ISSN 1866-8836
Клеточная терапия и трансплантация
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Since 70s, Prof. Vladimir A. Almazov became Head of the Chair. Since that time, the studies of leukemogenesis were launched here by new generation of clinical hematologists headed by Boris V. Afanasyev. The ex vivo cultures of colony-forming units of granulocyte-macrophage progenitor cells allowed them to get the first evidence for intrinsic factors of granulo-monocytopoiesis in acute leukemia, chronic myeloid leukemia, especially in different blast crisis types, myelodysplastic syndromes in adults, along with pioneering studies of aplastic anemia in children. The summarized data were published in Progenitor Hematopoietic Human Cells (1985), the first monograph in this field.

The notorious Chernobyl nuclear accident (1986) has promoted studies in the area of acute cytostatic syndrome in USSR and abroad. Boris Afanasyev, who worked at the Pavlov Medical Institute, was sent to Seattle for training at the famous clinic by E. Donnal Thomas, the Nobel Prize winner of 1990 for successful transplantation of hematopoietic cells in human patients. Several years later, by the initiative of Prof. Boris Afanasyev, the University management has arranged the Department of Bone Marrow Transplantation at the Pavlov University (1997) where the implementation of program for different types of hematopoietic stem cell transplantation was started in children and adults.

One should note the extensive clinical aid and consultative efforts from our foreign friends and colleagues in the field of leukemia treatment protocols, immunological typing, leukemia diagnostics and treatment schedules. This support was extremely important during 1990-1996, at the earlier steps of our BMT activity. The Hematology, Oncology and HSCT units at the Pavlov University could not succeed in the field without stable professional contacts with outstanding experts from Europe and USA. We should be appreciated, first of all, to close cooperation with Hamburg University (Germany) arranged by Prof. R. Neth, A. Zander, Th. Büchner, other German leading specialists – Prof. H.-J. Kolb, D. Hoelzer, B. Fehse. The leading specialists from other countries were also involved into these cooperative efforts, e.g., Prof. R. Gale (USA), Prof. G. Wagemaker (The Netherlands), Prof. A. Bacigalupo (Italy) and many other renown clinicians. Prof. Axel Zander, Axel Fauser, Gerard Wagemaker, Dieter Hoelzer were awarded the titles of Doctor Honoris Causa at the Pavlov University due to their merits in cooperation with Russian specialists in the field.

In the last 15 years, the development of hematology at the University is associated with RM Gorbacheva Memorial Research Institute organized by Prof. B. V. Afanasyev, being among the most active BMT centers in the Europe. During this period, over 4500 allogeneic and autologous transplants were performed in children and adults with leukemia, lymphomas, multiple myeloma, aplastic anemia, immunodeficiencies, solid tumors and metabolic disorders. The staff of the Institute conducts experimental and clinical research in the field of leukemia, myeloproliferative diseases, lymphomas, myeloma, bone marrow failure and other areas of hematology.

The Journal Cellular Therapy and Transplantation (CTT) is a joint project of German and Russian specialists in BMT and oncohematology, being issued since 2008. CTT publishes original data in hematopoietic stem cell transplantation, cellular and immunotherapy, gene therapy and adjacent areas of medicine and biology. We hope that clinical, research and publishing activities in this field will further develop at the Pavlov University, in close cooperation with our Russian and foreign colleagues for the benefit of patients with leukemia and other severe disorders that may be cured now by modern therapeutic approaches.


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Since 70s, Prof. Vladimir A. Almazov became Head of the Chair. Since that time, the studies of leukemogenesis were launched here by new generation of clinical hematologists headed by Boris V. Afanasyev. The ex vivo cultures of colony-forming units of granulocyte-macrophage progenitor cells allowed them to get the first evidence for intrinsic factors of granulo-monocytopoiesis in acute leukemia, chronic myeloid leukemia, especially in different blast crisis types, myelodysplastic syndromes in adults, along with pioneering studies of aplastic anemia in children. The summarized data were published in Progenitor Hematopoietic Human Cells (1985), the first monograph in this field.

The notorious Chernobyl nuclear accident (1986) has promoted studies in the area of acute cytostatic syndrome in USSR and abroad. Boris Afanasyev, who worked at the Pavlov Medical Institute, was sent to Seattle for training at the famous clinic by E. Donnal Thomas, the Nobel Prize winner of 1990 for successful transplantation of hematopoietic cells in human patients. Several years later, by the initiative of Prof. Boris Afanasyev, the University management has arranged the Department of Bone Marrow Transplantation at the Pavlov University (1997) where the implementation of program for different types of hematopoietic stem cell transplantation was started in children and adults.

One should note the extensive clinical aid and consultative efforts from our foreign friends and colleagues in the field of leukemia treatment protocols, immunological typing, leukemia diagnostics and treatment schedules. This support was extremely important during 1990-1996, at the earlier steps of our BMT activity. The Hematology, Oncology and HSCT units at the Pavlov University could not succeed in the field without stable professional contacts with outstanding experts from Europe and USA. We should be appreciated, first of all, to close cooperation with Hamburg University (Germany) arranged by Prof. R. Neth, A. Zander, Th. Büchner, other German leading specialists – Prof. H.-J. Kolb, D. Hoelzer, B. Fehse. The leading specialists from other countries were also involved into these cooperative efforts, e.g., Prof. R. Gale (USA), Prof. G. Wagemaker (The Netherlands), Prof. A. Bacigalupo (Italy) and many other renown clinicians. Prof. Axel Zander, Axel Fauser, Gerard Wagemaker, Dieter Hoelzer were awarded the titles of Doctor Honoris Causa at the Pavlov University due to their merits in cooperation with Russian specialists in the field.

In the last 15 years, the development of hematology at the University is associated with RM Gorbacheva Memorial Research Institute organized by Prof. B. V. Afanasyev, being among the most active BMT centers in the Europe. During this period, over 4500 allogeneic and autologous transplants were performed in children and adults with leukemia, lymphomas, multiple myeloma, aplastic anemia, immunodeficiencies, solid tumors and metabolic disorders. The staff of the Institute conducts experimental and clinical research in the field of leukemia, myeloproliferative diseases, lymphomas, myeloma, bone marrow failure and other areas of hematology.

The Journal Cellular Therapy and Transplantation (CTT) is a joint project of German and Russian specialists in BMT and oncohematology, being issued since 2008. CTT publishes original data in hematopoietic stem cell transplantation, cellular and immunotherapy, gene therapy and adjacent areas of medicine and biology. We hope that clinical, research and publishing activities in this field will further develop at the Pavlov University, in close cooperation with our Russian and foreign colleagues for the benefit of patients with leukemia and other severe disorders that may be cured now by modern therapeutic approaches.


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Кулагин, главный редактор журнала <i>«Клеточная Терапия и Трансплантация» (СТТ)</i></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(197) "

Профессор Александр Д. Кулагин, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)

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В 2022 году Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова отмечает свое 125-летие. Работы в области клинической гематологии и иммунологии развивались здесь с начала XX века на кафедре факультетской терапии. Заведующий кафедрой профессор Г. Ф. Ланг, ставший впоследствии выдающимся кардиологом, свою докторскую диссертацию (1901) посвятил изучению осмотической резистентности эритроцитов при раке желудка и других злокачественных новообразованиях, представил оригинальные экспериментальные исследования по регуляции клеток крови и гемолизу. Профессор Т. С. Истаманова, его преемница на этой кафедре, с 20-х гг. продолжала исследования в области физиологии и патологии эритропоэза, была одной из основоположников создания функциональной гематологии. Ее экспериментальные работы касались исследований роли селезенки в разрушении эритроцитов, нейрогенной регуляции кроветворения, функциональной роли ретикулоцитоза в процессе гемопоэза. Профессор Т. С. Истаманова глубоко изучала клинические аспекты полицитемии. Функциональная динамика эритроидных клеток широко изучалась в 40-х и 50-х годах, особенно с использованием передовых методов оценки метаболизма гемоглобина с применением 59Fe и других радиоактивных изотопов.

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Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal

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In 2022, the First St. Petersburg State Medical University (Pavlov University) is celebrating its 125th anniversary. The studies in clinical hematology and immunology developed here since early XX century at the Chair of Faculty Therapy. Its future head, Prof. Georg F. Lang later became a famous cardiologist. However, his Doctor’s Thesis (1901) was dedicated to osmotic resistance of red blood cells in stomach cancer and other malignancies. He presented original experimental studies on regulation of red blood cells and hemolysis. Later on, professor T. S. Istamanova headed the chair, being the best successor of his school. She was among founders of functional hematology, proceeded with studies in physiology and pathology of erythropoiesis performed since 20s. Her experimental works concerned the role of spleen in red blood cell destruction, neurogenic regulation of hematopoiesis, functional significance of reticulocytosis in hematopoietic function. Prof. T. S. Istamanova was deeply involved into clinical aspects of polycythemia. Functional dynamics of erythroid cells was extensively studied over 40s and 50s, especially, using innovative assays of hemoglobin metabolism with 59Fe and other radionuclides.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28499" ["VALUE"]=> string(46) "Pavlov University: 125 years in blood research" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(46) "Pavlov University: 125 years in blood research" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28500" ["VALUE"]=> array(2) { ["TEXT"]=> string(7751) "<p style="text-align: justify;">С 70-х годов кафедру возглавил проф. В. А. Алмазов. С этого времени здесь началось изучение лейкогенеза и регуляции кроветворения новым поколением клинических гематологов во главе с Б. В. Афанасьевым. Культивирование колониеобразующих единиц клеток-предшественников грануло-моноцитопоэза позволили получить первые данные о внутренних факторах регуляции грануломоноцитопоэза при острых лейкозах, хроническом миелолейкозе, особенно при различных типах бластных кризов, миелодиспластическом синдроме у взрослых и, впервые – при апластической анемии у детей. Эти данные были обобщены в первой монографии в этой области «Родоначальные стволовые кроветворные клетки человека» (1985). </p> <p style="text-align: justify;">Трагически известная Чернобыльская ядерная авария (1986 г.) способствовала развитию исследований в области острого цитостатического синдрома в СССР и за рубежом. Борис Владимирович Афанасьев, сотрудник 1-го Ленинградского медицинского института им. И. П. Павлова, был направлен в Сиэттл (США) для стажировки в знаменитую клинику Э. Доннела Томаса, в последующем лауреата Нобелевской премии 1990 г. за успешную трансплантацию гемопоэтических клеток в клинике. Через несколько лет, по инициативе профессора Б. В. Афанасьева, руководство Университета организовало отделение трансплантации костного мозга (1997 г.), где была начата программа по широкому внедрению различных видов трансплантации гемопоэтических стволовых клеток у детей и взрослых.</p> <p style="text-align: justify;">Следует отметить обширную клиническую помощь и консультационные усилия наших зарубежных друзей и коллег в области принципов лечения лейкозов, иммунологического типирования, диагностики лейкозов и схем лечения. Эта поддержка была чрезвычайно важной в 1990-1996 гг., на ранних этапах нашей работы по трансплантации костного мозга. Отделения гематологии, онкологии и ТГСК университета не смогли бы добиться успеха в этой области без устойчивых профессиональных контактов с выдающимися специалистами из Европы и США. Прежде всего, следует отметить тесное сотрудничество с Университетскими клиниками Гамбурга и другими университетами Германии при непосредственном участии проф. Р. Нета, А. Цандера, Т. Бюхнера, других ведущих германских специалистов – Х. И. Кольба, Д. Хёльцера, Б. Фезе. В эту совместную работу были вовлечены и ведущие специалисты из других стран, например, проф. Р. Гэйл, (США), Г. Вагемакер (Нидерланды), А. Бачигалупо (Италия) и многие другие известные клиницисты. Проф. Аксель Цандер, Аксель Фаузер, Герард Вaгемaкер, Дитер Хёльцер были удостоены звания почетных докторов ПСПбГМУ им. И. П. Павлова за заслуги в сотрудничестве с российскими специалистами в этой области. </p> <p style="text-align: justify;">В последние 15 лет развитие гематологии в Университете связано с организованным проф. Б. В. Афанасьевым НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, который входит в число крупнейших центров ТКМ в Европе. За этот период выполнено более 4500 аллогенных и аутологичных трансплантаций детям и взрослым с лейкозами, лимфомами, множественной миеломой, апластическими анемиями, солидными опухолями, иммунодефицитами заболеваниями и нарушениями обмена веществ. В Институте проводятся экспериментальные и клинические исследования в области лейкемий, миелопролиферативных заболеваний, лимфом, миеломы, костномозговой недостаточности и других областях гематологии.</p><p style="text-align: justify;"> Журнал «Клеточная терапия и трансплантация» (СТТ) – совместный проект немецких и российских специалистов в области ТКМ и онкогематологии, издается с 2008 года. Журнал публикует оригинальные данные по трансплантации гемопоэтических стволовых клеток, иммунотерапии, клеточной и генной терапии, а также смежным вопросам медицины и биологии. Мы надеемся, что клиническая, исследовательская и издательская деятельность в этой области будет и дальше развиваться в Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в тесном сотрудничестве с нашими российскими и зарубежными коллегами на благо пациентов с лейкозами и другими тяжелыми заболеваниями, которые сейчас могут быть излечены с помощью современных терапевтических подходов. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7641) "

С 70-х годов кафедру возглавил проф. В. А. Алмазов. С этого времени здесь началось изучение лейкогенеза и регуляции кроветворения новым поколением клинических гематологов во главе с Б. В. Афанасьевым. Культивирование колониеобразующих единиц клеток-предшественников грануло-моноцитопоэза позволили получить первые данные о внутренних факторах регуляции грануломоноцитопоэза при острых лейкозах, хроническом миелолейкозе, особенно при различных типах бластных кризов, миелодиспластическом синдроме у взрослых и, впервые – при апластической анемии у детей. Эти данные были обобщены в первой монографии в этой области «Родоначальные стволовые кроветворные клетки человека» (1985).

Трагически известная Чернобыльская ядерная авария (1986 г.) способствовала развитию исследований в области острого цитостатического синдрома в СССР и за рубежом. Борис Владимирович Афанасьев, сотрудник 1-го Ленинградского медицинского института им. И. П. Павлова, был направлен в Сиэттл (США) для стажировки в знаменитую клинику Э. Доннела Томаса, в последующем лауреата Нобелевской премии 1990 г. за успешную трансплантацию гемопоэтических клеток в клинике. Через несколько лет, по инициативе профессора Б. В. Афанасьева, руководство Университета организовало отделение трансплантации костного мозга (1997 г.), где была начата программа по широкому внедрению различных видов трансплантации гемопоэтических стволовых клеток у детей и взрослых.

Следует отметить обширную клиническую помощь и консультационные усилия наших зарубежных друзей и коллег в области принципов лечения лейкозов, иммунологического типирования, диагностики лейкозов и схем лечения. Эта поддержка была чрезвычайно важной в 1990-1996 гг., на ранних этапах нашей работы по трансплантации костного мозга. Отделения гематологии, онкологии и ТГСК университета не смогли бы добиться успеха в этой области без устойчивых профессиональных контактов с выдающимися специалистами из Европы и США. Прежде всего, следует отметить тесное сотрудничество с Университетскими клиниками Гамбурга и другими университетами Германии при непосредственном участии проф. Р. Нета, А. Цандера, Т. Бюхнера, других ведущих германских специалистов – Х. И. Кольба, Д. Хёльцера, Б. Фезе. В эту совместную работу были вовлечены и ведущие специалисты из других стран, например, проф. Р. Гэйл, (США), Г. Вагемакер (Нидерланды), А. Бачигалупо (Италия) и многие другие известные клиницисты. Проф. Аксель Цандер, Аксель Фаузер, Герард Вaгемaкер, Дитер Хёльцер были удостоены звания почетных докторов ПСПбГМУ им. И. П. Павлова за заслуги в сотрудничестве с российскими специалистами в этой области.

В последние 15 лет развитие гематологии в Университете связано с организованным проф. Б. В. Афанасьевым НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, который входит в число крупнейших центров ТКМ в Европе. За этот период выполнено более 4500 аллогенных и аутологичных трансплантаций детям и взрослым с лейкозами, лимфомами, множественной миеломой, апластическими анемиями, солидными опухолями, иммунодефицитами заболеваниями и нарушениями обмена веществ. В Институте проводятся экспериментальные и клинические исследования в области лейкемий, миелопролиферативных заболеваний, лимфом, миеломы, костномозговой недостаточности и других областях гематологии.

Журнал «Клеточная терапия и трансплантация» (СТТ) – совместный проект немецких и российских специалистов в области ТКМ и онкогематологии, издается с 2008 года. Журнал публикует оригинальные данные по трансплантации гемопоэтических стволовых клеток, иммунотерапии, клеточной и генной терапии, а также смежным вопросам медицины и биологии. Мы надеемся, что клиническая, исследовательская и издательская деятельность в этой области будет и дальше развиваться в Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в тесном сотрудничестве с нашими российскими и зарубежными коллегами на благо пациентов с лейкозами и другими тяжелыми заболеваниями, которые сейчас могут быть излечены с помощью современных терапевтических подходов.

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Kulagin, Editor-in-Chief, <i>Cellular Therapy and Transplantation Journal</i></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(107) "

Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal

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Professor Alexander D. Kulagin, Editor-in-Chief, Cellular Therapy and Transplantation Journal

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In 2022, the First St. Petersburg State Medical University (Pavlov University) is celebrating its 125th anniversary. The studies in clinical hematology and immunology developed here since early XX century at the Chair of Faculty Therapy. Its future head, Prof. Georg F. Lang later became a famous cardiologist. However, his Doctor’s Thesis (1901) was dedicated to osmotic resistance of red blood cells in stomach cancer and other malignancies. He presented original experimental studies on regulation of red blood cells and hemolysis. Later on, professor T. S. Istamanova headed the chair, being the best successor of his school. She was among founders of functional hematology, proceeded with studies in physiology and pathology of erythropoiesis performed since 20s. Her experimental works concerned the role of spleen in red blood cell destruction, neurogenic regulation of hematopoiesis, functional significance of reticulocytosis in hematopoietic function. Prof. T. S. Istamanova was deeply involved into clinical aspects of polycythemia. Functional dynamics of erythroid cells was extensively studied over 40s and 50s, especially, using innovative assays of hemoglobin metabolism with 59Fe and other radionuclides.

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In 2022, the First St. Petersburg State Medical University (Pavlov University) is celebrating its 125th anniversary. The studies in clinical hematology and immunology developed here since early XX century at the Chair of Faculty Therapy. Its future head, Prof. Georg F. Lang later became a famous cardiologist. However, his Doctor’s Thesis (1901) was dedicated to osmotic resistance of red blood cells in stomach cancer and other malignancies. He presented original experimental studies on regulation of red blood cells and hemolysis. Later on, professor T. S. Istamanova headed the chair, being the best successor of his school. She was among founders of functional hematology, proceeded with studies in physiology and pathology of erythropoiesis performed since 20s. Her experimental works concerned the role of spleen in red blood cell destruction, neurogenic regulation of hematopoiesis, functional significance of reticulocytosis in hematopoietic function. Prof. T. S. Istamanova was deeply involved into clinical aspects of polycythemia. Functional dynamics of erythroid cells was extensively studied over 40s and 50s, especially, using innovative assays of hemoglobin metabolism with 59Fe and other radionuclides.

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Профессор Александр Д. Кулагин, главный редактор журнала «Клеточная Терапия и Трансплантация» (СТТ)

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Профессор Александр Д. Кулагин, 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) "28496" ["VALUE"]=> array(2) { ["TEXT"]=> string(2396) "<p style="text-align: justify;">В 2022 году Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова отмечает свое 125-летие. Работы в области клинической гематологии и иммунологии развивались здесь с начала XX века на кафедре факультетской терапии. Заведующий кафедрой профессор Г. Ф. Ланг, ставший впоследствии выдающимся кардиологом, свою докторскую диссертацию (1901) посвятил изучению осмотической резистентности эритроцитов при раке желудка и других злокачественных новообразованиях, представил оригинальные экспериментальные исследования по регуляции клеток крови и гемолизу. Профессор Т. С. Истаманова, его преемница на этой кафедре, с 20-х гг. продолжала исследования в области физиологии и патологии эритропоэза, была одной из основоположников создания функциональной гематологии. Ее экспериментальные работы касались исследований роли селезенки в разрушении эритроцитов, нейрогенной регуляции кроветворения, функциональной роли ретикулоцитоза в процессе гемопоэза. Профессор Т. С. Истаманова глубоко изучала клинические аспекты полицитемии. Функциональная динамика эритроидных клеток широко изучалась в 40-х и 50-х годах, особенно с использованием передовых методов оценки метаболизма гемоглобина с применением <sup>59</sup>Fe и других радиоактивных изотопов.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2362) "

В 2022 году Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова отмечает свое 125-летие. Работы в области клинической гематологии и иммунологии развивались здесь с начала XX века на кафедре факультетской терапии. Заведующий кафедрой профессор Г. Ф. Ланг, ставший впоследствии выдающимся кардиологом, свою докторскую диссертацию (1901) посвятил изучению осмотической резистентности эритроцитов при раке желудка и других злокачественных новообразованиях, представил оригинальные экспериментальные исследования по регуляции клеток крови и гемолизу. Профессор Т. С. Истаманова, его преемница на этой кафедре, с 20-х гг. продолжала исследования в области физиологии и патологии эритропоэза, была одной из основоположников создания функциональной гематологии. Ее экспериментальные работы касались исследований роли селезенки в разрушении эритроцитов, нейрогенной регуляции кроветворения, функциональной роли ретикулоцитоза в процессе гемопоэза. Профессор Т. С. Истаманова глубоко изучала клинические аспекты полицитемии. Функциональная динамика эритроидных клеток широко изучалась в 40-х и 50-х годах, особенно с использованием передовых методов оценки метаболизма гемоглобина с применением 59Fe и других радиоактивных изотопов.

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В 2022 году Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова отмечает свое 125-летие. Работы в области клинической гематологии и иммунологии развивались здесь с начала XX века на кафедре факультетской терапии. Заведующий кафедрой профессор Г. Ф. Ланг, ставший впоследствии выдающимся кардиологом, свою докторскую диссертацию (1901) посвятил изучению осмотической резистентности эритроцитов при раке желудка и других злокачественных новообразованиях, представил оригинальные экспериментальные исследования по регуляции клеток крови и гемолизу. Профессор Т. С. Истаманова, его преемница на этой кафедре, с 20-х гг. продолжала исследования в области физиологии и патологии эритропоэза, была одной из основоположников создания функциональной гематологии. Ее экспериментальные работы касались исследований роли селезенки в разрушении эритроцитов, нейрогенной регуляции кроветворения, функциональной роли ретикулоцитоза в процессе гемопоэза. Профессор Т. С. Истаманова глубоко изучала клинические аспекты полицитемии. Функциональная динамика эритроидных клеток широко изучалась в 40-х и 50-х годах, особенно с использованием передовых методов оценки метаболизма гемоглобина с применением 59Fe и других радиоактивных изотопов.

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28500" ["VALUE"]=> array(2) { ["TEXT"]=> string(7751) "<p style="text-align: justify;">С 70-х годов кафедру возглавил проф. В. А. Алмазов. С этого времени здесь началось изучение лейкогенеза и регуляции кроветворения новым поколением клинических гематологов во главе с Б. В. Афанасьевым. Культивирование колониеобразующих единиц клеток-предшественников грануло-моноцитопоэза позволили получить первые данные о внутренних факторах регуляции грануломоноцитопоэза при острых лейкозах, хроническом миелолейкозе, особенно при различных типах бластных кризов, миелодиспластическом синдроме у взрослых и, впервые – при апластической анемии у детей. Эти данные были обобщены в первой монографии в этой области «Родоначальные стволовые кроветворные клетки человека» (1985). </p> <p style="text-align: justify;">Трагически известная Чернобыльская ядерная авария (1986 г.) способствовала развитию исследований в области острого цитостатического синдрома в СССР и за рубежом. Борис Владимирович Афанасьев, сотрудник 1-го Ленинградского медицинского института им. И. П. Павлова, был направлен в Сиэттл (США) для стажировки в знаменитую клинику Э. Доннела Томаса, в последующем лауреата Нобелевской премии 1990 г. за успешную трансплантацию гемопоэтических клеток в клинике. Через несколько лет, по инициативе профессора Б. В. Афанасьева, руководство Университета организовало отделение трансплантации костного мозга (1997 г.), где была начата программа по широкому внедрению различных видов трансплантации гемопоэтических стволовых клеток у детей и взрослых.</p> <p style="text-align: justify;">Следует отметить обширную клиническую помощь и консультационные усилия наших зарубежных друзей и коллег в области принципов лечения лейкозов, иммунологического типирования, диагностики лейкозов и схем лечения. Эта поддержка была чрезвычайно важной в 1990-1996 гг., на ранних этапах нашей работы по трансплантации костного мозга. Отделения гематологии, онкологии и ТГСК университета не смогли бы добиться успеха в этой области без устойчивых профессиональных контактов с выдающимися специалистами из Европы и США. Прежде всего, следует отметить тесное сотрудничество с Университетскими клиниками Гамбурга и другими университетами Германии при непосредственном участии проф. Р. Нета, А. Цандера, Т. Бюхнера, других ведущих германских специалистов – Х. И. Кольба, Д. Хёльцера, Б. Фезе. В эту совместную работу были вовлечены и ведущие специалисты из других стран, например, проф. Р. Гэйл, (США), Г. Вагемакер (Нидерланды), А. Бачигалупо (Италия) и многие другие известные клиницисты. Проф. Аксель Цандер, Аксель Фаузер, Герард Вaгемaкер, Дитер Хёльцер были удостоены звания почетных докторов ПСПбГМУ им. И. П. Павлова за заслуги в сотрудничестве с российскими специалистами в этой области. </p> <p style="text-align: justify;">В последние 15 лет развитие гематологии в Университете связано с организованным проф. Б. В. Афанасьевым НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, который входит в число крупнейших центров ТКМ в Европе. За этот период выполнено более 4500 аллогенных и аутологичных трансплантаций детям и взрослым с лейкозами, лимфомами, множественной миеломой, апластическими анемиями, солидными опухолями, иммунодефицитами заболеваниями и нарушениями обмена веществ. В Институте проводятся экспериментальные и клинические исследования в области лейкемий, миелопролиферативных заболеваний, лимфом, миеломы, костномозговой недостаточности и других областях гематологии.</p><p style="text-align: justify;"> Журнал «Клеточная терапия и трансплантация» (СТТ) – совместный проект немецких и российских специалистов в области ТКМ и онкогематологии, издается с 2008 года. Журнал публикует оригинальные данные по трансплантации гемопоэтических стволовых клеток, иммунотерапии, клеточной и генной терапии, а также смежным вопросам медицины и биологии. Мы надеемся, что клиническая, исследовательская и издательская деятельность в этой области будет и дальше развиваться в Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в тесном сотрудничестве с нашими российскими и зарубежными коллегами на благо пациентов с лейкозами и другими тяжелыми заболеваниями, которые сейчас могут быть излечены с помощью современных терапевтических подходов. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7641) "

С 70-х годов кафедру возглавил проф. В. А. Алмазов. С этого времени здесь началось изучение лейкогенеза и регуляции кроветворения новым поколением клинических гематологов во главе с Б. В. Афанасьевым. Культивирование колониеобразующих единиц клеток-предшественников грануло-моноцитопоэза позволили получить первые данные о внутренних факторах регуляции грануломоноцитопоэза при острых лейкозах, хроническом миелолейкозе, особенно при различных типах бластных кризов, миелодиспластическом синдроме у взрослых и, впервые – при апластической анемии у детей. Эти данные были обобщены в первой монографии в этой области «Родоначальные стволовые кроветворные клетки человека» (1985).

Трагически известная Чернобыльская ядерная авария (1986 г.) способствовала развитию исследований в области острого цитостатического синдрома в СССР и за рубежом. Борис Владимирович Афанасьев, сотрудник 1-го Ленинградского медицинского института им. И. П. Павлова, был направлен в Сиэттл (США) для стажировки в знаменитую клинику Э. Доннела Томаса, в последующем лауреата Нобелевской премии 1990 г. за успешную трансплантацию гемопоэтических клеток в клинике. Через несколько лет, по инициативе профессора Б. В. Афанасьева, руководство Университета организовало отделение трансплантации костного мозга (1997 г.), где была начата программа по широкому внедрению различных видов трансплантации гемопоэтических стволовых клеток у детей и взрослых.

Следует отметить обширную клиническую помощь и консультационные усилия наших зарубежных друзей и коллег в области принципов лечения лейкозов, иммунологического типирования, диагностики лейкозов и схем лечения. Эта поддержка была чрезвычайно важной в 1990-1996 гг., на ранних этапах нашей работы по трансплантации костного мозга. Отделения гематологии, онкологии и ТГСК университета не смогли бы добиться успеха в этой области без устойчивых профессиональных контактов с выдающимися специалистами из Европы и США. Прежде всего, следует отметить тесное сотрудничество с Университетскими клиниками Гамбурга и другими университетами Германии при непосредственном участии проф. Р. Нета, А. Цандера, Т. Бюхнера, других ведущих германских специалистов – Х. И. Кольба, Д. Хёльцера, Б. Фезе. В эту совместную работу были вовлечены и ведущие специалисты из других стран, например, проф. Р. Гэйл, (США), Г. Вагемакер (Нидерланды), А. Бачигалупо (Италия) и многие другие известные клиницисты. Проф. Аксель Цандер, Аксель Фаузер, Герард Вaгемaкер, Дитер Хёльцер были удостоены звания почетных докторов ПСПбГМУ им. И. П. Павлова за заслуги в сотрудничестве с российскими специалистами в этой области.

В последние 15 лет развитие гематологии в Университете связано с организованным проф. Б. В. Афанасьевым НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, который входит в число крупнейших центров ТКМ в Европе. За этот период выполнено более 4500 аллогенных и аутологичных трансплантаций детям и взрослым с лейкозами, лимфомами, множественной миеломой, апластическими анемиями, солидными опухолями, иммунодефицитами заболеваниями и нарушениями обмена веществ. В Институте проводятся экспериментальные и клинические исследования в области лейкемий, миелопролиферативных заболеваний, лимфом, миеломы, костномозговой недостаточности и других областях гематологии.

Журнал «Клеточная терапия и трансплантация» (СТТ) – совместный проект немецких и российских специалистов в области ТКМ и онкогематологии, издается с 2008 года. Журнал публикует оригинальные данные по трансплантации гемопоэтических стволовых клеток, иммунотерапии, клеточной и генной терапии, а также смежным вопросам медицины и биологии. Мы надеемся, что клиническая, исследовательская и издательская деятельность в этой области будет и дальше развиваться в Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в тесном сотрудничестве с нашими российскими и зарубежными коллегами на благо пациентов с лейкозами и другими тяжелыми заболеваниями, которые сейчас могут быть излечены с помощью современных терапевтических подходов.

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С 70-х годов кафедру возглавил проф. В. А. Алмазов. С этого времени здесь началось изучение лейкогенеза и регуляции кроветворения новым поколением клинических гематологов во главе с Б. В. Афанасьевым. Культивирование колониеобразующих единиц клеток-предшественников грануло-моноцитопоэза позволили получить первые данные о внутренних факторах регуляции грануломоноцитопоэза при острых лейкозах, хроническом миелолейкозе, особенно при различных типах бластных кризов, миелодиспластическом синдроме у взрослых и, впервые – при апластической анемии у детей. Эти данные были обобщены в первой монографии в этой области «Родоначальные стволовые кроветворные клетки человека» (1985).

Трагически известная Чернобыльская ядерная авария (1986 г.) способствовала развитию исследований в области острого цитостатического синдрома в СССР и за рубежом. Борис Владимирович Афанасьев, сотрудник 1-го Ленинградского медицинского института им. И. П. Павлова, был направлен в Сиэттл (США) для стажировки в знаменитую клинику Э. Доннела Томаса, в последующем лауреата Нобелевской премии 1990 г. за успешную трансплантацию гемопоэтических клеток в клинике. Через несколько лет, по инициативе профессора Б. В. Афанасьева, руководство Университета организовало отделение трансплантации костного мозга (1997 г.), где была начата программа по широкому внедрению различных видов трансплантации гемопоэтических стволовых клеток у детей и взрослых.

Следует отметить обширную клиническую помощь и консультационные усилия наших зарубежных друзей и коллег в области принципов лечения лейкозов, иммунологического типирования, диагностики лейкозов и схем лечения. Эта поддержка была чрезвычайно важной в 1990-1996 гг., на ранних этапах нашей работы по трансплантации костного мозга. Отделения гематологии, онкологии и ТГСК университета не смогли бы добиться успеха в этой области без устойчивых профессиональных контактов с выдающимися специалистами из Европы и США. Прежде всего, следует отметить тесное сотрудничество с Университетскими клиниками Гамбурга и другими университетами Германии при непосредственном участии проф. Р. Нета, А. Цандера, Т. Бюхнера, других ведущих германских специалистов – Х. И. Кольба, Д. Хёльцера, Б. Фезе. В эту совместную работу были вовлечены и ведущие специалисты из других стран, например, проф. Р. Гэйл, (США), Г. Вагемакер (Нидерланды), А. Бачигалупо (Италия) и многие другие известные клиницисты. Проф. Аксель Цандер, Аксель Фаузер, Герард Вaгемaкер, Дитер Хёльцер были удостоены звания почетных докторов ПСПбГМУ им. И. П. Павлова за заслуги в сотрудничестве с российскими специалистами в этой области.

В последние 15 лет развитие гематологии в Университете связано с организованным проф. Б. В. Афанасьевым НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, который входит в число крупнейших центров ТКМ в Европе. За этот период выполнено более 4500 аллогенных и аутологичных трансплантаций детям и взрослым с лейкозами, лимфомами, множественной миеломой, апластическими анемиями, солидными опухолями, иммунодефицитами заболеваниями и нарушениями обмена веществ. В Институте проводятся экспериментальные и клинические исследования в области лейкемий, миелопролиферативных заболеваний, лимфом, миеломы, костномозговой недостаточности и других областях гематологии.

Журнал «Клеточная терапия и трансплантация» (СТТ) – совместный проект немецких и российских специалистов в области ТКМ и онкогематологии, издается с 2008 года. Журнал публикует оригинальные данные по трансплантации гемопоэтических стволовых клеток, иммунотерапии, клеточной и генной терапии, а также смежным вопросам медицины и биологии. Мы надеемся, что клиническая, исследовательская и издательская деятельность в этой области будет и дальше развиваться в Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в тесном сотрудничестве с нашими российскими и зарубежными коллегами на благо пациентов с лейкозами и другими тяжелыми заболеваниями, которые сейчас могут быть излечены с помощью современных терапевтических подходов.

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Introduction

General issues

Retinoblastoma (RB) is the most common pediatric eye cancer developing from immature cells of the retina [1-3]. In infants it is most commonly associated with biallelic mutation of RB1 gene [4]. In these cases the tumor may involve one, as well as both, eyes and also may produce synchronous or metachronous ectopic lesions in the pineal gland (pineoblastoma). Based on extent of involvement these forms are classified as uni- bi- and trilateral [5]. The RB incidence is 1 in 15000-18000 newborn and about 5000 new cases are registered each year [6].

Most treatment programs in patients with RB combine different treatment modalities, which are chosen based in risk group and extent of tumor involvement [7, 8]. In high-risk patients the tumor spreads beyond the eye often developing ectopic metastatic lesions, which may become lethal if no systemic method is applied in addition to local control measures [9]. During the last few decades a number of methods were used to control the disease including systemic polychemotherapy (CT), external beam radiation therapy (EBRT) and other local treatment methods. However, these standard measures may still be ineffective in some cases, so we are ever in need of new global strategies aimed at survival improvement in high-risk RB.

High-dose chemotherapy with autologous hemopoietic stem cell transplantation in patients with RB

In developed countries most children with RB are referred to pediatric oncologist in early stages. Most advanced cases with extraocular and metastatic RB are therefore treated in developing countries. Most deaths in RB patients are due to metastatic disease, pineoblastoma development or secondary cancers, which are most often seen in patients with hereditary forms of disease. The treatment schedule is always personalized in accordance to individual tumor characteristics. Up to this moment the main therapeutic modalities are systemic polychemotherapy (PCT) and local one, which may be delivered as inraarterial chemotherapy (IAC) or intravitreal one (IVitC). There are also additional local control methods such as transpupillary thermotherapy (TTT), cryotherapy, and brachytherapy or enucleation, which may be performed in cases with optical nerve or choroidal invasion [10, 11].

Each of these methods has certain disadvantages and unwanted sequelae. Most clinics limit the use of external beam radiation therapy (EBRT) due to the risk of secondary cancers, facial bones growth disturbance and subsequent deformations. Enucleation is a radical surgical technique based on entire eye removal [12]. While chemoreduction (tumor shrinking in response to systemic chemotherapy) and local control measures are effective in patients with intraocular RB and have fewer adverse effects, they are less effective in patients high-risk disease characterized by initial extraocualr disease, tumor relapse involving extra- or intraocular structures (including distant metastases), tumor invasion of the optic nerve resection line, trilateral RB. As a result, high-risk patients may need more aggressive treatment modalities [10-13]. Therefore, there is still an ongoing search for more effective strategies able to improve long-term survival and quality of life in this cohort.

RB is a highly chemosensitive tumor with exponential log kill curve in tumor cell cultures, so dose-intensive consolidation regimens are expected to increase the overall treatment effectiveness. High-dose chemotherapy (HDCT) is being considered a viable option [14-17]. However, this method is associated with some drawbacks due to its toxic effects, primarily profound myelosuppression, which may lead to serious or even fatal complications if no attempts for bone marrow reconstitution via cryopreserved autologous hemopoietic stem cells (bone marrow or peripheral blood precursors) reinfusion are taken. Autologous hemopoietic stem cells transplantation (auto-HSCT) is the most effective measure to limit secondary myelotoxicity and allows using much higher peak doses of cytostatics potentially increasing RB treatment effectiveness [16].

A number of researchers have demonstrated different high-dose regimens effectiveness in auto-HSCT settings. These regimens are used as consolidation in patients with high-risk pediatric solid tumors as part of a multidisciplinary approach incorporating also surgical treatment and standard dose chemotherapy [12], in some cases they may also help to avoid bilateral enucleation preserving the vision in RB patients.

There is currently no consensus on optimal treatment regimen in late stage RB, although most experts agree on the use of several drugs in combination. These drugs, which may be potentially effective in RB patients, include platinum agents (carboplatin and cisplatin), etoposide, vincristine, cyclophosphamide and anthracyclines [18, 19]. Vincristine, etoposide and carboplatin are characterized by better eye penetration and are therefore most often used in conditioning regimens prior to auto-HSCT.

World experience with auto-HSCT in the RB patients

The HDCT with auto-HSCT is now being used in patients with high-risk RB for more than 20 years. The first patient cohort was described in 1997 by French researchers from Institut Curie (Paris). The HDCT was performed as consolidation for high-risk patients (initially extraocular disease, relapse or tumor invasion of optical nerve resection line). A total of 25 patents received a regimen consisting of carboplatin (250 mg/m2/day from day 1 day 5 in 6 initially high-risk patients after enucleation and standard-dose CT and 250 mg/m2/day in 19 patients with chemosensitive relapse), etoposide (350 mg/m2/day from day 1 to day 5), and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) with subsequent autologous stem cells reinfusion. The 3-year disease-free survival was 67.1%. In 7 of 19 patients with relapse it developed in central nervous system. All patients with CNS relapse except one died of disease progression. The main toxic complications were hematological toxicity and gastrointestinal mucositis (oral mucositis, enterocolitis). Also, 2 of 13 patients developed grade III-IV ototoxicity. In one case a grade I acute re-versible cardiotoxicity was registered. Therefore, while high-dose regimen consisting of carboplatin, etoposide and cyclophosphamide seemed a feasible strategy in high-risk RB patients, especially those with bones and bone marrow involvement, it did not improve the results in cases with CNS involvement [20].

In 2003, a group of German researchers published their data on auto-HSCT outcome in 5 RB patients, 4 of them with bone marrow metastases and one with extraorbital involvement. All patients have achieved response after previous enucleation and standard-dose chemotherapy, a child with extraorbital tumor also received EBRT. In 4 cases the conditioning regimen consisted of thiotepa (900 mg/m2), etoposide (40 mg/kg), and carboplatin (1.5 g/m2), and in 1 case it included carmustine (300 mg/m2), cyclophosphamide (6.8 g/m2), and etoposide (1.6 g/m2). A rapid hemopoiesis reconstitution was observed in all 5 cases. Main toxic complications were mucositis and cytopenia with consequent infections. None of the patients died due to regimen toxicity or experienced any long-term sequelae. A patient with initial extrorbital disease developed a relapse with meningheal involvement 10 months after auto-HSCT, but was salvaged by surgery and standard-dose chemotherapy and remained in remission after 105 months follow-up. Four other patients were still in remission 107, 57, 9, and 8 months after auto-HSCT. The conditioning regimen with thiotepa, etoposide and carboplatin may be a good option for children with extrabulbar or disseminated chemosensitive RB [21].

In 2021, a group of authors from the Faculty of Medicine, University of Indonesia published a review on available data in auto-HSCT for high-risk RB patients [22]. A total of 35 publications describing 160 patients were included. After auto-HSCT 108 of 160 (67.5%) patients are alive and disease free at the last follow-up. The secondary cancer developed in 16 of 160 (10%) patients, which is a comparably low rate. The most common side effects were hematological and gastrointestinal toxicity. As a whole, 41 of 160 (25.6%) died with signs of active disease due to primary CNS involvement (in 25 of 41; 60.9%), disease relapse (12 of 41; 29.3%), or secondary cancer (3 of 41; 7.3%). Only in 1 of 41 (2.4%) cases there was evident metastatic involvement outside CNS. Only 11 of 160 (6.7%) were alive, but not disease-free, at the last fol-low-up. According to this review, the use of HDCT with subsequent auto-HSCT is effective in patients with disseminated RB as 108 of 160 (67.5%) of auto-HSCT recipients stayed alive and disease-free. It corresponds to the data published in previous review by Jaradat I. et al. (2012) [23].

Russian experience with auto-HSCT in children with retinoblastoma

There are several large Russian centers treating most children with RB, i.e., the Helmholtz National Medical Ophthalmology Research Center, S. N. Fedorov National Medical Research Center for Eye Microsurgery, and Research Institute of Pediatric Oncology and Hematology at the N. N. Blokhin National Medical Research Center of Oncology. However, only the latter institution performed HDCT with auto-HSCT in these patients.

There is a description of earlier (2001-2008) experience of auto-HSCT performed in a cohort of 15 RB patients in the Institute of Pediatric Oncology and Hematology at the N. N.Blokhin National Medical Research Center of Oncology. The treatment program included IVitC, EBRT, and high-dose consolidation with busulfan and melphalan followed by auto-HSCT. During the follow-up 1 of 15 patients died of sepsis and 7 of disease progression with CNS involvement. Seven patients are currently alive (5 children with stage II, one with stage IIIа, one with stage IIIb). The new strategy allowed to double the disease- and event-free survival rate of RB patients. The overall survival in high-risk group (optical nerve resection line invasion, extrascleral spread of the tumor) reached 71.4%. The researchers concluded that HDCT with auto-HSCT is an effective method in patients with stage II and III, although more effective options are still warranted for children with disseminated RB [24].

Clinical cases

We present a series of 3 clinical cases of children (aged 3-6 years) with high-risk RB receiving HDCT with auto-HSCT treated at the Pediatric Hematology and Oncology Department (BMT unit) at N. N. Blokhin National Medical Research Center of Oncology (February to October 2021). All the patients achieved remission prior to HSCT after surgery and standard-dose systemic polychemotherapy. The patients’ characteristics are listed in Table 1. Patient 1 had initially demonstrated extraocular tumor growth by the optical nerve, there were also tumor cells in resected margin; patient 2 had initially disseminated disease with cervical lymph nodes involvement, and patient 3 had bilateral disease with extrabulbar and intracranial penetration of the right eye tumor via optical nerve with involvement of ipsilateral chiasma and optical tract.

Table 1. Initial characteristics of our retinoblastoma patients and autologous HSCT details

Sergeenko-tab01.jpg

In order to successfully collect autologous peripheral stem cells according to local standards, all the patients received granulocyte colony-stimulating factor (G-CSF). Stem cell mobilization started 14 days prior to the next chemotherapy course upon recovery of the blood counts. G-CSF was injected subcutaneously for 4-7 days at 5-10 mcg/kg/day, the last dose applied 2-4 hours prior to apheresis procedure. The median yield of СD34+ cells was 2×106/kg body mass.

Patient 1 is a six-year-old child with left-sided retinoblastoma. In October 2020, eye enucleation was performed, followed by microsurgical removal of the left optical nerve by orbitozygomatic approach (pathological study showed tumor cells at the resection line of optical nerve, thus corresponding to high-risk case), with 6 subsequent chemotherapy courses. No staging was performed at the clinic, where the patient was initially treated.

Patient 2, three-year-old, was diagnosed with left-sided retinoblastoma TхNxMх. In October 2020, left eye enucleation was performed. Subsequent staging showed disease progression with metastatic involvement of cervical lymph nodes. Therefore, 4 chemotherapy courses according to NB 2004 protocol and 2 СVC courses were performed. The patient was re-staged as TxN1.

Patient 3, three-year-old, manifested with bilateral RB: OD – group Е, stage T4N0M1; OS – Group B, stage T1N0M1. He received a complex treatment program consisting of 5 systemic chemotherapy courses and 5 courses of intrathecal chemotherapy (methotrexate + prednisolone/thiotepa), surgical treatment (right-sided bone plastic pterional craniotomy with prechiasmal optical nerve resection and eye enucleation) performed in December 2020.

Pre-transplant consolidation regimen consisted of carboplatin 1250 mg/m2, etoposide 1750 mg/m2, and cyclophosphamide 6000 mg/m2. Patients 1 and 2 have tolerated the high-dose regimen well. In patient 3, some complications were registered, i.e., anorexia, nausea, vomiting, and an episode of seizures in presence of arterial hypertension and hyponatremia, the most likely causes of this neurological disorder. The seizures were canceled by anticonvulsants, antihypertensive therapy and infusion of electrolytes. No signs of hemorrhage or ischemia were seen on the brain CT scan.

The HSCT procedure was well tolerated in all cases. During early post-transplant period, all patients received standard supportive therapy (decontamination, prophylaxis of herpesvirus infection, pneumocistic and fungal infections). The leukocyte engraftment was registered on day 11, 14, and 17; in all the cases, G-CSF was injected subcutaneously (5 µg/kg/day). All the patients became transfusion-independent since 14 days post-transplant. There were complaints for nausea and vomiting over the early post-transplant period. In all the cases, distinct infectious and toxic complications were developed, i.e., grade 1-3 oral mucositis, grade 2 neutropenic enterocolitis, and febrile neutropenias. Central line-associated bloodstream infection (CLABSI) was registered in one case. All these complications were controlled by standard therapies. All the patients were subsequently discharged in good clinical condition. The median follow-up is currently 6 (4-10) months. The clinical outcomes of the transplants are shown in Table 2.

Table 2. Results of autologous HSCT in the patients included in the study

Sergeenko-tab02.jpg

Discussion

High-dose consolidation chemotherapy was performed in 3 children with high-risk RB admitted to N. N. Blokhin National Medical Research Center of Oncology. All the patients have well tolerated the treatment. The blood counts recovered relatively early. All complications were successfully treated with standard antibacterial therapy within 14 days post-transplant. Then the patients were discharged from the BMT unit to the Somatic Department for further follow-up. The third patient developed a progressive CNS disease 6 months after auto-HSCT and subsequently died. Patients 1 and 2 have currently no signs of disease progression at the median follow-up of 6 (4-10) months.

Since the dose-intensive therapy is recommended in disseminated RB [9], we used a conditioning regimen including carboplatin, etoposide and cyclophosphamide. This schedule has already been successfully used in international cohorts and proved to be effective in cases of disseminated disease [14, 16-19]. The patients included in our series have also well tolerated the high-dose regimen which corresponds to the published data [20, 23, 26] and may confirm safety of HDCT procedure, even in heavily pretreated children with lower performance score.

Unfortunately, there is lack of effective and curative treatment methods for the patients with CNS involvement despite multiple options used by different centers, with HDCST with auto-HSCT included [9, 20]. We must search for new approaches, or modify the existing methods in order to improve our results in high-risk RB. Our experience shows that concentration of several RB patients with high-risk disease at a single center provides the necessary experience allowing most effective treatment [12, 20-23, 25].

During the last decade, some major shifts occur in the complex treatment of children with RB. Auto-HSCT became an integral part of the overall treatment strategy. Our case series demonstrate acceptable toxicity of this treatment mode, with side effects observed, mostly, in the form of gastrointestinal toxicity. No transplant-related mortality was registered. Therefore, this approach may be considered relatively safe. We should, however, keep in mind that clinical results in patients with CNS metastases are still unsatisfactory. Hence, we should perform more strict selection of the candidates for auto-HSCT. Of course, in order to obtain more reliable results, much larger groups should be studied, which is more likely in context of multicenter studies coordinated on national level.

Conclusion

Auto-HSCT may be considered a feasible, effective and well-tolerated consolidation option for patients with high-risk RB. A larger cohort study with longer follow-up is required to accurately evaluate its effectiveness. This may be achieved in multicenter cooperation.

Conflicts of interest

None reported.

References

  1. Sun J, Xi H, Shao Q, Liu Q. Biomarkers in retinoblastoma. Int J Ophthalmol. 2019; 13(2): 325-341. doi: 10.18240/ijo.2020.02.18
  2. Saakyan SV. Retinoblastoma (clinics, diagnostics, treatment). Moscow, Meditsina Publishers. 2005; 200 p. (In Russian).
  3. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995; 75(8): 2186-2195. doi: 10.1002/1097-0142(19950415)75:8<2186::AID-CNCR2820750825>3.0.CO;2-F
  4. Kaewkhaw R, Rojanaporn D. Retinoblastoma: Etiology, modeling, and treatment. Cancers. 2020; 12(8)8. doi: 10.3390/cancers12082304
  5. Berry JL, Biegel JA, Slavotinek A, Tirnauer JS, Armsby C, Shah S. Gene test interpretation: RB1. Up to date. Oct 2021. https://www.wolterskluwer.com/en/solutions/uptodate/
  6. Shields J, Shields C. Retinoblastoma: introduction, genetics, clinical features, classification. In: Shields J, Shields C, Eds. Atlas of Intraocular Tumors, 3rd ed., Philadelphia: Lippinocott, Wolters Kluwer; 2016. p. 311-314.
  7. Ushakova TL, Тrofimov IA, Gorovtsova OV, Yarovoy AA, Saakyan SV, Letyagin IA, et al. A new era of organ-preserving treatment in pediatric intraocular retinoblastoma in Russia: a multicenter cohort study. Oncopediatrics 2018;5(1):51-69. (In Russian).
    doi: 10.15690/onco.v5i1.1866
  8. Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, Abramson DH, Shields CL, Chantada GL, Njuguna F, Gallie BL. Retinoblastoma. Nat Rev Dis Primers. 2015 Aug 27;1:15021. doi: 10.1038/nrdp.2015.21
  9. Retinoblastoma: Clinical Guidelines (Russian Society of Pediatric Oncologists, Assocoation of Ophtalmologists). 2017; ID: КР71 (In Russian).
  10. Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediat Ophthalmol Strabismus. 1999; 36(1): 8-18. PMID: 9972509X
  11. Lee S, Yoo K, Sung K Kim J, Cho E, Koo H, Chung S, Kang S, Oh S, Ham D, Kim Y. Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma. Bone Marrow Transplant. 2008; 42(6): 385-391.
    doi: 10.1038/bmt.2008.181
  12. Matsubara H, Makimoto A, Higa T, Kawamoto H, Sakiyama S, Hosono A, Takayama J, Takaue Y, Murayama S, Sumi M, Kaneko A, Ohira M. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant. 2005; 35 (8): 763-766. doi: 10.1038/sj.bmt.1704882
  13. Ancona-Lezama D, Dalvin L, Shields C. Modern treatment of retinoblastoma: A 2020 review. Ind J Ophthalmol. 2020; 68(11):2356-2365. doi: 10.4103/ijo.IJO_721_20
  14. White L. Chemotherapy for retinoblastoma: where do we go from here?: a review of published literature and meeting abstracts, including discussions during the Vth International Symposium on Retinoblastoma, Oct 1991. Ophthalmic Paediatr Genet. 1991; 12(3): 115-130. doi: 10.3109/13816819109029393
  15. Seeger RC, Reynolds CP. Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplantation. Pediat Clin North Amer. 1991; 38: 393-424. doi: 10.1016/S0031-3955(16)38084-1
  16. Palma J, Sasso D, Dufort G, Koop K, Sampor C, Diez B, Richard L, Castillo L, Chantada G. Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America. Bone Marrow Transplant. 2012; 47(4): 522-527. doi: 10.1038/bmt.2011.108
  17. Stepanyan NG, Sidorova NV, Rubanskaya MV, Tupitsyn NN, Matinyan NV, Kirgizov KI, Varfolomeeva SR. Optimization of methods for collecting peripheral hematopoietic stem cells in children with cancer: literature review. Russian Journal of Pediatric Hematology аnd Oncology 2020;7(2):78-85. (In Russian.). doi: 10.21682/2311-1267-2020-7-2-78-85
  18. Mohty M, Hübel K, Kröger N, Aljurf M, Apperley J, Basak GW, Bazarbachi A, Douglas K, Gabriel I, Garderet L, et al. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation. Вone Marrow Transplant. 2014; 49(7): 865-872. doi: 10.1038/bmt.2014.39
  19. Zhernyakova AA, Chubukina ZhV, Zapreeva IM, Tiranova SA, Sel’tser AV, Semenova NYu, Bessmel’tsev SS, Chechetkin AV, Gritsaev SV, Kostroma II. Hematopoietic stem cell collection in multiple myeloma patients: influence of the lenalidomide-based therapy and mobilization regimen prior to auto-HSCT II, Klinicheskaya Onkogematologiya/Clinical Oncohematology. 2018; 11(2): 192-197 (In Russian.). doi: 10.21320/2500-2139-2018-11-2-192-197
  20. Namouni F, Doz F, Tanguy ML, Quintana E, J Michon, Pacquement H, Bouffet E, Gentet JC, Plantaz D, Lutz P, Vannier JP, Validire P, Neuenschwander S, Desjardins L, Zucker JM. High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer. 1997; 33(14): 2368-2375. doi: 10.1016/s0959-8049(97)10019-3
  21. Kremens B, Wieland R, Reinhard H, Neubert D, Beck JD, Klingebiel T, Bornfeld N, Havers W. Retinoblastoma: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma; Bone Marrow Transplant. 2003; 31, 281-284.
    doi: 10.1038/sj.bmt.1703832
  22. Clarissa A, Sutandi N, Abdul Fath A. Stem-cell therapy following high-dose chemotherapy in advanced retinoblastoma: A systematic review. Asia-Pacific J Ophthalmol. 2021; 10(4): 397-407. doi: 10.1097/APO.0000000000000372
  23. Jaradat I, Mubiden R, Salem A, Abdel-Rahman F, Al-Ahmad I, Almousa A. High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review. Hematol Oncol Stem Cell Ther. 2012; 5:107-117.
    doi: 10.5144/1658-3876.2012.107
  24. Ushakova TL, Dolgopolov IS, Gorovtsova OV, Matveeva II, Pavlovskaya AI, Glekov IV, Pimenov RI, Boyarshinov VK, Mentkevich GL, Polyakov VG. Analysis of treatment outcomes for high-risk retinoblastoma. Pediatric Oncology. 2009; 3-4: 61-67. (In Russian).
  25. Yamanaka R, Hayano A, Takashima Y. Trilateral retinoblastoma: A systematic review of 211 cases. Neurosurg Rev. 2019; 42(1):39-48. doi: 10.1007/s10143-017-0890-4
  26. Carreras E, Dufour C, Mohty M, Kroger N. Hematopoietic stem cell transplantation and cellular therapies. EBMT Handbook, 2019:117-130.

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Introduction

General issues

Retinoblastoma (RB) is the most common pediatric eye cancer developing from immature cells of the retina [1-3]. In infants it is most commonly associated with biallelic mutation of RB1 gene [4]. In these cases the tumor may involve one, as well as both, eyes and also may produce synchronous or metachronous ectopic lesions in the pineal gland (pineoblastoma). Based on extent of involvement these forms are classified as uni- bi- and trilateral [5]. The RB incidence is 1 in 15000-18000 newborn and about 5000 new cases are registered each year [6].

Most treatment programs in patients with RB combine different treatment modalities, which are chosen based in risk group and extent of tumor involvement [7, 8]. In high-risk patients the tumor spreads beyond the eye often developing ectopic metastatic lesions, which may become lethal if no systemic method is applied in addition to local control measures [9]. During the last few decades a number of methods were used to control the disease including systemic polychemotherapy (CT), external beam radiation therapy (EBRT) and other local treatment methods. However, these standard measures may still be ineffective in some cases, so we are ever in need of new global strategies aimed at survival improvement in high-risk RB.

High-dose chemotherapy with autologous hemopoietic stem cell transplantation in patients with RB

In developed countries most children with RB are referred to pediatric oncologist in early stages. Most advanced cases with extraocular and metastatic RB are therefore treated in developing countries. Most deaths in RB patients are due to metastatic disease, pineoblastoma development or secondary cancers, which are most often seen in patients with hereditary forms of disease. The treatment schedule is always personalized in accordance to individual tumor characteristics. Up to this moment the main therapeutic modalities are systemic polychemotherapy (PCT) and local one, which may be delivered as inraarterial chemotherapy (IAC) or intravitreal one (IVitC). There are also additional local control methods such as transpupillary thermotherapy (TTT), cryotherapy, and brachytherapy or enucleation, which may be performed in cases with optical nerve or choroidal invasion [10, 11].

Each of these methods has certain disadvantages and unwanted sequelae. Most clinics limit the use of external beam radiation therapy (EBRT) due to the risk of secondary cancers, facial bones growth disturbance and subsequent deformations. Enucleation is a radical surgical technique based on entire eye removal [12]. While chemoreduction (tumor shrinking in response to systemic chemotherapy) and local control measures are effective in patients with intraocular RB and have fewer adverse effects, they are less effective in patients high-risk disease characterized by initial extraocualr disease, tumor relapse involving extra- or intraocular structures (including distant metastases), tumor invasion of the optic nerve resection line, trilateral RB. As a result, high-risk patients may need more aggressive treatment modalities [10-13]. Therefore, there is still an ongoing search for more effective strategies able to improve long-term survival and quality of life in this cohort.

RB is a highly chemosensitive tumor with exponential log kill curve in tumor cell cultures, so dose-intensive consolidation regimens are expected to increase the overall treatment effectiveness. High-dose chemotherapy (HDCT) is being considered a viable option [14-17]. However, this method is associated with some drawbacks due to its toxic effects, primarily profound myelosuppression, which may lead to serious or even fatal complications if no attempts for bone marrow reconstitution via cryopreserved autologous hemopoietic stem cells (bone marrow or peripheral blood precursors) reinfusion are taken. Autologous hemopoietic stem cells transplantation (auto-HSCT) is the most effective measure to limit secondary myelotoxicity and allows using much higher peak doses of cytostatics potentially increasing RB treatment effectiveness [16].

A number of researchers have demonstrated different high-dose regimens effectiveness in auto-HSCT settings. These regimens are used as consolidation in patients with high-risk pediatric solid tumors as part of a multidisciplinary approach incorporating also surgical treatment and standard dose chemotherapy [12], in some cases they may also help to avoid bilateral enucleation preserving the vision in RB patients.

There is currently no consensus on optimal treatment regimen in late stage RB, although most experts agree on the use of several drugs in combination. These drugs, which may be potentially effective in RB patients, include platinum agents (carboplatin and cisplatin), etoposide, vincristine, cyclophosphamide and anthracyclines [18, 19]. Vincristine, etoposide and carboplatin are characterized by better eye penetration and are therefore most often used in conditioning regimens prior to auto-HSCT.

World experience with auto-HSCT in the RB patients

The HDCT with auto-HSCT is now being used in patients with high-risk RB for more than 20 years. The first patient cohort was described in 1997 by French researchers from Institut Curie (Paris). The HDCT was performed as consolidation for high-risk patients (initially extraocular disease, relapse or tumor invasion of optical nerve resection line). A total of 25 patents received a regimen consisting of carboplatin (250 mg/m2/day from day 1 day 5 in 6 initially high-risk patients after enucleation and standard-dose CT and 250 mg/m2/day in 19 patients with chemosensitive relapse), etoposide (350 mg/m2/day from day 1 to day 5), and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) with subsequent autologous stem cells reinfusion. The 3-year disease-free survival was 67.1%. In 7 of 19 patients with relapse it developed in central nervous system. All patients with CNS relapse except one died of disease progression. The main toxic complications were hematological toxicity and gastrointestinal mucositis (oral mucositis, enterocolitis). Also, 2 of 13 patients developed grade III-IV ototoxicity. In one case a grade I acute re-versible cardiotoxicity was registered. Therefore, while high-dose regimen consisting of carboplatin, etoposide and cyclophosphamide seemed a feasible strategy in high-risk RB patients, especially those with bones and bone marrow involvement, it did not improve the results in cases with CNS involvement [20].

In 2003, a group of German researchers published their data on auto-HSCT outcome in 5 RB patients, 4 of them with bone marrow metastases and one with extraorbital involvement. All patients have achieved response after previous enucleation and standard-dose chemotherapy, a child with extraorbital tumor also received EBRT. In 4 cases the conditioning regimen consisted of thiotepa (900 mg/m2), etoposide (40 mg/kg), and carboplatin (1.5 g/m2), and in 1 case it included carmustine (300 mg/m2), cyclophosphamide (6.8 g/m2), and etoposide (1.6 g/m2). A rapid hemopoiesis reconstitution was observed in all 5 cases. Main toxic complications were mucositis and cytopenia with consequent infections. None of the patients died due to regimen toxicity or experienced any long-term sequelae. A patient with initial extrorbital disease developed a relapse with meningheal involvement 10 months after auto-HSCT, but was salvaged by surgery and standard-dose chemotherapy and remained in remission after 105 months follow-up. Four other patients were still in remission 107, 57, 9, and 8 months after auto-HSCT. The conditioning regimen with thiotepa, etoposide and carboplatin may be a good option for children with extrabulbar or disseminated chemosensitive RB [21].

In 2021, a group of authors from the Faculty of Medicine, University of Indonesia published a review on available data in auto-HSCT for high-risk RB patients [22]. A total of 35 publications describing 160 patients were included. After auto-HSCT 108 of 160 (67.5%) patients are alive and disease free at the last follow-up. The secondary cancer developed in 16 of 160 (10%) patients, which is a comparably low rate. The most common side effects were hematological and gastrointestinal toxicity. As a whole, 41 of 160 (25.6%) died with signs of active disease due to primary CNS involvement (in 25 of 41; 60.9%), disease relapse (12 of 41; 29.3%), or secondary cancer (3 of 41; 7.3%). Only in 1 of 41 (2.4%) cases there was evident metastatic involvement outside CNS. Only 11 of 160 (6.7%) were alive, but not disease-free, at the last fol-low-up. According to this review, the use of HDCT with subsequent auto-HSCT is effective in patients with disseminated RB as 108 of 160 (67.5%) of auto-HSCT recipients stayed alive and disease-free. It corresponds to the data published in previous review by Jaradat I. et al. (2012) [23].

Russian experience with auto-HSCT in children with retinoblastoma

There are several large Russian centers treating most children with RB, i.e., the Helmholtz National Medical Ophthalmology Research Center, S. N. Fedorov National Medical Research Center for Eye Microsurgery, and Research Institute of Pediatric Oncology and Hematology at the N. N. Blokhin National Medical Research Center of Oncology. However, only the latter institution performed HDCT with auto-HSCT in these patients.

There is a description of earlier (2001-2008) experience of auto-HSCT performed in a cohort of 15 RB patients in the Institute of Pediatric Oncology and Hematology at the N. N.Blokhin National Medical Research Center of Oncology. The treatment program included IVitC, EBRT, and high-dose consolidation with busulfan and melphalan followed by auto-HSCT. During the follow-up 1 of 15 patients died of sepsis and 7 of disease progression with CNS involvement. Seven patients are currently alive (5 children with stage II, one with stage IIIа, one with stage IIIb). The new strategy allowed to double the disease- and event-free survival rate of RB patients. The overall survival in high-risk group (optical nerve resection line invasion, extrascleral spread of the tumor) reached 71.4%. The researchers concluded that HDCT with auto-HSCT is an effective method in patients with stage II and III, although more effective options are still warranted for children with disseminated RB [24].

Clinical cases

We present a series of 3 clinical cases of children (aged 3-6 years) with high-risk RB receiving HDCT with auto-HSCT treated at the Pediatric Hematology and Oncology Department (BMT unit) at N. N. Blokhin National Medical Research Center of Oncology (February to October 2021). All the patients achieved remission prior to HSCT after surgery and standard-dose systemic polychemotherapy. The patients’ characteristics are listed in Table 1. Patient 1 had initially demonstrated extraocular tumor growth by the optical nerve, there were also tumor cells in resected margin; patient 2 had initially disseminated disease with cervical lymph nodes involvement, and patient 3 had bilateral disease with extrabulbar and intracranial penetration of the right eye tumor via optical nerve with involvement of ipsilateral chiasma and optical tract.

Table 1. Initial characteristics of our retinoblastoma patients and autologous HSCT details

Sergeenko-tab01.jpg

In order to successfully collect autologous peripheral stem cells according to local standards, all the patients received granulocyte colony-stimulating factor (G-CSF). Stem cell mobilization started 14 days prior to the next chemotherapy course upon recovery of the blood counts. G-CSF was injected subcutaneously for 4-7 days at 5-10 mcg/kg/day, the last dose applied 2-4 hours prior to apheresis procedure. The median yield of СD34+ cells was 2×106/kg body mass.

Patient 1 is a six-year-old child with left-sided retinoblastoma. In October 2020, eye enucleation was performed, followed by microsurgical removal of the left optical nerve by orbitozygomatic approach (pathological study showed tumor cells at the resection line of optical nerve, thus corresponding to high-risk case), with 6 subsequent chemotherapy courses. No staging was performed at the clinic, where the patient was initially treated.

Patient 2, three-year-old, was diagnosed with left-sided retinoblastoma TхNxMх. In October 2020, left eye enucleation was performed. Subsequent staging showed disease progression with metastatic involvement of cervical lymph nodes. Therefore, 4 chemotherapy courses according to NB 2004 protocol and 2 СVC courses were performed. The patient was re-staged as TxN1.

Patient 3, three-year-old, manifested with bilateral RB: OD – group Е, stage T4N0M1; OS – Group B, stage T1N0M1. He received a complex treatment program consisting of 5 systemic chemotherapy courses and 5 courses of intrathecal chemotherapy (methotrexate + prednisolone/thiotepa), surgical treatment (right-sided bone plastic pterional craniotomy with prechiasmal optical nerve resection and eye enucleation) performed in December 2020.

Pre-transplant consolidation regimen consisted of carboplatin 1250 mg/m2, etoposide 1750 mg/m2, and cyclophosphamide 6000 mg/m2. Patients 1 and 2 have tolerated the high-dose regimen well. In patient 3, some complications were registered, i.e., anorexia, nausea, vomiting, and an episode of seizures in presence of arterial hypertension and hyponatremia, the most likely causes of this neurological disorder. The seizures were canceled by anticonvulsants, antihypertensive therapy and infusion of electrolytes. No signs of hemorrhage or ischemia were seen on the brain CT scan.

The HSCT procedure was well tolerated in all cases. During early post-transplant period, all patients received standard supportive therapy (decontamination, prophylaxis of herpesvirus infection, pneumocistic and fungal infections). The leukocyte engraftment was registered on day 11, 14, and 17; in all the cases, G-CSF was injected subcutaneously (5 µg/kg/day). All the patients became transfusion-independent since 14 days post-transplant. There were complaints for nausea and vomiting over the early post-transplant period. In all the cases, distinct infectious and toxic complications were developed, i.e., grade 1-3 oral mucositis, grade 2 neutropenic enterocolitis, and febrile neutropenias. Central line-associated bloodstream infection (CLABSI) was registered in one case. All these complications were controlled by standard therapies. All the patients were subsequently discharged in good clinical condition. The median follow-up is currently 6 (4-10) months. The clinical outcomes of the transplants are shown in Table 2.

Table 2. Results of autologous HSCT in the patients included in the study

Sergeenko-tab02.jpg

Discussion

High-dose consolidation chemotherapy was performed in 3 children with high-risk RB admitted to N. N. Blokhin National Medical Research Center of Oncology. All the patients have well tolerated the treatment. The blood counts recovered relatively early. All complications were successfully treated with standard antibacterial therapy within 14 days post-transplant. Then the patients were discharged from the BMT unit to the Somatic Department for further follow-up. The third patient developed a progressive CNS disease 6 months after auto-HSCT and subsequently died. Patients 1 and 2 have currently no signs of disease progression at the median follow-up of 6 (4-10) months.

Since the dose-intensive therapy is recommended in disseminated RB [9], we used a conditioning regimen including carboplatin, etoposide and cyclophosphamide. This schedule has already been successfully used in international cohorts and proved to be effective in cases of disseminated disease [14, 16-19]. The patients included in our series have also well tolerated the high-dose regimen which corresponds to the published data [20, 23, 26] and may confirm safety of HDCT procedure, even in heavily pretreated children with lower performance score.

Unfortunately, there is lack of effective and curative treatment methods for the patients with CNS involvement despite multiple options used by different centers, with HDCST with auto-HSCT included [9, 20]. We must search for new approaches, or modify the existing methods in order to improve our results in high-risk RB. Our experience shows that concentration of several RB patients with high-risk disease at a single center provides the necessary experience allowing most effective treatment [12, 20-23, 25].

During the last decade, some major shifts occur in the complex treatment of children with RB. Auto-HSCT became an integral part of the overall treatment strategy. Our case series demonstrate acceptable toxicity of this treatment mode, with side effects observed, mostly, in the form of gastrointestinal toxicity. No transplant-related mortality was registered. Therefore, this approach may be considered relatively safe. We should, however, keep in mind that clinical results in patients with CNS metastases are still unsatisfactory. Hence, we should perform more strict selection of the candidates for auto-HSCT. Of course, in order to obtain more reliable results, much larger groups should be studied, which is more likely in context of multicenter studies coordinated on national level.

Conclusion

Auto-HSCT may be considered a feasible, effective and well-tolerated consolidation option for patients with high-risk RB. A larger cohort study with longer follow-up is required to accurately evaluate its effectiveness. This may be achieved in multicenter cooperation.

Conflicts of interest

None reported.

References

  1. Sun J, Xi H, Shao Q, Liu Q. Biomarkers in retinoblastoma. Int J Ophthalmol. 2019; 13(2): 325-341. doi: 10.18240/ijo.2020.02.18
  2. Saakyan SV. Retinoblastoma (clinics, diagnostics, treatment). Moscow, Meditsina Publishers. 2005; 200 p. (In Russian).
  3. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995; 75(8): 2186-2195. doi: 10.1002/1097-0142(19950415)75:8<2186::AID-CNCR2820750825>3.0.CO;2-F
  4. Kaewkhaw R, Rojanaporn D. Retinoblastoma: Etiology, modeling, and treatment. Cancers. 2020; 12(8)8. doi: 10.3390/cancers12082304
  5. Berry JL, Biegel JA, Slavotinek A, Tirnauer JS, Armsby C, Shah S. Gene test interpretation: RB1. Up to date. Oct 2021. https://www.wolterskluwer.com/en/solutions/uptodate/
  6. Shields J, Shields C. Retinoblastoma: introduction, genetics, clinical features, classification. In: Shields J, Shields C, Eds. Atlas of Intraocular Tumors, 3rd ed., Philadelphia: Lippinocott, Wolters Kluwer; 2016. p. 311-314.
  7. Ushakova TL, Тrofimov IA, Gorovtsova OV, Yarovoy AA, Saakyan SV, Letyagin IA, et al. A new era of organ-preserving treatment in pediatric intraocular retinoblastoma in Russia: a multicenter cohort study. Oncopediatrics 2018;5(1):51-69. (In Russian).
    doi: 10.15690/onco.v5i1.1866
  8. Dimaras H, Corson TW, Cobrinik D, White A, Zhao J, Munier FL, Abramson DH, Shields CL, Chantada GL, Njuguna F, Gallie BL. Retinoblastoma. Nat Rev Dis Primers. 2015 Aug 27;1:15021. doi: 10.1038/nrdp.2015.21
  9. Retinoblastoma: Clinical Guidelines (Russian Society of Pediatric Oncologists, Assocoation of Ophtalmologists). 2017; ID: КР71 (In Russian).
  10. Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediat Ophthalmol Strabismus. 1999; 36(1): 8-18. PMID: 9972509X
  11. Lee S, Yoo K, Sung K Kim J, Cho E, Koo H, Chung S, Kang S, Oh S, Ham D, Kim Y. Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma. Bone Marrow Transplant. 2008; 42(6): 385-391.
    doi: 10.1038/bmt.2008.181
  12. Matsubara H, Makimoto A, Higa T, Kawamoto H, Sakiyama S, Hosono A, Takayama J, Takaue Y, Murayama S, Sumi M, Kaneko A, Ohira M. A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant. 2005; 35 (8): 763-766. doi: 10.1038/sj.bmt.1704882
  13. Ancona-Lezama D, Dalvin L, Shields C. Modern treatment of retinoblastoma: A 2020 review. Ind J Ophthalmol. 2020; 68(11):2356-2365. doi: 10.4103/ijo.IJO_721_20
  14. White L. Chemotherapy for retinoblastoma: where do we go from here?: a review of published literature and meeting abstracts, including discussions during the Vth International Symposium on Retinoblastoma, Oct 1991. Ophthalmic Paediatr Genet. 1991; 12(3): 115-130. doi: 10.3109/13816819109029393
  15. Seeger RC, Reynolds CP. Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplantation. Pediat Clin North Amer. 1991; 38: 393-424. doi: 10.1016/S0031-3955(16)38084-1
  16. Palma J, Sasso D, Dufort G, Koop K, Sampor C, Diez B, Richard L, Castillo L, Chantada G. Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America. Bone Marrow Transplant. 2012; 47(4): 522-527. doi: 10.1038/bmt.2011.108
  17. Stepanyan NG, Sidorova NV, Rubanskaya MV, Tupitsyn NN, Matinyan NV, Kirgizov KI, Varfolomeeva SR. Optimization of methods for collecting peripheral hematopoietic stem cells in children with cancer: literature review. Russian Journal of Pediatric Hematology аnd Oncology 2020;7(2):78-85. (In Russian.). doi: 10.21682/2311-1267-2020-7-2-78-85
  18. Mohty M, Hübel K, Kröger N, Aljurf M, Apperley J, Basak GW, Bazarbachi A, Douglas K, Gabriel I, Garderet L, et al. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation. Вone Marrow Transplant. 2014; 49(7): 865-872. doi: 10.1038/bmt.2014.39
  19. Zhernyakova AA, Chubukina ZhV, Zapreeva IM, Tiranova SA, Sel’tser AV, Semenova NYu, Bessmel’tsev SS, Chechetkin AV, Gritsaev SV, Kostroma II. Hematopoietic stem cell collection in multiple myeloma patients: influence of the lenalidomide-based therapy and mobilization regimen prior to auto-HSCT II, Klinicheskaya Onkogematologiya/Clinical Oncohematology. 2018; 11(2): 192-197 (In Russian.). doi: 10.21320/2500-2139-2018-11-2-192-197
  20. Namouni F, Doz F, Tanguy ML, Quintana E, J Michon, Pacquement H, Bouffet E, Gentet JC, Plantaz D, Lutz P, Vannier JP, Validire P, Neuenschwander S, Desjardins L, Zucker JM. High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study. Eur J Cancer. 1997; 33(14): 2368-2375. doi: 10.1016/s0959-8049(97)10019-3
  21. Kremens B, Wieland R, Reinhard H, Neubert D, Beck JD, Klingebiel T, Bornfeld N, Havers W. Retinoblastoma: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma; Bone Marrow Transplant. 2003; 31, 281-284.
    doi: 10.1038/sj.bmt.1703832
  22. Clarissa A, Sutandi N, Abdul Fath A. Stem-cell therapy following high-dose chemotherapy in advanced retinoblastoma: A systematic review. Asia-Pacific J Ophthalmol. 2021; 10(4): 397-407. doi: 10.1097/APO.0000000000000372
  23. Jaradat I, Mubiden R, Salem A, Abdel-Rahman F, Al-Ahmad I, Almousa A. High-dose chemotherapy followed by stem cell transplantation in the management of retinoblastoma: a systematic review. Hematol Oncol Stem Cell Ther. 2012; 5:107-117.
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  24. Ushakova TL, Dolgopolov IS, Gorovtsova OV, Matveeva II, Pavlovskaya AI, Glekov IV, Pimenov RI, Boyarshinov VK, Mentkevich GL, Polyakov VG. Analysis of treatment outcomes for high-risk retinoblastoma. Pediatric Oncology. 2009; 3-4: 61-67. (In Russian).
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Сергеенко<sup>1,3</sup>, Яна Ю. Докучаева<sup>1</sup>, Ирина О. Костарева<sup>1</sup>, Тим З. Алиев<sup>1</sup>, Анна Ю. Елфимова<sup>1</sup>, Николай Г. Степанян<sup>1</sup>, Юрий В. Лозован<sup>1</sup>, Наталья А. Бурлака<sup>1</sup>, Наталья В. Сидорова<sup>2</sup>, Елена Б. Мачнева<sup>1,2</sup>, Татьяна В. Горбунова<sup>1,5</sup>, Татьяна Л. Ушакова<sup>1,3</sup>, Владимир Г. Поляков<sup>1,3,4,5</sup>, Кирилл И. Киргизов<sup>1,5</sup>, Светлана Р. Варфоломеева<sup>1,2,5</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(727) "

Карина А. Сергеенко1,3, Яна Ю. Докучаева1, Ирина О. Костарева1, Тим З. Алиев1, Анна Ю. Елфимова1, Николай Г. Степанян1, Юрий В. Лозован1, Наталья А. Бурлака1, Наталья В. Сидорова2, Елена Б. Мачнева1,2, Татьяна В. Горбунова1,5, Татьяна Л. Ушакова1,3, Владимир Г. Поляков1,3,4,5, Кирилл И. Киргизов1,5, Светлана Р. Варфоломеева1,2,5

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1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России, Москва, Россия
2 Обособленное структурное подразделение Российская детская клиническая больница ФГАОУ ВО «РНИМУ им. Н. И. Пирогова» Минздрава России, Москва, Россия
3 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования», Москва, Россия
4 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н. И. Пирогова» Минздрава России, Москва, Россия
5 Кафедра последипломного образования врачей НМИЦ онкологии им. Н. Н. Блохина, Москва, 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) "28507" ["VALUE"]=> array(2) { ["TEXT"]=> string(3815) "<p style="text-align: justify;">Ретинобластома (РБ) – самое частое злокачественное новообразование (ЗНО) органа зрения у детей, составляет 10-15% от всех ЗНО детей первого года жизни. Несмотря на наличие стандартных подходов к лечению детей с РБ, в ряде случаев стандартные методы могут оказаться неэффективными, что требует поиска новых стратегий для улучшения выживаемости у детей группы высокого риска. В качестве интенсификации может использоваться высокодозная химиотерапия с последующей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК). Цель нашей работы – демонстрация опыта НМИЦ онкологии им. Н. Н. Блохина на примере случаев ауто-ТГСК у пациентов с РБ.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В 2021 г. в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина 3 пациента с РБ высокой группы риска получили в режиме кондиционирования: Карбоплатин 1250 мг/кв.м., Этопозид 1750 мг/кв.м., Циклофосфамид 6 гр/кв.м. с последующей ауто-ТГСК.</p> <h3>Результаты</h3> <p style="text-align: justify;">Восстановление гемопоэза произошло на 11, 14 и 17 сутки после ауто-ТГСК. Осложнения раннего посттрансплантационного периода: орофарингеальный мукозит, нейтропенический энтероколит, фебрильная нейтропения. В периоде кондиционирования у одного пациента зафискирован эпизод тонико-клонических судорог на фоне гипонатриемии, эпизод купирован, более не повторялся. У одного пациента констатирована прогрессия заболевания, что привело к летальному исходу. Два пациента – без признаков рецидива. Медиана наблюдения 6 ( 4-10) месяцев.</p> <h3>Выводы</h3> <p style="text-align: justify;">Ауто-ТГСК для пациентов с РБ группы высокого риска может рассматриваться как консолидация, в виду хорошей переносимости и эффективности. Требуется включение в исследование большего числа пациентов, длительное наблюдение, а также обмен опытом между трансплантационными центрами.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, ретинобластома, дети, высокодозная химиотерапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3657) "

Ретинобластома (РБ) – самое частое злокачественное новообразование (ЗНО) органа зрения у детей, составляет 10-15% от всех ЗНО детей первого года жизни. Несмотря на наличие стандартных подходов к лечению детей с РБ, в ряде случаев стандартные методы могут оказаться неэффективными, что требует поиска новых стратегий для улучшения выживаемости у детей группы высокого риска. В качестве интенсификации может использоваться высокодозная химиотерапия с последующей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК). Цель нашей работы – демонстрация опыта НМИЦ онкологии им. Н. Н. Блохина на примере случаев ауто-ТГСК у пациентов с РБ.

Материалы и методы

В 2021 г. в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина 3 пациента с РБ высокой группы риска получили в режиме кондиционирования: Карбоплатин 1250 мг/кв.м., Этопозид 1750 мг/кв.м., Циклофосфамид 6 гр/кв.м. с последующей ауто-ТГСК.

Результаты

Восстановление гемопоэза произошло на 11, 14 и 17 сутки после ауто-ТГСК. Осложнения раннего посттрансплантационного периода: орофарингеальный мукозит, нейтропенический энтероколит, фебрильная нейтропения. В периоде кондиционирования у одного пациента зафискирован эпизод тонико-клонических судорог на фоне гипонатриемии, эпизод купирован, более не повторялся. У одного пациента констатирована прогрессия заболевания, что привело к летальному исходу. Два пациента – без признаков рецидива. Медиана наблюдения 6 ( 4-10) месяцев.

Выводы

Ауто-ТГСК для пациентов с РБ группы высокого риска может рассматриваться как консолидация, в виду хорошей переносимости и эффективности. Требуется включение в исследование большего числа пациентов, длительное наблюдение, а также обмен опытом между трансплантационными центрами.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ретинобластома, дети, высокодозная химиотерапия.

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Karina A. Sergeenko1,3, Yana Yu. Dokuchaeva1, Irina O. Kostareva1, Tim Z. Aliev1, Anna Yu. Elfimova1, Nikolay G. Stepanian1, Yury V. Lozovan1, Natalya A. Burlaka1, Natalya V. Sidorova2, Elena B. Machneva1,2, Tatyana V. Gorbunova1,5, Tatyana L. Ushakova1,3, Vladimir G. Polyakov1,3,4,5, Kirill I. Kirgizov1,5, Svetlana R. Varfolomeeva1,2,5

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1 N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
2 Russian State Clinical Hospital, N. I. Pirogov Russian National Research Medical University, Moscow Russia
3 Russian Medical Academy for Continuous Professional Education, Moscow, Russia
4 N. I. Pirogov Russian National Medical University, Moscow, Russia
5 Department of Continious Medical Education, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia


Correspondence:
Dr. Karina A. Sergeenko, Resident, Department of Pediatric Oncology, Russian Medical Academy for Continuous Professional Education, Moscow, Russia
E-mail: karina_s19@mail.ru


Citation: Sergeenko KA, Dokuchaeva YaYu, Kostareva IO et al. High-dose chemotherapy with autologous hemopoietic stem cell transplantation in children with retinoblastoma. Literature review and case series. Cell Ther Transplant 2022; 11(1): 6-12.

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Retinoblastoma (RB) is the most common malignant eye tumor in children accounting for 10-15% of all cancer cases in infants. In spite of generally good standard treatment results there is still a subgroup of high-risk patients with by unfavorable prognosis, which warrants the search for additional treatment strategies. These children may benefit from treatment intensification in form of high-dose consolidation with subsequent autologous hemopoietic stem cell therapy (auto-HSCT). We here describe a case series illustrating N. N. Blokhin Cancer Center experience in this area.

Materials and methods

In 2021 a total of 3 children with high-risk RB were treated in N. N. Blokhin Cancer Center receiving high-dose regimen consisting of carboplatin (total dose of 1250 mg/m2), etoposide (1750 mg/m2), and cyclophosphamide (6000 mg/m2) with subsequent auto-HSCT.

Results

All 3 patients engrafted in day +11, +14, and +17 after auto-HSCT. The early post-transplant period was complicated by oral mucositis, neutropenic enterocolitis, and febrile neutropenia. One patient had a single episode of seizures due to hyponatremia. With a median follow-up of 6 (4-10) months two patients are alive and disease-free, one died due to disease progression.

Conclusions

The high-dose consolidation with subsequent auto- HSCT is a feasible option for high-risk RB patients. It is characterized by acceptable toxicity and is a potentially effective for disease control. In order to further evaluate the long-term results, there is a need for a larger prospective patient cohort. The multicenter study design may be beneficial in these settings.

Keywords

Autologous hematopoietic stem cell transplantation, retinoblastoma, children, high-dose chemotherapy.

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Sergeenko<sup>1,3</sup>, Yana Yu. Dokuchaeva<sup>1</sup>, Irina O. Kostareva<sup>1</sup>, Tim Z. Aliev<sup>1</sup>, Anna Yu. Elfimova<sup>1</sup>, Nikolay G. Stepanian<sup>1</sup>, Yury V. Lozovan<sup>1</sup>, Natalya A. Burlaka<sup>1</sup>, Natalya V. Sidorova<sup>2</sup>, Elena B. Machneva<sup>1,2</sup>, Tatyana V. Gorbunova<sup>1,5</sup>, Tatyana L. Ushakova<sup>1,3</sup>, Vladimir G. Polyakov<sup>1,3,4,5</sup>, Kirill I. Kirgizov<sup>1,5</sup>, Svetlana R. Varfolomeeva<sup>1,2,5</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(513) "

Karina A. Sergeenko1,3, Yana Yu. Dokuchaeva1, Irina O. Kostareva1, Tim Z. Aliev1, Anna Yu. Elfimova1, Nikolay G. Stepanian1, Yury V. Lozovan1, Natalya A. Burlaka1, Natalya V. Sidorova2, Elena B. Machneva1,2, Tatyana V. Gorbunova1,5, Tatyana L. Ushakova1,3, Vladimir G. Polyakov1,3,4,5, Kirill I. Kirgizov1,5, Svetlana R. Varfolomeeva1,2,5

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Karina A. Sergeenko1,3, Yana Yu. Dokuchaeva1, Irina O. Kostareva1, Tim Z. Aliev1, Anna Yu. Elfimova1, Nikolay G. Stepanian1, Yury V. Lozovan1, Natalya A. Burlaka1, Natalya V. Sidorova2, Elena B. Machneva1,2, Tatyana V. Gorbunova1,5, Tatyana L. Ushakova1,3, Vladimir G. Polyakov1,3,4,5, Kirill I. Kirgizov1,5, Svetlana R. Varfolomeeva1,2,5

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Retinoblastoma (RB) is the most common malignant eye tumor in children accounting for 10-15% of all cancer cases in infants. In spite of generally good standard treatment results there is still a subgroup of high-risk patients with by unfavorable prognosis, which warrants the search for additional treatment strategies. These children may benefit from treatment intensification in form of high-dose consolidation with subsequent autologous hemopoietic stem cell therapy (auto-HSCT). We here describe a case series illustrating N. N. Blokhin Cancer Center experience in this area.

Materials and methods

In 2021 a total of 3 children with high-risk RB were treated in N. N. Blokhin Cancer Center receiving high-dose regimen consisting of carboplatin (total dose of 1250 mg/m2), etoposide (1750 mg/m2), and cyclophosphamide (6000 mg/m2) with subsequent auto-HSCT.

Results

All 3 patients engrafted in day +11, +14, and +17 after auto-HSCT. The early post-transplant period was complicated by oral mucositis, neutropenic enterocolitis, and febrile neutropenia. One patient had a single episode of seizures due to hyponatremia. With a median follow-up of 6 (4-10) months two patients are alive and disease-free, one died due to disease progression.

Conclusions

The high-dose consolidation with subsequent auto- HSCT is a feasible option for high-risk RB patients. It is characterized by acceptable toxicity and is a potentially effective for disease control. In order to further evaluate the long-term results, there is a need for a larger prospective patient cohort. The multicenter study design may be beneficial in these settings.

Keywords

Autologous hematopoietic stem cell transplantation, retinoblastoma, children, high-dose chemotherapy.

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Retinoblastoma (RB) is the most common malignant eye tumor in children accounting for 10-15% of all cancer cases in infants. In spite of generally good standard treatment results there is still a subgroup of high-risk patients with by unfavorable prognosis, which warrants the search for additional treatment strategies. These children may benefit from treatment intensification in form of high-dose consolidation with subsequent autologous hemopoietic stem cell therapy (auto-HSCT). We here describe a case series illustrating N. N. Blokhin Cancer Center experience in this area.

Materials and methods

In 2021 a total of 3 children with high-risk RB were treated in N. N. Blokhin Cancer Center receiving high-dose regimen consisting of carboplatin (total dose of 1250 mg/m2), etoposide (1750 mg/m2), and cyclophosphamide (6000 mg/m2) with subsequent auto-HSCT.

Results

All 3 patients engrafted in day +11, +14, and +17 after auto-HSCT. The early post-transplant period was complicated by oral mucositis, neutropenic enterocolitis, and febrile neutropenia. One patient had a single episode of seizures due to hyponatremia. With a median follow-up of 6 (4-10) months two patients are alive and disease-free, one died due to disease progression.

Conclusions

The high-dose consolidation with subsequent auto- HSCT is a feasible option for high-risk RB patients. It is characterized by acceptable toxicity and is a potentially effective for disease control. In order to further evaluate the long-term results, there is a need for a larger prospective patient cohort. The multicenter study design may be beneficial in these settings.

Keywords

Autologous hematopoietic stem cell transplantation, retinoblastoma, children, high-dose chemotherapy.

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Blokhin National Medical Research Center of Oncology, Moscow, Russia<br> <sup>2</sup> Russian State Clinical Hospital, N. I. Pirogov Russian National Research Medical University, Moscow Russia<br> <sup>3</sup> Russian Medical Academy for Continuous Professional Education, Moscow, Russia <br> <sup>4</sup> N. I. Pirogov Russian National Medical University, Moscow, Russia <br> <sup>5</sup> Department of Continious Medical Education, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia</p><br> <p><b>Correspondence:</b><br> Dr. Karina A. Sergeenko, Resident, Department of Pediatric Oncology, Russian Medical Academy for Continuous Professional Education, Moscow, Russia<br> E-mail: karina_s19@mail.ru</p><br> <p><b>Citation:</b> Sergeenko KA, Dokuchaeva YaYu, Kostareva IO et al. High-dose chemotherapy with autologous hemopoietic stem cell transplantation in children with retinoblastoma. Literature review and case series. Cell Ther Transplant 2022; 11(1): 6-12.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1030) "

1 N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
2 Russian State Clinical Hospital, N. I. Pirogov Russian National Research Medical University, Moscow Russia
3 Russian Medical Academy for Continuous Professional Education, Moscow, Russia
4 N. I. Pirogov Russian National Medical University, Moscow, Russia
5 Department of Continious Medical Education, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia


Correspondence:
Dr. Karina A. Sergeenko, Resident, Department of Pediatric Oncology, Russian Medical Academy for Continuous Professional Education, Moscow, Russia
E-mail: karina_s19@mail.ru


Citation: Sergeenko KA, Dokuchaeva YaYu, Kostareva IO et al. High-dose chemotherapy with autologous hemopoietic stem cell transplantation in children with retinoblastoma. Literature review and case series. Cell Ther Transplant 2022; 11(1): 6-12.

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1 N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
2 Russian State Clinical Hospital, N. I. Pirogov Russian National Research Medical University, Moscow Russia
3 Russian Medical Academy for Continuous Professional Education, Moscow, Russia
4 N. I. Pirogov Russian National Medical University, Moscow, Russia
5 Department of Continious Medical Education, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia


Correspondence:
Dr. Karina A. Sergeenko, Resident, Department of Pediatric Oncology, Russian Medical Academy for Continuous Professional Education, Moscow, Russia
E-mail: karina_s19@mail.ru


Citation: Sergeenko KA, Dokuchaeva YaYu, Kostareva IO et al. High-dose chemotherapy with autologous hemopoietic stem cell transplantation in children with retinoblastoma. Literature review and case series. Cell Ther Transplant 2022; 11(1): 6-12.

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Карина А. Сергеенко1,3, Яна Ю. Докучаева1, Ирина О. Костарева1, Тим З. Алиев1, Анна Ю. Елфимова1, Николай Г. Степанян1, Юрий В. Лозован1, Наталья А. Бурлака1, Наталья В. Сидорова2, Елена Б. Мачнева1,2, Татьяна В. Горбунова1,5, Татьяна Л. Ушакова1,3, Владимир Г. Поляков1,3,4,5, Кирилл И. Киргизов1,5, Светлана Р. Варфоломеева1,2,5

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Карина А. Сергеенко1,3, Яна Ю. Докучаева1, Ирина О. Костарева1, Тим З. Алиев1, Анна Ю. Елфимова1, Николай Г. Степанян1, Юрий В. Лозован1, Наталья А. Бурлака1, Наталья В. Сидорова2, Елена Б. Мачнева1,2, Татьяна В. Горбунова1,5, Татьяна Л. Ушакова1,3, Владимир Г. Поляков1,3,4,5, Кирилл И. Киргизов1,5, Светлана Р. Варфоломеева1,2,5

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Несмотря на наличие стандартных подходов к лечению детей с РБ, в ряде случаев стандартные методы могут оказаться неэффективными, что требует поиска новых стратегий для улучшения выживаемости у детей группы высокого риска. В качестве интенсификации может использоваться высокодозная химиотерапия с последующей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК). Цель нашей работы – демонстрация опыта НМИЦ онкологии им. Н. Н. Блохина на примере случаев ауто-ТГСК у пациентов с РБ.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В 2021 г. в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина 3 пациента с РБ высокой группы риска получили в режиме кондиционирования: Карбоплатин 1250 мг/кв.м., Этопозид 1750 мг/кв.м., Циклофосфамид 6 гр/кв.м. с последующей ауто-ТГСК.</p> <h3>Результаты</h3> <p style="text-align: justify;">Восстановление гемопоэза произошло на 11, 14 и 17 сутки после ауто-ТГСК. Осложнения раннего посттрансплантационного периода: орофарингеальный мукозит, нейтропенический энтероколит, фебрильная нейтропения. В периоде кондиционирования у одного пациента зафискирован эпизод тонико-клонических судорог на фоне гипонатриемии, эпизод купирован, более не повторялся. У одного пациента констатирована прогрессия заболевания, что привело к летальному исходу. Два пациента – без признаков рецидива. Медиана наблюдения 6 ( 4-10) месяцев.</p> <h3>Выводы</h3> <p style="text-align: justify;">Ауто-ТГСК для пациентов с РБ группы высокого риска может рассматриваться как консолидация, в виду хорошей переносимости и эффективности. Требуется включение в исследование большего числа пациентов, длительное наблюдение, а также обмен опытом между трансплантационными центрами.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, ретинобластома, дети, высокодозная химиотерапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3657) "

Ретинобластома (РБ) – самое частое злокачественное новообразование (ЗНО) органа зрения у детей, составляет 10-15% от всех ЗНО детей первого года жизни. Несмотря на наличие стандартных подходов к лечению детей с РБ, в ряде случаев стандартные методы могут оказаться неэффективными, что требует поиска новых стратегий для улучшения выживаемости у детей группы высокого риска. В качестве интенсификации может использоваться высокодозная химиотерапия с последующей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК). Цель нашей работы – демонстрация опыта НМИЦ онкологии им. Н. Н. Блохина на примере случаев ауто-ТГСК у пациентов с РБ.

Материалы и методы

В 2021 г. в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина 3 пациента с РБ высокой группы риска получили в режиме кондиционирования: Карбоплатин 1250 мг/кв.м., Этопозид 1750 мг/кв.м., Циклофосфамид 6 гр/кв.м. с последующей ауто-ТГСК.

Результаты

Восстановление гемопоэза произошло на 11, 14 и 17 сутки после ауто-ТГСК. Осложнения раннего посттрансплантационного периода: орофарингеальный мукозит, нейтропенический энтероколит, фебрильная нейтропения. В периоде кондиционирования у одного пациента зафискирован эпизод тонико-клонических судорог на фоне гипонатриемии, эпизод купирован, более не повторялся. У одного пациента констатирована прогрессия заболевания, что привело к летальному исходу. Два пациента – без признаков рецидива. Медиана наблюдения 6 ( 4-10) месяцев.

Выводы

Ауто-ТГСК для пациентов с РБ группы высокого риска может рассматриваться как консолидация, в виду хорошей переносимости и эффективности. Требуется включение в исследование большего числа пациентов, длительное наблюдение, а также обмен опытом между трансплантационными центрами.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ретинобластома, дети, высокодозная химиотерапия.

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Ретинобластома (РБ) – самое частое злокачественное новообразование (ЗНО) органа зрения у детей, составляет 10-15% от всех ЗНО детей первого года жизни. Несмотря на наличие стандартных подходов к лечению детей с РБ, в ряде случаев стандартные методы могут оказаться неэффективными, что требует поиска новых стратегий для улучшения выживаемости у детей группы высокого риска. В качестве интенсификации может использоваться высокодозная химиотерапия с последующей аутологичной трансплантацией гемопоэтических стволовых клеток (ауто-ТГСК). Цель нашей работы – демонстрация опыта НМИЦ онкологии им. Н. Н. Блохина на примере случаев ауто-ТГСК у пациентов с РБ.

Материалы и методы

В 2021 г. в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина 3 пациента с РБ высокой группы риска получили в режиме кондиционирования: Карбоплатин 1250 мг/кв.м., Этопозид 1750 мг/кв.м., Циклофосфамид 6 гр/кв.м. с последующей ауто-ТГСК.

Результаты

Восстановление гемопоэза произошло на 11, 14 и 17 сутки после ауто-ТГСК. Осложнения раннего посттрансплантационного периода: орофарингеальный мукозит, нейтропенический энтероколит, фебрильная нейтропения. В периоде кондиционирования у одного пациента зафискирован эпизод тонико-клонических судорог на фоне гипонатриемии, эпизод купирован, более не повторялся. У одного пациента констатирована прогрессия заболевания, что привело к летальному исходу. Два пациента – без признаков рецидива. Медиана наблюдения 6 ( 4-10) месяцев.

Выводы

Ауто-ТГСК для пациентов с РБ группы высокого риска может рассматриваться как консолидация, в виду хорошей переносимости и эффективности. Требуется включение в исследование большего числа пациентов, длительное наблюдение, а также обмен опытом между трансплантационными центрами.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, ретинобластома, дети, высокодозная химиотерапия.

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1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России, Москва, Россия
2 Обособленное структурное подразделение Российская детская клиническая больница ФГАОУ ВО «РНИМУ им. Н. И. Пирогова» Минздрава России, Москва, Россия
3 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования», Москва, Россия
4 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н. И. Пирогова» Минздрава России, Москва, Россия
5 Кафедра последипломного образования врачей НМИЦ онкологии им. Н. Н. Блохина, Москва, Россия

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1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России, Москва, Россия
2 Обособленное структурное подразделение Российская детская клиническая больница ФГАОУ ВО «РНИМУ им. Н. И. Пирогова» Минздрава России, Москва, Россия
3 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования», Москва, Россия
4 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н. И. Пирогова» Минздрава России, Москва, Россия
5 Кафедра последипломного образования врачей НМИЦ онкологии им. Н. Н. Блохина, Москва, Россия

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Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative option for acute leukemia nowadays. Many different parameters have significant impact on the final results of HSCT, especially on the more recently defined graft-versus-host disease (GvHD)-free/relapse-free survival (GFRFS) rate, including the pre-HSCT characteristics, such as disease profile at diagnosis and the disease status at the time of transplant, as well as the peri-HSCT factors, i.e. donor type, stem cell source, implemented conditioning regimen and potential post-transplant complications. Aiming to reduce the relapse rates after HSCT, myeloablative conditioning (MAC) regimens at higher dose intensity using busulfan or total body irradiation (TBI) has shown promising results [1]. However, due to higher vulnerability of younger patients to adverse effects of therapeutic irradiation, MAC regimens without TBI are preferred [2, 3]. Moreover, in view of relative complexity for bone marrow collection procedure, along with potentially enhanced graft-versus-leukemia (GvL) effect, peripheral blood (PB) is the preferred source of stem cells for allogeneic HSCT ever more. On the other hand, the increasing number of transplants from human leukocyte antigen (HLA)-haploidentical donors in the patients with acute leukemia is performed due to the absence of suitable related or unrelated HLA-matched donors, thus raising the necessity of understanding, whether HSCT outcomes with this approach are similar to those of more common modes. Over last years, several reports have shown comparable outcomes between HSCT from haploidentical donors and historical HLA-matched related or unrelated donors [4-6]. Hence, additional reports regarding the comparison of different donor types could be a guide to the upcoming therapeutic strategies. To address this issue, we carried out a single-center study, using HSCT with radiation-free MAC regimen, in order to evaluate the results of unmanipulated peripheral blood stem cell transplantation (PBSCT) performed from matched and mismatched related and unrelated donors compared with haploidentical donors in children, adolescents and young adults (CAYA) affected by acute leukemia.

Patients and methods

Patient characteristics

Our study included 180 patients who underwent first allogeneic HSCT for acute leukemia in the CAYA HSCT Department of the Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Tehran, Iran, between January 2014 and January 2021. All data were retrieved retrospectively from clinical records according to the policy approved by the Committee for Medical Ethics of Tehran University of Medical Sciences (TUMS) and after obtaining informed consent from the patients, or their legal guardians.

HSCT parameters

In all patients and their donors, high-resolution HLA molecular typing for HLA-A, -B, -C, -DRB1, and -DQB1 loci was performed. The first donor preference was a 10/10 HLA-matched related donor (MRD), or a 9/10 HLA-mismatched related donor (MMRD). In absence of related donors, an alternative donor including 10/10 HLA-matched unrelated donors (MUD), or 9/10 HLA-mismatched unrelated donors (MMUD), or a related haploidentical donor (Haplo) was chosen, depending on their availability and accessibility.

We proceeded to HSCT if the result of a pre-HSCT bone marrow examination pointed to morphologically complete remission (CR), regardless of the minimal residual disease status. The HSCT procedure was based on irradiation-free MAC regimen including busulfan (a total dose of 3.2-4.8 mg/kg/day, according to patients' ideal body weight, from day -6 to -3), and cyclophosphamide (60 mg/kg/day, day -2 to -1). The GvHD prophylaxis was based on administration of cyclosporine A (CsA) in all the patients, and a short course of methotrexate (10 mg/m2 on day +1, 6 mg/m2 on day +3, +6, and +11) in HSCT from matched and mismatched related and unrelated donors, plus rabbit anti-human thymocytes globulins (ATG-Thymoglobuline, Sanofi, 2.5 mg/kg/day from days -3 to -1) in MMRD, MUD/MMUD and haplo-HSCT groups, and high-dose Pt-Cy treatment (40 mg/kg/day on days +3 and +4) in the Haplo group. We only included patients who received unmanipulated peripheral blood hematopoietic stem cells as graft source.

Considering hazards of CMV reactivation after HSCT, the patients were classified, according to their serological status, into low-risk (donor [D]-/recipient [R]-), intermediate-risk (D+/R-), or high-risk groups (D-/R+ or D+/R+) [7].

Definitions and endpoints

The main purpose of this study was to compare the survival rates of acute leukemia patients who had undergone allogeneic HSCT from different donor types. Overall survival (OS) was defined as the probability of survival, irrespective of the disease state at any point in time. GvHD-free/relapse-free survival (GFRFS) which is regarded as an endpoint more precisely reflective of health status and quality of life post-transplant, was defined as the probability of survival at complete remission of the disease, with sustained donor cell engraftment and absence of either grade III–IV acute GvHD, or chronic GvHD requiring immunosuppressive treatment [8]. Non-relapse mortality (NRM) was defined as probability of death without a relapse after HSCT. The relapse incidence (RI) was defined as the probability to develop a disease relapse.

Donor chimerism was determined on day +15, +30, +60 and +90 after HSCT, and then, if clinically indicated, in whole bone marrow mononuclear cells by means of quantitative PCR of informative short tandem repeats in the donor and recipient [9]. Sustained donor cell engraftment was defined at >0.5×109/L neutrophils and >20×109/L platelets for three consecutive days without blood transfusion support. Graft rejection was defined as a lack of initial engraftment of donor cells (primary), or loss of donor cell engraftment (secondary graft failure), regardless of peripheral cell blood counts. Acute GvHD (aGvHD) and chronic GvHD (cGvHD) were diagnosed and graded according to the published criteria [10, 11]. The mentioned HSCT outcomes were compared between the three categorized groups of different donor types, i.e., the patients transplanted from HLA-matched related (10/10), HLA-mismatched related (9/10) donors (MRD/MMRD), HLA-matched unrelated (10/10), HLA-mismatched (9/10) unrelated donors (MUD/MMUD), and HLA-haploidentical (Haplo) donors.

Statistical evaluation

The patients followed-up beyond 36 months were censored, for better comparison between the groups because some sub-groups had shorter follow-up periods than the other sub-groups. Homogeneity within treatment pairs was evaluated using the Chi-square test or Fisher exact test for qualitative variables and Student's T-test, or Wilcoxon rank-sum test for continuous variables. The endpoints were as follows: OS, GFRFS, relapse-associated, and non-relapse mortality incidence. Kaplan-Meier curves were derived to determine OS and GFRFS, having been compared with log-rank test.

Median follow-up time was established by means of reverse Kaplan-Meier method. After selection of baseline characteristics and clinical variables based on univariable Cox proportional hazards models, multivariable Cox proportional hazards models were fitted.

Variables in the multivariable OS and GFRFS were determined, as based on the P-values of <0.2 in the univariable Cox proportional hazards models. The proportionality of hazards assumption was checked using the global proportionality of hazard test based on Schoenfeld residuals in each of the three multivariable models. There were no deviations from the proportionality of hazards assumption in all multivariable models (results not shown). To account for informative censoring in presence of multiple endpoints, the competing risks in survival analysis were evaluated with nonparametric methods using the cumulative incidence competing risk method. CI for relapses and NRM were calculated by Gray's method. Death beyond relapses was considered a competing event for relapse, and the relapse was considered a competing event for NRM. The Fine-Gray proportional hazard regression model was used to assess the effects of covariates on the relapse frequency and NRM incidence. Like multivariate Cox proportional hazard regression, all the variables at P values of <0.2 in the univariate Fine-Gray proportional hazard regression were included in appropriate multivariate analyses. A two-sided P-value of <0.05 was considered to be statistically significant. The data evaluation was done with STATA version 16 and the packages "survival" and "cmprsk" in R software version 3.3.1.

Results

Patients

The study included 180 patients (120 males and 60 females) at a median age of 12 years (4 months to 24 years) at the time of HSCT, and 123 patients (68.3%) were transplanted at the age of ≤15 years. The donor types were as follows: matched (n=103) and mismatched (n=2) relatives including siblings (n=94) and other relatives (n=11) for a total of 105 cases (58.3%); matched (n=20) and mismatched (n=10) unrelated donors (a total of 30 patients, 16.7%), and haploidentical donors for 45 patients (25%). The patients’ characteristics are summarized in Table 1.

Table 1. Characteristics of the patients and transplant procedure

Rostami-tab01.jpg

Notes: ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, BM: bone marrow, BM+: involvement of bone marrow together with other sites, CR: complete remission, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUD/MMUD: HLA-matched unrelated and HLA-mismatched unrelated donors, R/D: recipient/donor, WBC: white blood cell.

The median follow-up time was 28.7 months for the patients enrolled into the study who were still alive at the end of the study (range: 21.9-34.9). A total of 96 patients presented with B-cell lineage acute lymphoblastic leukemia (ALL); 22 cases, with T-lineage ALL, and 62 patients had acute myeloblastic leukemia (AML). A total of 12 patients suffered from Ph chromosome-positive ALL. All the patients were in complete hematological remission before HSCT, including 93 patients (51.7%) transplanted in their first complete remission (CR1), 67 patients (37.2%) in the second complete remission (CR2), and 20 patients (11.1%) had experienced more than 2 relapses before HSCT. A pre-HSCT cytomegalovirus (CMV) serology showed that more than 90% of the patients were at high risk (recipient [R]+, donor [D]+) for CMV reactivation after HSCT.

Donor cell engraftment

All the patients (180/180) achieved neutrophil counts over 0.5×109/L at a median time of 11 days (range: 7-16). A total of 178 patients achieved platelet counts above 20×109/L, with a median time of 11 days (range: 0-130), and 4 patients died before the platelet engraftment (Table 2). The median time for neutrophil and platelet engraftment in Haplo vs MUD/MMUD vs MRD/MMRD was 12.20 and 14.67 days vs 12.17 and 16.21 days vs 10.73 and 14.30 days, respectively. Two patients from the Haplo group experienced secondary graft failure following CMV reactivation with high viral load after HSCT; one patient was successfully rescued by the second haploidentical HSCT from the same sibling donor, whereas other patient received a second allograft from other parent followed by sustained engraftment and hematopoietic recovery.

Table 2. Engraftment terms and GVHD incidence for the different donor types

Rostami-tab02.jpg

Notes: GvHD: graft-versus-host disease, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUD/MMUD: HLA-matched unrelated and HLA-mismatched unrelated donors.

Acute and chronic GVHD

Grade II to IV of aGvHD was diagnosed in 70 patients (38.9%), being developed at the median term of 15 days after HSCT. Cumulative aGVHD incidence at day 100 was highest in the MUD/MMUD group compared to Haplo and MRD/MMRD, but this difference was not statistically significant [31.6% (±11.8) versus 10.5% (±7.0) versus 27.3% (±6.0), respectively (P=0.845)].

Among 165 patients who survived more than 100 days after HSCT, 27 patients (15%) developed cGvHD, and we observed lower incidence of 3-year cGVHD in the haploidentical group compared to the MUD/MMUD group [7.0% (±5.0) versus 22.5% (±10.3), respectively]. Table 2 represents the comparison for GvHD incidence in the 3 donor types.

Relapse incidence (RI)

The 1-year and 3-year RI of the entire study population was 20.47% (95% CI 14.66-26.97) and 33.85% (95% CI 25.81-41.98), respectively. The 3-year RI in patients of the Haplo group was higher when compared to MUD/MMUD and MRD/MMRD: 40.95% (95% CI 18.41-62.44) versus 32.94% (95% CI 11.92-56.01) versus 33.17% (95% CI 23.64-42.99), respectively (Table 3). This difference was not statistically significant (P=0.902). In the Cox analysis, using both univariate and multivariate approaches, RI was not significantly different among the three donor type groups. In adjusted multivariable RI modeling, the hazard of relapse in the patients from MUD/MMUD group was only 10% lower than for the patients from Haplo group [HR=0.90 (95% CI 0.37-2.19), P=0.826].

Table 3. One- and three-year relapse incidence (RI) and non-relapse mortality (NRM) following HSCT

Rostami-tab03.jpg

Notes: ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, BM: bone marrow, BM+: involvement of bone marrow together with other sites, CR: complete remission, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUDMMUD: HLA-matched unrelated and HLA-mismatched unrelated donors, NRM: non-relapse mortality, R/D: recipient/donor, RI: relapse incidence, WBC: white blood cell.

Survival rates and post-HSCT complications

The 3-year OS and GFRFS rates for the entire study cohort were 68.81% (95% CI 60.08-76.01), and 44.19% (95% CI 35.52-54.49), respectively (Fig. 1). Patients in the MUD/MMUD group had the lowest OS and GFRFS compared to other donor types (Table 4).

Rostami-fig01.jpg

Figure 1. Clinical outcomes in the cohort of young patients subjected to HSCT from different types of donors. A. Overall survival, B. GvHD-free, relapse-free survival, C. Relapse incidence, D. Non-relapse mortality of patients included in the study. Abscissa, observation terms

Note: Haplo: HLA-haploidentical donors, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUDMMUD: HLA-matched unrelated and HLA-mismatched unrelated donors.

Table 4. One- and three-year overall survival (OS) and GFRFS rates following HSCT in young patients

Rostami-tab04-01.jpg Rostami-tab04-02.jpg

Notes: ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, BM: bone marrow, BM+: involvement of bone marrow together with other sites, CR: complete remission, GFRFS: GvHD-free/relapse-free survival, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUD/MMUD: HLA-matched unrelated and HLA-mismatched.

The 3-year OS rates were 73.58% (95% CI 62.98-81.59), 54.21% (95% CI 29.61-73.49), and 64.18% (95% CI 39.76-80.79) for MRD/MMRD, MUD/MMUD, and Haplo groups, respectively (P=0.08); The 3-year GFRFS rates were 47.11% (95% CI 36.48-57.02), 30.89% (95% CI 10.70-53.80), and 42.46% (95% CI 20.41-63.01) for MRD/MMRD, MUD/MMUD, and Haplo groups, respectively (P=0.26). In the Cox analysis, using both univariate and multivariate approaches, OS and GFRFS were not significantly different among the 3 donor type groups. Adjusted multivariable modeling of OS based on the variables selected in unadjusted univariate models (see Patients and methods) showed that hazard of death in the patients who received HSCT from MUD/MMUD was about 3.6 times higher than in cases of HSCT from haploidentical donors, and this difference was statistically significant (P=0.05). Moreover, in those patients who received HSCT from MRD/MMRD, the hazard of death was 12 percent higher than for those who received HSCT from haploidentical donors [HR=1.12, (95% CI 0.34-3.67), P=0.84].

The 3-year NRM in all patients was 7.84% (95% CI 4.36-12.62). The patients who underwent MUD/MMUD HSCT showed significantly higher NRM compared to the patients who received Haplo and MRD/MMRD transplants (Table 3): 21.40% (95% CI 8.36-38.36) versus 10.61% (95% CI 3.21-23.14) versus 3.06% (95% CI 0.81-8.01), respectively (P=0.003).

Considering the causes of NRM among patients from MUD/MMUD group who died in the disease remission, we observed six cases of infection and one case of heart failure. In the Haplo group, one patient deceased from NRM had aGvHD, and four others developed infection. In the MRD/MMRD group, one patient was lost due to aGvHD, three patients died with infectious complications, and one case, due to unknown reason.

Adjusted multivariable modeling of NRM showed that hazard of death in the patients who received HSCT from MUD/MMUD was 6 times higher than the hazard of death for the patients who received HSCT from haploidentical donors. This difference was statistically significant (P=0.002). In those patients who received HSCT from MRD/MMRD, the hazard of death was not higher than in those who received HSCT from haploidentical donors (P=0.23).

Although the estimated risk of CMV reactivation prior to HSCT was high in most patients, CMV reactivation after HSCT was detected in a total of 61 cases (33.9%). CMV reactivation after HSCT occurred significantly more often in Haplo and MUD/MMUD group compared with the MRD/MMRD group (55.6% and 43.3% versus 21.9%, respectively, P=0.001). Worth of note, the CMV reactivation post-HSCT was associated with decreased OS and GFRFS in all three groups, being, however, statistically non-significant (P=0.09).

Hemorrhagic cystitis (HC) was another documented complication post-HSCT which occurred in 36 patients (20%), and it mostly affected the patients from Haplo and MUD/MMUD groups compared with MRD/MMRD group (35.6% and 33.3% versus 9.5%, respectively, P=0.000). Sinusoidal obstruction syndrome (SOS) was documented in only 5 patients, i.e. one case from Haplo group, two patients transplanted with MUD/MMUD grafts, and two, from the MRD/MMRD group.

Discussion

Allogeneic HSCT has augmented the potential of cure in patients with acute leukemia [12-15]. Although HLA-compatible related and unrelated donors have been traditionally used for treating acute leukemia patients requiring an allograft, there remains a significant proportion of patients for whom HLA-identical acceptable donor is not available. For these patients, the use of a haploidentical donor combined with alloreactive T cell elimination by Pt-Cy is the most widely adopted strategy [16]. Our study has shown that, for children, adolescents and young adults (CAYA) affected by acute leukemia, haploidentical HSCT followed by Pt-Cy may offer a better and more accessible chance of cure in terms of NRM and survival rates when compared with HSCT from unrelated donors who are hardly available, especially in the COVID-19 pandemic era.

Different studies reported that haploidentical HSCT could provide similar results to those of MUD and MMUD [17-19]. Several reports have shown, at least, comparable outcomes between Haplo and historical MRD, MUD, and MMUD series [20-23]. In our work, in consistence with most studies, the MRD/MMRD group had the best survival rates within the three donor types. Nevertheless, surprisingly, the survival rates were higher in the Haplo group compared to MUD/MMUD group.

Saglio et al., using a TBI-based conditioning regimen, have reported similar OS rates for Haplo and MUD/MMUD in CAYA patients [24]. In our study, OS rates were much higher in Haplo group compared to the MUD/MMUD group. Likewise, in our patients who had undergone haploidentical HSCT, GFRFS was higher and NRM was much lower than the results attained after HSCT from MUD/MMUD.

In terms of GvHD, it has been emphasized that Pt-Cy is able to significantly eliminate alloreactive T cells and, therefore, to reduce the incidence of GvHD, especially its acute form [25]. In addition, ATG has been shown to reduce the rates of severe acute and chronic GvHD in cases of matched or mismatched, unrelated allogeneic HSCT [26, 27]. Chronic GvHD is the leading cause of late complications and death after allogeneic HSCT. Usage of peripheral blood stem cells as a graft source presents a sufficient risk factor for its development, since the T-cell levels in allografts are higher than those in bone marrow [28-30]. Low incidence of GvHD, particularly chronic GvHD, in our patients, as compared to other reports in the literature, despite application of MAC regimen, along with usage of peripheral blood stem cells, could be attributed to high doses of ATG in the conditioning regimen for HSCT in the patients undergoing Haplo and MUD/MMUD HSCT. In our study, the rates of acute and chronic GvHD were even lower in the Haplo group than among the patients in MUD/MMUD group. This could be ascribed to dual in vivo T-cell depletion caused by ATG and Pt-Cy in the Haplo group. However, adoption of the highly effective GvHD prophylaxis may potentially lead to increased risk of relapse. It seems to be true in our study, as we had the highest relapse incidence (RI) in the Haplo group. However, one should note that the difference in RI among our three donor types was not statistically significant. It is presumed that HLA disparity could be considered a contributing factor to allo-reactivity and GvL [31]. In the matched donor transplant setting, the frequency of donor T-cell precursors directed against leukemia-specific antigens mediating GvL may be more limited [32]. Other studies with less rigorous GvHD prophylaxis strategies compared to our approaches, have reported similar RI in Haplo and MUD/MMUD HSCT [24, 34].

With respect to transplant toxicity, our data confirm that the patients undergoing Haplo HSCT have much lower NRM rates compared to patients undergoing MUD/MMUD HSCT, and the rates of complications, such as hemorrhagic cystitis and sinusoidal obstruction syndrome, seem to be comparable within the two groups. Previous studies comparing NRM rates in Haplo (with Pt-Cy) with MRD and MUD transplants (with standard GvHD prophylaxis) have reported inconsistent results. Meanwhile, some studies reported a higher NRM rates in Haplo HSCT [17, 35, 36].

This study was limited by its retrospective design, inability to adjust for unknown factors, the heterogeneity for conditioning regimens and supportive therapy that could affect the study outcomes.

Conclusions

Our study shows that inclusion of ATG into the myeloablative conditioning regimen before transplantation of peripheral blood stem cells from MUD/MMUD and Haplo donors is associated with reduced rates of chronic GvHD and graft failure, concomitantly. The rates of OS and GFRFS were higher in the Haplo group compared to MUD/MMUD, hence, our data supports the view that haploidentical HSCT with peripheral blood stem cells is a practical and valuable clinical option that offers CAYA patients with acute leukemia requiring HSCT and lacking matched available donors, a reasonable opportunity for the disease control. However, further progress is necessary to decrease the relapse rate in these patients.

Declarations

The study was approved by the Committee on Medical Ethics of Tehran University of Medical Sciences (TUMS) and informed consent was obtained from patients or their legal guardians. Authors provide a consent for publication. Primary data and materials are available on request.

Authors' contributions: TR designed and coordinated the study, and managed the patients. AK, MR and NA participated in the management of patients. AK carried out statistical evaluation. SA conceived of the study. All the authors read and approved the final manuscript.

Acknowledgements

We would like to thank Ashraf Sadat Hoseini and other nursing staff for their undeniable assistance in care for our patients.

Competing Interests

None of the authors have any relevant conflict of interest to disclaim about the present article. No funding support for the study is declared.

References

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    https://doi.org/10.1182/bloodadvances.2019000050

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Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative option for acute leukemia nowadays. Many different parameters have significant impact on the final results of HSCT, especially on the more recently defined graft-versus-host disease (GvHD)-free/relapse-free survival (GFRFS) rate, including the pre-HSCT characteristics, such as disease profile at diagnosis and the disease status at the time of transplant, as well as the peri-HSCT factors, i.e. donor type, stem cell source, implemented conditioning regimen and potential post-transplant complications. Aiming to reduce the relapse rates after HSCT, myeloablative conditioning (MAC) regimens at higher dose intensity using busulfan or total body irradiation (TBI) has shown promising results [1]. However, due to higher vulnerability of younger patients to adverse effects of therapeutic irradiation, MAC regimens without TBI are preferred [2, 3]. Moreover, in view of relative complexity for bone marrow collection procedure, along with potentially enhanced graft-versus-leukemia (GvL) effect, peripheral blood (PB) is the preferred source of stem cells for allogeneic HSCT ever more. On the other hand, the increasing number of transplants from human leukocyte antigen (HLA)-haploidentical donors in the patients with acute leukemia is performed due to the absence of suitable related or unrelated HLA-matched donors, thus raising the necessity of understanding, whether HSCT outcomes with this approach are similar to those of more common modes. Over last years, several reports have shown comparable outcomes between HSCT from haploidentical donors and historical HLA-matched related or unrelated donors [4-6]. Hence, additional reports regarding the comparison of different donor types could be a guide to the upcoming therapeutic strategies. To address this issue, we carried out a single-center study, using HSCT with radiation-free MAC regimen, in order to evaluate the results of unmanipulated peripheral blood stem cell transplantation (PBSCT) performed from matched and mismatched related and unrelated donors compared with haploidentical donors in children, adolescents and young adults (CAYA) affected by acute leukemia.

Patients and methods

Patient characteristics

Our study included 180 patients who underwent first allogeneic HSCT for acute leukemia in the CAYA HSCT Department of the Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Tehran, Iran, between January 2014 and January 2021. All data were retrieved retrospectively from clinical records according to the policy approved by the Committee for Medical Ethics of Tehran University of Medical Sciences (TUMS) and after obtaining informed consent from the patients, or their legal guardians.

HSCT parameters

In all patients and their donors, high-resolution HLA molecular typing for HLA-A, -B, -C, -DRB1, and -DQB1 loci was performed. The first donor preference was a 10/10 HLA-matched related donor (MRD), or a 9/10 HLA-mismatched related donor (MMRD). In absence of related donors, an alternative donor including 10/10 HLA-matched unrelated donors (MUD), or 9/10 HLA-mismatched unrelated donors (MMUD), or a related haploidentical donor (Haplo) was chosen, depending on their availability and accessibility.

We proceeded to HSCT if the result of a pre-HSCT bone marrow examination pointed to morphologically complete remission (CR), regardless of the minimal residual disease status. The HSCT procedure was based on irradiation-free MAC regimen including busulfan (a total dose of 3.2-4.8 mg/kg/day, according to patients' ideal body weight, from day -6 to -3), and cyclophosphamide (60 mg/kg/day, day -2 to -1). The GvHD prophylaxis was based on administration of cyclosporine A (CsA) in all the patients, and a short course of methotrexate (10 mg/m2 on day +1, 6 mg/m2 on day +3, +6, and +11) in HSCT from matched and mismatched related and unrelated donors, plus rabbit anti-human thymocytes globulins (ATG-Thymoglobuline, Sanofi, 2.5 mg/kg/day from days -3 to -1) in MMRD, MUD/MMUD and haplo-HSCT groups, and high-dose Pt-Cy treatment (40 mg/kg/day on days +3 and +4) in the Haplo group. We only included patients who received unmanipulated peripheral blood hematopoietic stem cells as graft source.

Considering hazards of CMV reactivation after HSCT, the patients were classified, according to their serological status, into low-risk (donor [D]-/recipient [R]-), intermediate-risk (D+/R-), or high-risk groups (D-/R+ or D+/R+) [7].

Definitions and endpoints

The main purpose of this study was to compare the survival rates of acute leukemia patients who had undergone allogeneic HSCT from different donor types. Overall survival (OS) was defined as the probability of survival, irrespective of the disease state at any point in time. GvHD-free/relapse-free survival (GFRFS) which is regarded as an endpoint more precisely reflective of health status and quality of life post-transplant, was defined as the probability of survival at complete remission of the disease, with sustained donor cell engraftment and absence of either grade III–IV acute GvHD, or chronic GvHD requiring immunosuppressive treatment [8]. Non-relapse mortality (NRM) was defined as probability of death without a relapse after HSCT. The relapse incidence (RI) was defined as the probability to develop a disease relapse.

Donor chimerism was determined on day +15, +30, +60 and +90 after HSCT, and then, if clinically indicated, in whole bone marrow mononuclear cells by means of quantitative PCR of informative short tandem repeats in the donor and recipient [9]. Sustained donor cell engraftment was defined at >0.5×109/L neutrophils and >20×109/L platelets for three consecutive days without blood transfusion support. Graft rejection was defined as a lack of initial engraftment of donor cells (primary), or loss of donor cell engraftment (secondary graft failure), regardless of peripheral cell blood counts. Acute GvHD (aGvHD) and chronic GvHD (cGvHD) were diagnosed and graded according to the published criteria [10, 11]. The mentioned HSCT outcomes were compared between the three categorized groups of different donor types, i.e., the patients transplanted from HLA-matched related (10/10), HLA-mismatched related (9/10) donors (MRD/MMRD), HLA-matched unrelated (10/10), HLA-mismatched (9/10) unrelated donors (MUD/MMUD), and HLA-haploidentical (Haplo) donors.

Statistical evaluation

The patients followed-up beyond 36 months were censored, for better comparison between the groups because some sub-groups had shorter follow-up periods than the other sub-groups. Homogeneity within treatment pairs was evaluated using the Chi-square test or Fisher exact test for qualitative variables and Student's T-test, or Wilcoxon rank-sum test for continuous variables. The endpoints were as follows: OS, GFRFS, relapse-associated, and non-relapse mortality incidence. Kaplan-Meier curves were derived to determine OS and GFRFS, having been compared with log-rank test.

Median follow-up time was established by means of reverse Kaplan-Meier method. After selection of baseline characteristics and clinical variables based on univariable Cox proportional hazards models, multivariable Cox proportional hazards models were fitted.

Variables in the multivariable OS and GFRFS were determined, as based on the P-values of <0.2 in the univariable Cox proportional hazards models. The proportionality of hazards assumption was checked using the global proportionality of hazard test based on Schoenfeld residuals in each of the three multivariable models. There were no deviations from the proportionality of hazards assumption in all multivariable models (results not shown). To account for informative censoring in presence of multiple endpoints, the competing risks in survival analysis were evaluated with nonparametric methods using the cumulative incidence competing risk method. CI for relapses and NRM were calculated by Gray's method. Death beyond relapses was considered a competing event for relapse, and the relapse was considered a competing event for NRM. The Fine-Gray proportional hazard regression model was used to assess the effects of covariates on the relapse frequency and NRM incidence. Like multivariate Cox proportional hazard regression, all the variables at P values of <0.2 in the univariate Fine-Gray proportional hazard regression were included in appropriate multivariate analyses. A two-sided P-value of <0.05 was considered to be statistically significant. The data evaluation was done with STATA version 16 and the packages "survival" and "cmprsk" in R software version 3.3.1.

Results

Patients

The study included 180 patients (120 males and 60 females) at a median age of 12 years (4 months to 24 years) at the time of HSCT, and 123 patients (68.3%) were transplanted at the age of ≤15 years. The donor types were as follows: matched (n=103) and mismatched (n=2) relatives including siblings (n=94) and other relatives (n=11) for a total of 105 cases (58.3%); matched (n=20) and mismatched (n=10) unrelated donors (a total of 30 patients, 16.7%), and haploidentical donors for 45 patients (25%). The patients’ characteristics are summarized in Table 1.

Table 1. Characteristics of the patients and transplant procedure

Rostami-tab01.jpg

Notes: ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, BM: bone marrow, BM+: involvement of bone marrow together with other sites, CR: complete remission, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUD/MMUD: HLA-matched unrelated and HLA-mismatched unrelated donors, R/D: recipient/donor, WBC: white blood cell.

The median follow-up time was 28.7 months for the patients enrolled into the study who were still alive at the end of the study (range: 21.9-34.9). A total of 96 patients presented with B-cell lineage acute lymphoblastic leukemia (ALL); 22 cases, with T-lineage ALL, and 62 patients had acute myeloblastic leukemia (AML). A total of 12 patients suffered from Ph chromosome-positive ALL. All the patients were in complete hematological remission before HSCT, including 93 patients (51.7%) transplanted in their first complete remission (CR1), 67 patients (37.2%) in the second complete remission (CR2), and 20 patients (11.1%) had experienced more than 2 relapses before HSCT. A pre-HSCT cytomegalovirus (CMV) serology showed that more than 90% of the patients were at high risk (recipient [R]+, donor [D]+) for CMV reactivation after HSCT.

Donor cell engraftment

All the patients (180/180) achieved neutrophil counts over 0.5×109/L at a median time of 11 days (range: 7-16). A total of 178 patients achieved platelet counts above 20×109/L, with a median time of 11 days (range: 0-130), and 4 patients died before the platelet engraftment (Table 2). The median time for neutrophil and platelet engraftment in Haplo vs MUD/MMUD vs MRD/MMRD was 12.20 and 14.67 days vs 12.17 and 16.21 days vs 10.73 and 14.30 days, respectively. Two patients from the Haplo group experienced secondary graft failure following CMV reactivation with high viral load after HSCT; one patient was successfully rescued by the second haploidentical HSCT from the same sibling donor, whereas other patient received a second allograft from other parent followed by sustained engraftment and hematopoietic recovery.

Table 2. Engraftment terms and GVHD incidence for the different donor types

Rostami-tab02.jpg

Notes: GvHD: graft-versus-host disease, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUD/MMUD: HLA-matched unrelated and HLA-mismatched unrelated donors.

Acute and chronic GVHD

Grade II to IV of aGvHD was diagnosed in 70 patients (38.9%), being developed at the median term of 15 days after HSCT. Cumulative aGVHD incidence at day 100 was highest in the MUD/MMUD group compared to Haplo and MRD/MMRD, but this difference was not statistically significant [31.6% (±11.8) versus 10.5% (±7.0) versus 27.3% (±6.0), respectively (P=0.845)].

Among 165 patients who survived more than 100 days after HSCT, 27 patients (15%) developed cGvHD, and we observed lower incidence of 3-year cGVHD in the haploidentical group compared to the MUD/MMUD group [7.0% (±5.0) versus 22.5% (±10.3), respectively]. Table 2 represents the comparison for GvHD incidence in the 3 donor types.

Relapse incidence (RI)

The 1-year and 3-year RI of the entire study population was 20.47% (95% CI 14.66-26.97) and 33.85% (95% CI 25.81-41.98), respectively. The 3-year RI in patients of the Haplo group was higher when compared to MUD/MMUD and MRD/MMRD: 40.95% (95% CI 18.41-62.44) versus 32.94% (95% CI 11.92-56.01) versus 33.17% (95% CI 23.64-42.99), respectively (Table 3). This difference was not statistically significant (P=0.902). In the Cox analysis, using both univariate and multivariate approaches, RI was not significantly different among the three donor type groups. In adjusted multivariable RI modeling, the hazard of relapse in the patients from MUD/MMUD group was only 10% lower than for the patients from Haplo group [HR=0.90 (95% CI 0.37-2.19), P=0.826].

Table 3. One- and three-year relapse incidence (RI) and non-relapse mortality (NRM) following HSCT

Rostami-tab03.jpg

Notes: ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, BM: bone marrow, BM+: involvement of bone marrow together with other sites, CR: complete remission, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUDMMUD: HLA-matched unrelated and HLA-mismatched unrelated donors, NRM: non-relapse mortality, R/D: recipient/donor, RI: relapse incidence, WBC: white blood cell.

Survival rates and post-HSCT complications

The 3-year OS and GFRFS rates for the entire study cohort were 68.81% (95% CI 60.08-76.01), and 44.19% (95% CI 35.52-54.49), respectively (Fig. 1). Patients in the MUD/MMUD group had the lowest OS and GFRFS compared to other donor types (Table 4).

Rostami-fig01.jpg

Figure 1. Clinical outcomes in the cohort of young patients subjected to HSCT from different types of donors. A. Overall survival, B. GvHD-free, relapse-free survival, C. Relapse incidence, D. Non-relapse mortality of patients included in the study. Abscissa, observation terms

Note: Haplo: HLA-haploidentical donors, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUDMMUD: HLA-matched unrelated and HLA-mismatched unrelated donors.

Table 4. One- and three-year overall survival (OS) and GFRFS rates following HSCT in young patients

Rostami-tab04-01.jpg Rostami-tab04-02.jpg

Notes: ALL: acute lymphoblastic leukemia, AML: acute myeloblastic leukemia, BM: bone marrow, BM+: involvement of bone marrow together with other sites, CR: complete remission, GFRFS: GvHD-free/relapse-free survival, Haplo: HLA-haploidentical donors, MM: mismatched, MRD/MMRD: HLA-matched related and HLA-mismatched related donors, MUD/MMUD: HLA-matched unrelated and HLA-mismatched.

The 3-year OS rates were 73.58% (95% CI 62.98-81.59), 54.21% (95% CI 29.61-73.49), and 64.18% (95% CI 39.76-80.79) for MRD/MMRD, MUD/MMUD, and Haplo groups, respectively (P=0.08); The 3-year GFRFS rates were 47.11% (95% CI 36.48-57.02), 30.89% (95% CI 10.70-53.80), and 42.46% (95% CI 20.41-63.01) for MRD/MMRD, MUD/MMUD, and Haplo groups, respectively (P=0.26). In the Cox analysis, using both univariate and multivariate approaches, OS and GFRFS were not significantly different among the 3 donor type groups. Adjusted multivariable modeling of OS based on the variables selected in unadjusted univariate models (see Patients and methods) showed that hazard of death in the patients who received HSCT from MUD/MMUD was about 3.6 times higher than in cases of HSCT from haploidentical donors, and this difference was statistically significant (P=0.05). Moreover, in those patients who received HSCT from MRD/MMRD, the hazard of death was 12 percent higher than for those who received HSCT from haploidentical donors [HR=1.12, (95% CI 0.34-3.67), P=0.84].

The 3-year NRM in all patients was 7.84% (95% CI 4.36-12.62). The patients who underwent MUD/MMUD HSCT showed significantly higher NRM compared to the patients who received Haplo and MRD/MMRD transplants (Table 3): 21.40% (95% CI 8.36-38.36) versus 10.61% (95% CI 3.21-23.14) versus 3.06% (95% CI 0.81-8.01), respectively (P=0.003).

Considering the causes of NRM among patients from MUD/MMUD group who died in the disease remission, we observed six cases of infection and one case of heart failure. In the Haplo group, one patient deceased from NRM had aGvHD, and four others developed infection. In the MRD/MMRD group, one patient was lost due to aGvHD, three patients died with infectious complications, and one case, due to unknown reason.

Adjusted multivariable modeling of NRM showed that hazard of death in the patients who received HSCT from MUD/MMUD was 6 times higher than the hazard of death for the patients who received HSCT from haploidentical donors. This difference was statistically significant (P=0.002). In those patients who received HSCT from MRD/MMRD, the hazard of death was not higher than in those who received HSCT from haploidentical donors (P=0.23).

Although the estimated risk of CMV reactivation prior to HSCT was high in most patients, CMV reactivation after HSCT was detected in a total of 61 cases (33.9%). CMV reactivation after HSCT occurred significantly more often in Haplo and MUD/MMUD group compared with the MRD/MMRD group (55.6% and 43.3% versus 21.9%, respectively, P=0.001). Worth of note, the CMV reactivation post-HSCT was associated with decreased OS and GFRFS in all three groups, being, however, statistically non-significant (P=0.09).

Hemorrhagic cystitis (HC) was another documented complication post-HSCT which occurred in 36 patients (20%), and it mostly affected the patients from Haplo and MUD/MMUD groups compared with MRD/MMRD group (35.6% and 33.3% versus 9.5%, respectively, P=0.000). Sinusoidal obstruction syndrome (SOS) was documented in only 5 patients, i.e. one case from Haplo group, two patients transplanted with MUD/MMUD grafts, and two, from the MRD/MMRD group.

Discussion

Allogeneic HSCT has augmented the potential of cure in patients with acute leukemia [12-15]. Although HLA-compatible related and unrelated donors have been traditionally used for treating acute leukemia patients requiring an allograft, there remains a significant proportion of patients for whom HLA-identical acceptable donor is not available. For these patients, the use of a haploidentical donor combined with alloreactive T cell elimination by Pt-Cy is the most widely adopted strategy [16]. Our study has shown that, for children, adolescents and young adults (CAYA) affected by acute leukemia, haploidentical HSCT followed by Pt-Cy may offer a better and more accessible chance of cure in terms of NRM and survival rates when compared with HSCT from unrelated donors who are hardly available, especially in the COVID-19 pandemic era.

Different studies reported that haploidentical HSCT could provide similar results to those of MUD and MMUD [17-19]. Several reports have shown, at least, comparable outcomes between Haplo and historical MRD, MUD, and MMUD series [20-23]. In our work, in consistence with most studies, the MRD/MMRD group had the best survival rates within the three donor types. Nevertheless, surprisingly, the survival rates were higher in the Haplo group compared to MUD/MMUD group.

Saglio et al., using a TBI-based conditioning regimen, have reported similar OS rates for Haplo and MUD/MMUD in CAYA patients [24]. In our study, OS rates were much higher in Haplo group compared to the MUD/MMUD group. Likewise, in our patients who had undergone haploidentical HSCT, GFRFS was higher and NRM was much lower than the results attained after HSCT from MUD/MMUD.

In terms of GvHD, it has been emphasized that Pt-Cy is able to significantly eliminate alloreactive T cells and, therefore, to reduce the incidence of GvHD, especially its acute form [25]. In addition, ATG has been shown to reduce the rates of severe acute and chronic GvHD in cases of matched or mismatched, unrelated allogeneic HSCT [26, 27]. Chronic GvHD is the leading cause of late complications and death after allogeneic HSCT. Usage of peripheral blood stem cells as a graft source presents a sufficient risk factor for its development, since the T-cell levels in allografts are higher than those in bone marrow [28-30]. Low incidence of GvHD, particularly chronic GvHD, in our patients, as compared to other reports in the literature, despite application of MAC regimen, along with usage of peripheral blood stem cells, could be attributed to high doses of ATG in the conditioning regimen for HSCT in the patients undergoing Haplo and MUD/MMUD HSCT. In our study, the rates of acute and chronic GvHD were even lower in the Haplo group than among the patients in MUD/MMUD group. This could be ascribed to dual in vivo T-cell depletion caused by ATG and Pt-Cy in the Haplo group. However, adoption of the highly effective GvHD prophylaxis may potentially lead to increased risk of relapse. It seems to be true in our study, as we had the highest relapse incidence (RI) in the Haplo group. However, one should note that the difference in RI among our three donor types was not statistically significant. It is presumed that HLA disparity could be considered a contributing factor to allo-reactivity and GvL [31]. In the matched donor transplant setting, the frequency of donor T-cell precursors directed against leukemia-specific antigens mediating GvL may be more limited [32]. Other studies with less rigorous GvHD prophylaxis strategies compared to our approaches, have reported similar RI in Haplo and MUD/MMUD HSCT [24, 34].

With respect to transplant toxicity, our data confirm that the patients undergoing Haplo HSCT have much lower NRM rates compared to patients undergoing MUD/MMUD HSCT, and the rates of complications, such as hemorrhagic cystitis and sinusoidal obstruction syndrome, seem to be comparable within the two groups. Previous studies comparing NRM rates in Haplo (with Pt-Cy) with MRD and MUD transplants (with standard GvHD prophylaxis) have reported inconsistent results. Meanwhile, some studies reported a higher NRM rates in Haplo HSCT [17, 35, 36].

This study was limited by its retrospective design, inability to adjust for unknown factors, the heterogeneity for conditioning regimens and supportive therapy that could affect the study outcomes.

Conclusions

Our study shows that inclusion of ATG into the myeloablative conditioning regimen before transplantation of peripheral blood stem cells from MUD/MMUD and Haplo donors is associated with reduced rates of chronic GvHD and graft failure, concomitantly. The rates of OS and GFRFS were higher in the Haplo group compared to MUD/MMUD, hence, our data supports the view that haploidentical HSCT with peripheral blood stem cells is a practical and valuable clinical option that offers CAYA patients with acute leukemia requiring HSCT and lacking matched available donors, a reasonable opportunity for the disease control. However, further progress is necessary to decrease the relapse rate in these patients.

Declarations

The study was approved by the Committee on Medical Ethics of Tehran University of Medical Sciences (TUMS) and informed consent was obtained from patients or their legal guardians. Authors provide a consent for publication. Primary data and materials are available on request.

Authors' contributions: TR designed and coordinated the study, and managed the patients. AK, MR and NA participated in the management of patients. AK carried out statistical evaluation. SA conceived of the study. All the authors read and approved the final manuscript.

Acknowledgements

We would like to thank Ashraf Sadat Hoseini and other nursing staff for their undeniable assistance in care for our patients.

Competing Interests

None of the authors have any relevant conflict of interest to disclaim about the present article. No funding support for the study is declared.

References

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    https://doi.org/10.1182/bloodadvances.2019000050

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Профилактика РТПХ включала назначение циклоспорина А всем пациентам, кроличий антитимоцитарный глобулин для неродственных и гаплоидентичных доноров, и циклофосфамид при ТГСК от гаплоидентичных доноров. Статистическую обработку проводили с помощью многовариантного пропорционального анализа рисков по Коксу и анализ конкурирующих рисков.</p> <h3>Результаты</h3> <p style="text-align: justify;">Средний срок наблюдения составлял 28,7 мес. (95% CI: 21,9-34,9). Трехлетняя общая выживаемость (ОВ) и выживаемости без РТПХ и рецидивов были, соответственно, 68,81% (95% CI: 60,08%-76,01%) и 44.19% (95% CI: 35,52%-52,49%). Пациенты после ТГСК от неродственных совместимых доноров имели более низкие уровни ОВ и выживаемости без РТПХ и рецидивов по сравнению с другими типами доноров. Трехлетние показатели безрецидивной летальности (NRM) среди всех пациентов составляли 7,84% (95% CI 4,36-12,62). Адаптированное многовариантное моделирование общей выживаемости показало, что риск гибели пациентов после ТГСК от неродственного донора был в 3,6 раза выше, чем у пациентов, получивших ТГСК от гаплоидентичных доноров (P=0.05). Аналогично, риск безрецидивной смертности (NRM) после ТГСК от неродственных доноров был в 6 раз выше, чем при ТГСК от гаплоидентичных доноров (P=0.002). Однако частота рецидивов не различалась существенно между двумя указанными группами.</p> <h3>Выводы</h3> <p style="text-align: justify;">В данном исследовании показано, что ТГСК от гаплоидентичных доноров была ассоциирована с более высокими уровнями выживаемости, по сравнению с ТГСК от неродственных совместимых доноров. Таким образом, ТГСК от гаплоидентичных доноров может быть предложена в качестве практичной и ценной клинической опции, для пациентов молодых возрастов с острыми лейкозами в случае отсутствия совместимых доноров.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лейкоз, аллогенная трансплантация гемопоэтических клеток, совместимые родственные доноры, неродственные доноры, гаплоидентичные доноры, клинические исходы.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_META_TITLE"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_META_KEYWORDS"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_META_DESCRIPTION"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_PICTURE_FILE_ALT"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_PICTURE_FILE_TITLE"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_PICTURE_FILE_NAME"]=> string(101) "transplantatsiya-gemopoeticheskikh-kletok-perifericheskoy-krovi-ot-gaploidentichnykh-i-nerodstvennykh" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(353) "Трансплантация гемопоэтических клеток периферической крови от гаплоидентичных и неродственных доноров при острых лейкозах у детей, подростков и молодых взрослых: анализ конкурентного риска" 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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28532" ["VALUE"]=> array(2) { ["TEXT"]=> string(714) "<p>Тахерех Ростами<sup>1</sup>, Мохамад Р. Ростами<sup>2</sup>, Азадех Кьюмарси<sup>1</sup>, Амир Казаэйян<sup>3</sup>, Неда Алиджани<sup>4</sup>, Хосейн К. Фумани<sup>2</sup>, Соруш Рад<sup>2</sup>, Давуд Бабахани<sup>2</sup>, Таназ Бахри<sup>2</sup>, Мохаммад Ваези<sup>2</sup>, Мариам Бахордар<sup>2</sup>, Сейед А. Мирхоссейни<sup>2</sup>, Сейед А. Моусави<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(546) "

Тахерех Ростами1, Мохамад Р. Ростами2, Азадех Кьюмарси1, Амир Казаэйян3, Неда Алиджани4, Хосейн К. Фумани2, Соруш Рад2, Давуд Бабахани2, Таназ Бахри2, Мохаммад Ваези2, Мариам Бахордар2, Сейед А. Мирхоссейни2, Сейед А. Моусави2

" ["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) "28533" ["VALUE"]=> array(2) { ["TEXT"]=> string(1215) "<p><sup>1</sup> Отдел клеточной терапии у детей, НИИ онкологии, гематологии и клеточной терапии (RIOHCT), Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран<br> <sup>2</sup> НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран<br> <sup>3</sup> Отдел биостатистики и эпидемиологии, НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран<br> <sup>4</sup> Отдел инфекционных болезней, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1137) "

1 Отдел клеточной терапии у детей, НИИ онкологии, гематологии и клеточной терапии (RIOHCT), Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
2 НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
3 Отдел биостатистики и эпидемиологии, НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
4 Отдел инфекционных болезней, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран

" ["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) "28534" ["VALUE"]=> array(2) { ["TEXT"]=> string(6200) "<p style="text-align: justify;">Трансплантация аллогенных гематопоэтических клеток (алло-ТГСК) является единственной потенциальной возможностью излечения острого лейкоза. Многие параметры существенно влияют на конечный исход ТГСК, в т.ч. тип донора, источник стволовых клеток и применяемый режим кондиционирования. При отсутствии HLA-совместимого родственного донора, возможными кандидатами могут быть неродственные совместимые или гаплоидентичные доноры для пациентов с показаниями к ТГСК. Для того, чтобы сопоставить исходы ТГСК от доноров различного типа с кондиционированием без облучения, мы сравнили в рамках одноцентрового исследования результаты трансплантации интактных ГСК периферической крови от совместимых и несовместимых, родственных и неродственных доноров, и гаплоидентичных доноров реципиентам детского, подросткового возрастов и молодым взрослым с острыми лейкозами.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В данном ретроспективном исследовании, проводившемся с 2014 по 2021 г., мы оценивали исходы ТГСК с реплецией Т-лимфоцитов от гаплоидентичных доноров или неродственных доноров (совместимость – 10/10 или 9/10), а также в сравнении с неродственными донорами у пациентов с острыми лейкозами этих возрастных групп. Кондиционирование при ТГСК проводили с применением миелоаблативного режима с бусульфаном и циклофосфамидом и без ионизирующего облучения. Профилактика РТПХ включала назначение циклоспорина А всем пациентам, кроличий антитимоцитарный глобулин для неродственных и гаплоидентичных доноров, и циклофосфамид при ТГСК от гаплоидентичных доноров. Статистическую обработку проводили с помощью многовариантного пропорционального анализа рисков по Коксу и анализ конкурирующих рисков.</p> <h3>Результаты</h3> <p style="text-align: justify;">Средний срок наблюдения составлял 28,7 мес. (95% CI: 21,9-34,9). Трехлетняя общая выживаемость (ОВ) и выживаемости без РТПХ и рецидивов были, соответственно, 68,81% (95% CI: 60,08%-76,01%) и 44.19% (95% CI: 35,52%-52,49%). Пациенты после ТГСК от неродственных совместимых доноров имели более низкие уровни ОВ и выживаемости без РТПХ и рецидивов по сравнению с другими типами доноров. Трехлетние показатели безрецидивной летальности (NRM) среди всех пациентов составляли 7,84% (95% CI 4,36-12,62). Адаптированное многовариантное моделирование общей выживаемости показало, что риск гибели пациентов после ТГСК от неродственного донора был в 3,6 раза выше, чем у пациентов, получивших ТГСК от гаплоидентичных доноров (P=0.05). Аналогично, риск безрецидивной смертности (NRM) после ТГСК от неродственных доноров был в 6 раз выше, чем при ТГСК от гаплоидентичных доноров (P=0.002). Однако частота рецидивов не различалась существенно между двумя указанными группами.</p> <h3>Выводы</h3> <p style="text-align: justify;">В данном исследовании показано, что ТГСК от гаплоидентичных доноров была ассоциирована с более высокими уровнями выживаемости, по сравнению с ТГСК от неродственных совместимых доноров. Таким образом, ТГСК от гаплоидентичных доноров может быть предложена в качестве практичной и ценной клинической опции, для пациентов молодых возрастов с острыми лейкозами в случае отсутствия совместимых доноров.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лейкоз, аллогенная трансплантация гемопоэтических клеток, совместимые родственные доноры, неродственные доноры, гаплоидентичные доноры, клинические исходы.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6042) "

Трансплантация аллогенных гематопоэтических клеток (алло-ТГСК) является единственной потенциальной возможностью излечения острого лейкоза. Многие параметры существенно влияют на конечный исход ТГСК, в т.ч. тип донора, источник стволовых клеток и применяемый режим кондиционирования. При отсутствии HLA-совместимого родственного донора, возможными кандидатами могут быть неродственные совместимые или гаплоидентичные доноры для пациентов с показаниями к ТГСК. Для того, чтобы сопоставить исходы ТГСК от доноров различного типа с кондиционированием без облучения, мы сравнили в рамках одноцентрового исследования результаты трансплантации интактных ГСК периферической крови от совместимых и несовместимых, родственных и неродственных доноров, и гаплоидентичных доноров реципиентам детского, подросткового возрастов и молодым взрослым с острыми лейкозами.

Пациенты и методы

В данном ретроспективном исследовании, проводившемся с 2014 по 2021 г., мы оценивали исходы ТГСК с реплецией Т-лимфоцитов от гаплоидентичных доноров или неродственных доноров (совместимость – 10/10 или 9/10), а также в сравнении с неродственными донорами у пациентов с острыми лейкозами этих возрастных групп. Кондиционирование при ТГСК проводили с применением миелоаблативного режима с бусульфаном и циклофосфамидом и без ионизирующего облучения. Профилактика РТПХ включала назначение циклоспорина А всем пациентам, кроличий антитимоцитарный глобулин для неродственных и гаплоидентичных доноров, и циклофосфамид при ТГСК от гаплоидентичных доноров. Статистическую обработку проводили с помощью многовариантного пропорционального анализа рисков по Коксу и анализ конкурирующих рисков.

Результаты

Средний срок наблюдения составлял 28,7 мес. (95% CI: 21,9-34,9). Трехлетняя общая выживаемость (ОВ) и выживаемости без РТПХ и рецидивов были, соответственно, 68,81% (95% CI: 60,08%-76,01%) и 44.19% (95% CI: 35,52%-52,49%). Пациенты после ТГСК от неродственных совместимых доноров имели более низкие уровни ОВ и выживаемости без РТПХ и рецидивов по сравнению с другими типами доноров. Трехлетние показатели безрецидивной летальности (NRM) среди всех пациентов составляли 7,84% (95% CI 4,36-12,62). Адаптированное многовариантное моделирование общей выживаемости показало, что риск гибели пациентов после ТГСК от неродственного донора был в 3,6 раза выше, чем у пациентов, получивших ТГСК от гаплоидентичных доноров (P=0.05). Аналогично, риск безрецидивной смертности (NRM) после ТГСК от неродственных доноров был в 6 раз выше, чем при ТГСК от гаплоидентичных доноров (P=0.002). Однако частота рецидивов не различалась существенно между двумя указанными группами.

Выводы

В данном исследовании показано, что ТГСК от гаплоидентичных доноров была ассоциирована с более высокими уровнями выживаемости, по сравнению с ТГСК от неродственных совместимых доноров. Таким образом, ТГСК от гаплоидентичных доноров может быть предложена в качестве практичной и ценной клинической опции, для пациентов молодых возрастов с острыми лейкозами в случае отсутствия совместимых доноров.

Ключевые слова

Острый лейкоз, аллогенная трансплантация гемопоэтических клеток, совместимые родственные доноры, неродственные доноры, гаплоидентичные доноры, клинические исходы.

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Tahereh Rostami1, Mohammad R. Rostami2, Azadeh Kiumarsi1, Amir Kasaeian3, Neda Alijani4, Hosein K. Fumani2, Soroush Rad2, Davood Babakhani2, Tanaz Bahri2, Mohammad Vaezi2, Maryam Barkhordar2, Seied A. Mirhosseini2, Seied A. Mousavi2

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1 Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
2 Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
3 Department of Biostatistics and Epidemiology, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
4 Department of lnfectious Diseases, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran


Correspondence:
Dr. Azadeh Kiumarsi, MD, Assistant Professor, Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Kargar Shomali Street, 1411713131, Tehran, Iran
Phone: +98 9121037104
Fax: +98 (21) 8802 9397
Email: akiumarsi@sina.tums.ac.ir


Citation: Tahereh Rostami, Mohammad R. Rostami, Azadeh Kiumarsi et al. Peripheral blood stem cell transplantation from haploidentical and unrelated versus related donors for acute leukemia in children, adolescents and young adults (CAYA): A competing risk analysis. Cell Ther Transplant 2022; 11(1): 24-35.

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for acute leukemia. Various parameters have significant impact on the final results of HSCT, such as donor type, stem cell source, and the applied conditioning regimen. In the absence of HLA-matched related or unrelated donors, haploidentical donors present a possible alternative for the patients with indications for HSCT. The present single-center study compared the outcomes of HSCT from different donor types using a radiation-free MAC regimen. We compared the results of unmanipulated peripheral blood stem cell transplantation (PBSCT) from matched, or mismatched related, and unrelated donors with those from haploidentical donors in the children, adolescents and young adults (CAYA) treated for acute leukemia.

Patients and methods

In this retrospective study performed since 2014 to 2021, we have evaluated the clinical outcomes among CAYA patients with acute leukemia who underwent peripheral blood T cell-replete HSCT from haploidentical donors versus unrelated donors (including 10/10 or 9/10 HLA-matched), and versus related donors (including 10/10 or 9/10 HLA-matched). The myeloablative conditioning for HSCT was performed as irradiation-free regimen including busulfan and cyclophosphamide. GvHD prophylaxis was based on administration of cyclosporine A in all the patients, accomplished by rabbit anti-human thymocyte globulin in HSCT from unrelated and haploidentical donors, and post-transplant cyclophosphamide in cases of haploidentical donors. For statistical evaluation, an adjusted multivariable proportional hazard Cox and competing risk analyses were used.

Results

Median follow-up time period was 28.7 months (95% CI: 21.9-34.9). Three-year overall survival rate (OS) and GvHD-free/relapse-free survival (GFRFS) rate were 68.81% (95% CI: 60.08%-76.01%) and 44.19% (95% CI: 35.52%-52.49%), respectively. The patients who underwent HSCT from unrelated HLA-matched donors had the lowest OS and GFRFS compared to other donor types. The 3-year non-relapse mortality (NRM) in all patients was 7.84% (95% CI 4.36-12.62). Adjusted multivariable modeling of OS showed that the hazard of death in patients who had undergone HSCT from an unrelated donor, was 3.6 times more than for the patients who underwent HSCT from their haploidentical donors (P=0.05). Likewise, the hazard of NRM after HSCT from unrelated donors was 6 times more than with haploidentical donors (P=0.002). However, the relapse incidence was not significantly different between the two mentioned groups.

Conclusions

In this study, HSCT from haploidentical donors was associated with superior survival rates compared to HSCT from unrelated HLA-matched donors. Hence, haploidentical transplantation with peripheral blood stem cells could be a practical and valuable clinical option that offers a reasonable opportunity for the disease control in CAYA patients with acute leukemia requiring HSCT and lacking matched available donors.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, matched related donors, unrelated donors, haploidentical donors, clinical outcomes.

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Rostami<sup>2</sup>, Azadeh Kiumarsi<sup>1</sup>, Amir Kasaeian<sup>3</sup>, Neda Alijani<sup>4</sup>, Hosein K. Fumani<sup>2</sup>, Soroush Rad<sup>2</sup>, Davood Babakhani<sup>2</sup>, Tanaz Bahri<sup>2</sup>, Mohammad Vaezi<sup>2</sup>, Maryam Barkhordar<sup>2</sup>, Seied A. Mirhosseini<sup>2</sup>, Seied A. Mousavi<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(382) "

Tahereh Rostami1, Mohammad R. Rostami2, Azadeh Kiumarsi1, Amir Kasaeian3, Neda Alijani4, Hosein K. Fumani2, Soroush Rad2, Davood Babakhani2, Tanaz Bahri2, Mohammad Vaezi2, Maryam Barkhordar2, Seied A. Mirhosseini2, Seied A. Mousavi2

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Tahereh Rostami1, Mohammad R. Rostami2, Azadeh Kiumarsi1, Amir Kasaeian3, Neda Alijani4, Hosein K. Fumani2, Soroush Rad2, Davood Babakhani2, Tanaz Bahri2, Mohammad Vaezi2, Maryam Barkhordar2, Seied A. Mirhosseini2, Seied A. Mousavi2

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for acute leukemia. Various parameters have significant impact on the final results of HSCT, such as donor type, stem cell source, and the applied conditioning regimen. In the absence of HLA-matched related or unrelated donors, haploidentical donors present a possible alternative for the patients with indications for HSCT. The present single-center study compared the outcomes of HSCT from different donor types using a radiation-free MAC regimen. We compared the results of unmanipulated peripheral blood stem cell transplantation (PBSCT) from matched, or mismatched related, and unrelated donors with those from haploidentical donors in the children, adolescents and young adults (CAYA) treated for acute leukemia.

Patients and methods

In this retrospective study performed since 2014 to 2021, we have evaluated the clinical outcomes among CAYA patients with acute leukemia who underwent peripheral blood T cell-replete HSCT from haploidentical donors versus unrelated donors (including 10/10 or 9/10 HLA-matched), and versus related donors (including 10/10 or 9/10 HLA-matched). The myeloablative conditioning for HSCT was performed as irradiation-free regimen including busulfan and cyclophosphamide. GvHD prophylaxis was based on administration of cyclosporine A in all the patients, accomplished by rabbit anti-human thymocyte globulin in HSCT from unrelated and haploidentical donors, and post-transplant cyclophosphamide in cases of haploidentical donors. For statistical evaluation, an adjusted multivariable proportional hazard Cox and competing risk analyses were used.

Results

Median follow-up time period was 28.7 months (95% CI: 21.9-34.9). Three-year overall survival rate (OS) and GvHD-free/relapse-free survival (GFRFS) rate were 68.81% (95% CI: 60.08%-76.01%) and 44.19% (95% CI: 35.52%-52.49%), respectively. The patients who underwent HSCT from unrelated HLA-matched donors had the lowest OS and GFRFS compared to other donor types. The 3-year non-relapse mortality (NRM) in all patients was 7.84% (95% CI 4.36-12.62). Adjusted multivariable modeling of OS showed that the hazard of death in patients who had undergone HSCT from an unrelated donor, was 3.6 times more than for the patients who underwent HSCT from their haploidentical donors (P=0.05). Likewise, the hazard of NRM after HSCT from unrelated donors was 6 times more than with haploidentical donors (P=0.002). However, the relapse incidence was not significantly different between the two mentioned groups.

Conclusions

In this study, HSCT from haploidentical donors was associated with superior survival rates compared to HSCT from unrelated HLA-matched donors. Hence, haploidentical transplantation with peripheral blood stem cells could be a practical and valuable clinical option that offers a reasonable opportunity for the disease control in CAYA patients with acute leukemia requiring HSCT and lacking matched available donors.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, matched related donors, unrelated donors, haploidentical donors, clinical outcomes.

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for acute leukemia. Various parameters have significant impact on the final results of HSCT, such as donor type, stem cell source, and the applied conditioning regimen. In the absence of HLA-matched related or unrelated donors, haploidentical donors present a possible alternative for the patients with indications for HSCT. The present single-center study compared the outcomes of HSCT from different donor types using a radiation-free MAC regimen. We compared the results of unmanipulated peripheral blood stem cell transplantation (PBSCT) from matched, or mismatched related, and unrelated donors with those from haploidentical donors in the children, adolescents and young adults (CAYA) treated for acute leukemia.

Patients and methods

In this retrospective study performed since 2014 to 2021, we have evaluated the clinical outcomes among CAYA patients with acute leukemia who underwent peripheral blood T cell-replete HSCT from haploidentical donors versus unrelated donors (including 10/10 or 9/10 HLA-matched), and versus related donors (including 10/10 or 9/10 HLA-matched). The myeloablative conditioning for HSCT was performed as irradiation-free regimen including busulfan and cyclophosphamide. GvHD prophylaxis was based on administration of cyclosporine A in all the patients, accomplished by rabbit anti-human thymocyte globulin in HSCT from unrelated and haploidentical donors, and post-transplant cyclophosphamide in cases of haploidentical donors. For statistical evaluation, an adjusted multivariable proportional hazard Cox and competing risk analyses were used.

Results

Median follow-up time period was 28.7 months (95% CI: 21.9-34.9). Three-year overall survival rate (OS) and GvHD-free/relapse-free survival (GFRFS) rate were 68.81% (95% CI: 60.08%-76.01%) and 44.19% (95% CI: 35.52%-52.49%), respectively. The patients who underwent HSCT from unrelated HLA-matched donors had the lowest OS and GFRFS compared to other donor types. The 3-year non-relapse mortality (NRM) in all patients was 7.84% (95% CI 4.36-12.62). Adjusted multivariable modeling of OS showed that the hazard of death in patients who had undergone HSCT from an unrelated donor, was 3.6 times more than for the patients who underwent HSCT from their haploidentical donors (P=0.05). Likewise, the hazard of NRM after HSCT from unrelated donors was 6 times more than with haploidentical donors (P=0.002). However, the relapse incidence was not significantly different between the two mentioned groups.

Conclusions

In this study, HSCT from haploidentical donors was associated with superior survival rates compared to HSCT from unrelated HLA-matched donors. Hence, haploidentical transplantation with peripheral blood stem cells could be a practical and valuable clinical option that offers a reasonable opportunity for the disease control in CAYA patients with acute leukemia requiring HSCT and lacking matched available donors.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, matched related donors, unrelated donors, haploidentical donors, clinical outcomes.

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["TEXT"]=> string(1607) "<p><sup>1</sup> Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran<br> <sup>2</sup> Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran<br> <sup>3</sup> Department of Biostatistics and Epidemiology, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran<br> <sup>4</sup> Department of lnfectious Diseases, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran</p><br> <p><b>Correspondence:</b><br> Dr. Azadeh Kiumarsi, MD, Assistant Professor, Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Kargar Shomali Street, 1411713131, Tehran, Iran<br> Phone: +98 9121037104<br> Fax: +98 (21) 8802 9397<br> Email: akiumarsi@sina.tums.ac.ir</p><br> <p><b>Citation:</b> Tahereh Rostami, Mohammad R. Rostami, Azadeh Kiumarsi et al. Peripheral blood stem cell transplantation from haploidentical and unrelated versus related donors for acute leukemia in children, adolescents and young adults (CAYA): A competing risk analysis. Cell Ther Transplant 2022; 11(1): 24-35. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1445) "

1 Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
2 Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
3 Department of Biostatistics and Epidemiology, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
4 Department of lnfectious Diseases, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran


Correspondence:
Dr. Azadeh Kiumarsi, MD, Assistant Professor, Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Kargar Shomali Street, 1411713131, Tehran, Iran
Phone: +98 9121037104
Fax: +98 (21) 8802 9397
Email: akiumarsi@sina.tums.ac.ir


Citation: Tahereh Rostami, Mohammad R. Rostami, Azadeh Kiumarsi et al. Peripheral blood stem cell transplantation from haploidentical and unrelated versus related donors for acute leukemia in children, adolescents and young adults (CAYA): A competing risk analysis. Cell Ther Transplant 2022; 11(1): 24-35.

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1 Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
2 Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
3 Department of Biostatistics and Epidemiology, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
4 Department of lnfectious Diseases, Shariati Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran


Correspondence:
Dr. Azadeh Kiumarsi, MD, Assistant Professor, Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatric Cell Therapy, Research Institute for Oncology, Hematology and Cell Therapy, Shariati Hospital, Kargar Shomali Street, 1411713131, Tehran, Iran
Phone: +98 9121037104
Fax: +98 (21) 8802 9397
Email: akiumarsi@sina.tums.ac.ir


Citation: Tahereh Rostami, Mohammad R. Rostami, Azadeh Kiumarsi et al. Peripheral blood stem cell transplantation from haploidentical and unrelated versus related donors for acute leukemia in children, adolescents and young adults (CAYA): A competing risk analysis. Cell Ther Transplant 2022; 11(1): 24-35.

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Многие параметры существенно влияют на конечный исход ТГСК, в т.ч. тип донора, источник стволовых клеток и применяемый режим кондиционирования. При отсутствии HLA-совместимого родственного донора, возможными кандидатами могут быть неродственные совместимые или гаплоидентичные доноры для пациентов с показаниями к ТГСК. Для того, чтобы сопоставить исходы ТГСК от доноров различного типа с кондиционированием без облучения, мы сравнили в рамках одноцентрового исследования результаты трансплантации интактных ГСК периферической крови от совместимых и несовместимых, родственных и неродственных доноров, и гаплоидентичных доноров реципиентам детского, подросткового возрастов и молодым взрослым с острыми лейкозами.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В данном ретроспективном исследовании, проводившемся с 2014 по 2021 г., мы оценивали исходы ТГСК с реплецией Т-лимфоцитов от гаплоидентичных доноров или неродственных доноров (совместимость – 10/10 или 9/10), а также в сравнении с неродственными донорами у пациентов с острыми лейкозами этих возрастных групп. Кондиционирование при ТГСК проводили с применением миелоаблативного режима с бусульфаном и циклофосфамидом и без ионизирующего облучения. Профилактика РТПХ включала назначение циклоспорина А всем пациентам, кроличий антитимоцитарный глобулин для неродственных и гаплоидентичных доноров, и циклофосфамид при ТГСК от гаплоидентичных доноров. Статистическую обработку проводили с помощью многовариантного пропорционального анализа рисков по Коксу и анализ конкурирующих рисков.</p> <h3>Результаты</h3> <p style="text-align: justify;">Средний срок наблюдения составлял 28,7 мес. (95% CI: 21,9-34,9). Трехлетняя общая выживаемость (ОВ) и выживаемости без РТПХ и рецидивов были, соответственно, 68,81% (95% CI: 60,08%-76,01%) и 44.19% (95% CI: 35,52%-52,49%). Пациенты после ТГСК от неродственных совместимых доноров имели более низкие уровни ОВ и выживаемости без РТПХ и рецидивов по сравнению с другими типами доноров. Трехлетние показатели безрецидивной летальности (NRM) среди всех пациентов составляли 7,84% (95% CI 4,36-12,62). Адаптированное многовариантное моделирование общей выживаемости показало, что риск гибели пациентов после ТГСК от неродственного донора был в 3,6 раза выше, чем у пациентов, получивших ТГСК от гаплоидентичных доноров (P=0.05). Аналогично, риск безрецидивной смертности (NRM) после ТГСК от неродственных доноров был в 6 раз выше, чем при ТГСК от гаплоидентичных доноров (P=0.002). Однако частота рецидивов не различалась существенно между двумя указанными группами.</p> <h3>Выводы</h3> <p style="text-align: justify;">В данном исследовании показано, что ТГСК от гаплоидентичных доноров была ассоциирована с более высокими уровнями выживаемости, по сравнению с ТГСК от неродственных совместимых доноров. Таким образом, ТГСК от гаплоидентичных доноров может быть предложена в качестве практичной и ценной клинической опции, для пациентов молодых возрастов с острыми лейкозами в случае отсутствия совместимых доноров.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лейкоз, аллогенная трансплантация гемопоэтических клеток, совместимые родственные доноры, неродственные доноры, гаплоидентичные доноры, клинические исходы.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6042) "

Трансплантация аллогенных гематопоэтических клеток (алло-ТГСК) является единственной потенциальной возможностью излечения острого лейкоза. Многие параметры существенно влияют на конечный исход ТГСК, в т.ч. тип донора, источник стволовых клеток и применяемый режим кондиционирования. При отсутствии HLA-совместимого родственного донора, возможными кандидатами могут быть неродственные совместимые или гаплоидентичные доноры для пациентов с показаниями к ТГСК. Для того, чтобы сопоставить исходы ТГСК от доноров различного типа с кондиционированием без облучения, мы сравнили в рамках одноцентрового исследования результаты трансплантации интактных ГСК периферической крови от совместимых и несовместимых, родственных и неродственных доноров, и гаплоидентичных доноров реципиентам детского, подросткового возрастов и молодым взрослым с острыми лейкозами.

Пациенты и методы

В данном ретроспективном исследовании, проводившемся с 2014 по 2021 г., мы оценивали исходы ТГСК с реплецией Т-лимфоцитов от гаплоидентичных доноров или неродственных доноров (совместимость – 10/10 или 9/10), а также в сравнении с неродственными донорами у пациентов с острыми лейкозами этих возрастных групп. Кондиционирование при ТГСК проводили с применением миелоаблативного режима с бусульфаном и циклофосфамидом и без ионизирующего облучения. Профилактика РТПХ включала назначение циклоспорина А всем пациентам, кроличий антитимоцитарный глобулин для неродственных и гаплоидентичных доноров, и циклофосфамид при ТГСК от гаплоидентичных доноров. Статистическую обработку проводили с помощью многовариантного пропорционального анализа рисков по Коксу и анализ конкурирующих рисков.

Результаты

Средний срок наблюдения составлял 28,7 мес. (95% CI: 21,9-34,9). Трехлетняя общая выживаемость (ОВ) и выживаемости без РТПХ и рецидивов были, соответственно, 68,81% (95% CI: 60,08%-76,01%) и 44.19% (95% CI: 35,52%-52,49%). Пациенты после ТГСК от неродственных совместимых доноров имели более низкие уровни ОВ и выживаемости без РТПХ и рецидивов по сравнению с другими типами доноров. Трехлетние показатели безрецидивной летальности (NRM) среди всех пациентов составляли 7,84% (95% CI 4,36-12,62). Адаптированное многовариантное моделирование общей выживаемости показало, что риск гибели пациентов после ТГСК от неродственного донора был в 3,6 раза выше, чем у пациентов, получивших ТГСК от гаплоидентичных доноров (P=0.05). Аналогично, риск безрецидивной смертности (NRM) после ТГСК от неродственных доноров был в 6 раз выше, чем при ТГСК от гаплоидентичных доноров (P=0.002). Однако частота рецидивов не различалась существенно между двумя указанными группами.

Выводы

В данном исследовании показано, что ТГСК от гаплоидентичных доноров была ассоциирована с более высокими уровнями выживаемости, по сравнению с ТГСК от неродственных совместимых доноров. Таким образом, ТГСК от гаплоидентичных доноров может быть предложена в качестве практичной и ценной клинической опции, для пациентов молодых возрастов с острыми лейкозами в случае отсутствия совместимых доноров.

Ключевые слова

Острый лейкоз, аллогенная трансплантация гемопоэтических клеток, совместимые родственные доноры, неродственные доноры, гаплоидентичные доноры, клинические исходы.

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Трансплантация аллогенных гематопоэтических клеток (алло-ТГСК) является единственной потенциальной возможностью излечения острого лейкоза. Многие параметры существенно влияют на конечный исход ТГСК, в т.ч. тип донора, источник стволовых клеток и применяемый режим кондиционирования. При отсутствии HLA-совместимого родственного донора, возможными кандидатами могут быть неродственные совместимые или гаплоидентичные доноры для пациентов с показаниями к ТГСК. Для того, чтобы сопоставить исходы ТГСК от доноров различного типа с кондиционированием без облучения, мы сравнили в рамках одноцентрового исследования результаты трансплантации интактных ГСК периферической крови от совместимых и несовместимых, родственных и неродственных доноров, и гаплоидентичных доноров реципиентам детского, подросткового возрастов и молодым взрослым с острыми лейкозами.

Пациенты и методы

В данном ретроспективном исследовании, проводившемся с 2014 по 2021 г., мы оценивали исходы ТГСК с реплецией Т-лимфоцитов от гаплоидентичных доноров или неродственных доноров (совместимость – 10/10 или 9/10), а также в сравнении с неродственными донорами у пациентов с острыми лейкозами этих возрастных групп. Кондиционирование при ТГСК проводили с применением миелоаблативного режима с бусульфаном и циклофосфамидом и без ионизирующего облучения. Профилактика РТПХ включала назначение циклоспорина А всем пациентам, кроличий антитимоцитарный глобулин для неродственных и гаплоидентичных доноров, и циклофосфамид при ТГСК от гаплоидентичных доноров. Статистическую обработку проводили с помощью многовариантного пропорционального анализа рисков по Коксу и анализ конкурирующих рисков.

Результаты

Средний срок наблюдения составлял 28,7 мес. (95% CI: 21,9-34,9). Трехлетняя общая выживаемость (ОВ) и выживаемости без РТПХ и рецидивов были, соответственно, 68,81% (95% CI: 60,08%-76,01%) и 44.19% (95% CI: 35,52%-52,49%). Пациенты после ТГСК от неродственных совместимых доноров имели более низкие уровни ОВ и выживаемости без РТПХ и рецидивов по сравнению с другими типами доноров. Трехлетние показатели безрецидивной летальности (NRM) среди всех пациентов составляли 7,84% (95% CI 4,36-12,62). Адаптированное многовариантное моделирование общей выживаемости показало, что риск гибели пациентов после ТГСК от неродственного донора был в 3,6 раза выше, чем у пациентов, получивших ТГСК от гаплоидентичных доноров (P=0.05). Аналогично, риск безрецидивной смертности (NRM) после ТГСК от неродственных доноров был в 6 раз выше, чем при ТГСК от гаплоидентичных доноров (P=0.002). Однако частота рецидивов не различалась существенно между двумя указанными группами.

Выводы

В данном исследовании показано, что ТГСК от гаплоидентичных доноров была ассоциирована с более высокими уровнями выживаемости, по сравнению с ТГСК от неродственных совместимых доноров. Таким образом, ТГСК от гаплоидентичных доноров может быть предложена в качестве практичной и ценной клинической опции, для пациентов молодых возрастов с острыми лейкозами в случае отсутствия совместимых доноров.

Ключевые слова

Острый лейкоз, аллогенная трансплантация гемопоэтических клеток, совместимые родственные доноры, неродственные доноры, гаплоидентичные доноры, клинические исходы.

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1 Отдел клеточной терапии у детей, НИИ онкологии, гематологии и клеточной терапии (RIOHCT), Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
2 НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
3 Отдел биостатистики и эпидемиологии, НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
4 Отдел инфекционных болезней, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран

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1 Отдел клеточной терапии у детей, НИИ онкологии, гематологии и клеточной терапии (RIOHCT), Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
2 НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
3 Отдел биостатистики и эпидемиологии, НИИ онкологии, гематологии и клеточной терапии, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран
4 Отдел инфекционных болезней, Шариатский госпиталь, Тегеранский университет медицинских наук (TUMS), Тегеран, Иран

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Introduction

Over the past decades, allogeneic stem cell transplantation (allo-HSCT) has been used worldwide as a technology aimed both the long-term management and cure of malignant hematological diseases [1]. Allo-HSCT remains a valuable option for treatment of chronic myeloid leukemia (CML) in era of tyrosine kinase inhibitors (TKI) [2-6]. The transplant-eligible population consists of the CML patients with predicted poor outcome if treated with TKIs alone. Despite the superiority of drug treatment, the development of transplant technology, i.e., usage of reduced intensity conditioning regimens, increased donor availability, led to improvement in the results of allo-HSCT in these patients [7,8]. Thus, transplantation is still a potentially curative therapeutic mode in all fit patients who are unable to achieve a durable complete cytogenetic response after treatment with 2 TKIs, and patients with advanced-phase CML.

Unfavorable results are mostly associated with impaired graft function, which is manifested in the lack of control over the underlying disease and subsequent relapse, as well as in primary graft failure (PrGF) and poor graft function (PoGF) [9-12]. Several risk factors of post-transplant graft failure were revealed, e.g., patient’s age, donor-recipient blood mismatch and CMV infection (13]. Treatment options for poor graft functioning are still limited. In addition to reinfusion of stem cell, some recent studies report, e.g., positive effects of Eltrombopag, a thrombopoietin mimetic [14].

The aim of the study was to assess the incidence and outcome of PrGF and severe poor graft function (sPGF) after allo-HSCT in CML patients.

Materials and methods

Patients and data collection

We carried out retrospective analysis of 121 consecutive patients with CML who received allo-HSCT in R. M. Gorbacheva Research Institute at the Pavlov University between 1995 and 2020. Information on the disease stage at diagnosis, time to allo-HSCT, transplantation procedure, relapse, and treatment following allo-HSCT was gathered via systematic reviews of the patient records. General approaches to evaluation of HSCT patients at our clinic were described elsewhere [15].

Definitions

CML was diagnosed on the basis of clinical and laboratory data, the detection of Philadelphia (Ph) chromosome and/or the chimeric BCR-ABL gene. Disease phase was defined according to the WHO classification [16]. The first chronic phase (CP1) was recognized in the absence of accelerated phase (AP) and/or blast crisis (BC) in the patient’s history, otherwise CP≥2 was registered. Hematological, cytogenetic and molecular response to the treatment prior to allo-HSCT was defined using ELN criteria [17].

Indications for HSCT

Indications for HSCT were as follows: 1) AP/BC at diagnosis or progression to AP/BC; 2) treatment failure in pre-TKI era; 3) treatment failure due to TKI resistance/intolerance; 4) T315I mutation. TKI resistance and TKI intolerance were defined according to ELN criteria [17].

Laboratory studies

For cytogenetic evaluation, conventional synchronized culture was performed for 48 hours with at least 20 metaphases analyzed per a sample (GTG method). Leukemia cell karyotype was evaluated according to International System for Human Cytogenetic Nomenclature (ISCN) [18]. In cases when the standard cytogenetic investigation was not available (i.e., insufficient material), the bone marrow was assessed with fluorescence in situ hybridization (FISH) probes aimed for detection of (9;22) variants (LSI BCR-ABL, Dual Color, Dual Fusion, "Vysis").

Additional chromosomal abnormalities (ACA) were defined as any structural and numerical chromosomal aberrations other than t(9;22)(q34;q11) (detected by cytogenetic or molecular assays for cryptic abnormalities).

Molecular response after allo-HSCT was evaluated according to the National Comprehensive Cancer Network (NCCN) criteria (2021). PCR monitoring of BCR/ABL was carried out according to NCCN Guidelines once in 3 months for 2 years, then once in every 3 to 6 months. The relative BCR-ABL1 expression level was evaluated according to method described by Gabert et al [19]. This technique includes the following stages: 1) total RNA extraction from peripheral blood of patients with CML, 2) reverse transcription with random hexameric primers, 3) real-time PCR with primers and probes specific to р210, р190 control ABL gene sequences.

Assessment of relative expression levels was based on evaluation of BCR-ABL1/ABL1 ratios in the studied cDNA samples. The ABL1 gene was used for normalization of the results. In order to determine copy numbers of the BCR-ABL1 and ABL1 transcripts, and to assess the reaction effectiveness, standard dilution curves were plotted using a plasmid with inserts of known target gene sequences (Invitrogen, USA), at a standard concentration ranges of 102-106 copies/mcl, according to 2020 European LeukemiaNet (ELN) Recommendations [17]. ABL kinase domain mutations were determined by Sanger direct sequencing.

Post-transplant monitoring

Post-transplant engraftment was defined as absolute neutrophil count (ANC) of >0.5×109/L without administration of colony-stimulating factor within 3 days. Primary graft failure (PrGF) was diagnosed in absence of donor cells in recipient’s bone marrow by the day +30. Donor chimerism was checked at the time of myelopoiesis recovery, i.e. ANC> 0.5×109/L, and by the days +30, 60, +100, +200, and in case of any cytopenia, or signs of relapse. Post-transplant relapse was diagnosed in cases of clinical progression to AP/BC, cytogenetic relapse, or molecular relapse defined as two consecutive positive PCR tests, or, at least, 1-log persistent increase of BCR/ABL transcript level.

The criteria for severe poor graft function (sPGF) were as follows: cytopenia in two or more hematopoietic lineages (platelets <20×109/l, ANC <0.5×109/l, hemoglobin <70 g/l) any time after documented engraftment in presence of full or stable mixed donor chimerism >90% without signs of relapse of underlying disease, rejection or acute graft-versus-host disease (GVHD) grade III-IV.

Secondary graft failure was defined as loss of donor hematopoiesis to <5% and/or ANC counts to <0.5×109/L after initial engraftment being not related to relapse, infection, or drug toxicity [20].

Statistical evaluation

Descriptive characteristics of the cohort included number of cases, proportions for discrete factors, medians and range for continuous values. Individual pre-transplant risk for the HSCT patients was evaluated according to Gratwohl [21]. Overall survival (OS) was assessed using the Kaplan-Meier method from the time of allo-HSCT to the date of last contact or the date of death. Death from any cause was considered as an event.

Survival analysis was performed using log-rank test. Relapse and non-relapse mortality (NRM) rates were summarized using cumulative incidence estimates, with NRM as competing risk for relapse, and relapse regarded as competing risk for NRM.

The event-free survival (EFS) was estimated as a period from allo-HSCT until last contact date, death, or any of the following events: any kind of post-transplant relapse, graft-versus-host disease (GVHD) grade III-IV, severe poor graft function, or secondary graft failure. PrGF and sPGF were estimated as a proportion of cases in the total cohort. Cumulative incidence of sPGF was calculated with respect to competing risks (death before day +30, any type of relapse, GVHD grade III-IV).

The differences between groups were assessed using Fisher's exact test, Pearson χ2 test, and Mann-Whitney U-test for categorical and quantitative characteristics respectively, and Gray’s test for cumulative incidences. All the tests were two-sided, and P-values <0.05 were assessed as indicating for significant associations. Statistical analysis was performed using SPSS, IBM Statistics and EZR free statistical environment, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

General characteristics of the patients and HSCT procedure

A total of 121 patients diagnosed with CML had undergone allo-HSCT. The median patients’ age was 37 years (range: 18-66). Other baseline characteristics for these patients are presented in Table 1.

The median time between CML diagnosis and allo-HSCT was 31 months (4.5-260). A total of 80 (66%) patients were transplanted in chronic phase (CP), the remaining 41 (34%) patients were in the active phase (AP or BC) at the time of HSCT. The median follow-up from allo-HSCT to the time of the last contact was 15 months (0.5-294).

HLA-matched or partially mismatched unrelated donors were used in 78 cases (65%), while matched related donors were employed in 34 cases (28%), and 9 (7%) patients received haploidentical allo-HSCT. The proportion of bone marrow (BM) and peripheral blood stem cells (PBSC) as the graft sources was almost equal: 49% (n=59) versus 51% (n=62).

Conditioning regimen included oral busulfan 8-12 mg/kg or melphalan 140 mg/m2 in combination with fludarabine 180 mg/m2 or cyclophosphamide. GVHD prophylaxis included calcineurin inhibitor (tacrolimus or cyclosporine A) and mycophenolate mofetil (30 mg/kg), or short course of posttransplant metotrexate, with or without antithymocyte globulin (horse, 60 mg/kg, or rabbit preparations, 5 mg/kg on day -3, -2, or high-dose), post-transplant cyclophosphamide (50 mg/kg, day +3 and +4 after allo-HSCT)/Alemtuzumab was used in two cases (Table 2).

Morozova-tab01-02.jpg

Morozova-fig01.jpg

Figure 1. Cumulative incidence of poor graft function post-HSCT in CML patients

Survival and relapse rates

Engraftment was documented in 106 (88%) patients, with median time to neutrophil recovery of 22 (8-58) days. Early death with no signs of engraftment before day +30 occurred in two cases. Thirty-one patients developed post-transplant relapse of any type with median time after allo-HSCT of 106 days (range: 15-333), included early CML relapse/progression before day +30 in 5 cases.

PrGF was documented in 8 (7%) cases. Two patients developed secondary graft failure, both in about two months after initial engraftment with lethal outcome due to severe bacterial infection. Severe poor graft function was diagnosed in 11 (9% of engrafted patients) with cumulative incidence of 10% (95% CI, 5-19) within 1 year after allo-HSCT (Fig. 1). Median time from HSCT to sPGF diagnosis was 43 (18-114) days.

The 1-year cumulative incidence rates of relapse and NRM comprised 35% (95% CI, 26-46) and 26% (95% CI, 18-35), respectively (Fig. 2).

A total of 57 (47%) patients died, the 1-year OS was 60% (95% CI, 51-69). Median OS was not reached. One-year EFS was 41% (95% CI, 32-50), median EFS was 271 (95% CI, 96-365) days (Fig. 3).

Morozova-fig02.jpg

Figure 2. One-year cumulative incidence of relapses and NRM after allo-HSCT in CML patients

Morozova-fig03.jpg

Figure 3. One-year overall and event-free survival after allogeneic HSCT in CML patients

Factors associated with primary graft failure and severe poor graft function

Among various pre-transplant characteristics, the presence of additional chromosomal abnormalities (ACA) was associated with cumulative incidence of PrGF and sPGF after HSCT. Thus, PrGF was 14% in the group with detectable ACA versus 3% in the group without ACA, (p=0.02), whereas incidence of sPGF in patients with ACA was 2% versus 12% in those without ACA, p=0.09. HLA-matched allo-HSCTs were beneficial for engraftment: 96% for HLA-matched transplantations vs 89% for allo-HSCT from HLA-mismatched donors, and 78% for haploidentical donors (p=0.05). Other pre-transplant factors didn’t show any statistical correlation with graft failure syndromes after HSCT (Table 3).

Table 3. Potential risk factors for the graft failure after allo-HSCT in CML patients

Morozova-tab03.jpg

Clinical features and outcomes of graft failure and severe poor graft function

The median follow-up time after allo-HSCT was 68 days (range: 43-1792). All the patients with primary graft failure (PrGF) (n=8) were administered G-CSF, antimicrobial therapy and transfusion support. Two patients received donor lymphocyte infusions without any effect. The second allo-HSCT was performed in 4 cases. A total of 7 patients had lethal outcome (6, of infectious complications; 1, of relapse), whereas one patient is alive after the 2nd allo-HSCT (Fig. 4).

Morozova-fig04.jpg

Figure 4. Treatment and outcomes of primary graft failure (PrGF) in CML patients after HSCT

Eleven patients exhibited severe poor graft function (sPGF) within median time of 21 (0-92) days after engraftment. Median length of sPGF was 52 days (range: 14-215). The median time of follow-up after allo-HSCT was 977 days (range: 45-2712).

Early sPGF with criterial cytopenia persisting after engraftment was diagnosed in 4 cases (36%), the remaining patients developed cytopenia after a period of normal graft function. A total of 3 cases of sPGF (27%) developed within 30 days after acute GVHD 2-3 grade (Fig. 5).

Morozova-fig05.jpg

Figure 5. Timeline of severe poor graft function (SPGF) in a group of CML patients

All the patients with sPGF received antimicrobial therapy, transfusion support, and G-CSF in case of neutropenia. Other therapeutic options for sPGF therapy were: rituximab (n=4), the second allo-HSCT, or boost stem cell infusion (n=3); eltrombopag (n=1); supportive care (n=5), as seen from Fig. 4. Normal graft function was restored in 8 patients.

A total of 4 patients died. The causes of death were infectious complications (n=3) and late post-transplant relapse (n=1) (Fig. 6).

Morozova-fig06.jpg

Figure 6. Treatment and outcomes of severe poor graft function (sPGF) in CML patients post-HSCT

Two cases of secondary graft failure occurred in about 3 months after allo-HSCT. Both patients died due to severe infection.

The incidence of post-transplant relapses did not differ in the patients with PrGF and sPGF as compared with those, who were free of these complications. Cumulative incidence of leukemia relapses was 31% (95% CI, 23-42), and 25% (95% CI, 4-87) in the patients with PrGF and engraftment (p=0.97), compared with 22% (95% CI, 3-54) and 32% (95% CI, 24-43) in the patients with sPGF and without sPGF (p=0.52), respectively.

Primary graft failure (PrGF) but not severe poor graft failure (sPGF) significantly increased non-relapse mortality during the first year after allo-HSCT. One-year NRM was 23% (95% CI, 15-32) in engrafted patients versus 71% (95% CI, 39-96) in the patients with PrGF (p<0.0001). Patients with and without sPGF had similar NRM: 20% (95% CI, 5-59) versus 26% (95% CI, 18-36) (p=0.74).

One-year OS was significantly lower in patients with PrGF: 13% (95% CI, 0.7-42) versus 64% (95% CI, 54-72) (p<0.0001) (Fig. 7). On the contrary, sPGF had no statistically significant influence on OS: 73% (95% CI, 37-90) versus 59% (95% CI, 49-69) (p=0.47).

Morozova-fig07.jpg

Figure 7. Impact of primary graft failure (PrGF, A), and severe poor graft function (sPGF, B) on overall survival post-HSCT in CML patients

Discussion

In context of TKI therapy progress, the indications for allo-HSCT in CML are becoming more stringent, with respect both to selective TKI choice, relapse diagnostics, and improved transplant technologies [22]. In this regard, it becomes relevant to investigate the causes of allo-HSCT failure and to determine the risk factors for PrGF and sPGF in CML patients. While the factor of post-transplant relapse is discussed in most publications, the issues of PrGF and sPGF remain poorly reflected. Only few authors provided clear definitions and data on the incidence of these complications (mostly PrGF) in the patients with CML. At the same time, most studies of posttransplant graft failure syndromes show that the diagnosis of CML may be among risk factors of this complication. However, most previous studies concerned a heterogeneous range of diagnoses, e.g., acute leukemia, chronic myelo- and lymphoproliferative and non-malignant diseases. To our knowledge, the present work evaluates for the first time the incidence of both PrGF and PGF in a homogeneous cohort of CML patients.

According to our results, PrGF occurred in 7% of cases, thus being higher than in patients with acute leukemia as confirmed by other publications [10]. On the contrary, cumulative incidence of sPGF during the first year after allo-HSCT was 10%. This level is less than in general population of patients after allo-HSCT [15]. A prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT also showed increased rate of graft dysfunction in CML patients after allo-HSCT. Impact of pre-transplant treatment with tyrosine kinase inhibitors of second generation on the allograft function due to myelotoxicity is still under discussion [23]. Presumably, the similar factors may contribute to the development of both PrGF and sPoGF.

We analyzed the data associated with characteristics of patients, donors, and the HSCT procedure. Due to small number of cases in the target groups, only univariate analysis was performed. In contrast to many studies, conditioning regimen, the source and cellularity of the graft, CMV status of the donor and the patient, ABO incompatibility did not show any statistical significance of the disease status, although it is proved an important characteristic for the prognosis of primary graft failure and poor graft function [10, 11, 24, 25, 26, 27, 28, 29, 30].

Nevertheless, it was the presence of ACA that showed statistical significance for PrGF. This may suggest insufficient control of the underlying disease to be among the main causes of any type of graft dysfunction. However, no association between post-transplant relapse and sPGF was noted in our study. The disease recurrence after resolution of graft failure remains an important cause of treatment failure. Contribution of the underlying disease to development of PrGF and sPGF needs to be investigated in future.

HLA incompatibility was another factor for PrGF in univariate analysis. The importance of this characteristic for HSC engraftment is well known [13, 15, 30]. Haploidentical HSCTs in this analysis showed larger proportion of PrGF and sPGF, but this result needs further proofs, as our group was small and mostly retrospective.

The question still exists if the intensity of conditioning regimen may contribute to insufficient hematopoietic reconstitution after allo-HSCT. Impairment of bone marrow microenvironment exposed to high doses of alkylating agents may be one of the possible pathogenic pathways [13, 31]. Nevertheless, our study did not show significant influence of conditioning intensity upon the clinical outcomes.

Natural history of the patients who developed graft failure and poor graft function was of particular interest in this retrospective study. Despite various interventions, primary graft failure is still associated with poor outcomes and death, mostly, due to infectious complications.

Survival and NRM analysis showed that, despite the rare occurrence, PrGF and sPGF are life-threatening and resource-consuming problems. Both PrGF and sPGF need aggressive approach in order to improve outcomes of allo- HSCT. Intensive interventions might be a rescue for, at least, a part of the patients and lead to prolonged survival. Stimulation of residual HSCs by TPO agonists using in the setting of persistent cytopenia after HSCT by several groups might be a promising strategy, although influence of TPO agonists on the leukemic stem cells and risk of relapse is debated. Early employment of a CD34+-selected stem cell boost, or a second allogeneic HSCT to restore an effective haematopoiesis might also be a life-saving option. Identification of patients at high risk for these complications and development strategies for early intervention might be in scope of further investigation.

Conclusion

Both PrGF and sPGF are significant life-threatening problems in allo-HSCT. Specifically, PrGF but not severe poor graft failure (sPGF) significantly increased non-relapse mortality during the first year after allo-HSCT. Meanwhile, the incidence of post-transplant relapses did not differ in the CML patients exhibiting primary graft failure or severe poor graft function. Identification of risk factors for these complications can improve the results of this treatment, by planning HSCT technology, to minimize them and modify approaches to post-transplant therapy.

Conflict of interest

None declared.

References

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Introduction

Over the past decades, allogeneic stem cell transplantation (allo-HSCT) has been used worldwide as a technology aimed both the long-term management and cure of malignant hematological diseases [1]. Allo-HSCT remains a valuable option for treatment of chronic myeloid leukemia (CML) in era of tyrosine kinase inhibitors (TKI) [2-6]. The transplant-eligible population consists of the CML patients with predicted poor outcome if treated with TKIs alone. Despite the superiority of drug treatment, the development of transplant technology, i.e., usage of reduced intensity conditioning regimens, increased donor availability, led to improvement in the results of allo-HSCT in these patients [7,8]. Thus, transplantation is still a potentially curative therapeutic mode in all fit patients who are unable to achieve a durable complete cytogenetic response after treatment with 2 TKIs, and patients with advanced-phase CML.

Unfavorable results are mostly associated with impaired graft function, which is manifested in the lack of control over the underlying disease and subsequent relapse, as well as in primary graft failure (PrGF) and poor graft function (PoGF) [9-12]. Several risk factors of post-transplant graft failure were revealed, e.g., patient’s age, donor-recipient blood mismatch and CMV infection (13]. Treatment options for poor graft functioning are still limited. In addition to reinfusion of stem cell, some recent studies report, e.g., positive effects of Eltrombopag, a thrombopoietin mimetic [14].

The aim of the study was to assess the incidence and outcome of PrGF and severe poor graft function (sPGF) after allo-HSCT in CML patients.

Materials and methods

Patients and data collection

We carried out retrospective analysis of 121 consecutive patients with CML who received allo-HSCT in R. M. Gorbacheva Research Institute at the Pavlov University between 1995 and 2020. Information on the disease stage at diagnosis, time to allo-HSCT, transplantation procedure, relapse, and treatment following allo-HSCT was gathered via systematic reviews of the patient records. General approaches to evaluation of HSCT patients at our clinic were described elsewhere [15].

Definitions

CML was diagnosed on the basis of clinical and laboratory data, the detection of Philadelphia (Ph) chromosome and/or the chimeric BCR-ABL gene. Disease phase was defined according to the WHO classification [16]. The first chronic phase (CP1) was recognized in the absence of accelerated phase (AP) and/or blast crisis (BC) in the patient’s history, otherwise CP≥2 was registered. Hematological, cytogenetic and molecular response to the treatment prior to allo-HSCT was defined using ELN criteria [17].

Indications for HSCT

Indications for HSCT were as follows: 1) AP/BC at diagnosis or progression to AP/BC; 2) treatment failure in pre-TKI era; 3) treatment failure due to TKI resistance/intolerance; 4) T315I mutation. TKI resistance and TKI intolerance were defined according to ELN criteria [17].

Laboratory studies

For cytogenetic evaluation, conventional synchronized culture was performed for 48 hours with at least 20 metaphases analyzed per a sample (GTG method). Leukemia cell karyotype was evaluated according to International System for Human Cytogenetic Nomenclature (ISCN) [18]. In cases when the standard cytogenetic investigation was not available (i.e., insufficient material), the bone marrow was assessed with fluorescence in situ hybridization (FISH) probes aimed for detection of (9;22) variants (LSI BCR-ABL, Dual Color, Dual Fusion, "Vysis").

Additional chromosomal abnormalities (ACA) were defined as any structural and numerical chromosomal aberrations other than t(9;22)(q34;q11) (detected by cytogenetic or molecular assays for cryptic abnormalities).

Molecular response after allo-HSCT was evaluated according to the National Comprehensive Cancer Network (NCCN) criteria (2021). PCR monitoring of BCR/ABL was carried out according to NCCN Guidelines once in 3 months for 2 years, then once in every 3 to 6 months. The relative BCR-ABL1 expression level was evaluated according to method described by Gabert et al [19]. This technique includes the following stages: 1) total RNA extraction from peripheral blood of patients with CML, 2) reverse transcription with random hexameric primers, 3) real-time PCR with primers and probes specific to р210, р190 control ABL gene sequences.

Assessment of relative expression levels was based on evaluation of BCR-ABL1/ABL1 ratios in the studied cDNA samples. The ABL1 gene was used for normalization of the results. In order to determine copy numbers of the BCR-ABL1 and ABL1 transcripts, and to assess the reaction effectiveness, standard dilution curves were plotted using a plasmid with inserts of known target gene sequences (Invitrogen, USA), at a standard concentration ranges of 102-106 copies/mcl, according to 2020 European LeukemiaNet (ELN) Recommendations [17]. ABL kinase domain mutations were determined by Sanger direct sequencing.

Post-transplant monitoring

Post-transplant engraftment was defined as absolute neutrophil count (ANC) of >0.5×109/L without administration of colony-stimulating factor within 3 days. Primary graft failure (PrGF) was diagnosed in absence of donor cells in recipient’s bone marrow by the day +30. Donor chimerism was checked at the time of myelopoiesis recovery, i.e. ANC> 0.5×109/L, and by the days +30, 60, +100, +200, and in case of any cytopenia, or signs of relapse. Post-transplant relapse was diagnosed in cases of clinical progression to AP/BC, cytogenetic relapse, or molecular relapse defined as two consecutive positive PCR tests, or, at least, 1-log persistent increase of BCR/ABL transcript level.

The criteria for severe poor graft function (sPGF) were as follows: cytopenia in two or more hematopoietic lineages (platelets <20×109/l, ANC <0.5×109/l, hemoglobin <70 g/l) any time after documented engraftment in presence of full or stable mixed donor chimerism >90% without signs of relapse of underlying disease, rejection or acute graft-versus-host disease (GVHD) grade III-IV.

Secondary graft failure was defined as loss of donor hematopoiesis to <5% and/or ANC counts to <0.5×109/L after initial engraftment being not related to relapse, infection, or drug toxicity [20].

Statistical evaluation

Descriptive characteristics of the cohort included number of cases, proportions for discrete factors, medians and range for continuous values. Individual pre-transplant risk for the HSCT patients was evaluated according to Gratwohl [21]. Overall survival (OS) was assessed using the Kaplan-Meier method from the time of allo-HSCT to the date of last contact or the date of death. Death from any cause was considered as an event.

Survival analysis was performed using log-rank test. Relapse and non-relapse mortality (NRM) rates were summarized using cumulative incidence estimates, with NRM as competing risk for relapse, and relapse regarded as competing risk for NRM.

The event-free survival (EFS) was estimated as a period from allo-HSCT until last contact date, death, or any of the following events: any kind of post-transplant relapse, graft-versus-host disease (GVHD) grade III-IV, severe poor graft function, or secondary graft failure. PrGF and sPGF were estimated as a proportion of cases in the total cohort. Cumulative incidence of sPGF was calculated with respect to competing risks (death before day +30, any type of relapse, GVHD grade III-IV).

The differences between groups were assessed using Fisher's exact test, Pearson χ2 test, and Mann-Whitney U-test for categorical and quantitative characteristics respectively, and Gray’s test for cumulative incidences. All the tests were two-sided, and P-values <0.05 were assessed as indicating for significant associations. Statistical analysis was performed using SPSS, IBM Statistics and EZR free statistical environment, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

General characteristics of the patients and HSCT procedure

A total of 121 patients diagnosed with CML had undergone allo-HSCT. The median patients’ age was 37 years (range: 18-66). Other baseline characteristics for these patients are presented in Table 1.

The median time between CML diagnosis and allo-HSCT was 31 months (4.5-260). A total of 80 (66%) patients were transplanted in chronic phase (CP), the remaining 41 (34%) patients were in the active phase (AP or BC) at the time of HSCT. The median follow-up from allo-HSCT to the time of the last contact was 15 months (0.5-294).

HLA-matched or partially mismatched unrelated donors were used in 78 cases (65%), while matched related donors were employed in 34 cases (28%), and 9 (7%) patients received haploidentical allo-HSCT. The proportion of bone marrow (BM) and peripheral blood stem cells (PBSC) as the graft sources was almost equal: 49% (n=59) versus 51% (n=62).

Conditioning regimen included oral busulfan 8-12 mg/kg or melphalan 140 mg/m2 in combination with fludarabine 180 mg/m2 or cyclophosphamide. GVHD prophylaxis included calcineurin inhibitor (tacrolimus or cyclosporine A) and mycophenolate mofetil (30 mg/kg), or short course of posttransplant metotrexate, with or without antithymocyte globulin (horse, 60 mg/kg, or rabbit preparations, 5 mg/kg on day -3, -2, or high-dose), post-transplant cyclophosphamide (50 mg/kg, day +3 and +4 after allo-HSCT)/Alemtuzumab was used in two cases (Table 2).

Morozova-tab01-02.jpg

Morozova-fig01.jpg

Figure 1. Cumulative incidence of poor graft function post-HSCT in CML patients

Survival and relapse rates

Engraftment was documented in 106 (88%) patients, with median time to neutrophil recovery of 22 (8-58) days. Early death with no signs of engraftment before day +30 occurred in two cases. Thirty-one patients developed post-transplant relapse of any type with median time after allo-HSCT of 106 days (range: 15-333), included early CML relapse/progression before day +30 in 5 cases.

PrGF was documented in 8 (7%) cases. Two patients developed secondary graft failure, both in about two months after initial engraftment with lethal outcome due to severe bacterial infection. Severe poor graft function was diagnosed in 11 (9% of engrafted patients) with cumulative incidence of 10% (95% CI, 5-19) within 1 year after allo-HSCT (Fig. 1). Median time from HSCT to sPGF diagnosis was 43 (18-114) days.

The 1-year cumulative incidence rates of relapse and NRM comprised 35% (95% CI, 26-46) and 26% (95% CI, 18-35), respectively (Fig. 2).

A total of 57 (47%) patients died, the 1-year OS was 60% (95% CI, 51-69). Median OS was not reached. One-year EFS was 41% (95% CI, 32-50), median EFS was 271 (95% CI, 96-365) days (Fig. 3).

Morozova-fig02.jpg

Figure 2. One-year cumulative incidence of relapses and NRM after allo-HSCT in CML patients

Morozova-fig03.jpg

Figure 3. One-year overall and event-free survival after allogeneic HSCT in CML patients

Factors associated with primary graft failure and severe poor graft function

Among various pre-transplant characteristics, the presence of additional chromosomal abnormalities (ACA) was associated with cumulative incidence of PrGF and sPGF after HSCT. Thus, PrGF was 14% in the group with detectable ACA versus 3% in the group without ACA, (p=0.02), whereas incidence of sPGF in patients with ACA was 2% versus 12% in those without ACA, p=0.09. HLA-matched allo-HSCTs were beneficial for engraftment: 96% for HLA-matched transplantations vs 89% for allo-HSCT from HLA-mismatched donors, and 78% for haploidentical donors (p=0.05). Other pre-transplant factors didn’t show any statistical correlation with graft failure syndromes after HSCT (Table 3).

Table 3. Potential risk factors for the graft failure after allo-HSCT in CML patients

Morozova-tab03.jpg

Clinical features and outcomes of graft failure and severe poor graft function

The median follow-up time after allo-HSCT was 68 days (range: 43-1792). All the patients with primary graft failure (PrGF) (n=8) were administered G-CSF, antimicrobial therapy and transfusion support. Two patients received donor lymphocyte infusions without any effect. The second allo-HSCT was performed in 4 cases. A total of 7 patients had lethal outcome (6, of infectious complications; 1, of relapse), whereas one patient is alive after the 2nd allo-HSCT (Fig. 4).

Morozova-fig04.jpg

Figure 4. Treatment and outcomes of primary graft failure (PrGF) in CML patients after HSCT

Eleven patients exhibited severe poor graft function (sPGF) within median time of 21 (0-92) days after engraftment. Median length of sPGF was 52 days (range: 14-215). The median time of follow-up after allo-HSCT was 977 days (range: 45-2712).

Early sPGF with criterial cytopenia persisting after engraftment was diagnosed in 4 cases (36%), the remaining patients developed cytopenia after a period of normal graft function. A total of 3 cases of sPGF (27%) developed within 30 days after acute GVHD 2-3 grade (Fig. 5).

Morozova-fig05.jpg

Figure 5. Timeline of severe poor graft function (SPGF) in a group of CML patients

All the patients with sPGF received antimicrobial therapy, transfusion support, and G-CSF in case of neutropenia. Other therapeutic options for sPGF therapy were: rituximab (n=4), the second allo-HSCT, or boost stem cell infusion (n=3); eltrombopag (n=1); supportive care (n=5), as seen from Fig. 4. Normal graft function was restored in 8 patients.

A total of 4 patients died. The causes of death were infectious complications (n=3) and late post-transplant relapse (n=1) (Fig. 6).

Morozova-fig06.jpg

Figure 6. Treatment and outcomes of severe poor graft function (sPGF) in CML patients post-HSCT

Two cases of secondary graft failure occurred in about 3 months after allo-HSCT. Both patients died due to severe infection.

The incidence of post-transplant relapses did not differ in the patients with PrGF and sPGF as compared with those, who were free of these complications. Cumulative incidence of leukemia relapses was 31% (95% CI, 23-42), and 25% (95% CI, 4-87) in the patients with PrGF and engraftment (p=0.97), compared with 22% (95% CI, 3-54) and 32% (95% CI, 24-43) in the patients with sPGF and without sPGF (p=0.52), respectively.

Primary graft failure (PrGF) but not severe poor graft failure (sPGF) significantly increased non-relapse mortality during the first year after allo-HSCT. One-year NRM was 23% (95% CI, 15-32) in engrafted patients versus 71% (95% CI, 39-96) in the patients with PrGF (p<0.0001). Patients with and without sPGF had similar NRM: 20% (95% CI, 5-59) versus 26% (95% CI, 18-36) (p=0.74).

One-year OS was significantly lower in patients with PrGF: 13% (95% CI, 0.7-42) versus 64% (95% CI, 54-72) (p<0.0001) (Fig. 7). On the contrary, sPGF had no statistically significant influence on OS: 73% (95% CI, 37-90) versus 59% (95% CI, 49-69) (p=0.47).

Morozova-fig07.jpg

Figure 7. Impact of primary graft failure (PrGF, A), and severe poor graft function (sPGF, B) on overall survival post-HSCT in CML patients

Discussion

In context of TKI therapy progress, the indications for allo-HSCT in CML are becoming more stringent, with respect both to selective TKI choice, relapse diagnostics, and improved transplant technologies [22]. In this regard, it becomes relevant to investigate the causes of allo-HSCT failure and to determine the risk factors for PrGF and sPGF in CML patients. While the factor of post-transplant relapse is discussed in most publications, the issues of PrGF and sPGF remain poorly reflected. Only few authors provided clear definitions and data on the incidence of these complications (mostly PrGF) in the patients with CML. At the same time, most studies of posttransplant graft failure syndromes show that the diagnosis of CML may be among risk factors of this complication. However, most previous studies concerned a heterogeneous range of diagnoses, e.g., acute leukemia, chronic myelo- and lymphoproliferative and non-malignant diseases. To our knowledge, the present work evaluates for the first time the incidence of both PrGF and PGF in a homogeneous cohort of CML patients.

According to our results, PrGF occurred in 7% of cases, thus being higher than in patients with acute leukemia as confirmed by other publications [10]. On the contrary, cumulative incidence of sPGF during the first year after allo-HSCT was 10%. This level is less than in general population of patients after allo-HSCT [15]. A prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT also showed increased rate of graft dysfunction in CML patients after allo-HSCT. Impact of pre-transplant treatment with tyrosine kinase inhibitors of second generation on the allograft function due to myelotoxicity is still under discussion [23]. Presumably, the similar factors may contribute to the development of both PrGF and sPoGF.

We analyzed the data associated with characteristics of patients, donors, and the HSCT procedure. Due to small number of cases in the target groups, only univariate analysis was performed. In contrast to many studies, conditioning regimen, the source and cellularity of the graft, CMV status of the donor and the patient, ABO incompatibility did not show any statistical significance of the disease status, although it is proved an important characteristic for the prognosis of primary graft failure and poor graft function [10, 11, 24, 25, 26, 27, 28, 29, 30].

Nevertheless, it was the presence of ACA that showed statistical significance for PrGF. This may suggest insufficient control of the underlying disease to be among the main causes of any type of graft dysfunction. However, no association between post-transplant relapse and sPGF was noted in our study. The disease recurrence after resolution of graft failure remains an important cause of treatment failure. Contribution of the underlying disease to development of PrGF and sPGF needs to be investigated in future.

HLA incompatibility was another factor for PrGF in univariate analysis. The importance of this characteristic for HSC engraftment is well known [13, 15, 30]. Haploidentical HSCTs in this analysis showed larger proportion of PrGF and sPGF, but this result needs further proofs, as our group was small and mostly retrospective.

The question still exists if the intensity of conditioning regimen may contribute to insufficient hematopoietic reconstitution after allo-HSCT. Impairment of bone marrow microenvironment exposed to high doses of alkylating agents may be one of the possible pathogenic pathways [13, 31]. Nevertheless, our study did not show significant influence of conditioning intensity upon the clinical outcomes.

Natural history of the patients who developed graft failure and poor graft function was of particular interest in this retrospective study. Despite various interventions, primary graft failure is still associated with poor outcomes and death, mostly, due to infectious complications.

Survival and NRM analysis showed that, despite the rare occurrence, PrGF and sPGF are life-threatening and resource-consuming problems. Both PrGF and sPGF need aggressive approach in order to improve outcomes of allo- HSCT. Intensive interventions might be a rescue for, at least, a part of the patients and lead to prolonged survival. Stimulation of residual HSCs by TPO agonists using in the setting of persistent cytopenia after HSCT by several groups might be a promising strategy, although influence of TPO agonists on the leukemic stem cells and risk of relapse is debated. Early employment of a CD34+-selected stem cell boost, or a second allogeneic HSCT to restore an effective haematopoiesis might also be a life-saving option. Identification of patients at high risk for these complications and development strategies for early intervention might be in scope of further investigation.

Conclusion

Both PrGF and sPGF are significant life-threatening problems in allo-HSCT. Specifically, PrGF but not severe poor graft failure (sPGF) significantly increased non-relapse mortality during the first year after allo-HSCT. Meanwhile, the incidence of post-transplant relapses did not differ in the CML patients exhibiting primary graft failure or severe poor graft function. Identification of risk factors for these complications can improve the results of this treatment, by planning HSCT technology, to minimize them and modify approaches to post-transplant therapy.

Conflict of interest

None declared.

References

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Наряду с риском рецидива, неблагоприятные результаты ТГСК могут быть связаны с первичной недостаточностью (ПНТ) или плохой функцией трансплантата (ПФТ). Следовательно, целью нашего исследования было оценить частоту и исход ПНТ и тяжелой плохой функции трансплантата (ПФТ) после алло-ТГСК у пациентов с ХМЛ.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">Мы провели ретроспективный анализ 121 случая ХМЛ, которым проводилась алло-ТГСК в НИИ им. Р. М. Горбачевой ПСПбГМУ им. И. Павлова за последние 25 лет. ТГСК была показана в случаях продвинутой фазы заболевания или резистентности/непереносимости ИТК у пациентов с ХМЛ. Уровни транскриптов BCR/ABL и дополнительные хромосомные аномалии использовались в качестве лабораторных маркеров персистирующего заболевания. 80 пациентам (66%) трансплантацию проводили в хронической фазе заболевания (ХФ); 41 пациент (34%) находился в фазе акселерации (ФА) или бластном кризе (БК) на момент ТГСК. Трансплантацию от совместимых неродственных доноров выполняли в 65% случаев; от совместимых родственных доноров – в 28%, и от гаплоидентичных доноров – в 7% случаев. </p> <h3>Результаты</h3> <p style="text-align: justify;">Приживление трансплантата отмечено у 106 пациентов (88%). Посттрансплантационные рецидивы зарегистрированы у 31 пациента в сроки от 15 до 333 дней после ТГСК. ПНТ была зарегистрирована в 8 случаях (7%). У двух пациентов развилась вторичная недостаточность трансплантата в течение двух месяцев после первичного приживления с летальными инфекционными осложнениями. Тяжелое нарушение функции трансплантата (ПФТ) диагностировано в 11 случаях (9%), при кумулятивной частоте 10% в течение 1-го года после трансплантации. Среди различных предтрансплантационных характеристик, фактор возраста и, особенно – наличие дополнительных хромосомных аномалий (ДХА) были связаны с кумулятивной частотой первичной и тяжелой вторичной недостаточности трансплантата после ТГСК. Т.е. ПНТ составил 14% в группе с выявленными ДХА по сравнению с 3% в группе без ДХА, (p=0,02), тогда как частота вторичной недостаточности трансплантата у пациентов с ДХА составила 2% против 12% в группе без АЦА (p=0,09). Частота посттрансплантационных рецидивов у пациентов с ПНТ и ПФТ не различалась.</p> <h3>Выводы</h3> <p style="text-align: justify;">Первичная недостаточность трансплантата (ПНТ) способствует безрецидивной смертности в течение первого года после алло-ТГСК у пациентов с ХМЛ. Возникновение посттрансплантационных рецидивов не было связано с ПНТ И ПФТ при ХМЛ. Для улучшения эффективности технологий ТГСК необходима дальнейшая оценка факторов риска несостоятельности или плохой функции трансплантата.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, показания, несостоятельность трансплантата, факторы риска.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_META_TITLE"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_META_KEYWORDS"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_META_DESCRIPTION"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_PICTURE_FILE_ALT"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_PICTURE_FILE_TITLE"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "pre-i-posttransplantatsionnye-faktory-assotsiirovannye-s-pervichnoy-nedostatochnostyu-i-tyazheloy-di" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(415) "Пре- и посттрансплантационные факторы, ассоциированные с первичной недостаточностью и тяжелой дисфункцией трансплантата после аллогенной трансплантации гемопоэтических стволовых клеток при хроническом миелоидном лейкозе" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "pre-i-posttransplantatsionnye-faktory-assotsiirovannye-s-pervichnoy-nedostatochnostyu-i-tyazheloy-di" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "pre-i-posttransplantatsionnye-faktory-assotsiirovannye-s-pervichnoy-nedostatochnostyu-i-tyazheloy-di" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "pre-i-posttransplantatsionnye-faktory-assotsiirovannye-s-pervichnoy-nedostatochnostyu-i-tyazheloy-di" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "207" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" 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["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28523" ["VALUE"]=> array(2) { ["TEXT"]=> string(384) "<p>Елена В. Морозова, Татьяна А. Рудакова, Юлия Ю. Власова, Мария В. Барабанщикова, Татьяна Л. Гиндина, Александр Л. Алянский, Мария Д. Владовская, Иван С. Моисеев, Людмила С. Зубаровская, Александр Д. Кулагин</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(372) "

Елена В. Морозова, Татьяна А. Рудакова, Юлия Ю. Власова, Мария В. Барабанщикова, Татьяна Л. Гиндина, Александр Л. Алянский, Мария Д. Владовская, Иван С. Моисеев, Людмила С. Зубаровская, Александр Д. Кулагин

" ["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) "28524" ["VALUE"]=> array(2) { ["TEXT"]=> string(373) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(361) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Аллогенная трансплантация стволовых клеток (алло-ТГСК) используется во всем мире для долгосрочного контроля и лечения злокачественных новообразований системы крови, по-прежнему оставаясь методом выбора в лечении хронического миелоидного лейкоза (ХМЛ) у пациентов, которые не могут достичь длительного полного цитогенетического ответа после лечения ингибиторами тирозинкиназы (ИТК), а также на поздних стадиях заболевания. Наряду с риском рецидива, неблагоприятные результаты ТГСК могут быть связаны с первичной недостаточностью (ПНТ) или плохой функцией трансплантата (ПФТ). Следовательно, целью нашего исследования было оценить частоту и исход ПНТ и тяжелой плохой функции трансплантата (ПФТ) после алло-ТГСК у пациентов с ХМЛ.

Пациенты и методы

Мы провели ретроспективный анализ 121 случая ХМЛ, которым проводилась алло-ТГСК в НИИ им. Р. М. Горбачевой ПСПбГМУ им. И. Павлова за последние 25 лет. ТГСК была показана в случаях продвинутой фазы заболевания или резистентности/непереносимости ИТК у пациентов с ХМЛ. Уровни транскриптов BCR/ABL и дополнительные хромосомные аномалии использовались в качестве лабораторных маркеров персистирующего заболевания. 80 пациентам (66%) трансплантацию проводили в хронической фазе заболевания (ХФ); 41 пациент (34%) находился в фазе акселерации (ФА) или бластном кризе (БК) на момент ТГСК. Трансплантацию от совместимых неродственных доноров выполняли в 65% случаев; от совместимых родственных доноров – в 28%, и от гаплоидентичных доноров – в 7% случаев.

Результаты

Приживление трансплантата отмечено у 106 пациентов (88%). Посттрансплантационные рецидивы зарегистрированы у 31 пациента в сроки от 15 до 333 дней после ТГСК. ПНТ была зарегистрирована в 8 случаях (7%). У двух пациентов развилась вторичная недостаточность трансплантата в течение двух месяцев после первичного приживления с летальными инфекционными осложнениями. Тяжелое нарушение функции трансплантата (ПФТ) диагностировано в 11 случаях (9%), при кумулятивной частоте 10% в течение 1-го года после трансплантации. Среди различных предтрансплантационных характеристик, фактор возраста и, особенно – наличие дополнительных хромосомных аномалий (ДХА) были связаны с кумулятивной частотой первичной и тяжелой вторичной недостаточности трансплантата после ТГСК. Т.е. ПНТ составил 14% в группе с выявленными ДХА по сравнению с 3% в группе без ДХА, (p=0,02), тогда как частота вторичной недостаточности трансплантата у пациентов с ДХА составила 2% против 12% в группе без АЦА (p=0,09). Частота посттрансплантационных рецидивов у пациентов с ПНТ и ПФТ не различалась.

Выводы

Первичная недостаточность трансплантата (ПНТ) способствует безрецидивной смертности в течение первого года после алло-ТГСК у пациентов с ХМЛ. Возникновение посттрансплантационных рецидивов не было связано с ПНТ И ПФТ при ХМЛ. Для улучшения эффективности технологий ТГСК необходима дальнейшая оценка факторов риска несостоятельности или плохой функции трансплантата.

Ключевые слова

Хронический миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, показания, несостоятельность трансплантата, факторы риска.

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Elena V. Morozova, Tatiana A. Rudakova, Julia Ju. Vlasova, Maria V. Barabanshchikova, Tatiana L. Gindina, Alexander L. Alyanskiy, Maria D. Vladovskaya, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Alexander D. Kulagin

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Elena V. Morozova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 927-82-29
E-mail: dr_morozova@mail.ru


Citation: Morozova EV, Rudakova TA, Vlasova JJ, et al. Pre- and post-transplantation factors associated with primary graft failure and severe poor graft function after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. Cell Ther Transplant 2022; 11(1): 13-23.

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Allogeneic stem cell transplantation (allo-HSCT) is used worldwide for long-term management and cure of hematological malignancies, still remaining a valuable option for treatment of chronic myeloid leukemia (CML) in all fit patients who are unable to achieve a durable complete cytogenetic response after treatment with tyrosine kinase inhibitors (TKIs), and in advanced-phase disease. Along with relapse risk, the unfavorable HSCT results may be associated with primary graft failure (PrGF), or poor graft function (PoGF). Hence, the aim of our study was to assess frequency and outcome of PrGF and severe poor graft function (sPGF) after allo-HSCT in CML patients.

Patients and methods

We performed a retrospective analysis of 121 consecutive patients with CML who received allo-HSCT in the RM Gorbacheva Research Institute at the Pavlov University over 25 years. HSCT was indicated in cases of advanced-phase disease, or TKI resistance/intolerance of CML patients. BCR/ABL transcript levels and additional chromosomal abnormalities were used as laboratory markers of advanced disease. 80 patients (66%) were transplanted in chronic phase (CP); 41 patients (34%) were in acceleration phase (AP), or blast crisis (BC) at the time of HSCT. Matched unrelated donors were used in 65% of the cases; matched related donors, in 28%, and haploidentical donors, in 7% of cases.

Results

Engraftment was documented in 106 (88%) patients. Post-transplant relapses were registered in 31 patients within 15-333 days after HSCT. PrGF was documented in 8 cases (7%). Two patients developed secondary graft failure within two months after initial engraftment, with lethal infectious complications. Severe poor graft function (PoGF) was diagnosed in 11 cases (9%) at cumulative incidence of 10% within 1 year post-transplant. Among various pre-transplant characteristics, age factor, and, especially, presence of additional chromosomal abnormalities (ACA) were associated with cumulative incidence of PrGF and sPGF after HSCT. I.e., PrGF was 14% in the group with detectable ACA versus 3% in the group without ACA, (p=0.02), whereas incidence of sPGF in patients with ACA was 2% versus 12% in those without ACA (p=0.09). The incidence of post-transplant relapses did not differ in the patients with PrGF and sPGF.

Conclusions

Primary graft failure (PrGF) contributes to the non-relapse mortality during the first year after allo-HSCT in CML patients. Emergence of post-transplant relapses was not associated with PrGF and sPGF in CML. Further assessment of risk factors for the graft failure or poor graft function is required in order to improve the results of HSCT technologies.

Keywords

Chronic myeloid leukemia, hematopoietic stem cell transplantation, indications, graft failure, risk factors.

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Morozova, Tatiana A. Rudakova, Julia Ju. Vlasova, Maria V. Barabanshchikova, Tatiana L. Gindina, Alexander L. Alyanskiy, Maria D. Vladovskaya, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Alexander D. Kulagin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(222) "

Elena V. Morozova, Tatiana A. Rudakova, Julia Ju. Vlasova, Maria V. Barabanshchikova, Tatiana L. Gindina, Alexander L. Alyanskiy, Maria D. Vladovskaya, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Alexander D. Kulagin

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Elena V. Morozova, Tatiana A. Rudakova, Julia Ju. Vlasova, Maria V. Barabanshchikova, Tatiana L. Gindina, Alexander L. Alyanskiy, Maria D. Vladovskaya, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Alexander D. Kulagin

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Allogeneic stem cell transplantation (allo-HSCT) is used worldwide for long-term management and cure of hematological malignancies, still remaining a valuable option for treatment of chronic myeloid leukemia (CML) in all fit patients who are unable to achieve a durable complete cytogenetic response after treatment with tyrosine kinase inhibitors (TKIs), and in advanced-phase disease. Along with relapse risk, the unfavorable HSCT results may be associated with primary graft failure (PrGF), or poor graft function (PoGF). Hence, the aim of our study was to assess frequency and outcome of PrGF and severe poor graft function (sPGF) after allo-HSCT in CML patients.

Patients and methods

We performed a retrospective analysis of 121 consecutive patients with CML who received allo-HSCT in the RM Gorbacheva Research Institute at the Pavlov University over 25 years. HSCT was indicated in cases of advanced-phase disease, or TKI resistance/intolerance of CML patients. BCR/ABL transcript levels and additional chromosomal abnormalities were used as laboratory markers of advanced disease. 80 patients (66%) were transplanted in chronic phase (CP); 41 patients (34%) were in acceleration phase (AP), or blast crisis (BC) at the time of HSCT. Matched unrelated donors were used in 65% of the cases; matched related donors, in 28%, and haploidentical donors, in 7% of cases.

Results

Engraftment was documented in 106 (88%) patients. Post-transplant relapses were registered in 31 patients within 15-333 days after HSCT. PrGF was documented in 8 cases (7%). Two patients developed secondary graft failure within two months after initial engraftment, with lethal infectious complications. Severe poor graft function (PoGF) was diagnosed in 11 cases (9%) at cumulative incidence of 10% within 1 year post-transplant. Among various pre-transplant characteristics, age factor, and, especially, presence of additional chromosomal abnormalities (ACA) were associated with cumulative incidence of PrGF and sPGF after HSCT. I.e., PrGF was 14% in the group with detectable ACA versus 3% in the group without ACA, (p=0.02), whereas incidence of sPGF in patients with ACA was 2% versus 12% in those without ACA (p=0.09). The incidence of post-transplant relapses did not differ in the patients with PrGF and sPGF.

Conclusions

Primary graft failure (PrGF) contributes to the non-relapse mortality during the first year after allo-HSCT in CML patients. Emergence of post-transplant relapses was not associated with PrGF and sPGF in CML. Further assessment of risk factors for the graft failure or poor graft function is required in order to improve the results of HSCT technologies.

Keywords

Chronic myeloid leukemia, hematopoietic stem cell transplantation, indications, graft failure, risk factors.

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Allogeneic stem cell transplantation (allo-HSCT) is used worldwide for long-term management and cure of hematological malignancies, still remaining a valuable option for treatment of chronic myeloid leukemia (CML) in all fit patients who are unable to achieve a durable complete cytogenetic response after treatment with tyrosine kinase inhibitors (TKIs), and in advanced-phase disease. Along with relapse risk, the unfavorable HSCT results may be associated with primary graft failure (PrGF), or poor graft function (PoGF). Hence, the aim of our study was to assess frequency and outcome of PrGF and severe poor graft function (sPGF) after allo-HSCT in CML patients.

Patients and methods

We performed a retrospective analysis of 121 consecutive patients with CML who received allo-HSCT in the RM Gorbacheva Research Institute at the Pavlov University over 25 years. HSCT was indicated in cases of advanced-phase disease, or TKI resistance/intolerance of CML patients. BCR/ABL transcript levels and additional chromosomal abnormalities were used as laboratory markers of advanced disease. 80 patients (66%) were transplanted in chronic phase (CP); 41 patients (34%) were in acceleration phase (AP), or blast crisis (BC) at the time of HSCT. Matched unrelated donors were used in 65% of the cases; matched related donors, in 28%, and haploidentical donors, in 7% of cases.

Results

Engraftment was documented in 106 (88%) patients. Post-transplant relapses were registered in 31 patients within 15-333 days after HSCT. PrGF was documented in 8 cases (7%). Two patients developed secondary graft failure within two months after initial engraftment, with lethal infectious complications. Severe poor graft function (PoGF) was diagnosed in 11 cases (9%) at cumulative incidence of 10% within 1 year post-transplant. Among various pre-transplant characteristics, age factor, and, especially, presence of additional chromosomal abnormalities (ACA) were associated with cumulative incidence of PrGF and sPGF after HSCT. I.e., PrGF was 14% in the group with detectable ACA versus 3% in the group without ACA, (p=0.02), whereas incidence of sPGF in patients with ACA was 2% versus 12% in those without ACA (p=0.09). The incidence of post-transplant relapses did not differ in the patients with PrGF and sPGF.

Conclusions

Primary graft failure (PrGF) contributes to the non-relapse mortality during the first year after allo-HSCT in CML patients. Emergence of post-transplant relapses was not associated with PrGF and sPGF in CML. Further assessment of risk factors for the graft failure or poor graft function is required in order to improve the results of HSCT technologies.

Keywords

Chronic myeloid leukemia, hematopoietic stem cell transplantation, indications, graft failure, risk factors.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Elena V. Morozova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 927-82-29
E-mail: dr_morozova@mail.ru


Citation: Morozova EV, Rudakova TA, Vlasova JJ, et al. Pre- and post-transplantation factors associated with primary graft failure and severe poor graft function after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. Cell Ther Transplant 2022; 11(1): 13-23.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Elena V. Morozova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 927-82-29
E-mail: dr_morozova@mail.ru


Citation: Morozova EV, Rudakova TA, Vlasova JJ, et al. Pre- and post-transplantation factors associated with primary graft failure and severe poor graft function after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia. Cell Ther Transplant 2022; 11(1): 13-23.

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Елена В. Морозова, Татьяна А. Рудакова, Юлия Ю. Власова, Мария В. Барабанщикова, Татьяна Л. Гиндина, Александр Л. Алянский, Мария Д. Владовская, Иван С. Моисеев, Людмила С. Зубаровская, Александр Д. Кулагин

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Елена В. Морозова, Татьяна А. Рудакова, Юлия Ю. Власова, Мария В. Барабанщикова, Татьяна Л. Гиндина, Александр Л. Алянский, Мария Д. Владовская, Иван С. Моисеев, Людмила С. Зубаровская, Александр Д. Кулагин

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Наряду с риском рецидива, неблагоприятные результаты ТГСК могут быть связаны с первичной недостаточностью (ПНТ) или плохой функцией трансплантата (ПФТ). Следовательно, целью нашего исследования было оценить частоту и исход ПНТ и тяжелой плохой функции трансплантата (ПФТ) после алло-ТГСК у пациентов с ХМЛ.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">Мы провели ретроспективный анализ 121 случая ХМЛ, которым проводилась алло-ТГСК в НИИ им. Р. М. Горбачевой ПСПбГМУ им. И. Павлова за последние 25 лет. ТГСК была показана в случаях продвинутой фазы заболевания или резистентности/непереносимости ИТК у пациентов с ХМЛ. Уровни транскриптов BCR/ABL и дополнительные хромосомные аномалии использовались в качестве лабораторных маркеров персистирующего заболевания. 80 пациентам (66%) трансплантацию проводили в хронической фазе заболевания (ХФ); 41 пациент (34%) находился в фазе акселерации (ФА) или бластном кризе (БК) на момент ТГСК. Трансплантацию от совместимых неродственных доноров выполняли в 65% случаев; от совместимых родственных доноров – в 28%, и от гаплоидентичных доноров – в 7% случаев. </p> <h3>Результаты</h3> <p style="text-align: justify;">Приживление трансплантата отмечено у 106 пациентов (88%). Посттрансплантационные рецидивы зарегистрированы у 31 пациента в сроки от 15 до 333 дней после ТГСК. ПНТ была зарегистрирована в 8 случаях (7%). У двух пациентов развилась вторичная недостаточность трансплантата в течение двух месяцев после первичного приживления с летальными инфекционными осложнениями. Тяжелое нарушение функции трансплантата (ПФТ) диагностировано в 11 случаях (9%), при кумулятивной частоте 10% в течение 1-го года после трансплантации. Среди различных предтрансплантационных характеристик, фактор возраста и, особенно – наличие дополнительных хромосомных аномалий (ДХА) были связаны с кумулятивной частотой первичной и тяжелой вторичной недостаточности трансплантата после ТГСК. Т.е. ПНТ составил 14% в группе с выявленными ДХА по сравнению с 3% в группе без ДХА, (p=0,02), тогда как частота вторичной недостаточности трансплантата у пациентов с ДХА составила 2% против 12% в группе без АЦА (p=0,09). Частота посттрансплантационных рецидивов у пациентов с ПНТ и ПФТ не различалась.</p> <h3>Выводы</h3> <p style="text-align: justify;">Первичная недостаточность трансплантата (ПНТ) способствует безрецидивной смертности в течение первого года после алло-ТГСК у пациентов с ХМЛ. Возникновение посттрансплантационных рецидивов не было связано с ПНТ И ПФТ при ХМЛ. Для улучшения эффективности технологий ТГСК необходима дальнейшая оценка факторов риска несостоятельности или плохой функции трансплантата.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, показания, несостоятельность трансплантата, факторы риска.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5856) "

Аллогенная трансплантация стволовых клеток (алло-ТГСК) используется во всем мире для долгосрочного контроля и лечения злокачественных новообразований системы крови, по-прежнему оставаясь методом выбора в лечении хронического миелоидного лейкоза (ХМЛ) у пациентов, которые не могут достичь длительного полного цитогенетического ответа после лечения ингибиторами тирозинкиназы (ИТК), а также на поздних стадиях заболевания. Наряду с риском рецидива, неблагоприятные результаты ТГСК могут быть связаны с первичной недостаточностью (ПНТ) или плохой функцией трансплантата (ПФТ). Следовательно, целью нашего исследования было оценить частоту и исход ПНТ и тяжелой плохой функции трансплантата (ПФТ) после алло-ТГСК у пациентов с ХМЛ.

Пациенты и методы

Мы провели ретроспективный анализ 121 случая ХМЛ, которым проводилась алло-ТГСК в НИИ им. Р. М. Горбачевой ПСПбГМУ им. И. Павлова за последние 25 лет. ТГСК была показана в случаях продвинутой фазы заболевания или резистентности/непереносимости ИТК у пациентов с ХМЛ. Уровни транскриптов BCR/ABL и дополнительные хромосомные аномалии использовались в качестве лабораторных маркеров персистирующего заболевания. 80 пациентам (66%) трансплантацию проводили в хронической фазе заболевания (ХФ); 41 пациент (34%) находился в фазе акселерации (ФА) или бластном кризе (БК) на момент ТГСК. Трансплантацию от совместимых неродственных доноров выполняли в 65% случаев; от совместимых родственных доноров – в 28%, и от гаплоидентичных доноров – в 7% случаев.

Результаты

Приживление трансплантата отмечено у 106 пациентов (88%). Посттрансплантационные рецидивы зарегистрированы у 31 пациента в сроки от 15 до 333 дней после ТГСК. ПНТ была зарегистрирована в 8 случаях (7%). У двух пациентов развилась вторичная недостаточность трансплантата в течение двух месяцев после первичного приживления с летальными инфекционными осложнениями. Тяжелое нарушение функции трансплантата (ПФТ) диагностировано в 11 случаях (9%), при кумулятивной частоте 10% в течение 1-го года после трансплантации. Среди различных предтрансплантационных характеристик, фактор возраста и, особенно – наличие дополнительных хромосомных аномалий (ДХА) были связаны с кумулятивной частотой первичной и тяжелой вторичной недостаточности трансплантата после ТГСК. Т.е. ПНТ составил 14% в группе с выявленными ДХА по сравнению с 3% в группе без ДХА, (p=0,02), тогда как частота вторичной недостаточности трансплантата у пациентов с ДХА составила 2% против 12% в группе без АЦА (p=0,09). Частота посттрансплантационных рецидивов у пациентов с ПНТ и ПФТ не различалась.

Выводы

Первичная недостаточность трансплантата (ПНТ) способствует безрецидивной смертности в течение первого года после алло-ТГСК у пациентов с ХМЛ. Возникновение посттрансплантационных рецидивов не было связано с ПНТ И ПФТ при ХМЛ. Для улучшения эффективности технологий ТГСК необходима дальнейшая оценка факторов риска несостоятельности или плохой функции трансплантата.

Ключевые слова

Хронический миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, показания, несостоятельность трансплантата, факторы риска.

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Аллогенная трансплантация стволовых клеток (алло-ТГСК) используется во всем мире для долгосрочного контроля и лечения злокачественных новообразований системы крови, по-прежнему оставаясь методом выбора в лечении хронического миелоидного лейкоза (ХМЛ) у пациентов, которые не могут достичь длительного полного цитогенетического ответа после лечения ингибиторами тирозинкиназы (ИТК), а также на поздних стадиях заболевания. Наряду с риском рецидива, неблагоприятные результаты ТГСК могут быть связаны с первичной недостаточностью (ПНТ) или плохой функцией трансплантата (ПФТ). Следовательно, целью нашего исследования было оценить частоту и исход ПНТ и тяжелой плохой функции трансплантата (ПФТ) после алло-ТГСК у пациентов с ХМЛ.

Пациенты и методы

Мы провели ретроспективный анализ 121 случая ХМЛ, которым проводилась алло-ТГСК в НИИ им. Р. М. Горбачевой ПСПбГМУ им. И. Павлова за последние 25 лет. ТГСК была показана в случаях продвинутой фазы заболевания или резистентности/непереносимости ИТК у пациентов с ХМЛ. Уровни транскриптов BCR/ABL и дополнительные хромосомные аномалии использовались в качестве лабораторных маркеров персистирующего заболевания. 80 пациентам (66%) трансплантацию проводили в хронической фазе заболевания (ХФ); 41 пациент (34%) находился в фазе акселерации (ФА) или бластном кризе (БК) на момент ТГСК. Трансплантацию от совместимых неродственных доноров выполняли в 65% случаев; от совместимых родственных доноров – в 28%, и от гаплоидентичных доноров – в 7% случаев.

Результаты

Приживление трансплантата отмечено у 106 пациентов (88%). Посттрансплантационные рецидивы зарегистрированы у 31 пациента в сроки от 15 до 333 дней после ТГСК. ПНТ была зарегистрирована в 8 случаях (7%). У двух пациентов развилась вторичная недостаточность трансплантата в течение двух месяцев после первичного приживления с летальными инфекционными осложнениями. Тяжелое нарушение функции трансплантата (ПФТ) диагностировано в 11 случаях (9%), при кумулятивной частоте 10% в течение 1-го года после трансплантации. Среди различных предтрансплантационных характеристик, фактор возраста и, особенно – наличие дополнительных хромосомных аномалий (ДХА) были связаны с кумулятивной частотой первичной и тяжелой вторичной недостаточности трансплантата после ТГСК. Т.е. ПНТ составил 14% в группе с выявленными ДХА по сравнению с 3% в группе без ДХА, (p=0,02), тогда как частота вторичной недостаточности трансплантата у пациентов с ДХА составила 2% против 12% в группе без АЦА (p=0,09). Частота посттрансплантационных рецидивов у пациентов с ПНТ и ПФТ не различалась.

Выводы

Первичная недостаточность трансплантата (ПНТ) способствует безрецидивной смертности в течение первого года после алло-ТГСК у пациентов с ХМЛ. Возникновение посттрансплантационных рецидивов не было связано с ПНТ И ПФТ при ХМЛ. Для улучшения эффективности технологий ТГСК необходима дальнейшая оценка факторов риска несостоятельности или плохой функции трансплантата.

Ключевые слова

Хронический миелоидный лейкоз, трансплантация гемопоэтических стволовых клеток, показания, несостоятельность трансплантата, факторы риска.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has witnessed a historic change after the milestone article published by Mazzaferro et al. [1], who confirmed favorable outcomes for HCC patients similar to outcomes of LT for non-HCC indications. Since then, LT and its main option, the deceased-donor liver transplantation (DDLT) has become a well-established line of treatment with a highly curative profile for cirrhotic patients with HCC, but if only a liver graft is available.

The living-donor liver transplantation (LDLT) was introduced in order to reduce the organ shortage, due to expanding waiting lists for the patients awaiting liver transplant. In some countries, where the number of deceased donor is extremely small, the LDLT has been developed as an alternative treatment for the end-stage liver diseases, thus becoming an established treatment in HCC cases [2].

Nevertheless, recurrent HCC (rHCC) is still reported in up to 15% of cases following LT. HCC relapse is associated with dismal prognosis and, subsequently, LT failure in most instances [3]. Currently, LT for HCC has increased four-fold since early 2000s [4]. The impact of recurrent HCC is further enhanced by scarcity of liver grafts and fast expansion of LT waiting lists, whereas hepatic resection and other ablative modalities can offer up to 50% patient survival for HCC relapse [5].

Patient survival was shown to be better following LDLT for HCC compared to those transplanted from Deceased Donor (DD) [6, 7]. Many factors were held responsible for such results, including shorter time to transplant, better graft quality with shorter ischemia period.

Moreover, with the accumulation of cases, the impact of LDLT on the rHCC rates after LT has drawn attention of transplant community, since some reports showed higher incidence of rHCC following LDLT [8].

Many pathogenetic mechanisms were considered to explain these reports, including higher cytokine production in regenerating liver grafts and reduced time to transplant that could conceal aggressive tumor biology promoting the HCC recurrence [9-11]. These data were further analyzed to compare rHCC for patients transplanted from LDLT and DDLT source [12-15].

Hence, the aim of our single-center study was to compare overall and tumor-free survival among HCC patients subjected to liver transplantation from living donor (LDLT) versus liver transplant from deceased donor (DDLT).

Materials and methods

The study was started after obtaining the approval of Research Ethics Committee at our institution. All the patients were consented for the use of their clinical and pathological data for research purposes in anonymous manner, the patients were also informed that their decision to approve or disapprove the research consent will not influence their clinical management.

The cases of pediatric LT or liver retransplantation were excluded from this study. Finally, 136 patients diagnosed with HCC approved the research consent, being subsequently included in the study. Medical charts of the included patients were retrospectively reviewed. HCC was diagnosed by contrast-enhanced computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). The disease staging was based on chest CT, cranial CT, and technetium-99m bone scintigraphy, to exclude extra-hepatic disease. The following exclusion criteria were considered absolute contraindications for LT at our center:
• Failed or unfeasible downstaging of HCC originally beyond Milan, or UCSF transplant criteria, i.e., stable disease (SD), progressive disease (PD) according to modified RECIST criteria (16);
• Active extra-hepatic malignancies (excluding non-melanoma skin cancers);
• Untreatable advanced cardiopulmonary disease;
• Active infections e.g., active tuberculosis, uncontrollable sepsis;
• Unstable major psychiatric disorders;
• Disabling extensive intracranial neurological deficit;
• Substance abuse or active alcohol abuse over last 6 months;
• Documented medical non-compliance.

A total of 115 adult patients underwent LT for HCC at our institution between August 2006 and December 2019. LT was performed using either cadaveric, or living donor liver transplantation (LDLT). In LDLT setting, the donors were first- and second-degree relatives of respective patients.

Seventy-three patients conformed with Milan liver transplant criteria (MC) and, for the sake of comparison, they were divided into two groups as follows: Group A included forty-four HCC patients transplanted from living donors (LDLT); Group B consisted of twenty-nine HCC patients who received DDLT.

Fig. 1 illustrates the distribution of HCC patients with respect to decision for LT, and if the transplant was performed as LDLT or DDLT. The patients beyond Milan criteria, or those subjected to downstaging locoregional therapy were excluded from the study.

Abdelfattah-fig01.jpg

Figure 1. Flowchart of HCC patients enrolled during the study period

Details of the transplant procedure were documented; tumor characteristics were based on the pathological findings. HCC size, number of foci, tumor grade, and lymphatic invasion were diagnosed by an experienced pathologist. Demographic data, pre-transplant features, procedure-related variables, pathological findings were retrieved from the patient charts. Triple immunosuppression protocol was applied for the LT recipients including calcineurin inhibitor (CNI), glucocorticosteroids, and mycophenolate mofetil. Clinical and laboratory data were analyzed with t-test and Chi-square test. P-value of <0.05 was considered statistically significant. Kaplan-Meier curves were used to express survival outcomes, and statistical significance was determined by log-rank test. Overall and tumor-free survival were determined during the control contacts and examination of the patients.

Patient survival was calculated from the date of LT to the date of death or the date of the last follow-up for surviving patients. Graft survival was estimated as a death-censored graft survival. It was calculated from the date of transplantation to the date of irreversible graft failure signified by relisting of the patient on liver transplant waiting list, this method was used to avoid estimation of death with a functioning graft as a graft failure. Tumor-free survival was estimated from the date of transplant to the date of confirmed pathological evidence of recurrent HCC.

Results

Seventy-three patients underwent LT between August 2006 and December 2019 at our center for HCC which met MC. Table 1 is summarizing pre-transplant and pathological variables for these patients.

Table 1. Comparison of pre-transplant and pathological findings in LDLT and DDLT groups of the patients with hepatocellular carcinoma

Abdelfattah-tab01.jpg

Time to transplant ranged from 10 to 185 days, patients’ age, and time to transplant differed significantly between group A (living donors) and B (deceased donors), (P value, 0.002 and <0.001 respectively). On the other hand, pathological variables did not show significant difference between both groups.

The mean post-transplant follow-up for the studied patients was 46±33.3 months, ranging from 24.3 to 149.9 months. The overall 5-year patient survival, graft survival and tumor-free survival were 78.6%, 90.1% and 86.3% respectively. During the follow-up, a total of six patients manifested with rHCC (8.2%), i.e., four patients (9.1%) developed rHCC in group A, compared to two-cases (6.9%) of rHCC in group B patients, p value was 0.99. With respect to survival outcomes, LDLT group slightly differed from those who received DDLT. The overall patient survival was higher in Group A, at P=0.09 (log-rank test).

Conversely, tumor-free survival was only marginally better in group B, but it did not reach the significance level (P=0.6). On the other hand, graft survival was almost the same in both groups (P=0.99), as seen in Fig. 2 (A, B, C).

Abdelfattah-fig02.jpg

Figure 2. Comparisons for overall survival (A), tumor-free survival (B) and graft survival (C) between the groups A (LDLT) and B (DDLT) using the Kaplan-Meier approach

Discussion

There is a convincing evidence, that LT offers an excellent chance for cure of patients presenting with HCC, especially when their tumor burden is still within Milan criteria. The main concern regarding LT for HCC patients is the issue of liver graft availability and ethical costs to obtain it. Ethical concerns always overshadow the excellent results for LT in HCC patients, especially when allocation system favors HCC patients by the addition of 22 points [3, 4]. Consequently, more liver grafts are being allocated to HCC patients on the expense of patient suffering from liver insufficiency only. Furthermore, the use of LDLT to partially alleviate graft shortage is accompanied by inherent risk for healthy donor. Thus, outcomes of LT for HCC must be at optimal levels, to justify the ethical concerns encountered either in DDLT or LDLT settings. Hence, evaluation of clinical outcomes after LT for HCC in general, and comparative assessment of either LDLT or DDLT advantages over other options is quite important, especially in transplant centers where both LT modes are available.

DDLT is associated with long waiting times and consequently increased mortality and delisting rate while awaiting liver transplant. Hogen et al. [17], reported significantly higher waiting list mortality in UNOS regions with long waiting times compared to regions with short waiting times.

One of the main LDLT benefits is its ability to reduce the time to transplant and decrease the waiting list dropout. This is especially vital to the patients with HCC, to avoid tumor progression. Sandhu et al. [18], described a significantly shorter waiting time for LDLT compared to DDLT (3.1 vs 5.3 months respectively). Similarly, the current study reported significant data from the current study which showed 15% dropout rate for the patients originally presenting with HCC within Milan criteria. More than one third of this dropout rate was due to tumor progression. These patients underwent downstaging protocol using different locoregional neoadjuvant techniques.

The dropout rates vary considerably according to graft allocation policies. In the USA, there is a considerable variability of dropout rate based on the transplant waiting times. Mehta et al. [18], compared the dropout risk for HCC patients who received MELD exception points from 2005 and 2014. They described a significantly higher risk for dropout in UNOS regions with long transplant waiting times, the difference was three times higher than in the areas with short transplant waiting times (24% vs 8% dropout rate, respectively).

Few studies addressed the question of whether LDLT is associated with higher recurrence rate for HCC compared to DDLT, or not. One of the earliest reports on this issue (Lo et al.) described a significantly more common HCC recurrence at their LDLT arm (43 patients), compared to DDLT arm which included 17 patients. The study included heterogenous patient groups, i.e., corresponding the Milan or UCSF criteria, and beyond them. The cases subjected to downstaging locoregional therapy were not excluded from the study [12]. Similar findings were reported by Fischer et al. in their large cohort of patients, and they referred to different tumor characteristics, pretransplant locoregional therapies and short time to transplant as the key factors that explain the higher reported rHCC rates following LDLT [13].

On the other hand, Di Sandro et al., reported that LDLT had the same tumor-free survival compared to DDLT in the patients presenting within Milan transplant criteria, when tumor characteristics were kept unified during the study, and MC was recommended as the selection tool for further comparison of both LT modes [14]. Hence, this study reports similar findings, since LDLT was found to be insignificantly different from DDLT regarding tumor-free survival.

Such results were again confirmed by Sandhu et al., where the similar tumor-free survival rates were described in both LDLT and DDLT in a well-matched cohort of patients, especially for the tumor characteristics [15]. Ogawa et al., and Akamatsu et al., described comparable outcomes for both LDLT and DLT [19, 20]. Furthermore, Zhu et al., and Zhang et al. in their recently reported meta-analysis concluded that LDLT was not inferior to DDLT regarding overall or tumor-free survival [21, 22].

Conclusion

The results of the current study conclude that LDLT – while offering a slightly better overall survival – has insignificantly shorter tumor-free survival compared to DDLT. This is especially true, when the bias from different tumor characteristics was eliminated by studying a perfectly matched cohort of patients presenting with HCC within MC. Furthermore, LDLT group had a significantly shorter time to transplant compared to DDLT group. Consequently, the resulting decrease in dropout rate should be considered when comparing LLDT and DDLT options.

Conflict of interestsWith respect to the current study, the authors declare neither any conflict of interest, nor financial issues to be disclosed.

References

  1. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693-699. doi: 10.1056/NEJM199603143341104
  2. Akamatsu N, Sugawara Y, Kokudo N. Living donor liver transplantation for patients with hepatocellular carcinoma. Liver Cancer. 2014; 3: 108-118. doi: 10.1159/000343866
  3. Ioannou GN, Perkins JD, Carithers RL Jr. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology. 2008; 134:1342-1351. doi: 10.1053/j.gastro.2008.02.013
  4. Massie AB, Caffo B, Gentry SE, Hall EC, Axelrod DA, Lentine KL, et al. MELD exceptions and rates of waiting list outcomes. Am J Transplant. 2011;11:2362-2371. doi: 10.1111/j.1600-6143.2011.03735.x
  5. Bodzin AS, Lunsford KE, Markovic D, Harlander-Locke MP, Busuttil RW, Agopian VG. Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann Surg. 2017;266:118-125. doi: 10.1097/SLA.0000000000001894
  6. Gondolesi GE, Roayaie S, Muñoz L, Kim-Schluger L, Schiano T, Fishbein TM, et al. Adult living donor liver transplantation for patients with hepatocellular carcinoma: extending UNOS priority criteria. Ann Surg. 2004; 239:142-149. doi: 10.1097/01.sla.0000109022.32391.eb
  7. Kulik L, Abecassis M. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology. 2004; 127:S277-S282.
    doi: 10.1053/j.gastro.2004.09.042
  8. Vakili K, Pomposelli JJ, Cheah YL, Akoad M, Lewis WD, Khettry U, et al. Living donor liver transplantation for hepatocellular carcinoma: increased recurrence but improved survival. Liver Transpl. 2009; 15:1861-1866. doi: 10.1002/lt.21940
  9. Yang ZF, Poon RT, Luo Y, Cheung CK, Ho DW, Lo CM, et al. Up-regulation of vascular endothelial growth factor (VEGF) in small-for-size liver grafts enhances macrophage activities through VEGF receptor 2-dependent pathway. J Immunol. 2004; 173:2507-2515.
    doi: 10.4049/jimmunol.173.4.2507
  10. Shi JH, Huitfeldt HS, Suo ZH, Line PD. Growth of hepatocellular carcinoma in the regenerating liver. Liver Transpl. 2011;17:866-874.
    doi: 10.1002/lt.22325
  11. Efimova EA, Glanemann M, Liu L, Schumacher G, Settmacher U, Jonas S, et al. Effects of human hepatocyte growth factor on the proliferation of human hepatocytes and hepatocellular carcinoma cell lines. Eur Surg Res. 2004; 36:300-307. doi: 10.1159/000079915
  12. Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007; 94:78-86. doi: 10.1002/bjs.5528
  13. Fisher RA, Kulik LM, Freise CE, Lok AS, Shearon TH, Brown RS Jr, et al, for A2ALL Study Group. Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transplant. 2007; 7: 1601-1608.
    doi: 10.1111/j.1600-6143.2007.01802.x
  14. Di Sandro S, Slim AO, Giacomoni A, Lauterio A, Mangoni I, Aseni P, et al. Living donor liver transplantation for hepatocellular carcinoma: long-term results compared with deceased donor liver transplantation. Transplant Proc. 2009; 41: 1283-1285.
    doi: 10.1016/j.transproceed.2009.03.022
  15. Sandhu L, Sandroussi C, Guba M, Selzner M, Ghanekar A, Cattral MS, et al. Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: comparable survival and recurrence. Liver Transpl. 2012; 18(3):315-22.
    doi: 10.1002/lt.22477
  16. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52-60.
    doi: 10.1055/s-0030-1247132
  17. Hogen R, Dinorcia J, Lo M, Nguyen B, Genyk Y, Sher L, Dhanireddy K. Long wait time regions for liver transplantation for HCC have a higher cumulative incidence of death. [abstract]. Am J Transplant. 2017; 17 (suppl 3).
  18. Mehta N, Dodge JL, Hirose R, Roberts JP, Yao FY. Increasing liver transplantation wait-list dropout for hepatocellular carcinoma with widening geographical disparities: implications for organ allocation. Liver Transpl. 2018; 24(10):1346-1356. doi: 10.1002/lt.25317
  19. Ogawa K, Takada Y. Living vs. deceased-donor liver transplantation for patients with hepatocellular carcinoma. Transl Gastroenterol Hepatol. 2016;1:35. doi: 10.21037/tgh.2016.04.03. eCollection 2016
  20. Akamatsu N, Sugawara Y, Kokudo N. Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma. World J Hepatol. 2014; 6(9):626-631. doi: 10.4254/wjh.v6.i9.626
  21. Zhu B, Wang J, Li H, Chen X, Zeng Y. Living or deceased organ donors in liver transplantation for hepatocellular carcinoma: a systematic review and meta-analysis. HPB (Oxford). 2019; 21(2):133-147. doi: 10.1016/j.hpb.2018.11.004
  22. Zhang HM, Shi YX, Sun LY, Zhu ZJ. Hepatocellular carcinoma recurrence in living and deceased donor liver transplantation: a systematic review and meta-analysis. Chin Med J. 2019; 132(13):1599-1609. doi: 10.1097/CM9.0000000000000287

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Introduction

Liver transplantation (LT) for hepatocellular carcinoma (HCC) has witnessed a historic change after the milestone article published by Mazzaferro et al. [1], who confirmed favorable outcomes for HCC patients similar to outcomes of LT for non-HCC indications. Since then, LT and its main option, the deceased-donor liver transplantation (DDLT) has become a well-established line of treatment with a highly curative profile for cirrhotic patients with HCC, but if only a liver graft is available.

The living-donor liver transplantation (LDLT) was introduced in order to reduce the organ shortage, due to expanding waiting lists for the patients awaiting liver transplant. In some countries, where the number of deceased donor is extremely small, the LDLT has been developed as an alternative treatment for the end-stage liver diseases, thus becoming an established treatment in HCC cases [2].

Nevertheless, recurrent HCC (rHCC) is still reported in up to 15% of cases following LT. HCC relapse is associated with dismal prognosis and, subsequently, LT failure in most instances [3]. Currently, LT for HCC has increased four-fold since early 2000s [4]. The impact of recurrent HCC is further enhanced by scarcity of liver grafts and fast expansion of LT waiting lists, whereas hepatic resection and other ablative modalities can offer up to 50% patient survival for HCC relapse [5].

Patient survival was shown to be better following LDLT for HCC compared to those transplanted from Deceased Donor (DD) [6, 7]. Many factors were held responsible for such results, including shorter time to transplant, better graft quality with shorter ischemia period.

Moreover, with the accumulation of cases, the impact of LDLT on the rHCC rates after LT has drawn attention of transplant community, since some reports showed higher incidence of rHCC following LDLT [8].

Many pathogenetic mechanisms were considered to explain these reports, including higher cytokine production in regenerating liver grafts and reduced time to transplant that could conceal aggressive tumor biology promoting the HCC recurrence [9-11]. These data were further analyzed to compare rHCC for patients transplanted from LDLT and DDLT source [12-15].

Hence, the aim of our single-center study was to compare overall and tumor-free survival among HCC patients subjected to liver transplantation from living donor (LDLT) versus liver transplant from deceased donor (DDLT).

Materials and methods

The study was started after obtaining the approval of Research Ethics Committee at our institution. All the patients were consented for the use of their clinical and pathological data for research purposes in anonymous manner, the patients were also informed that their decision to approve or disapprove the research consent will not influence their clinical management.

The cases of pediatric LT or liver retransplantation were excluded from this study. Finally, 136 patients diagnosed with HCC approved the research consent, being subsequently included in the study. Medical charts of the included patients were retrospectively reviewed. HCC was diagnosed by contrast-enhanced computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). The disease staging was based on chest CT, cranial CT, and technetium-99m bone scintigraphy, to exclude extra-hepatic disease. The following exclusion criteria were considered absolute contraindications for LT at our center:
• Failed or unfeasible downstaging of HCC originally beyond Milan, or UCSF transplant criteria, i.e., stable disease (SD), progressive disease (PD) according to modified RECIST criteria (16);
• Active extra-hepatic malignancies (excluding non-melanoma skin cancers);
• Untreatable advanced cardiopulmonary disease;
• Active infections e.g., active tuberculosis, uncontrollable sepsis;
• Unstable major psychiatric disorders;
• Disabling extensive intracranial neurological deficit;
• Substance abuse or active alcohol abuse over last 6 months;
• Documented medical non-compliance.

A total of 115 adult patients underwent LT for HCC at our institution between August 2006 and December 2019. LT was performed using either cadaveric, or living donor liver transplantation (LDLT). In LDLT setting, the donors were first- and second-degree relatives of respective patients.

Seventy-three patients conformed with Milan liver transplant criteria (MC) and, for the sake of comparison, they were divided into two groups as follows: Group A included forty-four HCC patients transplanted from living donors (LDLT); Group B consisted of twenty-nine HCC patients who received DDLT.

Fig. 1 illustrates the distribution of HCC patients with respect to decision for LT, and if the transplant was performed as LDLT or DDLT. The patients beyond Milan criteria, or those subjected to downstaging locoregional therapy were excluded from the study.

Abdelfattah-fig01.jpg

Figure 1. Flowchart of HCC patients enrolled during the study period

Details of the transplant procedure were documented; tumor characteristics were based on the pathological findings. HCC size, number of foci, tumor grade, and lymphatic invasion were diagnosed by an experienced pathologist. Demographic data, pre-transplant features, procedure-related variables, pathological findings were retrieved from the patient charts. Triple immunosuppression protocol was applied for the LT recipients including calcineurin inhibitor (CNI), glucocorticosteroids, and mycophenolate mofetil. Clinical and laboratory data were analyzed with t-test and Chi-square test. P-value of <0.05 was considered statistically significant. Kaplan-Meier curves were used to express survival outcomes, and statistical significance was determined by log-rank test. Overall and tumor-free survival were determined during the control contacts and examination of the patients.

Patient survival was calculated from the date of LT to the date of death or the date of the last follow-up for surviving patients. Graft survival was estimated as a death-censored graft survival. It was calculated from the date of transplantation to the date of irreversible graft failure signified by relisting of the patient on liver transplant waiting list, this method was used to avoid estimation of death with a functioning graft as a graft failure. Tumor-free survival was estimated from the date of transplant to the date of confirmed pathological evidence of recurrent HCC.

Results

Seventy-three patients underwent LT between August 2006 and December 2019 at our center for HCC which met MC. Table 1 is summarizing pre-transplant and pathological variables for these patients.

Table 1. Comparison of pre-transplant and pathological findings in LDLT and DDLT groups of the patients with hepatocellular carcinoma

Abdelfattah-tab01.jpg

Time to transplant ranged from 10 to 185 days, patients’ age, and time to transplant differed significantly between group A (living donors) and B (deceased donors), (P value, 0.002 and <0.001 respectively). On the other hand, pathological variables did not show significant difference between both groups.

The mean post-transplant follow-up for the studied patients was 46±33.3 months, ranging from 24.3 to 149.9 months. The overall 5-year patient survival, graft survival and tumor-free survival were 78.6%, 90.1% and 86.3% respectively. During the follow-up, a total of six patients manifested with rHCC (8.2%), i.e., four patients (9.1%) developed rHCC in group A, compared to two-cases (6.9%) of rHCC in group B patients, p value was 0.99. With respect to survival outcomes, LDLT group slightly differed from those who received DDLT. The overall patient survival was higher in Group A, at P=0.09 (log-rank test).

Conversely, tumor-free survival was only marginally better in group B, but it did not reach the significance level (P=0.6). On the other hand, graft survival was almost the same in both groups (P=0.99), as seen in Fig. 2 (A, B, C).

Abdelfattah-fig02.jpg

Figure 2. Comparisons for overall survival (A), tumor-free survival (B) and graft survival (C) between the groups A (LDLT) and B (DDLT) using the Kaplan-Meier approach

Discussion

There is a convincing evidence, that LT offers an excellent chance for cure of patients presenting with HCC, especially when their tumor burden is still within Milan criteria. The main concern regarding LT for HCC patients is the issue of liver graft availability and ethical costs to obtain it. Ethical concerns always overshadow the excellent results for LT in HCC patients, especially when allocation system favors HCC patients by the addition of 22 points [3, 4]. Consequently, more liver grafts are being allocated to HCC patients on the expense of patient suffering from liver insufficiency only. Furthermore, the use of LDLT to partially alleviate graft shortage is accompanied by inherent risk for healthy donor. Thus, outcomes of LT for HCC must be at optimal levels, to justify the ethical concerns encountered either in DDLT or LDLT settings. Hence, evaluation of clinical outcomes after LT for HCC in general, and comparative assessment of either LDLT or DDLT advantages over other options is quite important, especially in transplant centers where both LT modes are available.

DDLT is associated with long waiting times and consequently increased mortality and delisting rate while awaiting liver transplant. Hogen et al. [17], reported significantly higher waiting list mortality in UNOS regions with long waiting times compared to regions with short waiting times.

One of the main LDLT benefits is its ability to reduce the time to transplant and decrease the waiting list dropout. This is especially vital to the patients with HCC, to avoid tumor progression. Sandhu et al. [18], described a significantly shorter waiting time for LDLT compared to DDLT (3.1 vs 5.3 months respectively). Similarly, the current study reported significant data from the current study which showed 15% dropout rate for the patients originally presenting with HCC within Milan criteria. More than one third of this dropout rate was due to tumor progression. These patients underwent downstaging protocol using different locoregional neoadjuvant techniques.

The dropout rates vary considerably according to graft allocation policies. In the USA, there is a considerable variability of dropout rate based on the transplant waiting times. Mehta et al. [18], compared the dropout risk for HCC patients who received MELD exception points from 2005 and 2014. They described a significantly higher risk for dropout in UNOS regions with long transplant waiting times, the difference was three times higher than in the areas with short transplant waiting times (24% vs 8% dropout rate, respectively).

Few studies addressed the question of whether LDLT is associated with higher recurrence rate for HCC compared to DDLT, or not. One of the earliest reports on this issue (Lo et al.) described a significantly more common HCC recurrence at their LDLT arm (43 patients), compared to DDLT arm which included 17 patients. The study included heterogenous patient groups, i.e., corresponding the Milan or UCSF criteria, and beyond them. The cases subjected to downstaging locoregional therapy were not excluded from the study [12]. Similar findings were reported by Fischer et al. in their large cohort of patients, and they referred to different tumor characteristics, pretransplant locoregional therapies and short time to transplant as the key factors that explain the higher reported rHCC rates following LDLT [13].

On the other hand, Di Sandro et al., reported that LDLT had the same tumor-free survival compared to DDLT in the patients presenting within Milan transplant criteria, when tumor characteristics were kept unified during the study, and MC was recommended as the selection tool for further comparison of both LT modes [14]. Hence, this study reports similar findings, since LDLT was found to be insignificantly different from DDLT regarding tumor-free survival.

Such results were again confirmed by Sandhu et al., where the similar tumor-free survival rates were described in both LDLT and DDLT in a well-matched cohort of patients, especially for the tumor characteristics [15]. Ogawa et al., and Akamatsu et al., described comparable outcomes for both LDLT and DLT [19, 20]. Furthermore, Zhu et al., and Zhang et al. in their recently reported meta-analysis concluded that LDLT was not inferior to DDLT regarding overall or tumor-free survival [21, 22].

Conclusion

The results of the current study conclude that LDLT – while offering a slightly better overall survival – has insignificantly shorter tumor-free survival compared to DDLT. This is especially true, when the bias from different tumor characteristics was eliminated by studying a perfectly matched cohort of patients presenting with HCC within MC. Furthermore, LDLT group had a significantly shorter time to transplant compared to DDLT group. Consequently, the resulting decrease in dropout rate should be considered when comparing LLDT and DDLT options.

Conflict of interestsWith respect to the current study, the authors declare neither any conflict of interest, nor financial issues to be disclosed.

References

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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(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" 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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) "28558" ["VALUE"]=> array(2) { ["TEXT"]=> string(95) "<p>Мохамед Р. Абдельфаттах, Хуссейн Эльсиеси</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(83) "

Мохамед Р. Абдельфаттах, Хуссейн Эльсиеси

" ["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) "28559" ["VALUE"]=> array(2) { ["TEXT"]=> string(169) "<p>Отдел хирургии, Факультет медицины, Университет Александрии, Александрия, Египет </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(157) "

Отдел хирургии, Факультет медицины, Университет Александрии, Александрия, Египет

" ["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) "28560" ["VALUE"]=> array(2) { ["TEXT"]=> string(3396) "<p style="text-align: justify;">Целью нашей работы было сравнение общей и безопухолевой заболеваемости у пациентов с гепатоцеллюлярной карциномой (ГЦК), леченных в нашем центре, после трансплантации печени от живых доноров (ЖД) и погибших доноров (ПД).</p> <h3?Пациенты и методы</h3> <p style="text-align: justify;">73 пациентам была выполнена трансплантация печени по поводу ГЦК, стадированной по Миланским критериям (MК). Эти пациенты были распределены по 2 группам: (a) 44 больных трансплантированных от ЖД, и (б) 29 пациентов получидли трансплантаты от ПД. Из исследования были искючены больные, не соответствующие Миланским критериям или пациенты после циторедуктивной локорегионарной терапии.</p> <h3>Результаты</h3> <p style="text-align: justify;">5-летняя выживаемость составила, соответственно, 80,3% и 70,4% среди реципиентов печени от ЖД и ПД, тогда как безопухолевая выживаемость составляла 79,1% и 76%, соответственно, в группах больных, трансплантированных от живых и погибших доноров. Трансплантация печени от живых доноров показала несколько лучшие результаты, нежели трансплантация от погибшиз доноров (P=0.09). Однако разница по безопухолевой выживаемости между этими двумя группами не выявлена (P=0.6). </p> <h3>Выводы</h3> <p style="text-align: justify;">Данное исследование подтвердило, что трансплантация печени от живых доноров, при несколько лучшей общей выживаемости, ассоциирована со сходными сроками безопухолевой выживаемости по сравнению с трансплантацией от погибших доноров. Это сходство особенно выражено при устранении возможных факторов, связанных с особенностями опухолей и анализом данных в хорошо сравнимых группах пациентов с ГЦК, классифицированных по Миланским критериям.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Гепатоцеллюлярная карцинома, трансплантация печени, живые доноры, погибшие доноры, выживаемость. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3241) "

Целью нашей работы было сравнение общей и безопухолевой заболеваемости у пациентов с гепатоцеллюлярной карциномой (ГЦК), леченных в нашем центре, после трансплантации печени от живых доноров (ЖД) и погибших доноров (ПД).

73 пациентам была выполнена трансплантация печени по поводу ГЦК, стадированной по Миланским критериям (MК). Эти пациенты были распределены по 2 группам: (a) 44 больных трансплантированных от ЖД, и (б) 29 пациентов получидли трансплантаты от ПД. Из исследования были искючены больные, не соответствующие Миланским критериям или пациенты после циторедуктивной локорегионарной терапии.

Результаты

5-летняя выживаемость составила, соответственно, 80,3% и 70,4% среди реципиентов печени от ЖД и ПД, тогда как безопухолевая выживаемость составляла 79,1% и 76%, соответственно, в группах больных, трансплантированных от живых и погибших доноров. Трансплантация печени от живых доноров показала несколько лучшие результаты, нежели трансплантация от погибшиз доноров (P=0.09). Однако разница по безопухолевой выживаемости между этими двумя группами не выявлена (P=0.6).

Выводы

Данное исследование подтвердило, что трансплантация печени от живых доноров, при несколько лучшей общей выживаемости, ассоциирована со сходными сроками безопухолевой выживаемости по сравнению с трансплантацией от погибших доноров. Это сходство особенно выражено при устранении возможных факторов, связанных с особенностями опухолей и анализом данных в хорошо сравнимых группах пациентов с ГЦК, классифицированных по Миланским критериям.

Ключевые слова

Гепатоцеллюлярная карцинома, трансплантация печени, живые доноры, погибшие доноры, выживаемость.

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Mohamed R. Abdelfattah, Hussein Elsiesy

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Department of Surgery, Faculty of Medicine, University of Alexandria, Alexandria, Egypt


Correspondence:
Prof. Dr. Mohamed Rabei Abdelfattah, Associate Professor, Department of Surgery, Faculty of Medicine, University of Alexandria, Azzaritta, Alexandria, Egypt, PO BOX 21131
Phone: 002010 2306 1111
Email: mohamad.rabie@gmail.com


Citation: Abdelfattah MR, Elsiesy H. Outcomes of liver transplantation to the patients with hepatocellular carcinoma from living donors versus transplants from deceased donors. Cell Ther Transplant 2022; 11(1): 43-49.

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Our objective was to compare overall and tumor-free survival for the hepatocellular carcinoma (HCC) patients subjected to liver transplantation from living donor (LDLT) versus liver transplantation from deceased donor (DDLT) treated at our center.

Patients and methods

Seventy-three patients underwent liver transplantation for HCC staged according to Milan criteria (MC). The cases have been divided into two groups: (a) forty-four patients transplanted by means of LDLT, and (b) twenty-nine patients underwent DDLT. The patients beyond MC, or those who underwent downstaging locoregional therapy were excluded from the study.

Results

Overall survival outcomes at 5 years were, respectively, 80.3% vs 70.4%, in LDLT and DDLT groups whereas tumor-free survival was 79.1% vs 76% for LDLT and DDLT cases. LT from living donors showed slightly better patients’ survival compared to liver transplantation from deceased donors DDLT (P=0.09). However, the difference in tumor-free survival between both groups was virtually absent (P=0.6).

Conclusion

The present study confirmed that LDLT, while offering a slightly better overall survival, is associated with similar terms of tumor-free survival compared to transplants from deceased donors. This similarity is especially clear when avoiding biases caused by different tumor features and analyzing a perfectly matched cohort of patients presenting with HCC classified according to the Milan criteria.

Keywords

Hepatocellular carcinoma, liver transplant, living donor, deceased donor, survival.

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Mohamed R. Abdelfattah, Hussein Elsiesy

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Mohamed R. Abdelfattah, Hussein Elsiesy

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Our objective was to compare overall and tumor-free survival for the hepatocellular carcinoma (HCC) patients subjected to liver transplantation from living donor (LDLT) versus liver transplantation from deceased donor (DDLT) treated at our center.

Patients and methods

Seventy-three patients underwent liver transplantation for HCC staged according to Milan criteria (MC). The cases have been divided into two groups: (a) forty-four patients transplanted by means of LDLT, and (b) twenty-nine patients underwent DDLT. The patients beyond MC, or those who underwent downstaging locoregional therapy were excluded from the study.

Results

Overall survival outcomes at 5 years were, respectively, 80.3% vs 70.4%, in LDLT and DDLT groups whereas tumor-free survival was 79.1% vs 76% for LDLT and DDLT cases. LT from living donors showed slightly better patients’ survival compared to liver transplantation from deceased donors DDLT (P=0.09). However, the difference in tumor-free survival between both groups was virtually absent (P=0.6).

Conclusion

The present study confirmed that LDLT, while offering a slightly better overall survival, is associated with similar terms of tumor-free survival compared to transplants from deceased donors. This similarity is especially clear when avoiding biases caused by different tumor features and analyzing a perfectly matched cohort of patients presenting with HCC classified according to the Milan criteria.

Keywords

Hepatocellular carcinoma, liver transplant, living donor, deceased donor, survival.

" ["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(1797) "

Our objective was to compare overall and tumor-free survival for the hepatocellular carcinoma (HCC) patients subjected to liver transplantation from living donor (LDLT) versus liver transplantation from deceased donor (DDLT) treated at our center.

Patients and methods

Seventy-three patients underwent liver transplantation for HCC staged according to Milan criteria (MC). The cases have been divided into two groups: (a) forty-four patients transplanted by means of LDLT, and (b) twenty-nine patients underwent DDLT. The patients beyond MC, or those who underwent downstaging locoregional therapy were excluded from the study.

Results

Overall survival outcomes at 5 years were, respectively, 80.3% vs 70.4%, in LDLT and DDLT groups whereas tumor-free survival was 79.1% vs 76% for LDLT and DDLT cases. LT from living donors showed slightly better patients’ survival compared to liver transplantation from deceased donors DDLT (P=0.09). However, the difference in tumor-free survival between both groups was virtually absent (P=0.6).

Conclusion

The present study confirmed that LDLT, while offering a slightly better overall survival, is associated with similar terms of tumor-free survival compared to transplants from deceased donors. This similarity is especially clear when avoiding biases caused by different tumor features and analyzing a perfectly matched cohort of patients presenting with HCC classified according to the Milan criteria.

Keywords

Hepatocellular carcinoma, liver transplant, living donor, deceased donor, survival.

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Department of Surgery, Faculty of Medicine, University of Alexandria, Alexandria, Egypt


Correspondence:
Prof. Dr. Mohamed Rabei Abdelfattah, Associate Professor, Department of Surgery, Faculty of Medicine, University of Alexandria, Azzaritta, Alexandria, Egypt, PO BOX 21131
Phone: 002010 2306 1111
Email: mohamad.rabie@gmail.com


Citation: Abdelfattah MR, Elsiesy H. Outcomes of liver transplantation to the patients with hepatocellular carcinoma from living donors versus transplants from deceased donors. Cell Ther Transplant 2022; 11(1): 43-49.

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Department of Surgery, Faculty of Medicine, University of Alexandria, Alexandria, Egypt


Correspondence:
Prof. Dr. Mohamed Rabei Abdelfattah, Associate Professor, Department of Surgery, Faculty of Medicine, University of Alexandria, Azzaritta, Alexandria, Egypt, PO BOX 21131
Phone: 002010 2306 1111
Email: mohamad.rabie@gmail.com


Citation: Abdelfattah MR, Elsiesy H. Outcomes of liver transplantation to the patients with hepatocellular carcinoma from living donors versus transplants from deceased donors. Cell Ther Transplant 2022; 11(1): 43-49.

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Мохамед Р. Абдельфаттах, Хуссейн Эльсиеси

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Мохамед Р. Абдельфаттах, Хуссейн Эльсиеси

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Эти пациенты были распределены по 2 группам: (a) 44 больных трансплантированных от ЖД, и (б) 29 пациентов получидли трансплантаты от ПД. Из исследования были искючены больные, не соответствующие Миланским критериям или пациенты после циторедуктивной локорегионарной терапии.</p> <h3>Результаты</h3> <p style="text-align: justify;">5-летняя выживаемость составила, соответственно, 80,3% и 70,4% среди реципиентов печени от ЖД и ПД, тогда как безопухолевая выживаемость составляла 79,1% и 76%, соответственно, в группах больных, трансплантированных от живых и погибших доноров. Трансплантация печени от живых доноров показала несколько лучшие результаты, нежели трансплантация от погибшиз доноров (P=0.09). Однако разница по безопухолевой выживаемости между этими двумя группами не выявлена (P=0.6). </p> <h3>Выводы</h3> <p style="text-align: justify;">Данное исследование подтвердило, что трансплантация печени от живых доноров, при несколько лучшей общей выживаемости, ассоциирована со сходными сроками безопухолевой выживаемости по сравнению с трансплантацией от погибших доноров. Это сходство особенно выражено при устранении возможных факторов, связанных с особенностями опухолей и анализом данных в хорошо сравнимых группах пациентов с ГЦК, классифицированных по Миланским критериям.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Гепатоцеллюлярная карцинома, трансплантация печени, живые доноры, погибшие доноры, выживаемость. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3241) "

Целью нашей работы было сравнение общей и безопухолевой заболеваемости у пациентов с гепатоцеллюлярной карциномой (ГЦК), леченных в нашем центре, после трансплантации печени от живых доноров (ЖД) и погибших доноров (ПД).

73 пациентам была выполнена трансплантация печени по поводу ГЦК, стадированной по Миланским критериям (MК). Эти пациенты были распределены по 2 группам: (a) 44 больных трансплантированных от ЖД, и (б) 29 пациентов получидли трансплантаты от ПД. Из исследования были искючены больные, не соответствующие Миланским критериям или пациенты после циторедуктивной локорегионарной терапии.

Результаты

5-летняя выживаемость составила, соответственно, 80,3% и 70,4% среди реципиентов печени от ЖД и ПД, тогда как безопухолевая выживаемость составляла 79,1% и 76%, соответственно, в группах больных, трансплантированных от живых и погибших доноров. Трансплантация печени от живых доноров показала несколько лучшие результаты, нежели трансплантация от погибшиз доноров (P=0.09). Однако разница по безопухолевой выживаемости между этими двумя группами не выявлена (P=0.6).

Выводы

Данное исследование подтвердило, что трансплантация печени от живых доноров, при несколько лучшей общей выживаемости, ассоциирована со сходными сроками безопухолевой выживаемости по сравнению с трансплантацией от погибших доноров. Это сходство особенно выражено при устранении возможных факторов, связанных с особенностями опухолей и анализом данных в хорошо сравнимых группах пациентов с ГЦК, классифицированных по Миланским критериям.

Ключевые слова

Гепатоцеллюлярная карцинома, трансплантация печени, живые доноры, погибшие доноры, выживаемость.

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Целью нашей работы было сравнение общей и безопухолевой заболеваемости у пациентов с гепатоцеллюлярной карциномой (ГЦК), леченных в нашем центре, после трансплантации печени от живых доноров (ЖД) и погибших доноров (ПД).

73 пациентам была выполнена трансплантация печени по поводу ГЦК, стадированной по Миланским критериям (MК). Эти пациенты были распределены по 2 группам: (a) 44 больных трансплантированных от ЖД, и (б) 29 пациентов получидли трансплантаты от ПД. Из исследования были искючены больные, не соответствующие Миланским критериям или пациенты после циторедуктивной локорегионарной терапии.

Результаты

5-летняя выживаемость составила, соответственно, 80,3% и 70,4% среди реципиентов печени от ЖД и ПД, тогда как безопухолевая выживаемость составляла 79,1% и 76%, соответственно, в группах больных, трансплантированных от живых и погибших доноров. Трансплантация печени от живых доноров показала несколько лучшие результаты, нежели трансплантация от погибшиз доноров (P=0.09). Однако разница по безопухолевой выживаемости между этими двумя группами не выявлена (P=0.6).

Выводы

Данное исследование подтвердило, что трансплантация печени от живых доноров, при несколько лучшей общей выживаемости, ассоциирована со сходными сроками безопухолевой выживаемости по сравнению с трансплантацией от погибших доноров. Это сходство особенно выражено при устранении возможных факторов, связанных с особенностями опухолей и анализом данных в хорошо сравнимых группах пациентов с ГЦК, классифицированных по Миланским критериям.

Ключевые слова

Гепатоцеллюлярная карцинома, трансплантация печени, живые доноры, погибшие доноры, выживаемость.

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Отдел хирургии, Факультет медицины, Университет Александрии, Александрия, Египет

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Отдел хирургии, Факультет медицины, Университет Александрии, Александрия, Египет

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Introduction

Hematopoietic stem cell transplantation (HSCT) is used as an efficient therapeutic approach for treatment of oncohematological diseases. This mode of treatment causes profound immunosuppression affecting non-specific and specific immunity. This temporary disorder results into frequent infectious complications over post-transplant period, which have been sufficiently studied. However, bacterial and fungal paranasal sinusitis, which is common in general population, has been scarcely studied in immunocompromised patients after HSCT [1].

According to numerous studies, sinusitis affects approximately 5-44% of all the patients in post-transplant period, mainly, at early terms after HSCT. In this regard, searching for bacteria which colonize nasal cavity and paranasal sinuses during the sinusitis seems to be an urgent task. In general excessive microbiota at the surface of nasal mucosa, paranasal sinuses and upper respiratory tract is of similar composition. Bacteriological studies of cultivable microbiota from the nasal cavity and aspirates of maxillary sinuses in chronic rhinosinusitis were carried out in different clinics of Russian Federation and revealed 154 isolates of aerobic bacteria belonging to 32 species, and 90 anaerobic lines, with predominance of Streptococci, Prevotella in aspirates, less often S.pneumoniae, H.influenza, and S.aureus [2]. Although many other microbial species were isolated from these samples, the authors did not reveal their clear relations to pathogenesis of chronic rhinosinusitis.

Over the last decade, the microbiota of paranasal sinuses has also been studied by molecular biology techniques (quantitative PCR, microarray methods, like as by NGS studies of polymorphisms in 16S rRNA gene which is universal to bacterial microbiota), thus making it possible to identify a lot of non-cultivable and previously unknown types of bacteria [3]. The authors have shown that, along with S.epidermidis, S.aureus, Corynebacteria spp, maxillar sinuses in the patients may harbor, e.g., Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as Stenotrophomonas maltophilia, Enterobacter which may be associated with chronic rhinosinusitis. Significant differences in the composition and diversity of the microbiota of the paranasal sinuses largely depend on the methods used in distinct studies. E.g., analysis of the microbiota at these sites by means of next-generation sequencing (NGS) showed persistence of Staphylococci, Streptococci, Neisseria, Corynebacteria and reduced biodiversity of local microbiota in chronic rhinosinusitis [4]. In general, however, bacteriological evaluation of biological samples retains its diagnostic value because of its ability to assess antibiotic resistance of microbial isolates. The aim of this study was a comparative assessment of aerobic and facultative anaerobic microbiota components of nasal and paranasal cavities in sinusitis, which is often observed in immunocompromised patients after intensive chemotherapy, antibiotic therapy and subsequent HSCT.

Patients and methods

The study involved 194 patients with various myelo- and lymphoproliferative diseases aged from 1 to 62 years treated at the R. M. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation under the protocols of intensive chemotherapy and allogeneic HSCT over the period of 2016 to 2021 as described in our previous work [5]. During HSCT, patients received an antibiotic prophylaxis regimen that included intravenous administration of fluoroquinolones (sometimes switching to oral administration) from D+1 to D+60. To this purpose, amoxicillin was also prescribed, in particular to pediatric patients. In febrile neutropenia, broad-spectrum antibiotics were empirically administered. Later on, upon occurrence of resistant microbial strains, the patients were treated with antibiotics, orally or systemically, as guided by the in vitro sensitivity testing of the microbial isolates.

As indicated by consulting specialist (ORL clinician), according to clinical indications, the biomaterial was taken from patients (nasal swabs or washings from the paranasal sinuses) at the terms of -100 to +180 days after the day of allogeneic HSCT. Of these specimens, we have examined 124 samples of the maxillary sinus punctures from 97 patients, and 973 scrapings from nasal cavity of the patients from general HSCT group.

Seeding and isolation of bacteria from the biological samples were made by classical bacteriological techniques, The isolated microorganisms were identified by means of commercial biochemical test systems (BBL Crystal), as well as with MALDI-TOF mass spectrometry using VITEK MS instrument. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems. The results of microbial sensitivity tests were interpreted according to the Guidelines of European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. For statistical analysis, the groups of patients were also divided by age: 0-5 years (group 1); 6-14 children (2); 15-21 years old (3); >22 years (4). Moreover, the results of bacteriological examination were classified by terms post-transplant, starting from <100 days before HSCT (point 0); during the 1st month (point 1); 2nd month (point 2); 3rd month (point 3), etc., up to 6 months after HSCT (point 6). Statistical analysis of the data was carried out by means of parametric and nonparametric statistics, concerning individual types of inoculated microorganisms, and for distinct microbial associations at different times after HSCT using the STATISTICA 10 program.

Results

The detection frequency of cultured bacteria from nasal cavity and maxillary sinuses in the oncohematological patients with ORL disorders was as follows: S.epidermidis, 34.7% of biological samples (377/1097); S.viridans, 2.2% (24/1097); S.aureus, 1.91% (21/1097); Klebsiella spp., 1% (11/1097); Corynebacteria spp., 0.9% (10/1097); Pseudomonas spp., 0.54% (6/1097); E. coli, 0.36% (4/1097); Neisseria spp., 0.36% (4/1097); E.faecalis, 0.18% (2/1097). Meanwhile, Proteus, M.luteus, Citrobacter isolates were not revealed. Seeding rates for the most common bacterial species by the age groups are shown in Fig. 1A and 1B.

Dolgov-fig01.jpg

Figure 1. Age dependence of bacterial seeding rates for the dominant bacterial species in oncohematological patients (group 1: 0-5 years; group 2: 6-14 years; group 3: 15-21 years; group 4: >22 years)

As seen from Fig. 1, the frequency of S.epidermidis detection was minimal in younger age group and increases at the age of >15 years (1A). Also, the occurrence of S.viridans is minimal among younger patients, with a maximum in the older group (>15 years). Moreover, we assessed the dynamics for these species at various times after HSCT (Fig. 2A and 2B).

Dolgov-fig02.jpg

Figure 2. Dynamics of detection for the main types of bacteria at different terms after HSCT

As seen from Fig. 2A, the detection rate of S.epidermidis is sharply reduced over the first 2 months after HSCT, thus confirming significant depletion of this microbial population due to antibiotic prophylaxis and anti-infectious therapy at the early stages after HSCT. At the same time, frequency of S.viridans did not change significantly during the post-transplant period (up to 6 months).

Dolgov-fig03.jpg

Figure 3. Frequency of S.epidermidis detection in nasal swabs (squares) and maxillary sinuses (circles) at various terms after HSCT

Separate analysis in adjacent infection loci (nasal and maxillar cavities) showed that the most profound suppression of S.epidermidis growth was observed in paranasal sinuses, especially, within 1 month after HSCT (Fig. 3). Of interest, the frequency of S.epidermidis isolation in the presence of clinically sound sinusitis was even more reduced during the 1st month after HSCT, as well as in later periods (>4 months after HSCT), as shown in Fig. 4.

High frequency of Klebsiella spp. isolation in the samples from maxillar sinuses proved to be the most pronounced feature of pathogenic microbiota in the patients at the late terms after HSCT (an average of 16.3% (20/123) versus 2.1% (18/864), p=2×10^14), along with low frequency detection in nasal swabs (Fig. 5). Similarly, high seeding rates from sinus washes were shown for Pseudomonas spp. (8.1%, 10/123 versus 0.7%, 5/864, p=1.5×10^10).

Dolgov-fig04-05.jpg

As can be seen from Table 1, S.epidermidis, the most common microflora for the nasopharynx, is found in material from the nose much more often than in swabs from the maxillary sinuses (Fig. 4). Meanwhile, inoculation with S.epidermidis from the maxillary sinuses is minimal during 1 and 5 months after HSCT. At the same time, opportunistic pathogens (E. coli, Klebsiella spp., Pseudomonas spp.) in the lavage from maxillary sinuses of the patients with sinusitis were detected more frequently than in nasal cavity lavage.

Table 1. Comparative detection frequency of main bacterial species in the samples from nasal cavity and paranasal sinuses in the patients with ORL disorders after HSCT

Dolgov-tab01.jpg

This confirms the diagnostic significance of the bacteriological analysis of the exudate obtained by sinus puncture and, possibly, the protective function of S.epidermidis on the skin and mucous membranes.

Next, we determined the isolation frequency of distinct microbes from the general data massive (nasal cavity + maxillary sinuses) and found that Klebsiella spp. with symptoms of sinusitis occurs significantly more often than in patients free of these symptoms, respectively, 6/102 (5.9%) versus 8/501 (1.6%), p=0.009. A similar increase was shown for Pseudomonas spp. and E.coli (see Table 2). A higher frequency of detection of Klebsiella spp. in the punctures from maxillary sinuses was noted in cases of clinical sinusitis at the 1st, 2nd month, as well as from the 4th month and later post-HSCT.

Table 2. Incidence of different bacterial species in the samples from nasal cavity and/or maxillary sinuses in the patients with sinusitis compared with sinusitis-free patients subjected to HSCT

Dolgov-fig02.jpg

Moreover, we estimated the frequency of bacterial findings within +30 days since clinical diagnosis of sinusitis. Higher frequency of Pseudomonas spp. (1/378 vs 7/217) was revealed in the samples from paranasal sinuses in 5 patients within 3 weeks after clinical diagnosis of sinusitis.

Antibiotic resistance

Several resistant bacterial strains were isolated from nasal cavity and paranasal sinuses in the patients with sinusitis, mostly, at later terms (>2 months post-transplant).

Over the entire period of time (2019 to 2021), the clinical staphylococcal isolates were tested for their sensitivity to cefoxitin, erythromycin, clindamycin, gentamycin, norfloxacin, tetracycline, tigecycline, and linezolid. According to the expert Guidelines of European Committee on Antimicrobial Susceptibility Testing (EUCAST). Cefoxitin is considered a screening drug in order to discriminate between the categories of methicillin-resistant staphylococci (MRS) and methicillin-sensitive strains (MSS). Throughout the observation terms, the methicillin-resistant S.aureus (MRSA) were isolated in 4% of lavage and puncture samples obtained from maxillar sinuses in the patients with oncohematological disorders. Over this period of time, we did not reveal any S. aureus strains resistant to linezolid or tigecycline. 31% of S.aureus isolates were resistant to erythromycin. The revealed category of erythromycin sensitivity, in accordance with EUCAST rules, is also extended to clarithromycin and roxytromycin. Norfloxacin resistance was shown for 5% of S.aureus strains. The norfloxacin-sensitive staphylococci are regarded as sensitive to moxifloxacin and, at higher doses (or with prolonged infusion), to levofloxacin and ciprofloxacin. Tetracycline resistance of S. aureus strains was shown in 10%. The tetracycline-sensitive staphylococci are also considered sensitive to doxycycline and minocycline. Maximal percentage of antibiotic resistance for staphylococcal strains was found with gentamycin (24%). Gradient diffusion tests for vancomycin resistance were applied to methycillin-resistant staphylococci (E-test). All the MRSA strains proved to be vancomycin-sensitive.

All the E.faecalis isolates obtained from nasal cavity of the patients treated for oncohematological disorders who suffered from sinusitis have shown good sensitivity level with antibacterial drugs, i.e., 100% to ampicillin, linezolid, vancomycin and tigecycline.

100% of S.pneumoniae strains isolated in this study were sensitive to oxacillin, and therefore, to all β-lactam antibiotics. Among them, 90% showed sensitivity to norfloxacin and, hence, to moxifloxacin. Over the study period, we have not revealed any Pneumococcus strains resistant to vancomycin and linezolid. Resistance to tetracycline and erythromycin was detected for 70% of S.pneumoniae strains.

The species of Enterobacterales exhibited different patterns of antibiotic resistance. E.g., all E. coli strains were sensitive to amikacine, 3rd-generation cephalosporins (cefotaxim, ceftazidim, ceftriaxone), protected aminopenicillines, and meropenem. Meanwhile, resistance of Klebsiella pneumoniae ssp pneumoniae, the actual nosocomial pathogen, proved to be increased over this observation period, being as high as 85% to cephalosporins (III generation) and to meropenem (60%).

Discussion

Acute sinusitis is a common complication following HSCT, and several studies addressed this issue [6, 7]. Immunosuppressive drugs, chemotherapy, radiation treatment, prolonged antibiotic therapy, autoaggressive graft-versus-host disease (GVHD), and long periods of hospitalization are predisposing factors for the upper respiratory tract infections. Current clinical diagnostics of sinusitis, both before and after HSCT, is often based on computed tomography (CT) findings, which in many cases correlate with history and clinical examination data [8]. The authors have shown that the severity of pre-transplant sinus lesions revealed on CT scans correlated with clinical and radiological signs of sinusitis later post-transplant, having been associated with a trend for reduced survival. Therefore, the clinical background before HSCT is also important for assessing further risks of developing ORL disorders. Our results of bacteriological testing are based on the clinical cohort treated at the R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation [5]. Infectious complications in allogeneic HSCT are significantly more common than in autologous HSCT, with respect to cytopenic period and rates of hematopoietic recovery. Our data refer to the patients who received allogeneic HSCT. Acute symptoms of rhinosinusitis may be registered at any term after HSCT, reaching 5.3% (95% CI 5.0%-5.6%) at the stage before transplantation; 3.01% (95% CI 2.8%-3.2%) in the course of engraftment, and 8.13% (95% CI 7.67%-8.60%), post-engraftment. From this comparison, one may suggest that massive antibiotic therapy after HSCT appears to prevent some of infectious conditions at the early stages post-transplant. However, later recolonization of pathogenic microorganisms is possible, including Klebsiella spp., S. aureus, S.pneumoniae, at a high risk of resistant strain selection, which was confirmed by us in the present work. One should note, however, that these 3 types of pathogenic bacteria were detected in a total of 13% of patients with sinusitis, i.e. the pathogen remained unknown in most cases. For additional diagnostics, along with search for pathogenic fungi and viruses, the extended diagnostics, e.g., of strictly anaerobic microbiota, are needed. In this aspect, implementation of advanced sequencing (NGS technique) will be of great importance, thus making it possible to assess biological diversity and the ratio of main microbiota classes in complex clinical samples, e.g., from mucosal surfaces.

Conclusions

1. The studies of relationships between the presence of facultative anaerobic, opportunistic microbiota in maxillar punctures and nasal cavities, and clinical course of sinusitis in the patients undergoing allogeneic HSCT did not reveal any significant correlations with severity of the disease (mild versus moderate grade).

2. Standard bacteriological testing aimed for detection of facultative anaerobic microorganisms in the maxillary sinus punctures after HSCT is of limited value within 1 month after HSCT, due to massive antibiotic therapy and suppressed growth of antibiotic-sensitive bacteria.

3. Massive antimicrobial therapy leads to the selection of resistant strains of Klebsiella spp., Pseudomonas spp., E.coli, S.aureus, mainly within 2 or more months after HSCT.

4. Low frequency of cultivable potentially pathogenic microorganisms in sino-nasal exudates cultures suggests reduced detection efficiency for the etiologically important bacteria which may cause sinusitis.

5. More sensitive and specific methods for detecting bacteria on the oropharyngeal and nasopharyngeal mucosa could be based on DNA diagnostics and multiplex PCR techniques, especially due to possible contamination of these sites with anaerobic bacteria of intestinal origin.

Conflict of interest

None declared.

References

  1. Bento LR, Ortiz E, Nicola EM, Vigorito AC, Sakano E. Sinonasal disorders in hematopoietic stem cell transplantation. Braz J Otorhinolaryngol. 2014; 80: 285-289. doi: 10.1016/j.bjorl.2014.05.009
  2. Ivanchenko OA, Karpishchenko SA, Kozlov RS, Krechikova OI, Otvagin IV, Sopko ON, Piskunov GZ, Lopatin AS. The microbiome of the maxillary sinus and middle nasal meatus in chronic rhinosinusitis. Rhinology. 2016; 54: 68-74. doi: 10.4193/Rhino15.018
  3. Lee JT, Frank DN, Ramakrishnan V. Microbiome of the paranasal sinuses: Update and literature review. Am J Rhinol Allergy 2016; 30: 3-16. doi: 10.2500/ajra.2016.30.4255
  4. De Boeck I, Wittouck S, Martens K, Claes J, Jorissen M, Steelant B, van den Broek, MFL, Seys SF, Hellings PW, Vanderveken OM, Lebeer S. Anterior nares diversity and pathobionts represent sinus microbiome in chronic rhinosinusitis. mSphere 2019; 4:e00532-19. doi: 10.1128/mSphere.00532-19
  5. Dolgov OI, Karpishchenko SA, Rodneva YA, Utimisheva ES, Moiseev IS, Zubarovskaya LS, Kulagin AD. Prevalence of acute inflammatory otorhinolaryngological diseases in hematopoietic stem cell transplant recipients. Russian Otorhinolaryngology. 2021;20(3):20-26 (In Russian.). doi: 10.18692/1810-4800-2021-3-20-26
  6. Drozd-Sokolowska JE, Sokolowski J, Wiktor-Jedrzejczak W, Niemczyk K. Sinusitis in patients undergoing allogeneic bone marrow transplantation – a review. Braz J Otorhinolaryngol. 2017 Jan-Feb;83(1):105-111. doi: 10.1016/j.bjorl.2016.02.012
  7. Utimisheva ES, Dolgov OI, Paina OV, Ekushov KA, Vitrischak AA, Smirnov BI, Zubarovskaya LS, Karpischenko SA, Afanasyev BV. Incidence, diagnosis and treatment of sinusitis in children and adolescents after hematopoietic stem cell transplantation. Cell Ther Transplant. 2019; 8(1):46-53.
  8. Billings KR, Lowe LH, AquinoVM, Biavati MJ. Screening sinus CT scans in pediatric bone marrow transplant patients. Otorhinolaryngology. 2000; 52(3): 253-260.

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Introduction

Hematopoietic stem cell transplantation (HSCT) is used as an efficient therapeutic approach for treatment of oncohematological diseases. This mode of treatment causes profound immunosuppression affecting non-specific and specific immunity. This temporary disorder results into frequent infectious complications over post-transplant period, which have been sufficiently studied. However, bacterial and fungal paranasal sinusitis, which is common in general population, has been scarcely studied in immunocompromised patients after HSCT [1].

According to numerous studies, sinusitis affects approximately 5-44% of all the patients in post-transplant period, mainly, at early terms after HSCT. In this regard, searching for bacteria which colonize nasal cavity and paranasal sinuses during the sinusitis seems to be an urgent task. In general excessive microbiota at the surface of nasal mucosa, paranasal sinuses and upper respiratory tract is of similar composition. Bacteriological studies of cultivable microbiota from the nasal cavity and aspirates of maxillary sinuses in chronic rhinosinusitis were carried out in different clinics of Russian Federation and revealed 154 isolates of aerobic bacteria belonging to 32 species, and 90 anaerobic lines, with predominance of Streptococci, Prevotella in aspirates, less often S.pneumoniae, H.influenza, and S.aureus [2]. Although many other microbial species were isolated from these samples, the authors did not reveal their clear relations to pathogenesis of chronic rhinosinusitis.

Over the last decade, the microbiota of paranasal sinuses has also been studied by molecular biology techniques (quantitative PCR, microarray methods, like as by NGS studies of polymorphisms in 16S rRNA gene which is universal to bacterial microbiota), thus making it possible to identify a lot of non-cultivable and previously unknown types of bacteria [3]. The authors have shown that, along with S.epidermidis, S.aureus, Corynebacteria spp, maxillar sinuses in the patients may harbor, e.g., Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as Stenotrophomonas maltophilia, Enterobacter which may be associated with chronic rhinosinusitis. Significant differences in the composition and diversity of the microbiota of the paranasal sinuses largely depend on the methods used in distinct studies. E.g., analysis of the microbiota at these sites by means of next-generation sequencing (NGS) showed persistence of Staphylococci, Streptococci, Neisseria, Corynebacteria and reduced biodiversity of local microbiota in chronic rhinosinusitis [4]. In general, however, bacteriological evaluation of biological samples retains its diagnostic value because of its ability to assess antibiotic resistance of microbial isolates. The aim of this study was a comparative assessment of aerobic and facultative anaerobic microbiota components of nasal and paranasal cavities in sinusitis, which is often observed in immunocompromised patients after intensive chemotherapy, antibiotic therapy and subsequent HSCT.

Patients and methods

The study involved 194 patients with various myelo- and lymphoproliferative diseases aged from 1 to 62 years treated at the R. M. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation under the protocols of intensive chemotherapy and allogeneic HSCT over the period of 2016 to 2021 as described in our previous work [5]. During HSCT, patients received an antibiotic prophylaxis regimen that included intravenous administration of fluoroquinolones (sometimes switching to oral administration) from D+1 to D+60. To this purpose, amoxicillin was also prescribed, in particular to pediatric patients. In febrile neutropenia, broad-spectrum antibiotics were empirically administered. Later on, upon occurrence of resistant microbial strains, the patients were treated with antibiotics, orally or systemically, as guided by the in vitro sensitivity testing of the microbial isolates.

As indicated by consulting specialist (ORL clinician), according to clinical indications, the biomaterial was taken from patients (nasal swabs or washings from the paranasal sinuses) at the terms of -100 to +180 days after the day of allogeneic HSCT. Of these specimens, we have examined 124 samples of the maxillary sinus punctures from 97 patients, and 973 scrapings from nasal cavity of the patients from general HSCT group.

Seeding and isolation of bacteria from the biological samples were made by classical bacteriological techniques, The isolated microorganisms were identified by means of commercial biochemical test systems (BBL Crystal), as well as with MALDI-TOF mass spectrometry using VITEK MS instrument. The sensitivity of clinical isolates to antibiotics was determined by means of disk diffusion test systems. The results of microbial sensitivity tests were interpreted according to the Guidelines of European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. For statistical analysis, the groups of patients were also divided by age: 0-5 years (group 1); 6-14 children (2); 15-21 years old (3); >22 years (4). Moreover, the results of bacteriological examination were classified by terms post-transplant, starting from <100 days before HSCT (point 0); during the 1st month (point 1); 2nd month (point 2); 3rd month (point 3), etc., up to 6 months after HSCT (point 6). Statistical analysis of the data was carried out by means of parametric and nonparametric statistics, concerning individual types of inoculated microorganisms, and for distinct microbial associations at different times after HSCT using the STATISTICA 10 program.

Results

The detection frequency of cultured bacteria from nasal cavity and maxillary sinuses in the oncohematological patients with ORL disorders was as follows: S.epidermidis, 34.7% of biological samples (377/1097); S.viridans, 2.2% (24/1097); S.aureus, 1.91% (21/1097); Klebsiella spp., 1% (11/1097); Corynebacteria spp., 0.9% (10/1097); Pseudomonas spp., 0.54% (6/1097); E. coli, 0.36% (4/1097); Neisseria spp., 0.36% (4/1097); E.faecalis, 0.18% (2/1097). Meanwhile, Proteus, M.luteus, Citrobacter isolates were not revealed. Seeding rates for the most common bacterial species by the age groups are shown in Fig. 1A and 1B.

Dolgov-fig01.jpg

Figure 1. Age dependence of bacterial seeding rates for the dominant bacterial species in oncohematological patients (group 1: 0-5 years; group 2: 6-14 years; group 3: 15-21 years; group 4: >22 years)

As seen from Fig. 1, the frequency of S.epidermidis detection was minimal in younger age group and increases at the age of >15 years (1A). Also, the occurrence of S.viridans is minimal among younger patients, with a maximum in the older group (>15 years). Moreover, we assessed the dynamics for these species at various times after HSCT (Fig. 2A and 2B).

Dolgov-fig02.jpg

Figure 2. Dynamics of detection for the main types of bacteria at different terms after HSCT

As seen from Fig. 2A, the detection rate of S.epidermidis is sharply reduced over the first 2 months after HSCT, thus confirming significant depletion of this microbial population due to antibiotic prophylaxis and anti-infectious therapy at the early stages after HSCT. At the same time, frequency of S.viridans did not change significantly during the post-transplant period (up to 6 months).

Dolgov-fig03.jpg

Figure 3. Frequency of S.epidermidis detection in nasal swabs (squares) and maxillary sinuses (circles) at various terms after HSCT

Separate analysis in adjacent infection loci (nasal and maxillar cavities) showed that the most profound suppression of S.epidermidis growth was observed in paranasal sinuses, especially, within 1 month after HSCT (Fig. 3). Of interest, the frequency of S.epidermidis isolation in the presence of clinically sound sinusitis was even more reduced during the 1st month after HSCT, as well as in later periods (>4 months after HSCT), as shown in Fig. 4.

High frequency of Klebsiella spp. isolation in the samples from maxillar sinuses proved to be the most pronounced feature of pathogenic microbiota in the patients at the late terms after HSCT (an average of 16.3% (20/123) versus 2.1% (18/864), p=2×10^14), along with low frequency detection in nasal swabs (Fig. 5). Similarly, high seeding rates from sinus washes were shown for Pseudomonas spp. (8.1%, 10/123 versus 0.7%, 5/864, p=1.5×10^10).

Dolgov-fig04-05.jpg

As can be seen from Table 1, S.epidermidis, the most common microflora for the nasopharynx, is found in material from the nose much more often than in swabs from the maxillary sinuses (Fig. 4). Meanwhile, inoculation with S.epidermidis from the maxillary sinuses is minimal during 1 and 5 months after HSCT. At the same time, opportunistic pathogens (E. coli, Klebsiella spp., Pseudomonas spp.) in the lavage from maxillary sinuses of the patients with sinusitis were detected more frequently than in nasal cavity lavage.

Table 1. Comparative detection frequency of main bacterial species in the samples from nasal cavity and paranasal sinuses in the patients with ORL disorders after HSCT

Dolgov-tab01.jpg

This confirms the diagnostic significance of the bacteriological analysis of the exudate obtained by sinus puncture and, possibly, the protective function of S.epidermidis on the skin and mucous membranes.

Next, we determined the isolation frequency of distinct microbes from the general data massive (nasal cavity + maxillary sinuses) and found that Klebsiella spp. with symptoms of sinusitis occurs significantly more often than in patients free of these symptoms, respectively, 6/102 (5.9%) versus 8/501 (1.6%), p=0.009. A similar increase was shown for Pseudomonas spp. and E.coli (see Table 2). A higher frequency of detection of Klebsiella spp. in the punctures from maxillary sinuses was noted in cases of clinical sinusitis at the 1st, 2nd month, as well as from the 4th month and later post-HSCT.

Table 2. Incidence of different bacterial species in the samples from nasal cavity and/or maxillary sinuses in the patients with sinusitis compared with sinusitis-free patients subjected to HSCT

Dolgov-fig02.jpg

Moreover, we estimated the frequency of bacterial findings within +30 days since clinical diagnosis of sinusitis. Higher frequency of Pseudomonas spp. (1/378 vs 7/217) was revealed in the samples from paranasal sinuses in 5 patients within 3 weeks after clinical diagnosis of sinusitis.

Antibiotic resistance

Several resistant bacterial strains were isolated from nasal cavity and paranasal sinuses in the patients with sinusitis, mostly, at later terms (>2 months post-transplant).

Over the entire period of time (2019 to 2021), the clinical staphylococcal isolates were tested for their sensitivity to cefoxitin, erythromycin, clindamycin, gentamycin, norfloxacin, tetracycline, tigecycline, and linezolid. According to the expert Guidelines of European Committee on Antimicrobial Susceptibility Testing (EUCAST). Cefoxitin is considered a screening drug in order to discriminate between the categories of methicillin-resistant staphylococci (MRS) and methicillin-sensitive strains (MSS). Throughout the observation terms, the methicillin-resistant S.aureus (MRSA) were isolated in 4% of lavage and puncture samples obtained from maxillar sinuses in the patients with oncohematological disorders. Over this period of time, we did not reveal any S. aureus strains resistant to linezolid or tigecycline. 31% of S.aureus isolates were resistant to erythromycin. The revealed category of erythromycin sensitivity, in accordance with EUCAST rules, is also extended to clarithromycin and roxytromycin. Norfloxacin resistance was shown for 5% of S.aureus strains. The norfloxacin-sensitive staphylococci are regarded as sensitive to moxifloxacin and, at higher doses (or with prolonged infusion), to levofloxacin and ciprofloxacin. Tetracycline resistance of S. aureus strains was shown in 10%. The tetracycline-sensitive staphylococci are also considered sensitive to doxycycline and minocycline. Maximal percentage of antibiotic resistance for staphylococcal strains was found with gentamycin (24%). Gradient diffusion tests for vancomycin resistance were applied to methycillin-resistant staphylococci (E-test). All the MRSA strains proved to be vancomycin-sensitive.

All the E.faecalis isolates obtained from nasal cavity of the patients treated for oncohematological disorders who suffered from sinusitis have shown good sensitivity level with antibacterial drugs, i.e., 100% to ampicillin, linezolid, vancomycin and tigecycline.

100% of S.pneumoniae strains isolated in this study were sensitive to oxacillin, and therefore, to all β-lactam antibiotics. Among them, 90% showed sensitivity to norfloxacin and, hence, to moxifloxacin. Over the study period, we have not revealed any Pneumococcus strains resistant to vancomycin and linezolid. Resistance to tetracycline and erythromycin was detected for 70% of S.pneumoniae strains.

The species of Enterobacterales exhibited different patterns of antibiotic resistance. E.g., all E. coli strains were sensitive to amikacine, 3rd-generation cephalosporins (cefotaxim, ceftazidim, ceftriaxone), protected aminopenicillines, and meropenem. Meanwhile, resistance of Klebsiella pneumoniae ssp pneumoniae, the actual nosocomial pathogen, proved to be increased over this observation period, being as high as 85% to cephalosporins (III generation) and to meropenem (60%).

Discussion

Acute sinusitis is a common complication following HSCT, and several studies addressed this issue [6, 7]. Immunosuppressive drugs, chemotherapy, radiation treatment, prolonged antibiotic therapy, autoaggressive graft-versus-host disease (GVHD), and long periods of hospitalization are predisposing factors for the upper respiratory tract infections. Current clinical diagnostics of sinusitis, both before and after HSCT, is often based on computed tomography (CT) findings, which in many cases correlate with history and clinical examination data [8]. The authors have shown that the severity of pre-transplant sinus lesions revealed on CT scans correlated with clinical and radiological signs of sinusitis later post-transplant, having been associated with a trend for reduced survival. Therefore, the clinical background before HSCT is also important for assessing further risks of developing ORL disorders. Our results of bacteriological testing are based on the clinical cohort treated at the R. M. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation [5]. Infectious complications in allogeneic HSCT are significantly more common than in autologous HSCT, with respect to cytopenic period and rates of hematopoietic recovery. Our data refer to the patients who received allogeneic HSCT. Acute symptoms of rhinosinusitis may be registered at any term after HSCT, reaching 5.3% (95% CI 5.0%-5.6%) at the stage before transplantation; 3.01% (95% CI 2.8%-3.2%) in the course of engraftment, and 8.13% (95% CI 7.67%-8.60%), post-engraftment. From this comparison, one may suggest that massive antibiotic therapy after HSCT appears to prevent some of infectious conditions at the early stages post-transplant. However, later recolonization of pathogenic microorganisms is possible, including Klebsiella spp., S. aureus, S.pneumoniae, at a high risk of resistant strain selection, which was confirmed by us in the present work. One should note, however, that these 3 types of pathogenic bacteria were detected in a total of 13% of patients with sinusitis, i.e. the pathogen remained unknown in most cases. For additional diagnostics, along with search for pathogenic fungi and viruses, the extended diagnostics, e.g., of strictly anaerobic microbiota, are needed. In this aspect, implementation of advanced sequencing (NGS technique) will be of great importance, thus making it possible to assess biological diversity and the ratio of main microbiota classes in complex clinical samples, e.g., from mucosal surfaces.

Conclusions

1. The studies of relationships between the presence of facultative anaerobic, opportunistic microbiota in maxillar punctures and nasal cavities, and clinical course of sinusitis in the patients undergoing allogeneic HSCT did not reveal any significant correlations with severity of the disease (mild versus moderate grade).

2. Standard bacteriological testing aimed for detection of facultative anaerobic microorganisms in the maxillary sinus punctures after HSCT is of limited value within 1 month after HSCT, due to massive antibiotic therapy and suppressed growth of antibiotic-sensitive bacteria.

3. Massive antimicrobial therapy leads to the selection of resistant strains of Klebsiella spp., Pseudomonas spp., E.coli, S.aureus, mainly within 2 or more months after HSCT.

4. Low frequency of cultivable potentially pathogenic microorganisms in sino-nasal exudates cultures suggests reduced detection efficiency for the etiologically important bacteria which may cause sinusitis.

5. More sensitive and specific methods for detecting bacteria on the oropharyngeal and nasopharyngeal mucosa could be based on DNA diagnostics and multiplex PCR techniques, especially due to possible contamination of these sites with anaerobic bacteria of intestinal origin.

Conflict of interest

None declared.

References

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  2. Ivanchenko OA, Karpishchenko SA, Kozlov RS, Krechikova OI, Otvagin IV, Sopko ON, Piskunov GZ, Lopatin AS. The microbiome of the maxillary sinus and middle nasal meatus in chronic rhinosinusitis. Rhinology. 2016; 54: 68-74. doi: 10.4193/Rhino15.018
  3. Lee JT, Frank DN, Ramakrishnan V. Microbiome of the paranasal sinuses: Update and literature review. Am J Rhinol Allergy 2016; 30: 3-16. doi: 10.2500/ajra.2016.30.4255
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  5. Dolgov OI, Karpishchenko SA, Rodneva YA, Utimisheva ES, Moiseev IS, Zubarovskaya LS, Kulagin AD. Prevalence of acute inflammatory otorhinolaryngological diseases in hematopoietic stem cell transplant recipients. Russian Otorhinolaryngology. 2021;20(3):20-26 (In Russian.). doi: 10.18692/1810-4800-2021-3-20-26
  6. Drozd-Sokolowska JE, Sokolowski J, Wiktor-Jedrzejczak W, Niemczyk K. Sinusitis in patients undergoing allogeneic bone marrow transplantation – a review. Braz J Otorhinolaryngol. 2017 Jan-Feb;83(1):105-111. doi: 10.1016/j.bjorl.2016.02.012
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  8. Billings KR, Lowe LH, AquinoVM, Biavati MJ. Screening sinus CT scans in pediatric bone marrow transplant patients. Otorhinolaryngology. 2000; 52(3): 253-260.

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Целью настоящего исследования была сравнительная оценка состава факультативно-анаэробных представителей микробиоты полости носа и его придаточных пазух при синусите, который нередко развивается у иммунокомпромиссных пациентов после интенсивной химио- и антибиотикотерапии и трансплантации гемопоэтических клеток (ТГСК). </p> <h3>Материалы и методы</h3> <p style="text-align: justify;"> В исследовании участвовали 194 пациента с различными миело- и лимфопролиферативными заболеваниями в возрасте от 1 до 62 лет, проходившие интенсивную химиотерапию и аллогенную ТГСК. При наличии клинических показаний у пациентов забирали биоматериал (смывы из околоносовых пазух и/или назальные мазки) в сроки от -100 до +180 суток после аллогенной ТГСК. Исследовано 124 образца пунктатов верхнечелюстных пазух от 97 пациентов и 973 мазка-соскоба из полости носа. Посев биоматериала и выделение микроорганизмов проводили классическими бактериологическими методами. 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Долгов<sup>1</sup>, Сергей А. Карпищенко<sup>1</sup>, Екатерина С. Утимишева<sup>1</sup>, Диана А. Григорьянц<sup>1</sup>, Анна А. Спиридонова<sup>1,2</sup>, Иван С. Моисеев<sup>1</sup>, Людмила С. Зубаровская<sup>1</sup>, Алексей Б. Чухловин<sup>1</sup>, Александр Д. Кулагин<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(446) "

Олег И. Долгов1, Сергей А. Карпищенко1, Екатерина С. Утимишева1, Диана А. Григорьянц1, Анна А. Спиридонова1,2, Иван С. Моисеев1, Людмила С. Зубаровская1, Алексей Б. Чухловин1, Александр Д. Кулагин1

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 ФБУН НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург, Россия

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Трансплантация гемопоэтических стволовых клеток (ТГСК) часто сопровождается инфекционными осложнениями. Целью настоящего исследования была сравнительная оценка состава факультативно-анаэробных представителей микробиоты полости носа и его придаточных пазух при синусите, который нередко развивается у иммунокомпромиссных пациентов после интенсивной химио- и антибиотикотерапии и трансплантации гемопоэтических клеток (ТГСК).

Материалы и методы

В исследовании участвовали 194 пациента с различными миело- и лимфопролиферативными заболеваниями в возрасте от 1 до 62 лет, проходившие интенсивную химиотерапию и аллогенную ТГСК. При наличии клинических показаний у пациентов забирали биоматериал (смывы из околоносовых пазух и/или назальные мазки) в сроки от -100 до +180 суток после аллогенной ТГСК. Исследовано 124 образца пунктатов верхнечелюстных пазух от 97 пациентов и 973 мазка-соскоба из полости носа. Посев биоматериала и выделение микроорганизмов проводили классическими бактериологическими методами. Чувствительность клинических изолятов к антибиотикам определяли диско-диффузионным методом. Интерпретацию результатов чувствительности осуществляли согласно критериям EUCAST.

Результаты

В биоматериале из полости носа и околоносовых пазух наиболее часто высевали S.epidermidis – 34,7% (377/1097); S.viridans – 2,2% (24/1097); S. aureus – 1,91% (21/1097); Klebsiella spp – 1% (11/1097). Частота выявления S.epidermidis и S.viridans была минимальной в младшей возрастной группе (до 5 лет) и возрастала в группах от 15 лет и выше. Глубокое подавление роста S.epidermidis отмечалось (в особенности – в околоносовых синусах) в течение 1-го мес. после ТГСК на фоне массивной антибиотикотерапии. Отмечена высокая частота выявления Klebsiella spp в материале из синусов в поздние сроки (2-3 мес.) после ТГСК при малой частоте выявления в материале из полости носа (в среднем 16,3% против 2.1%, р=2×10^14). Кроме того, мы оценили частоту высеваемости бактерий в сроки +30 сут. от постановки диагноза синусита. При этом была выявлена повышенная частота выделения Pseudomonas spp (1/378 vs 7/217) в материале из придаточных пазух.

Заключение

Бактериологические исследование материала из гайморовых пазух имеет ограниченную ценность в течение 1-го мес. после ТГСК в связи с массивной антибиотикотерапией, которая сопровождается селекцией резистентных штаммов Klebsiella spp, Pseudomonas spp, E.coli, S.aureus, главным образом – в сроки 2 и более мес. после ТГСК.

Ключевые слова

Tрансплантация гемопоэтических стволовых клеток, околоносовые пазухи, микробиота, антибиотикорезистентность.

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Oleg I. Dolgov1, Sergey A. Karpishchenko1, Ekaterina S. Utimisheva1, Diana A. Grigoryanz1, Anna A. Spiridonova1,2, Ivan S. Moiseev1, Ludmila S. Zubarovskaya1, Alexei B. Chukhlovin1, Alexander D. Kulagin1

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1 Pavlov University, St. Petersburg, Russia
2 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:
Dr. Oleg I. Dolgov, Department of Otorhinolaryngology, Pavlov University, 6-8 Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 845-03-51
E-mail: oidolgov@yandex.ru


Citation: Dolgov OI, Karpishchenko SA, Utimisheva ES, et al. Microbiota of nasal cavity in sinusitis following hematopoietic stem cell transplantation. Cell Ther Transplant 2022; 11(1): 36-42.

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Hematopoietic stem cell transplantation (HSCT) is often accompanied by infectious complications. The aim of this study was a comparative evaluation of facultative anaerobic microbiota members of nasal and paranasal cavity in sinusitis, which often develops in immunocompromised patients, due to intensive chemotherapy and massive antibiotic treatment followed by hematopoietic cell transplantation (HSCT).

Materials and methods

The study involved 194 patients with various myelo- and lymphoproliferative diseases aged 1 to 62 years who underwent intensive chemotherapy and allogeneic HSCT. As based on appropriate clinical indications, the biomaterial was taken from patients (washings from the paranasal sinuses and/or nasal swabs) within the time period of +100 to +180 days after allogeneic HSCT. We studied 124 samples from maxillary sinus punctures of 97 patients and 973 scrapings from the nasal cavity. Seeding of biological material and isolation of the microorganisms were performed by classical bacteriological techniques. Antibiotic susceptibility of clinical isolates was determined by disk diffusion methods. The data on microbial sensitivity were interpreted by the EUCAST criteria.

Results

In the samples from nasal cavity and paranasal sinuses, S. epidermidis was most often detected (34.7%, 377/1097); S.viridans (2.2%, 24/1097); S. aureus (1.91%, 21/1097); Klebsiella spp (1%, 11/1097). Detection frequency of S.epidermidis and S.viridans was minimal in the younger age group (up to 5 years), and increased in older groups (>15 years old). Profound suppression of S.epidermidis growth was noted, especially in paranasal sinuses, within 1 month after HSCT in presence of massive antibiotic therapy. High frequency of Klebsiella spp detection was noted in the samples from maxillar sinuses at later terms (2-3 months) after HSCT, at low detection frequency of the pathogen in the specimens from nasal cavity (average 16.3% vs 2.1%, p=2×10^14). In addition, we have estimated frequency of bacterial inoculation within +30 days upon the diagnosis of sinusitis. At the same time, an increased frequency of Pseudomonas spp isolation (1/378 vs 7/217) was revealed in the material from paranasal sinuses.

Conclusion

Bacteriological study of biological samples from maxillary sinuses is of limited value during the 1st month after HSCT accompanied by massive antibiotic therapy which was followed by selection of resistant strains of Klebsiella spp, Pseudomonas spp, E. coli, S. aureus, mainly at the terms of >2 months after HSCT.

Keywords

Hematopoietic stem cell transplantation, paranasal sinuses, microbiota, antibiotic resistance.

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Oleg I. Dolgov1, Sergey A. Karpishchenko1, Ekaterina S. Utimisheva1, Diana A. Grigoryanz1, Anna A. Spiridonova1,2, Ivan S. Moiseev1, Ludmila S. Zubarovskaya1, Alexei B. Chukhlovin1, Alexander D. Kulagin1

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "28552" ["VALUE"]=> array(2) { ["TEXT"]=> string(3275) "<p style="text-align: justify;"> Hematopoietic stem cell transplantation (HSCT) is often accompanied by infectious complications. The aim of this study was a comparative evaluation of facultative anaerobic microbiota members of nasal and paranasal cavity in sinusitis, which often develops in immunocompromised patients, due to intensive chemotherapy and massive antibiotic treatment followed by hematopoietic cell transplantation (HSCT). </p> <h3>Materials and methods</h3> <p style="text-align: justify;"> The study involved 194 patients with various myelo- and lymphoproliferative diseases aged 1 to 62 years who underwent intensive chemotherapy and allogeneic HSCT. As based on appropriate clinical indications, the biomaterial was taken from patients (washings from the paranasal sinuses and/or nasal swabs) within the time period of +100 to +180 days after allogeneic HSCT. We studied 124 samples from maxillary sinus punctures of 97 patients and 973 scrapings from the nasal cavity. Seeding of biological material and isolation of the microorganisms were performed by classical bacteriological techniques. Antibiotic susceptibility of clinical isolates was determined by disk diffusion methods. The data on microbial sensitivity were interpreted by the EUCAST criteria. </p> <h3>Results</h3> <p style="text-align: justify;"> In the samples from nasal cavity and paranasal sinuses, S. epidermidis was most often detected (34.7%, 377/1097); <i>S.viridans</i> (2.2%, 24/1097); <i>S. aureus</i> (1.91%, 21/1097); <i>Klebsiella spp</i> (1%, 11/1097). Detection frequency of <i>S.epidermidis</i> and <i>S.viridans</i> was minimal in the younger age group (up to 5 years), and increased in older groups (&gt;15 years old). Profound suppression of <i>S.epidermidis</i> growth was noted, especially in paranasal sinuses, within 1 month after HSCT in presence of massive antibiotic therapy. High frequency of <i>Klebsiella spp</i> detection was noted in the samples from maxillar sinuses at later terms (2-3 months) after HSCT, at low detection frequency of the pathogen in the specimens from nasal cavity (average 16.3% <i>vs</i> 2.1%, p=2×10^14). In addition, we have estimated frequency of bacterial inoculation within +30 days upon the diagnosis of sinusitis. At the same time, an increased frequency of <i>Pseudomonas spp</i> isolation (1/378 <i>vs </i>7/217) was revealed in the material from paranasal sinuses. </p> <h3>Conclusion</h3> <p style="text-align: justify;"> Bacteriological study of biological samples from maxillary sinuses is of limited value during the 1st month after HSCT accompanied by massive antibiotic therapy which was followed by selection of resistant strains of <i>Klebsiella spp, Pseudomonas spp, E. coli, S. aureus</i>, mainly at the terms of &gt;2 months after HSCT. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, paranasal sinuses, microbiota, antibiotic resistance. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2977) "

Hematopoietic stem cell transplantation (HSCT) is often accompanied by infectious complications. The aim of this study was a comparative evaluation of facultative anaerobic microbiota members of nasal and paranasal cavity in sinusitis, which often develops in immunocompromised patients, due to intensive chemotherapy and massive antibiotic treatment followed by hematopoietic cell transplantation (HSCT).

Materials and methods

The study involved 194 patients with various myelo- and lymphoproliferative diseases aged 1 to 62 years who underwent intensive chemotherapy and allogeneic HSCT. As based on appropriate clinical indications, the biomaterial was taken from patients (washings from the paranasal sinuses and/or nasal swabs) within the time period of +100 to +180 days after allogeneic HSCT. We studied 124 samples from maxillary sinus punctures of 97 patients and 973 scrapings from the nasal cavity. Seeding of biological material and isolation of the microorganisms were performed by classical bacteriological techniques. Antibiotic susceptibility of clinical isolates was determined by disk diffusion methods. The data on microbial sensitivity were interpreted by the EUCAST criteria.

Results

In the samples from nasal cavity and paranasal sinuses, S. epidermidis was most often detected (34.7%, 377/1097); S.viridans (2.2%, 24/1097); S. aureus (1.91%, 21/1097); Klebsiella spp (1%, 11/1097). Detection frequency of S.epidermidis and S.viridans was minimal in the younger age group (up to 5 years), and increased in older groups (>15 years old). Profound suppression of S.epidermidis growth was noted, especially in paranasal sinuses, within 1 month after HSCT in presence of massive antibiotic therapy. High frequency of Klebsiella spp detection was noted in the samples from maxillar sinuses at later terms (2-3 months) after HSCT, at low detection frequency of the pathogen in the specimens from nasal cavity (average 16.3% vs 2.1%, p=2×10^14). In addition, we have estimated frequency of bacterial inoculation within +30 days upon the diagnosis of sinusitis. At the same time, an increased frequency of Pseudomonas spp isolation (1/378 vs 7/217) was revealed in the material from paranasal sinuses.

Conclusion

Bacteriological study of biological samples from maxillary sinuses is of limited value during the 1st month after HSCT accompanied by massive antibiotic therapy which was followed by selection of resistant strains of Klebsiella spp, Pseudomonas spp, E. coli, S. aureus, mainly at the terms of >2 months after HSCT.

Keywords

Hematopoietic stem cell transplantation, paranasal sinuses, microbiota, antibiotic resistance.

" ["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(2977) "

Hematopoietic stem cell transplantation (HSCT) is often accompanied by infectious complications. The aim of this study was a comparative evaluation of facultative anaerobic microbiota members of nasal and paranasal cavity in sinusitis, which often develops in immunocompromised patients, due to intensive chemotherapy and massive antibiotic treatment followed by hematopoietic cell transplantation (HSCT).

Materials and methods

The study involved 194 patients with various myelo- and lymphoproliferative diseases aged 1 to 62 years who underwent intensive chemotherapy and allogeneic HSCT. As based on appropriate clinical indications, the biomaterial was taken from patients (washings from the paranasal sinuses and/or nasal swabs) within the time period of +100 to +180 days after allogeneic HSCT. We studied 124 samples from maxillary sinus punctures of 97 patients and 973 scrapings from the nasal cavity. Seeding of biological material and isolation of the microorganisms were performed by classical bacteriological techniques. Antibiotic susceptibility of clinical isolates was determined by disk diffusion methods. The data on microbial sensitivity were interpreted by the EUCAST criteria.

Results

In the samples from nasal cavity and paranasal sinuses, S. epidermidis was most often detected (34.7%, 377/1097); S.viridans (2.2%, 24/1097); S. aureus (1.91%, 21/1097); Klebsiella spp (1%, 11/1097). Detection frequency of S.epidermidis and S.viridans was minimal in the younger age group (up to 5 years), and increased in older groups (>15 years old). Profound suppression of S.epidermidis growth was noted, especially in paranasal sinuses, within 1 month after HSCT in presence of massive antibiotic therapy. High frequency of Klebsiella spp detection was noted in the samples from maxillar sinuses at later terms (2-3 months) after HSCT, at low detection frequency of the pathogen in the specimens from nasal cavity (average 16.3% vs 2.1%, p=2×10^14). In addition, we have estimated frequency of bacterial inoculation within +30 days upon the diagnosis of sinusitis. At the same time, an increased frequency of Pseudomonas spp isolation (1/378 vs 7/217) was revealed in the material from paranasal sinuses.

Conclusion

Bacteriological study of biological samples from maxillary sinuses is of limited value during the 1st month after HSCT accompanied by massive antibiotic therapy which was followed by selection of resistant strains of Klebsiella spp, Pseudomonas spp, E. coli, S. aureus, mainly at the terms of >2 months after HSCT.

Keywords

Hematopoietic stem cell transplantation, paranasal sinuses, microbiota, antibiotic resistance.

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1 Pavlov University, St. Petersburg, Russia
2 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:
Dr. Oleg I. Dolgov, Department of Otorhinolaryngology, Pavlov University, 6-8 Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 845-03-51
E-mail: oidolgov@yandex.ru


Citation: Dolgov OI, Karpishchenko SA, Utimisheva ES, et al. Microbiota of nasal cavity in sinusitis following hematopoietic stem cell transplantation. Cell Ther Transplant 2022; 11(1): 36-42.

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1 Pavlov University, St. Petersburg, Russia
2 St. Petersburg Pasteur Institute, St. Petersburg, Russia


Correspondence:
Dr. Oleg I. Dolgov, Department of Otorhinolaryngology, Pavlov University, 6-8 Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 845-03-51
E-mail: oidolgov@yandex.ru


Citation: Dolgov OI, Karpishchenko SA, Utimisheva ES, et al. Microbiota of nasal cavity in sinusitis following hematopoietic stem cell transplantation. Cell Ther Transplant 2022; 11(1): 36-42.

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Олег И. Долгов1, Сергей А. Карпищенко1, Екатерина С. Утимишева1, Диана А. Григорьянц1, Анна А. Спиридонова1,2, Иван С. Моисеев1, Людмила С. Зубаровская1, Алексей Б. Чухловин1, Александр Д. Кулагин1

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Целью настоящего исследования была сравнительная оценка состава факультативно-анаэробных представителей микробиоты полости носа и его придаточных пазух при синусите, который нередко развивается у иммунокомпромиссных пациентов после интенсивной химио- и антибиотикотерапии и трансплантации гемопоэтических клеток (ТГСК). </p> <h3>Материалы и методы</h3> <p style="text-align: justify;"> В исследовании участвовали 194 пациента с различными миело- и лимфопролиферативными заболеваниями в возрасте от 1 до 62 лет, проходившие интенсивную химиотерапию и аллогенную ТГСК. При наличии клинических показаний у пациентов забирали биоматериал (смывы из околоносовых пазух и/или назальные мазки) в сроки от -100 до +180 суток после аллогенной ТГСК. Исследовано 124 образца пунктатов верхнечелюстных пазух от 97 пациентов и 973 мазка-соскоба из полости носа. Посев биоматериала и выделение микроорганизмов проводили классическими бактериологическими методами. Чувствительность клинических изолятов к антибиотикам определяли диско-диффузионным методом. Интерпретацию результатов чувствительности осуществляли согласно критериям EUCAST. </p> <h3>Результаты</h3> <p style="text-align: justify;"> В биоматериале из полости носа и околоносовых пазух наиболее часто высевали <i>S.epidermidis</i> – 34,7% (377/1097); <i>S.viridans</i> – 2,2% (24/1097); <i>S. aureus</i> – 1,91% (21/1097); <i>Klebsiella spp</i> – 1% (11/1097). Частота выявления <i>S.epidermidis</i> и <i>S.viridans</i> была минимальной в младшей возрастной группе (до 5 лет) и возрастала в группах от 15 лет и выше. Глубокое подавление роста <i>S.epidermidis</i> отмечалось (в особенности – в околоносовых синусах) в течение 1-го мес. после ТГСК на фоне массивной антибиотикотерапии. Отмечена высокая частота выявления <i>Klebsiella spp</i> в материале из синусов в поздние сроки (2-3 мес.) после ТГСК при малой частоте выявления в материале из полости носа (в среднем 16,3% против 2.1%, р=2×10^14). Кроме того, мы оценили частоту высеваемости бактерий в сроки +30 сут. от постановки диагноза синусита. При этом была выявлена повышенная частота выделения <i>Pseudomonas spp</i> (1/378 <i>vs </i>7/217) в материале из придаточных пазух. </p> <h3>Заключение</h3> <p style="text-align: justify;"> Бактериологические исследование материала из гайморовых пазух имеет ограниченную ценность в течение 1-го мес. после ТГСК в связи с массивной антибиотикотерапией, которая сопровождается селекцией резистентных штаммов <i>Klebsiella spp, Pseudomonas spp, E.coli, S.aureus</i>, главным образом – в сроки 2 и более мес. после ТГСК. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Tрансплантация гемопоэтических стволовых клеток, околоносовые пазухи, микробиота, антибиотикорезистентность. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4836) "

Трансплантация гемопоэтических стволовых клеток (ТГСК) часто сопровождается инфекционными осложнениями. Целью настоящего исследования была сравнительная оценка состава факультативно-анаэробных представителей микробиоты полости носа и его придаточных пазух при синусите, который нередко развивается у иммунокомпромиссных пациентов после интенсивной химио- и антибиотикотерапии и трансплантации гемопоэтических клеток (ТГСК).

Материалы и методы

В исследовании участвовали 194 пациента с различными миело- и лимфопролиферативными заболеваниями в возрасте от 1 до 62 лет, проходившие интенсивную химиотерапию и аллогенную ТГСК. При наличии клинических показаний у пациентов забирали биоматериал (смывы из околоносовых пазух и/или назальные мазки) в сроки от -100 до +180 суток после аллогенной ТГСК. Исследовано 124 образца пунктатов верхнечелюстных пазух от 97 пациентов и 973 мазка-соскоба из полости носа. Посев биоматериала и выделение микроорганизмов проводили классическими бактериологическими методами. Чувствительность клинических изолятов к антибиотикам определяли диско-диффузионным методом. Интерпретацию результатов чувствительности осуществляли согласно критериям EUCAST.

Результаты

В биоматериале из полости носа и околоносовых пазух наиболее часто высевали S.epidermidis – 34,7% (377/1097); S.viridans – 2,2% (24/1097); S. aureus – 1,91% (21/1097); Klebsiella spp – 1% (11/1097). Частота выявления S.epidermidis и S.viridans была минимальной в младшей возрастной группе (до 5 лет) и возрастала в группах от 15 лет и выше. Глубокое подавление роста S.epidermidis отмечалось (в особенности – в околоносовых синусах) в течение 1-го мес. после ТГСК на фоне массивной антибиотикотерапии. Отмечена высокая частота выявления Klebsiella spp в материале из синусов в поздние сроки (2-3 мес.) после ТГСК при малой частоте выявления в материале из полости носа (в среднем 16,3% против 2.1%, р=2×10^14). Кроме того, мы оценили частоту высеваемости бактерий в сроки +30 сут. от постановки диагноза синусита. При этом была выявлена повышенная частота выделения Pseudomonas spp (1/378 vs 7/217) в материале из придаточных пазух.

Заключение

Бактериологические исследование материала из гайморовых пазух имеет ограниченную ценность в течение 1-го мес. после ТГСК в связи с массивной антибиотикотерапией, которая сопровождается селекцией резистентных штаммов Klebsiella spp, Pseudomonas spp, E.coli, S.aureus, главным образом – в сроки 2 и более мес. после ТГСК.

Ключевые слова

Tрансплантация гемопоэтических стволовых клеток, околоносовые пазухи, микробиота, антибиотикорезистентность.

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Трансплантация гемопоэтических стволовых клеток (ТГСК) часто сопровождается инфекционными осложнениями. Целью настоящего исследования была сравнительная оценка состава факультативно-анаэробных представителей микробиоты полости носа и его придаточных пазух при синусите, который нередко развивается у иммунокомпромиссных пациентов после интенсивной химио- и антибиотикотерапии и трансплантации гемопоэтических клеток (ТГСК).

Материалы и методы

В исследовании участвовали 194 пациента с различными миело- и лимфопролиферативными заболеваниями в возрасте от 1 до 62 лет, проходившие интенсивную химиотерапию и аллогенную ТГСК. При наличии клинических показаний у пациентов забирали биоматериал (смывы из околоносовых пазух и/или назальные мазки) в сроки от -100 до +180 суток после аллогенной ТГСК. Исследовано 124 образца пунктатов верхнечелюстных пазух от 97 пациентов и 973 мазка-соскоба из полости носа. Посев биоматериала и выделение микроорганизмов проводили классическими бактериологическими методами. Чувствительность клинических изолятов к антибиотикам определяли диско-диффузионным методом. Интерпретацию результатов чувствительности осуществляли согласно критериям EUCAST.

Результаты

В биоматериале из полости носа и околоносовых пазух наиболее часто высевали S.epidermidis – 34,7% (377/1097); S.viridans – 2,2% (24/1097); S. aureus – 1,91% (21/1097); Klebsiella spp – 1% (11/1097). Частота выявления S.epidermidis и S.viridans была минимальной в младшей возрастной группе (до 5 лет) и возрастала в группах от 15 лет и выше. Глубокое подавление роста S.epidermidis отмечалось (в особенности – в околоносовых синусах) в течение 1-го мес. после ТГСК на фоне массивной антибиотикотерапии. Отмечена высокая частота выявления Klebsiella spp в материале из синусов в поздние сроки (2-3 мес.) после ТГСК при малой частоте выявления в материале из полости носа (в среднем 16,3% против 2.1%, р=2×10^14). Кроме того, мы оценили частоту высеваемости бактерий в сроки +30 сут. от постановки диагноза синусита. При этом была выявлена повышенная частота выделения Pseudomonas spp (1/378 vs 7/217) в материале из придаточных пазух.

Заключение

Бактериологические исследование материала из гайморовых пазух имеет ограниченную ценность в течение 1-го мес. после ТГСК в связи с массивной антибиотикотерапией, которая сопровождается селекцией резистентных штаммов Klebsiella spp, Pseudomonas spp, E.coli, S.aureus, главным образом – в сроки 2 и более мес. после ТГСК.

Ключевые слова

Tрансплантация гемопоэтических стволовых клеток, околоносовые пазухи, микробиота, антибиотикорезистентность.

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 ФБУН НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург, Россия

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1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 ФБУН НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург, Россия

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Introduction

The development of solid organ transplantation and the subsequent lifelong immunosuppressive therapy (IST) is naturally accompanied by the development of complications associated with a specific spectrum of infections, organ dysfunctions, and also with the occurrence of tumor diseases of various etiology. Increasing the number of patients who underwent transplantation of kidneys, liver, heart, lungs, etc. results in the number of patients with post-transplant malignant neoplasms [1]. The most common of them are neoplastic diseases of the hemopoietic system and, mainly, various malignant lymphoproliferative diseases. Even separate forms of these types of tumors which is associated with previous long-term immunosuppression are distinguished in the modern WHO classification [2].

The risk of developing post-transplant lymphoproliferative disease (PTLD) increases by 20-120% in patients after solid organ transplantation compared with the general population and depends on the intensity of IST. PTLD was first described in 1968 by Doak P. B. in two patients after cadaveric kidney transplantation and IST with azathioprine and prednisolone [3]. The term PTLD was introduced by T. E. Starzl in 1984 [4]. The role of the Epstein-Barr virus (EBV) in the pathogenesis of PTLD was described in 1981 [5]. The developing of this disease most frequently associated with solid organ transplantation like heart, lung, intestine and multi-organ transplantation, while this complication develops less frequently in kidney and liver recipients [6, 7]. There was no increase in the incidence of PTLD when cyclosporine was used in comparison with therapy with azathioprine in combination with glucocorticosteroids. Tacrolimus also increases the risk of this complication [7]. Immunosuppressive therapy with antithymocyte globulin (ATG) increases the risk of PTLD within the first year after solid organ transplantation, and no such dependence was found when antibodies to the IL-2 receptor were used [7]. It has been established that in the pathogenesis of PTLD, the presence of certain human leukocyte antigens (HLA) in a patient is important. If alleles HLA-A26 and HLA-B38 are detected in a recipient, the risk of PTLD development increases, while donor haplotypes HLA-A1, HLA-B8, and HLA-DR3 were identified as factors in which this complication develops less frequently [8]. Other studies have identified an increased risk of PTLD in a recipient with HLA-A2, HLA-A11, HLA-B5, HLA-B18, HLA-B21, and HLA-B35 [9, 10].

The clinical manifestations of PTLD are often nonspecific. Involvement of the gastrointestinal (GI) tract, lungs, skin, bone marrow, and central nervous system (CNS) is common [11-15]. CNS involvement is present in about 10-15% of all PTLD cases [11]. B-symptoms such as pyrexia, sweating and weight loss are also common. Damage to the transplanted organ is noted in about a third of all PTLD cases [13]. According to the WHO classification 2017, there are the following types of PTLD: early lesions (plasmacytic hyperplasia, infectious mononucleosis, and florid follicular hyperplasia) – 5% of all PTLD, polymorphic PTLD – 15-20%, monomorphic B-cell neoplasm (diffuse large B-cell lymphoma, Burkitt lymphoma, plasma cell myeloma and other) – more than 70% of all PTLD, monomorphic T/NK-cell neoplasms PTLD (peripheral T-cell lymphoma and other) – less than 5%, and classic Hodgkin lymphoma PTLD – less than 5% [2].

The main goal of PTLD treatment is to achieve stable remission of the disease and preserve the transplanted organ. Due to the clinical and pathological heterogeneity of PTLD (type of transplant, risk of rejection and concomitant diseases, tumor burden, etc.), there is no standardized approach to treatment. Nevertheless, the key approach is the reduction of IST: complete cancellation or partial (by 50-75%) reduction the dose of immunosuppressive drugs to prevent rejection of the transplanted organ. In this case, the response is achieved in about half of the patients, but long-term remissions are rare [12, 14-16]. Other methods that can be used in the treatment of PTLD are monoclonal antibodies to the CD20 antigen (rituximab) as monotherapy or in combination with chemotherapy, surgery, and radiation therapy. In the event that the development of PTLD is associated with EBV infection, antiviral therapy (intravenous immunoglobulins) and/or EBV-specific T-lymphocytes are used, autologous or allogeneic hematopoietic stem cells transplantation are used less often as a consolidating treatment [11, 13, 14, 16.17]. Overall survival of patients after PTLD therapy has significantly improved in recent years, by the using of monoclonal antibodies. Mortality rate earlier was reached 50-70%, nowadays the 3-year overall survival rate is 60-70%, according published studies in recent years [7, 13, 14].

The role of allogeneic hematopoietic stem cells (allo-HSCT) transplantation in PTLD therapy after solid organ transplantation has not been determined. The use of high-dose chemotherapy can be accompanied by high toxicity for the transplanted organ. Graft-versus-host disease (GVHD), which develops after allo-HSCT, can contribute to the rejection of a transplanted solid organ. And the presence of a solid organ transplant before allo-HSCT may increase the probability of rejection of hematopoietic stem cells. Only a few successful clinical cases of allo-HSCT in PTLD after solid organ transplantation have been described [1, 18-20].

The aim of this work: to present a clinical case of a patient in whom transplantation of an allogeneic cadaveric kidney was complicated by the development of PTLD, which was initially successfully treated, but due to the ongoing IST, a relapse was established, which required HSCT from a haploidentical donor. Clinical case is presented with the consent of the patient.

Clinical case description

Patient B., female, the disease manifested at the age of 9 years, in 1996 with proteinuria (3 g/day) and increased arterial pressure up to 160/90 mm Hg. Acute glomerulonephritis was diagnosed, and prednisolone therapy was started. In 1998, the diagnosis of mesangioproliferative glomerulonephritis was confirmed by histological examination of a kidney biopsy. Progression to the terminal stage of chronic renal failure (stage 5) was documented in 2003, hemodialysis was started, with arteriovenous fistula arranged. Transplantation of allogeneic cadaveric kidney was performed at the N. V. Sklifosovsky Research Institute for Emergency Medicine in April 2011. Delayed recovery of renal transplant function was noted; hemodialysis was carried out within a month after the organ transplantation. Tacrolimus, mycophenolate mofetil, methylprednisolone were applied as immunosuppressive therapy. Blood creatinine level in the post-transplant period was 110-130 μmol/L, glomerular filtration rate (GFR), according to the CKD-EPI formula, was 48-61 ml/min/1.73 m2. Due to the pregnancy planning, mycophenolate mofetil was replaced by azathioprine in 2016. Pancytopenia was detected in June 2017, but the dose of immunosuppressive drugs was not reduced. Since the end of July 2017, the patient had febrile body temperature, decreasing body weight, dry cough, increased abdominal volume, and irregularity in the menstrual cycle, but the patient did not seek medical asssistance.

In August 2017 the examination revealed proteinuria 2.3 g/l, hypoalbuminemia 28 g/l, high level of blood creatinine (214 μmol/l) and C-reactive protein (115 mg/dl), an increased LDH activity to 923 U/l, ESR up to 70 mm/h, an increased IgM content in the blood (1288 mg/dl), mainly, due to IgMλ. Pancytopenia still persisted (leukocytes 1.9×109/l, platelets 90×109/l). Antibiotic therapy was carried out for suspected infection, azathioprine was canceled. Hepatosplenomegaly was revealed on the CT examination of abdominal organs. Given these findings, lymphoproliferative disease was suggested, thus requiring special examination.

The patient was examined at National Research Center for Hematology at 23.08.2017. Infiltrative-ulcerative defects of the gastric mucosa were found during esophagogastroduodenoscopy. The data of histological and immunohistochemical studies of gastric biopsy revealed the substrate of extranodal diffuse large B-cell lymphoma (tumor cells monomorphically expressed CD 20). In addition, the data of histological and immunohistochemical studies of the bone marrow also was determined: interstitial-small-focal B-cell infiltration with the presence of clusters of large CD 20+ cells, intravascular foci of small CD 20+ B-cells. The expression of EBER (EBV-encoded RNA) was not detected, but the virus replication was detected in blood. Paraprotein M lambda, 21.3 g/l; Bens-Jones protein lambda 0.35 g/l was revealed in blood serum by immunochemistry. Hyperpdiloid karyotype and complex cytogenetic rearrangements involving chromosomes 3, 7, 4, 9, 10, 14, 15, 17, 18 were registered by standard cytogenetic study of the bone marrow samples. According to CT scan, hepatosplenomegaly was determined: the vertical size of the liver was 23.5 cm, the size of the spleen was 160×60×235 mm. Based on the obtained data, the diagnosis of PTLD was specified as a diffuse large B-cell lymphoma (PTLD-DLBCL) associated with immunosuppressive therapy, with involvement of liver, spleen, stomach and bone marrow.

Despite the presence of a transplanted organ, taking into the variant of the disease and the generally accepted practice of managing such patients, the IST was reduced: methylprednisolone and tacrolimus were completely canceled since 24.08.2017.

From 26.08.2017 to 30.08.2017, a pre-phase with dexamethasone and cyclophosphamide was carried out and a positive trend was noted as decreasing size of the liver and spleen. From 31.08.2017 to 05.09.2017, the 1st course of CHOD protocol in combination with rituximab (600 mg) was administered (total drug doses: cyclophosphamide 1200 mg, doxorubicin 75 mg, vincristine 2 mg, dexamethasone 80 mg). The treatment was complicated by febrile fever, oropharyngeal candidiasis, bilateral pleuropneumonia; the patient underwent massive antimicrobial therapy: imipenem/cilastatin, sodium colistimethate, fluconazole, acyclovir and intravenous immunoglobulin. In addition, the patient developed hypotension (up to 80/50 mm Hg). Subsequent examination revealed adrenal insufficiency, which required administration of hydrocortisone (2.5-5 mg per day). A partial remission of the disease was obtained after first R-CHOD. From 26.09.2017 to 11.01.2018, five R-CHOD courses were performed. A complete remission of PTLD-DLBCL was achieved after second course of R-CHOD as confirmed by PET-CT (Fig. 1).

Parovichnikova-fig01.jpg

Figure 1. CT dynamics of internal organs. A, in the debut of PTLD-DLBCL (August 2017); B, first remission of PTLD-DLBCL (January 2018); C, relapse of PTLD-DLBCL (January 2019); D, before haplo-HSCT (May 2019)

Due to the risk of renal transplant rejection, the patient resumed immunosuppressive therapy with tacrolimus (2 mg/day) and prednisolone (5 mg/day) after completing chemotherapy (6 courses), since April 2018. In December 2018, 10 months after the completion of therapy for PTLD-DLBCL, the patient had a febrile episode of up to 40°C. Ultrasound examination revealed a focal lesion in the liver. At that moment, no other signs of PTLD progression (based on bone marrow and gastric biopsies) were present. However, a month later, in January 2019, the febrile fever was again observed. The patient was admitted to the hospital in an extremely severe condition with signs of septic shock, bilateral pneumonia with respiratory failure, and evolving acute renal injury (blood creatinine levels reached 522 μmol/l). At the intensive care unit, the patient underwent massive antimicrobial therapy (meropenem, linezolid, sodium colistimethate, fluconazole, acyclovir), and hemodiafiltration were performed, with immunosuppressive therapy still continued. Additional examination revealed an increasing size of the liver (vertical size 24 cm) and spleen (121×54×175 mm) (Fig. 1). B-cell clonality was revealed in the gastric tissue biopsy, infiltration with tumor CD20+ cells was noted in the bone marrow biopsy, monoclonal secretion of M lambda in serum was determined in blood (5.3 g/l), a trace amount of the Bence-Jones protein lambda was detected in the urine, standard cytogenetic study of bone marrow and gastric tissue biopsies no mitosis was detected. Thus, after 11 months of achievement of PET-CT-negative remission and 9 months after the resumption of the IST, a relapse of PTLD-DLBCL was documented.

The severity of the patient's condition was due to both septic condition and emerging relapse of the disease, including specific liver damage. As a result, severe coagulation disorders developed, with re-appearing signs of adrenal insufficiency (decreased concentration of cortisol in blood serum: 90.47 nmol/L (reference range of 185-624 nmol/L), which required administration of hydrocortisone (2.5-5 mg per day), blood transfusions and management of blood clotting problems.

Due to PTLD-DLBCL relapse and severe infectious complications, despite presence of a transplanted organ, the IST was canceled 01.05.2019, and the antitumor effect was not achieved again. The patient's condition remained extremely serious, and according to vital indications, from 01.11.2019 to 15.01.2019 the pre-phase therapy with cyclophosphamide and dexamethasone was started. Positive clinical dynamics was noted, i.e., normalization of body temperature and decrease in the liver and spleen size few days after pre-phase therapy.

Thereafter, a modified course of chemotherapy with cytarabine (=4 g) + etoposide (∑ = 400 mg) combined with lenalidomide (∑ = 30 mg) was carried out from 16.01.2019 to 17.01.2019. Lenalidomide was included in the treatment, according to the previously published data on improvement of overall and progression-free survival when using it in the patients with DLBCL [21, 22]. At the control examination (08.02.2019) we have revealed a decreased size of the liver (vertical size 18 cm) and spleen (115×47×130 mm), complete regression of focal liver lesion, regression of hystological changes in the bone marrow biopsy, and only trace secretion of paraprotein IgM.

Two more courses using cytarabine + etoposide + lenalidomide were performed from 15.02.2019 to 06.05.2019. The second PET-CT-negative remission of PTLD-DLBCL was achieved (Fig. 1).

Thus, the young patient re-achieved PET-СТ negative remission of PTLD-DLBCL, and still required resumption of IST to prevent kidney transplant rejection, which would entail another relapse of the disease. Program therapy for patients in the second remission of the DLBCL implies to consolidate remission by autologous hematopoietic stem cell transplantation. However, our patient would have to return again immunosuppressive therapy to prevent kidney transplant rejection. Therefore, we decided to perform allo-HSCT to induce tolerance of the donor-derived immune cells to the transplanted kidney. The patient didn’t have a fully matched related or unrelated donor, since the HSCT was planned from a related haploidentical (haplo-HSCT) donor (mother), however, with TCRαβ +/CD19+ depletion of the graft. The choice of such a transplant approach was determined by the fact that it does not use long-term (minimum 6 months) immunosuppressive therapy. The last injection of IST drugs (tocilizumab and abatacept) was administered on day +30 after haplo-HSCT with TCRαβ+/CD19+ depletion. Following HLA typing of the patient and her mother was performed, HLA-B18 was identified in the HLA genotype of the patient. This allele is associated with increased incidence of PTLD. The donor was diagnosed with microcytic hypochromic anemia (Hb 101 g/L), she was observed for a long time at a hematologist with a diagnosis of iron deficiency anemia and was treated with iron preparations.

Pre-transplant conditioning regimen included: treosulfan (∑ = 45 g) + melphalan (∑ = 100 mg) + fludarabine (∑ = 225 mg). Haplo-HSCT was performed 14.05.2019 the number of CD34 + cells in the graft was 10.8×106/kg, the number of TCRαβ + lymphocytes was 271.5×103/kg. GVHD prophylaxis consisted of rituximab (∑ = 170 mg) + bortezomib (∑ = 4.2 mg) + tocilizumab (∑ = 460 g) + abatacept (∑ = 1740 mg), the patient did not receive any other immunosuppressive therapy. The early post-transplant period was complicated by febrile fever, mucositis, and neutrope