchs E, Luznik L, Huang XJ, Ciceri F, Locatelli F, Aversa F, Castagna L, Bacigalupo A, Martelli M, Blaise D, Handgretinger R, Roy DC, O'Donnell P, Bashey A, Lazarus HM, Ballen K, Savani BN, Mohty M, Nagler A. The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation. Bone Marrow Transplant. 2018;53(5):521-534.
16. Barge AJ, Johnson G, Witherspoon R, Torok-Storb B. Antibody-mediated marrow failure after allogeneic bone marrow transplantation. Blood. 1989;74(5):1477-1480.
17. Santamaria C, Muntión S, Rosón B, Blanco B, López-Villar O, Carrancio S, Sánchez-Guijo FM, Díez-Campelo M, Alvarez-Fernández S, Sarasquete ME, de las Rivas J, González M, San Miguel JF, Del Cañizo MC. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica. 2012;97(8):1218-1224.
18. Chrysler G, McKenna D, Schierman T, Kadidlo D, Askari S, Miller J, Clay M, McCullough J. Cellular characteristics of cord blood and cord blood transplantation. In: Broxmeyer H, editor. Cord Blood: Biology, Immunology, Banking and Clinical Transplantation. AABB; Bethesda, MD: 2004. pp. 219–258.
19. Shaheen M, Ivanova MO, Moiseev IS, Bondarchuk SV, Afanasyev BV. Impact of initial serum ferritin on early post-HSCT complications: a single-center study.Cell Ther Transplant. 2016; 5(2): 40-49.
20. Estey E, Thall P, Andreeff M, Beran M, Kantarjian H, O'Brien S, Escudier S, Robertson LE, Koller C, Kornblau S, et al. Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J Clin Oncol. 1994;12(4):671-678.
21. Hakki M, Limaye AP, Kim HW, Kirby KA, Corey L, Boeckh M. Invasive Pseudomonas aeruginosa infections: high rate of recurrence and mortality after hematopoietic cell transplantation. Bone Marrow Transplant. 2007;39(11):687-693.
22. Saure C, Schroeder T, Zohren F, Groten A, Bruns I, Czibere A, Galonska L, Kondakci M, Weigelt C, Fenk R, Germing U, Haas R, Kobbe G. Upfront allogeneic blood stem cell transplantation for patients with high-risk myelodysplastic syndrome or secondary acute myeloid leukemia using a FLAMSA-based high-dose sequential conditioning regimen. Biol Blood Marrow Transplant. 2012;18(3):466-472.

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Introduction

Hematopoietic stem cell transplantation (HSCT) is a rapidly developing method for the treatment of various malignant and non-malignant diseases [1]. However, it requires synchronization between donor preparation to donation, conditioning regimen, donation and graft-versus-host disease (GVHD) prophylaxis. Thus situations occur, like unexpected infection in a recipient or fulminate relapse of the underling disease, when there is a dilemma whether to transplant a patient with these unexpected conditions or postpone the transplant and administer appropriate treatment . It is well known that grafting in relapse is the worst predictive factor for long-term survival [2]. On the other hand, active infections at the start of the conditioning also impact the outcome adversely [3, 4]. Thus in the majority of cases like these the decision is made to postpone the HSCT, however this is not possible in certain situations with unrelated donors, and also when a related donor has started the stimulation with granulocyte-colony stimulating factor. In these case the graft is usually cryopreserved before infusion. The other situation leading to cryopreservation is the poor graft cellularity collected from a donor. It is well known that low number of CD3 and CD34-positive cells in the graft significantly affect the incidence of primary graft failure and poor graft function after HSCT, which are associated with significant non-relapse mortality [5, 6]. Unlike the related setting when CD34-selected boost could be collected after unrelated transplantation this might be difficult due to donor decision or logistics. Thus several centers prefer to receive and access the graft quality before the start of the conditioning, and then transfuse the cryopreserved graft. Despite the safe use of freezing stage during autologous HSCT procedure, there is a lack of large comparative studies evaluating the effects of graft cryopreservation on the outcome of allogeneic HSCT. Despite the evidence that engraftment of the cryopreserved bone marrow is comparable [7, 8], there are reports that the risk of graft failure is increased with frozen peripheral blood stem cell (PBSC) graft [9], or the risk of the GVHD might be altered after thawing [10, 11]. We conducted a single-institution pair-matched retrospective study to evaluate the impact of graft cryopreservation on the outcomes and toxicity of allogeneic stem cell transplantation.

Patients and Methods

Patients and transplantation procedures

162 patients transplanted in 2006-2017 at the I. Pavlov First St. Petersburg State Medical University were included into the study. All patients signed informed consent for the use of their medical data for research purposes, according to the Helsinki Declaration. 81 patients received the cryopreserved graft. The graft was stored with 10% DMSO at -180⁰C until the day of the transplant. The reasons for freezing were: infection before the start of the conditioning (38.3%), relapse of the underlying disease (32.2%), unavailability of a related donor at the time of HSCT (17.2%), availability of the cryopreserved graft after the first donation due to restriction of CD34 cell count (11.1%), pregnancy before the conditioning (1.2%). The study group (Cryo group) comprised predominantly adult patients with unrelated donors, leukemia as an underlying disease and reduced intensity conditioning. The study group was represented by high-risk disease with 42% of patients having DRI 3 or 4 and active disease in 40% of patients. The control group (native group) comprised 81 pairmatched patients. The criteria for matching were type of the donor, graft source (bone marrow or PBSC), diagnosis, stage of the disease at the time of the performed HSCT, intensity of the conditioning, age ±5 years, CD34 count ± 1x106/kg and graft versus host disease prophylaxis. The significance of the matching factors was in the order listed above. The resulting groups were well matched and were not significantly different in any of the patient- or transplantation-related factors (Table 1). Median follow up was 25 months, thus the two year outcomes were used in the study.

Transplantation procedures

Myeloablative conditioning (MAC) was performed with oral busulfan 16 mg/kg and cyclophosphamide 100-120 mg/kg. Reduced intensity conditioning (RIC) was performed with fludarabine 180 mg/m2 and busulfan 8-10 mg/kg. Patients were assigned to RIC if they were 40 years or older, had hematopoietic cell transplantation-specific comorbidity index (HCT-CI)≥2, exbited, at least, grade 3 hepatic toxicity during previous therapy, or uncontrolled infection at the start of the conditioning. Patients subjected to second HSCT also received RIC. GVHD prophylaxis in the post-transplantation cyclophosphamide (PTCy) group consisted of cyclophosphamide (50 mg/kg) administered at days +3, +4, tacrolimus 0.03 mg/kg and mycophenolate mofetil (MMF) 30-45 mg/kg from day +5. The classical GVHD prophylaxis included either tacrolimus with target concentrations of 5-15 ng/ml, or cyclosporine A with target concentrations of 150-350 ng/ml from day -1. As second agents in the prophylaxis regimen we used short-course methotrexate 10-15 mg/m2 at days +1, +3, +6 or mycophenolate mofetil (MMF) 30 mg/kg from day -1 to day +30.

Clinical definitions

Time to disease relapse, acute GVHD (aGVHD), moderate to severe chronic GVHD (cGVHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GVHD-relapse free survival (GRFS) were defined as the time from transplantation to the event. All these parameters were calculated for the two-year interval. Incidence of aGVHD was calculated at 125 days after HSCT, and the time frame for the other outcomes was two years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grades III-IV acute GVHD or systemic therapy-requiring chronic GVHD. The Consensus Conference criteria and NIH criteria were used for aGVHD and cGVHD grading, respectively [12,13]. Primary graft failure was defined as the complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraftment was calculated as time from HSCT to unsupported neutrophil count > 500/ul and white blood cell count >1000/ul for 3 consecutive days.
Toxicity was assessed with CTCAE ver. 4.03. Sepsis in the study was defined as systemic inflammatory reaction with microbiologically confirmed bacteremia. The risk of the disease was accessed with disease risk index (DRI) by Armand et al. [14].

45-53_Babenko Table 1. Characteristics of patients and transplantations..png

AML=acute myeloid leukeina; ALL=acute lymphoblastic leukemia; MDS=myelodysplastic syndrome; MPN=myeloprolipherative neoplasm; CML=chronic myeloid leukemia; AA=aplastic anemia; BM=bone marrow; PBSC=peripheral blood stem cells; RIC=reduced-intensity conditioning; MAC=myeloablative conditioning; PTCy=post-transplantation cyclophosphamide.

Statistical Analysis

Comparison between the groups was performed by Chisquare test. The comparison of the quantitative parameters between groups were preformed with log-normalized t-test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGVHD, cGVHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate analysis was not performed, because patients were matched by the majority of significant variables. The subgroup analysis was performed for OS. Heterogeneities between the hazard ratios in the subgroup analysis were tested for significance using the Cochran’s Q test, with df degrees of freedom. Incidence and severity of complications were compared using Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

Engraftment

There was a trend towards higher incidence of graft failure in the Cryo group (15.7% vs 6.3%, p=0.0588). When the graft source was analyzed separately, there was a significant increase in graft failure for BM (26% vs 0%, p=0.025), but no difference for peripheral blood (12% vs 9%, p=0.483). Among patients who engrafted there was no difference for the time of neutrophil engraftment (median 19 vs 18 days, p=0.345 in the Cryo and control groups, respectively), white blood cell recovery (18 vs 16 days, p=0.419) and platelet engraftment (17 vs 14 days, p=0.442).

45-53_Babenko Figure 1. Influence of graft cryopreservation on clinical outcomes of stem cell transplantation.png

Graft-versus-host disease, mortality and survival

No differences were observed in the incidence of acute GVHD grade II-IV (39%, 95%CI 28-50% vs 37%, 95%CI 26-48% in the Cryo and control groups, respectively, p=0.8865, Fig. 1A) and grade III-IV acute GVHD (25%, 95%CI 16-36% vs 19%, 95%CI 11-29% in the Cryo and control groups, respectively, p=0.4708). Incidence of grade I GVHD (14.8% vs 13,5%, p=0.873) as well as the incidence of steroid-refractory GVHD (9.9% vs 9.9%, p=1.0) were also not different. The incidence of moderate and severe chronic GVHD was also comparable in the study groups: Cryo group, 29% (95%CI 17-42%) vs Control group, 30% (95%CI 14-48%), p=0.3918, Fig. 1B. A significantly higher non-relapse mortality was observed for patients with cryopreserved graft: 45% (95%CI 34-56%) vs 28% (95% CI 18-39%), p=0.0145, Fig. 1C. However, the incidence of relapse was reduced the Cryo group: 21% (95% CI 12-30%) vs 34% (95% CI 23-45%), p=0.0481, Fig. 1D. This bidirectional differences resulted in absence of statistically significant impact of graft thawing on overall survival (37%, 95% CI 27-48% vs 44%, 95% CI 32-55% in the Cryo Figure 2. Subgroup analysis of overall survival and control groups, respectively, p=0.2384, Fig. 1E), EFS (35%, 95% CI 24-45% vs 40%, 95% CI 29-51%, respectively, p=0.38) and GFRS (19% ,95% CI 10-28% vs 25% , 95% CI 15-26, respectively, p=0.2041, Fig. 1F). The subgroup analysis of the OS outcome revealed no differences between cryopreserved and native graft irrespective of the conditioning intensity, graft source, age of the patients, underlying disease, status of the disease and type of donor (p>0.2, Fig. 2).

Complications of transplantation

In general, toxicity of HSCT was comparable between the groups (Fig. 3), but we observed a significant increase in the incidence of acute clinically significant renal toxicity (30% vs 10%, p=0.0046). The mean maximal creatinine observed after HSCT was 143±108 vs 114±65 μmol/l in the Cryo and control groups, respectively. Borderline differences were observed in the incidence of sepsis before engraftment (24% vs 13%, p=0.0681) and severe sepsis before engraftment (17% vs 8%, p=0.0981). Although relatively high incidence of VOD (15%) for predominantly RIC regimen was observed in the Cryo group, the difference was not statistically significant.


45-53_Babenko Figure 2. Subgroup analysis of overall survival.png
45-53_Babenko Figure 3. Complications of stem cell transplantation.png

Discussion

In this well-matched cohort of patients, we have shown that the survival of patients after HSCT with cryopreserved graft is not significantly compromised. Also we have not observed any differences in the incidence of acute and chronic GVHD. These results are comparable to the ones previously reported by Medd et al. [11], despite their cohort included predominantly matched related donors and PBSC only. Despite the comparable OS levels, we observed that NRM was significantly higher in the Cryo group, which was compensated by lower relapse risk. To our knowledge, this observation hadnot been previously reported in the literature. The increment in non-relapse mortality was primary driven by higher incidence of graft failures. This corresponds to the data previously reported by M. Lioznov et al. [9]. In our study we observed increased incidence in the BM, but not in PBSC group. However, the number of graft failures in our dataset is relatively low to draw a definitive conclusion. Since primary graft failure is a multifactorial event [6] with significant impact of anti-HLA antibodies [15], other antibody types [16], microenvironment abnormalities, particularly in MDS and MPN [17], and other potential factors, this difference in graft failure should be confirmed in large registry studies. Nonetheless, the current understanding of immune mechanisms behind graft failure might partially explain the increased Figure 3. Complications of stem cell transplantation incidence of this complication after freezing the graft. The release of specific antigens during thawing, particularly from granulocytes, might trigger both the antibody-mediated and T-cell-mediated rejection [18]. The other complication leading to non-relapse mortality was the tendency to higher incidence of sepsis. It is unlikely that the mechanisms behind this observation are related to the cryopreservation of the graft. It was rather due to difference between groups. For the majority of patients in the Cryo group, the reason for freezing the graft was an unexpected infection. This indicates that this group might have been more prone to infections. In allo HSCT recipients this is usually associated by iron overload [19], and the groups were not matched by this parameter. Also the Cryo group included patients in whom the remissions were reinduced before HSCT, using high-dose cytarabine with fludarabine. This mode of chemotherapy is usually associated with relatively high incidence of bloodstream infections [20], and recurrence of septic episodes after HSCT has previously been reported [21]. The finding about reduced risk of relapse in the study group also lacks logical explanation, since the incidence of acute and chronic GVHD was not different between the groups, and it is hard to speculate about the augmentation of graft-versus-leukemia affect. Despite the groups were matched by the disease type and stage, the abovementioned mechanism of re-induction close to the start of the conditioning might play a role. Although chemotherapy and conditioning were not sequential like in certain protocols for high-risk leukemia [22], the factor of timing is likely to play a role in the observed results.

Conclusion

Despite certain differences between the groups compared and non-randomized study design, we have demonstrated that cryopreservation of allogeneic graft is a viable option in case of complications that increase the risk of HSCT, however the benefit from postponing a transplant should be weighed against the possible risk of primary graft failure. The results of the study require confirmation in the muticenter setting or in the studies with international registry data.

Acknowledgements

The authors declare no conflict of interest.

References

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Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». 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Бабенко, Иван С. Моисеев, Михаил М. Канунников, Александр Л. Алянский, Дмитрий Э. Певцов, Анастасия В. Фролова, Анна А. Осипова, Татьяна А. Быкова, Олеся В. Паина, Елена И. Дарская, Людмила С. Зубаровская, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(478) "Елена В. Бабенко, Иван С. Моисеев, Михаил М. Канунников, Александр Л. Алянский, Дмитрий Э. Певцов, Анастасия В. Фролова, Анна А. Осипова, Татьяна А. Быкова, Олеся В. Паина, Елена И. Дарская, Людмила С. Зубаровская, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20218" ["VALUE"]=> array(2) { ["TEXT"]=> string(345) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета, Санкт-Петербург, Российская Федерация" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(345) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета, Санкт-Петербург, Российская Федерация" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20219" ["VALUE"]=> array(2) { ["TEXT"]=> string(4474) "<p style="text-align: justify;"> Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4408) "

Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.

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Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(278) "Elena V. Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. 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We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2062) "

Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.

Keywords

Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.

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Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(278) "Elena V. Babenko, Ivan S. Moiseev, Mikhail M. Kanunnikov, Alexandr L. Alyanskiy, Dmitrii E. Pevcov, Anastasia V. Frolova, Anna A. Osipova, Tatyana A. Bykova, Olesya V. Paina, Elena I. Darskaya, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(278) "Elena V. Babenko, Ivan S. Moiseev, Mikhail M. 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We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). 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Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2062) "

Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.

Keywords

Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.

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Cryopreservation (Cryo) of a graft is a standard procedure in autologous hematopoietic stem cell transplantation (HSCT), however there is a lack of studies on the safety and efficacy of allogeneic HSCT with cryopreserved graft. We have conducted a pair-matched study in 81 patients transplanted with frozen graft and compared them to 81 control patients with fresh cell graft. The groups were matched by age, disease type and stage, conditioning, donor type, graft-versus-host disease (GVHD) prophylaxis and number of CD34-postive cells in the graft. The study group comprised 83% unrelated HSCTs, 72% of peripheral blood stem cell recipients and 40% of salvage patients. No differences were observed between the Cryo and control group in the incidence of grade II-IV acute GVHD (39% vs 37%, p=0.89), moderate and severe chronic GVHD (29% vs 30%, p=0.39), overall survival (37% vs 44%, p=0.24), event-free survival (35% vs 40%, p=0.38) and GVHD-relapse-free survival (19% vs 25% , p=0.20), respectively. However, non-relapse mortality (NRM) was significantly higher in the Cryo group (45% vs 28%, p=0.015), which was compensated by reduced relapse incidence (21% vs 34%, p=0.048). The leading factor for NRM were trends to higher incidence of primary graft failure (15,7% vs 6.3%, p=0.059) and sepsis during aplasia (24% vs 13%, p=0.068). No differences were observed in the time to neutrophil and platelet engraftment. Complications of HSCT were comparable between groups except higher incidence of grade II-IV nephrotoxicity in the Cryo group (30% vs 10%, p=0.0046). In conclusion, the study demonstrated that the results of allogeneic HSCT with cryopreserved graft are comparable to native graft ones. Trends to higher primary graft failure, infectious complications and NRM should be confirmed in the multicenter studies.

Keywords

Hematopoietic stem cell transplantation, allogeneic, cryopreservation, freezing, primary graft failure.

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Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4408) "

Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.

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Криоконсервация (Крио) трансплантата является неотъемлемой частью процедуры аутологичной трансплантации гемопоэтических стволовых клеток (ТГСК), тем не менее, в литературе крайне мало данных о безопасности и эффективности аллогенной ТГСК после стадии замораживания. Для определения клинического значения криоконсервации трансплантата было проведено исследование методом парных сравнений между 81 пациентом, получившим инфузию замороженного аллогенного трансплантата, и 81 пациентом, получившим инфузию нативного трансплантата. Критериями парного подбора были вариант и стадия заболевания, тип донора, источник трансплантата, возраст пациента, интенсивность кондиционирования, профилактика реакции «трансплантат против хозяина» (РТПХ) и количество CD34-положительных клеток в трансплантате. В исследуемой группе 83% выполнена неродственная ТГСК, 72% получили инфузию стволовых клеток периферической крови и 40% относились к группе «спасения». При сравнении группы Крио и контрольной группы не было выявлено различий в частоте острой РТПХ II-IV степени (39% vs 37%, p=0,89), средней и тяжелой хронической РТПХ (29% vs 30%, p=0,39), общей выживаемости (37% vs 44%, p=0,24), бессобытийной выживаемости (35% vs 40%, p=0,38) и выживаемости без рецидива и РТПХ (19% vs 25% , p=0,20), соответственно. Тем не менее, трансплантационная летальность (ТЛ) была значимо выше в группе Крио (45% vs 28%, p=0,015), что частично компенсировалось снижением вероятности рецидива (21% vs 34%, p=0,048). Основной причиной повышения ТЛ был тренд к большей частоте первичного неприживления трансплантата (15,7% vs 6.3%, p=0,059) и сепсиса в период аплазии кроветворения (24% vs 13%, p=0,068). Различий в скорости приживления нейтрофилов и тромбоцитов выявлено не было. Частота осложнений трансплантации была сравнима в двух группах, за исключением повышения вероятности развития нефротоксичности II-IV степени в группе криоконсервации (30% vs 10%, p=0,0046). В заключение можно сказать, что исследование показало сравнимые результаты при использовании замороженного и нативного трансплантата. Выявленное повышение частоты первичного неприживления трансплантата, сепсиса и трансплантационной летальности требуют подтверждения в многоцентровых исследованиях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, криоконсервирование трансплантата, замораживание трансплантата, первичное неприживление трансплантата.

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Introduction

The t(3;21)(q26.2;q22) translocation, as well as trisomy 13 are rare but recurrent chromosome abnormalities which, to our best knowledge, have not yet encountered simultaneously in MDS/AML patients and, hence, have not been treated by means of allo-HSCT. The t(3;21) translocation is not rarely found in patients with therapy-related MDS/AML [1-7]. This disorder is, generally, characterized by aggressive clinical course [8, 9] and short event-free survival [10]. The t(3;21)(q26.2;q22) translocation results into a fusion between the RUNT domain of RUNX1, and EVI1 gene [11]. The EVI1 gene is known to encode a dual domain of the zinc-finger transcription factor which exhibits DNA binding activity acting together with a histone methyltransferase (SET) domain [12-14]. This molecule promotes self-renewal in hematopoietic stem cells. The t(3;21) translocation has been reported to occur in approximately 1% of AML or MDS cases [15]. Its clinical significance in MDS has been poorly determined, though poor prognosis appears to be proven in CML patients with t(3;21) [16-18]. It has been recently shown that t-MDS and t-AML positive for t(3;21) (q26.2;q22) are resistant both to cytostatic chemotherapy, and to allo-HSCT treatment [19]. Moreover, according to multicentric cytogenetic studies, trisomy 13 was observed in 0.2% patients, detectable as an single aberration, or combined with an additional abnormality [20]. A sufficient gender imbalance was reported for this condition (21 males of 27 cases). The median age of patients was 73 years. Isolated trisomy 13 was revealed in 96% of the cases. Of note, these patients with higher-risk MDS did not respond to therapy with hypomethylating agents. In general, trisomy 13 rarely occurs in MDS (0.2 to 0.8% of total), mostly as an isolated event, being something more frequent in AML (1-2%). Most of these patients are males over 70 years old. Typically, MDS proceeds with blast excess and moderate pancytopenia having poor prognosis, with median survival ranging between <6 months and 1 year. The patients with AML and trisomy 13 do not respond to standard intensive chemotherapy. For instance, treatment with hypomethylating agents is inefficient in this MDS type, though high-dose lenolidomide could be an option here. It should be also kept in mind, that trisomy 13 is associated with overexpression of FLT3 gene located at the extra chromosome. Besides, a close association between trisomy 13 and mutations of RUNX1 have been recently found [21, 22].

Materials and methods

Cytogenetic and molecular techniques

Serial cytogenetic investigations were carried out by a standard G-banding technique which has been recently published [23]. Identification of chromosomes and chromosomal aberrations was carried out according to International System Human Cytogenetic Nomenclature (ISCN) [24]. A serial molecular biological testing of donor chimerism was done on peripheral blood or bone marrow samples at the time of hematologic engraftment, as well as every 2 weeks between 1 and 3 months and every month between 3 and 12 months after transplantation were obtained and processed. Shortly, the evaluation was done by means of PCR-based Chimerix FA Kit (Inogene, Russia), by analyzing selected polymorphic short tandem repeat (STR) loci: D11S488, HUMVWFA31, D13S317, D8S639, D19S246, D4S2366, D12S1064, D16S539 and the sex determination marker Amelogenin. The amplified sample was analyzed by capillary electrophoresis using an ABI Prism 3500xl Genetic Analyser (Applied Biosystems). Quantification of the mixed chimerism (calculated as percent of recipient DNA) was performed by analyzing the proportion of the fluorescent peak areas corresponding to donor and patient genotypes.

Clinical case description

The patient was a 22-year-old male, initially presented in August 2006 with complaints for moderate fatigue and fever (37.4°C). Peripheral blood examination showed pancytopenia. Bone marrow aspirate was hypocellular with features of aplastic anemia. Cyclosporin A (CSA) was given, but it was taken by the patient only for two weeks due to hepatic discomfort. During the following three years, the patient did not visit a hematologist, and his condition was stable. In January of 2009 he noted exacerbation of fatigue and skin hemorrhages which required hospitalization to the Hematology Department. Peripheral blood counts were as follows: Hb, 55 g/L; WBC, 1.5x109/L; platelets, 4x109/L. The bone marrow aspirate was hypocellular, contained 15.5% blasts with diffuse-type periodic acid Schiff (PAS) staining, and 30% ring sideroblasts, whereas most neutrophilic cells were peroxidase-deficient. Immunophenotyping of the blast cells showed positivity for CD34, CD13, CD33, and HLA-DRA. The results of serial cytogenetic investigations and chimerism testing using molecular biology approaches are presented in Table 1.

64-69_Mamaev Table 1.png

64-69_Mamaev Figure 1.png

Figure 1. Karyogram of bone marrow cell 47, XY, t(3;21) (q26;q22),+13 from patient with primary myelodysplastic syndrome (RAEB-II)

Initial marrow karyotype was as following: 47, XY, t(3;21) (q26.2;q22),+13, (Fig. 1) with involvement into arrangement EVI1 gene (Fig. 2), whereas 10% metaphases had normal chromosome complement. Meanwhile, a standard molecular investigation with primers for common chromosome translocations did not show any oncogene anomalies. Therefore, a diagnosis of MDS RAEB -II IPSS 3.0 was established. Since the patient was transfusion-dependent for a long time, his ferritine level reached 2500 mg/mm3.

64-69_Mamaev Figure 2.png

Figure 2. Fluorescence in situ hybridization (FISH) with BreakApart EVI1 probe (CytoCell, UK) showing one normal EVI1 gene (one fusion yellow signal) and one abnormal EVI1 gene (one green and one red split signals on interphase cells) in the patient with translocation t(3;21)(q26.2;q22) RUNX1/EVI1

64-69_Mamaev Figure 3.png

Figure 3. Karyotype of donor’s bone marrow cell 46,XY from a patient with primary myelodysplastic syndrome after allogeneic bone marrow transplantation prepared during a short-term hematological and cytogenetic remission

64-69_Mamaev Figure 4.png

Figure 4. Schematic presentation of clinical course in a patient with primary myelodysplastic syndrome with karyotype 47,XY,t(3;21)(q26.2;q22),+13 associated with resistance to standard chemotherapy, hypomethylating agents and allo-HSCT

Before bone marrow transplantation, the patient obtained one 5-day course of Dacogen (Decitabine) as demethylating therapy. It did not change common blood parameters, but allowed to reduce his transfusion dependence. Since the patient had an HLA-DQB1-mismatched related donor (Table 1), allo-HSCT was considered. The patient was enrolled into the RIC/MAC study protocol, and randomized to RIC branch (Busulfan + Fludarabine – 800 and 300 mg, respectively). Graft-versus-host-disease (GvHD) prophylaxis included CSA and Methotrexate (MTX). Following the allo-HSCT, stem cell engraftment was detected on day +15, when mixed chimerism was 45-55%. By this time, bone marrow contained only 2.4% of blasts, and the previously detected chromosomal abnormalities were not found (Fig. 3, Table 1). GvHD symptoms were absent, but a cytogenetic relapse was documented two weeks later (on day +29), due to appearance of the marker chromosomal aberrations and decreasing donor chimerism which could be caused by small number of CD34+ stem cells in the graft. Therefore, cyclosporine A was stopped on day +38, and, a week later, a donor lymphocyte infusion (DLI) was performed at a dose of 5.0х107 cells/kg, however, without any clinical effect. The graft rejection was diagnosed on day D+50 (Fig. 4). By that time, the patient had hemoglobin levels of 57 g/L; WBC, 1.7x109/L; and platelets, l3.0x109/L. Bone marrow aspirate was hypocellular with 3.4% blasts, and the donor chimerism faded away (<5%). Because of allo-BMT failure, a second allo-HSCT was administered, using peripheral blood stem cells from the same donor. It was performed after RIC preparative regimen containing Fludarabine 350 mg, Thiotepa 960 mg, and Campath 40 mg. GvHD prophylaxis included Tacrolymus and CellCept (Mycophenolate Mofetyl). Engraftment was registered since day D+10. Two days later, acute GvHD of gut and skin (grade I) was diagnosed. Steroids were added to the treatment schedule which resulted into a significant improvement of GvHD. Peripheral blood findings on the day +16 after 2nd transplant were as follows: Hb, 92.0 g/L; WBC, 4.3x109/L, and platelets, 35.0x109/L. Bone marrow aspirate was hypocellular without blast excess, and full donor chimerism was achieved. Cytogenetic study has shown a repeated karyotype normalization. Due to high risk of relapse, another DLI procedure was performed. Despite the immunotherapy, a new cytogenetic relapse, along with reduced donor chimerism levels, was diagnosed in July 2010. An attempt to achieve another remission with hypomethylating agents (5 courses of Dacogen) was not successful. A repeated cytogenetic relapse has been diagnosed in December 2010, causing his death at the BMT Center two months later.

Discussion

To our knowledge, it is the first clinical description of primary MDS with t(3;21)(q26.2;q22), combined with trisomy 13, and treated by two subsequent allo-HSCTs from a partially HLA-mismatched sibling (brother). The first earliest relapse occurred on the day 29, which could be, in part, explained by low cellularity of transplant. Since a second transplant was required, a reduced-intensity conditioning was chosen again, but peripheral blood stem cells were used for the 2nd transplant. The second engraftment was longer. A new cytological relapse was diagnosed 2 months later as evidenced by increased blast counts in bone marrow up to 12% accompanied by recurrence of the above cytogenetic aberrations, as well as decreasing donor chimerism. Moreover, the patient did not respond to hypomethylating agents (5 courses of Dacogen), aiming to correct the hematopoietic disorder. Recent studies have shown that distinct portions of RUNX1 gene may fuse in variable manner to MDS1 and EVI1 genes located within the 3q26 region. On the other hand, these different fusion products are capable of blocking myeloid differentiation interfering with normal transcriptional regulatory functions of RUNX1 [14]. As a result, our MDS case with combined t(3;21) chromosome anomalies and trisomy 13, showing poor clinical prognosis, appears to be related to imbalance of GATA, ERG, MEIS1, HOXA9 and FLT3 genes at the stem cell level which could be responsible for leukemia cells resistance to both chemotherapy and allo-HSCT.

Acknowledgements

The authors are grateful to colleagues for their excellent support.

Conflict of interest

No conflicts of interests are declared.

References

1. Loke J, Assl SA, Imperato MR, Ptasinska A, Cauchy P, Grabovska Y, Soria NM, Raghavan M, Delwel HR, Cockerill PN, Heidenreich O, Bonifer C. RUNX1-EVI1 differentially reprogram the chromatin landscape in t(8;21) and t(3;21) AML. Cell Reports. 2017;19(8):1654-1668.
2. Rubin CM, Larson RA, Anastasi J, Winter JN, Thangavelu M, Vardiman JW, Rowley JD, Le Beau MM. t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood. 1990; 76(12):2594-2598.
3. Pedersen-Bjergaard J, Philip P. Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasias and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II. Blood. 1991; 78(4):1147-1148.
4. Pedersen-Bjergaard J, Johansson B, Philip P. Translocation (3;21)(q26;q22) in therapy-related myelodysplasias following drugs targeting DNA-topoisomerase II combined with alkylating agents, and in myeloproliferative disorders undergoing spontaneous leukemic transformation. Cancer Genet Cytogenet. 1994; 76:50-55.
5. Schneider NR, Bowman WP, Frenkel EP. Translocation (3;21)(q26;q22) in secondary leukemia. Ann Génét 1991; 34(3-4):256-263.
6. Miyazaki H, Ino T, Sobue R, Kojima H, Wakita M, Nomura T, Tuzuki M, Hirano M. Translocation (3;21)(q26;q22) in treatment-related acute leukemia secondary to acute promyelocytic leukemia. Cancer Genet Cytogenet 1994; 74(2):84-86.
7. Tanaka R, Oshikawa G, Akiyama H, Ishida S, Nagao T, Yamamoto M, Miura O. Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low-dose Methotrexate therapy for rheumatoid arthritis and expressing two AML/MDS1/EVI1 fusion proteins. A case report. Oncology Letters. 2017;14(1):97-102.
8. Yin CC, Cortes J, Barkoh B, Hayes K, Kantarjian H, Jones D. t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy. Cancer. 2006; 106(8):1730-1738.
9. Park TS, Choi JR, Yoon SH, Song J, Kim J, Kim SJ, Kwon O, Min YH. Acute promyelocytic leukemia relapsing as secondary acute myelogenous leukemia with translocation t(3;21)(q26;q22) and RUNX1-MDS1-EVI1 fusion transcript. Cancer Genet Cytogenet 2008; 187(2):61-73.
10. Lugthart S, Groschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Bergde Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Kohne CH, Pfeundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Dohner K, Lowenber B, Dohner H. Clinical,
molecular, and prognostic significance of WHO type inv(3) (q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol. 2010; 28(24):3890-3898.
11. Nucifora G, Begy CR, Kobayashi H, Roulston D, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle JN, Rowley JD. Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocation. Proc Natl Acad Sci USA. 1994; 91(9):4004-4008.
12. Morishita K, Suzukawa K, Taki T, Ihle JN, Yokota J. EVI- 1 zinc finger protein works as a transcriptional activator via binding to a consensus sequence of GACAAGATAAGATAAN1-28 CTCATCTTC. Oncogene. 1995; 10(10):1961-1967.
13. Hirai H, Ogawa S, Kurokawa M, Yazaki Y, Mitani K. Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22). Genes Chromosomes Cancer. 1999; 26(1):92-96.
14. Tokita K, Maki K, Mitani K. RUNX1/EVI1, which blocks myeloid differentiation, inhibits CCAAT-enhancer binding protein α function. Cancer Sci. 2007; 98(11):1752-1757. 15. Secker-Walker L, Mehta A, Bain B. Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study. Br J Haematol. 1995; 91(2):490-501.
16. Rubin CM, Larson RA, Bitter MA, Carrino JJ, Le Beau MM, Diaz MO, Rowley JD. Association of chromosomal 3;21 translocation with the blast phase of chronic myelogenous leukemia. Blood 1987; 70(5):1338-1342 .
17. Coyle T, Najfeld V. Translocation (3;21) in Philadelphia chromosome-positive chronic myelogenous leukemia prior to the onset of blast crisis. Am J Hematol. 1988; 27(1):56-59.
18. Phan CL, Megat Baharuddin PJ, Chin LP, Zakaria Z, Yegappan S, Sathar J, Tan SM, Purushothaman V, Chang KM. Amplification of BCR-ABL and t(3;21) in a patient with blast crisis of chronic myelogenous leukemia. Cancer Genet Cytogenet 2008; 180(1):60-64.
19. Testoni N, Borsaru G, Martinelli G, Carboni C, Ruggeri D, Ottaviani E, Pelliconi S, Ricci P, Pastano R, Visani G, Zaccaria A, Tura S. 3q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features. Haematologica 1999; 84(8):690-694.
20. Bacher U, Schanz J, Braulke F, Haase D. Rare cytogenetic abnormalities in myelodysplastic syndromes. Mediterr J Hematol Infect Dis 2015; 7(1): e2015034, DOI: http://dx.doi.org/10.4084/MJHID.2015.034.
21. Dicker F, Haferlach C, Kern W, Haferlach T, Schnittger S. Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood 2007; 110(4):1308-1316.
22. Silva FPG, Lind A, Brouwer-Mandema G, Valk PJ, Giphart-Gassler M. Trisomy 13 correlates with RUNX1 mutation
and increased FLT3 expression in AML-M0 patients. Haematologica 2007; 92(8):1123-1126.
23. Gindina T, Mamaev N, Barkhatov I, Solomonova I, Semenova E, Zubarovskaya L, Morozova E, Rudnitskaya Yu, Popva M, Alexeev S, Uspenskaya O, Bondarenko S, Afanasyev B. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantation. Ther Arkhiv 2012; 84(8):61-66 (In Russian).
24. Schaffer L., McGovan-Jordan J., Schmid M. ISCN. An international System for Human Cytogenetic Nomenclature. S. Karger, Basel. Switzerland, 2013, p.140.

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Introduction

The t(3;21)(q26.2;q22) translocation, as well as trisomy 13 are rare but recurrent chromosome abnormalities which, to our best knowledge, have not yet encountered simultaneously in MDS/AML patients and, hence, have not been treated by means of allo-HSCT. The t(3;21) translocation is not rarely found in patients with therapy-related MDS/AML [1-7]. This disorder is, generally, characterized by aggressive clinical course [8, 9] and short event-free survival [10]. The t(3;21)(q26.2;q22) translocation results into a fusion between the RUNT domain of RUNX1, and EVI1 gene [11]. The EVI1 gene is known to encode a dual domain of the zinc-finger transcription factor which exhibits DNA binding activity acting together with a histone methyltransferase (SET) domain [12-14]. This molecule promotes self-renewal in hematopoietic stem cells. The t(3;21) translocation has been reported to occur in approximately 1% of AML or MDS cases [15]. Its clinical significance in MDS has been poorly determined, though poor prognosis appears to be proven in CML patients with t(3;21) [16-18]. It has been recently shown that t-MDS and t-AML positive for t(3;21) (q26.2;q22) are resistant both to cytostatic chemotherapy, and to allo-HSCT treatment [19]. Moreover, according to multicentric cytogenetic studies, trisomy 13 was observed in 0.2% patients, detectable as an single aberration, or combined with an additional abnormality [20]. A sufficient gender imbalance was reported for this condition (21 males of 27 cases). The median age of patients was 73 years. Isolated trisomy 13 was revealed in 96% of the cases. Of note, these patients with higher-risk MDS did not respond to therapy with hypomethylating agents. In general, trisomy 13 rarely occurs in MDS (0.2 to 0.8% of total), mostly as an isolated event, being something more frequent in AML (1-2%). Most of these patients are males over 70 years old. Typically, MDS proceeds with blast excess and moderate pancytopenia having poor prognosis, with median survival ranging between <6 months and 1 year. The patients with AML and trisomy 13 do not respond to standard intensive chemotherapy. For instance, treatment with hypomethylating agents is inefficient in this MDS type, though high-dose lenolidomide could be an option here. It should be also kept in mind, that trisomy 13 is associated with overexpression of FLT3 gene located at the extra chromosome. Besides, a close association between trisomy 13 and mutations of RUNX1 have been recently found [21, 22].

Materials and methods

Cytogenetic and molecular techniques

Serial cytogenetic investigations were carried out by a standard G-banding technique which has been recently published [23]. Identification of chromosomes and chromosomal aberrations was carried out according to International System Human Cytogenetic Nomenclature (ISCN) [24]. A serial molecular biological testing of donor chimerism was done on peripheral blood or bone marrow samples at the time of hematologic engraftment, as well as every 2 weeks between 1 and 3 months and every month between 3 and 12 months after transplantation were obtained and processed. Shortly, the evaluation was done by means of PCR-based Chimerix FA Kit (Inogene, Russia), by analyzing selected polymorphic short tandem repeat (STR) loci: D11S488, HUMVWFA31, D13S317, D8S639, D19S246, D4S2366, D12S1064, D16S539 and the sex determination marker Amelogenin. The amplified sample was analyzed by capillary electrophoresis using an ABI Prism 3500xl Genetic Analyser (Applied Biosystems). Quantification of the mixed chimerism (calculated as percent of recipient DNA) was performed by analyzing the proportion of the fluorescent peak areas corresponding to donor and patient genotypes.

Clinical case description

The patient was a 22-year-old male, initially presented in August 2006 with complaints for moderate fatigue and fever (37.4°C). Peripheral blood examination showed pancytopenia. Bone marrow aspirate was hypocellular with features of aplastic anemia. Cyclosporin A (CSA) was given, but it was taken by the patient only for two weeks due to hepatic discomfort. During the following three years, the patient did not visit a hematologist, and his condition was stable. In January of 2009 he noted exacerbation of fatigue and skin hemorrhages which required hospitalization to the Hematology Department. Peripheral blood counts were as follows: Hb, 55 g/L; WBC, 1.5x109/L; platelets, 4x109/L. The bone marrow aspirate was hypocellular, contained 15.5% blasts with diffuse-type periodic acid Schiff (PAS) staining, and 30% ring sideroblasts, whereas most neutrophilic cells were peroxidase-deficient. Immunophenotyping of the blast cells showed positivity for CD34, CD13, CD33, and HLA-DRA. The results of serial cytogenetic investigations and chimerism testing using molecular biology approaches are presented in Table 1.

64-69_Mamaev Table 1.png

64-69_Mamaev Figure 1.png

Figure 1. Karyogram of bone marrow cell 47, XY, t(3;21) (q26;q22),+13 from patient with primary myelodysplastic syndrome (RAEB-II)

Initial marrow karyotype was as following: 47, XY, t(3;21) (q26.2;q22),+13, (Fig. 1) with involvement into arrangement EVI1 gene (Fig. 2), whereas 10% metaphases had normal chromosome complement. Meanwhile, a standard molecular investigation with primers for common chromosome translocations did not show any oncogene anomalies. Therefore, a diagnosis of MDS RAEB -II IPSS 3.0 was established. Since the patient was transfusion-dependent for a long time, his ferritine level reached 2500 mg/mm3.

64-69_Mamaev Figure 2.png

Figure 2. Fluorescence in situ hybridization (FISH) with BreakApart EVI1 probe (CytoCell, UK) showing one normal EVI1 gene (one fusion yellow signal) and one abnormal EVI1 gene (one green and one red split signals on interphase cells) in the patient with translocation t(3;21)(q26.2;q22) RUNX1/EVI1

64-69_Mamaev Figure 3.png

Figure 3. Karyotype of donor’s bone marrow cell 46,XY from a patient with primary myelodysplastic syndrome after allogeneic bone marrow transplantation prepared during a short-term hematological and cytogenetic remission

64-69_Mamaev Figure 4.png

Figure 4. Schematic presentation of clinical course in a patient with primary myelodysplastic syndrome with karyotype 47,XY,t(3;21)(q26.2;q22),+13 associated with resistance to standard chemotherapy, hypomethylating agents and allo-HSCT

Before bone marrow transplantation, the patient obtained one 5-day course of Dacogen (Decitabine) as demethylating therapy. It did not change common blood parameters, but allowed to reduce his transfusion dependence. Since the patient had an HLA-DQB1-mismatched related donor (Table 1), allo-HSCT was considered. The patient was enrolled into the RIC/MAC study protocol, and randomized to RIC branch (Busulfan + Fludarabine – 800 and 300 mg, respectively). Graft-versus-host-disease (GvHD) prophylaxis included CSA and Methotrexate (MTX). Following the allo-HSCT, stem cell engraftment was detected on day +15, when mixed chimerism was 45-55%. By this time, bone marrow contained only 2.4% of blasts, and the previously detected chromosomal abnormalities were not found (Fig. 3, Table 1). GvHD symptoms were absent, but a cytogenetic relapse was documented two weeks later (on day +29), due to appearance of the marker chromosomal aberrations and decreasing donor chimerism which could be caused by small number of CD34+ stem cells in the graft. Therefore, cyclosporine A was stopped on day +38, and, a week later, a donor lymphocyte infusion (DLI) was performed at a dose of 5.0х107 cells/kg, however, without any clinical effect. The graft rejection was diagnosed on day D+50 (Fig. 4). By that time, the patient had hemoglobin levels of 57 g/L; WBC, 1.7x109/L; and platelets, l3.0x109/L. Bone marrow aspirate was hypocellular with 3.4% blasts, and the donor chimerism faded away (<5%). Because of allo-BMT failure, a second allo-HSCT was administered, using peripheral blood stem cells from the same donor. It was performed after RIC preparative regimen containing Fludarabine 350 mg, Thiotepa 960 mg, and Campath 40 mg. GvHD prophylaxis included Tacrolymus and CellCept (Mycophenolate Mofetyl). Engraftment was registered since day D+10. Two days later, acute GvHD of gut and skin (grade I) was diagnosed. Steroids were added to the treatment schedule which resulted into a significant improvement of GvHD. Peripheral blood findings on the day +16 after 2nd transplant were as follows: Hb, 92.0 g/L; WBC, 4.3x109/L, and platelets, 35.0x109/L. Bone marrow aspirate was hypocellular without blast excess, and full donor chimerism was achieved. Cytogenetic study has shown a repeated karyotype normalization. Due to high risk of relapse, another DLI procedure was performed. Despite the immunotherapy, a new cytogenetic relapse, along with reduced donor chimerism levels, was diagnosed in July 2010. An attempt to achieve another remission with hypomethylating agents (5 courses of Dacogen) was not successful. A repeated cytogenetic relapse has been diagnosed in December 2010, causing his death at the BMT Center two months later.

Discussion

To our knowledge, it is the first clinical description of primary MDS with t(3;21)(q26.2;q22), combined with trisomy 13, and treated by two subsequent allo-HSCTs from a partially HLA-mismatched sibling (brother). The first earliest relapse occurred on the day 29, which could be, in part, explained by low cellularity of transplant. Since a second transplant was required, a reduced-intensity conditioning was chosen again, but peripheral blood stem cells were used for the 2nd transplant. The second engraftment was longer. A new cytological relapse was diagnosed 2 months later as evidenced by increased blast counts in bone marrow up to 12% accompanied by recurrence of the above cytogenetic aberrations, as well as decreasing donor chimerism. Moreover, the patient did not respond to hypomethylating agents (5 courses of Dacogen), aiming to correct the hematopoietic disorder. Recent studies have shown that distinct portions of RUNX1 gene may fuse in variable manner to MDS1 and EVI1 genes located within the 3q26 region. On the other hand, these different fusion products are capable of blocking myeloid differentiation interfering with normal transcriptional regulatory functions of RUNX1 [14]. As a result, our MDS case with combined t(3;21) chromosome anomalies and trisomy 13, showing poor clinical prognosis, appears to be related to imbalance of GATA, ERG, MEIS1, HOXA9 and FLT3 genes at the stem cell level which could be responsible for leukemia cells resistance to both chemotherapy and allo-HSCT.

Acknowledgements

The authors are grateful to colleagues for their excellent support.

Conflict of interest

No conflicts of interests are declared.

References

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Мамаев, Татьяна Л. Гиндина, Елена В. Морозова, Юлия В. Рудницкая, Мария В. Губина, Ильдар М. Бархатов, Сергей Н. Бондаренко, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(272) "Николай Н. Мамаев, Татьяна Л. Гиндина, Елена В. Морозова, Юлия В. Рудницкая, Мария В. Губина, Ильдар М. Бархатов, Сергей Н. Бондаренко, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20238" ["VALUE"]=> array(2) { ["TEXT"]=> string(335) "НИИ детской онкологии, гематологии и трансплантологии имени Р. М. Горбачевой, Санкт-Петербургский государственный медицинский университет имени И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(335) "НИИ детской онкологии, гематологии и трансплантологии имени Р. М. Горбачевой, Санкт-Петербургский государственный медицинский университет имени И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20239" ["VALUE"]=> array(2) { ["TEXT"]=> string(1650) "<p style="text-align: justify;"> Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1584) "

Представлено наблюдение миелодиспластического синдрома (МДС) с двумя редкими, повторяющимися и прогностически неблагоприятными нарушениями хромосом: транслокацией t(3;21)(q26.2;q22) и трисомией 13, которые обеспечили патологическим элементам резистентность к химиотерапии и трансплантации гемопоэтических стволовых клеток от сиблинга. На основании полученных данных и обсуждения в свете недавно открытых молекулярных механизмов резистентности к терапии при данном виде хромосомной патологии сделано заключение об ответственности данных нарушений хромосом за развитие резистентности к терапии, включая алло-ТГСК у больных МДС.

Ключевые слова

Первичный миелодиспластический синдром, t(3;21) (q26.2;q22), трисомия 13, ген EVI1/RUNX1, аллогенная трансплантация гемопоэтических клеток, резистентность к терапии.

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Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(160) "Nikolay N. Mamaev, Tatiana L. Gindina, Elena V. Morozova, Yuliya V. Rudnitskaya, Maria V. Gubina, Ildar M. Barkhatov, Sergey N. Bondarenko, 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) "20242" ["VALUE"]=> array(2) { ["TEXT"]=> string(194) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantology at the St. Petersburg State I. Pavlov Medical University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(194) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantology at the St. Petersburg State I. Pavlov Medical University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20246" ["VALUE"]=> array(2) { ["TEXT"]=> string(1178) "<p style="text-align: justify;"> We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1112) "

We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.

Keywords

Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.

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He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1112) "

We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.

Keywords

Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.

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We present a case of primary myelodysplastic syndrome (MDS) in a young male with two rare but recurrent chromosome abnormalities, i.e., t(3;21)(q26.2;q22) and trisomy 13. He obtained one Dacogen course at the BMT Center followed by sequential transplantation of allogeneic bone marrow and peripheral blood hematopoietic stem cells from an HLA-DQB1 mismatched donor. The rejection of the first graft was documented on day 29 after transplantation, whereas the 2nd allo-HSCT grafting was more successful. The article contains serial cytogenetic findings and time-dependent changes in donor chimerism. We discuss individual resistance to the therapy, in view of recently proposed molecular mechanisms of resistance which might be responsible for resistance of cells in this case with complex chromosomal pathology.

Keywords

Myelodysplastic syndrome, primary translocation t(3;21)(q26.2;q22), trisomy 13, EVI1/RUNX1 gene, allogeneic hematopoietic stem cell transplantation, therapy resistance.

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