ISSN 1866-8836
Клеточная терапия и трансплантация
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January 8, 1952 – July 25, 2021" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(10789) "<img alt="Savchenko-1.jpg" src="/upload/medialibrary/e2e/savchenko_1.jpg" title="Savchenko-1.jpg" align="middle"> <p style="text-align: justify;"> Российская гематология потеряла всеми уважаемого лидера – профессора Валерия Савченко, который скоропостижно скончался 25 июля 2021 г. Он был выдающимся врачом, ученым и исследователем, возглавлял Национальный медицинский исследовательский центр гематологии России, был главным внештатным гематологом министерства здравоохранения РФ, президентом Национального гематологического общества и академиком Российской академии наук. На протяжении многих лет он отвечал за развитие гематологии в СССР и, позже – в России. </p> <p style="text-align: justify;"> Валерий Григорьевич Савченко родился 8 января 1952 года на Украине. После окончания в 1969 году второй московской физико-математической школы при МГУ, он поступил в 1-й Московский медицинский институт им. И. М. Сеченова, который с отличием закончил в 1975 г. </p> <p style="text-align: justify;"> Его жизнь в медицине и науке была посвящена гематологии. В 1980 г. В. Г. Савченко окончил ординатуру и аспирантуру на кафедре гематологии и интенсивной терапии Центрального института усовершенствования врачей, защитив кандидатскую диссертацию на тему «Патогенез и лечение идиопатической тромбоцитопенической пурпуры», затем в течение 7 лет работал ассистентом кафедры. В 1988 г. В. Г. Савченко, со своим учителем, профессором А. И. Воробьевым перешел в гематологический научный центр Минздрава СССР, где был назначен заведующим отделением химиотерапии гемобластозов и трансплантации костного мозга. В 1993 г. защитил докторскую диссертацию по теме «Современная стратегия терапии острых лейкозов». Ученое звание профессора было присвоено ему в 1996 г. В 2011 г. В. Г. Савченко был назначен Генеральным директором ФГБУ «Гематологический научный центр» Минздрава России (ныне – ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России). В 2004 г. он был избран членом-корреспондентом академии медицинских наук, а в 2013 г. – академиком Российской академии наук. </p> <p style="text-align: justify;"> Его пытливый ум, энциклопедические знания и аналитическое мышление позволили ему добиться превосходных результатов во многих областях современной гематологии. В. Г. Савченко мог четко сформулировать конкретные научные задачи и решать их, подсказать направление диагностического поиска и разработку алгоритмов лечения. Он разрабатывал программы терапии острых лейкозов и депрессий кроветворения, руководил проведением первых в России многоцентровых исследований в этой области и, наряду с профессором Б. В. Афанасьевым, был у истоков внедрения и совершенствования трансплантации костного мозга в СССР и России. </p> <p style="text-align: justify;"> Профессор Савченко руководил многими исследованиями в области молекулярной генетики, биологии, физиологии кроветворения, цитогенетики и трансплантационной иммунологии. Под его руководством были разработаны национальные алгоритмы диагностики и лечения заболеваний системы крови. У него было множество учеников, некоторые из которых теперь являются лидерами российской гематологии. Под руководством В. Г. Савченко защищено 30 кандидатских и 14 докторских диссертаций. Он является соавтором 14 авторских свидетельств на изобретения. Уделяя большое внимание сохранению школы в подготовке врачей- гематологов, он постоянно занимался преподавательской деятельностью и участвовал в междисциплинарных консилиумах. </p> <p style="text-align: justify;"> В. Г. Савченко являлся главным редактором журнала «Гематология и трансфузиология», входил в состав редколлегии журналов «Терапевтический архив», «Гематология. Трансфузиология. Восточная Европа», членом редакционного совета журналов «Cellular Therapy and Transplantation», «Биопрепараты. Профилактика, диагностика, лечение». </p> <p style="text-align: justify;"> Профессор Савченко был членом Всемирного комитета Международной ассоциации сравнительного изучения лейкозов и родственных заболеваний (МАСИЛР), в которую он вошел в начале 1990-х гг. по приглашению профессора Рольфа Нета и представлял Россию во Всемирном комитете с 1997 по 2007 г. и далее – с 2015 г. В 2019 г. он был переизбран во Всемирный комитет по 2023 г. В 2021 г. он был приглашен в качестве президента 31-го симпозиума МАСИЛР в Москве (2023 г). </p> <p style="text-align: justify;"> В. Г. Савченко развивал участие своего Центра гематологии в работе European LeukemiaNet (ELN), его организация стала одним из 6 первых российских участников ELN. В 2011 г. он прочел основную лекцию об остром миелоидном лейкозе на конгрессе ELN. Его группа продолжает вносить весомый вклад в кооперативные исследования по лейкозам, проводимые ELN. </p> <p style="text-align: justify;"> Аналитический ум В. Г. Савченко, его мягкая речь и сдержанный юмор незабываемы. Мы выражаем соболезнования его жене и многолетнему соратнику – профессору Елене Паровичниковой, известному в мире гематологу, его сыну Павлу, дочери Софье, и внукам. </p> <p style="text-align: justify;"> Есть люди, которых трудно заменить, Валерий Григорьевич Савченко был одним из них. Пословица гласит: Смерть – великан, против которого даже цари должны обратить оружие. Эта утрата огромна. </p> <p> <b> Александр Д. Кулагин,</b> проф., директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, <br> Санкт-Петербургский государственный медицинский университет <br> им. И. П. Павлова, Санкт-Петербург, Россия<br> <b>Рюдигер Хельманн,</b> проф., почетный доктор, Медицинский факультет Манхайм, Гейдельбергский университет, Германия<br> <b>Роберт Питер Гэйл,</b> проф., доктор, приглашенный профессор, почетный доктор, Центр гематологических исследований, Имперский колледж, Лондон, Соединенное Королевство<br> <b>Аксель Цандер,</b> проф., почетный доктор, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия<br> <b>Борис Фезе,</b> проф., доктор, Гамбургский университет, Германия </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(150) "Памяти профессора Валерия Григорьевича Савченко. 8 января 1952 года – 25 июля 2021 года" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(150) "Памяти профессора Валерия Григорьевича Савченко. 8 января 1952 года – 25 июля 2021 года" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(150) "Памяти профессора Валерия Григорьевича Савченко. 8 января 1952 года – 25 июля 2021 года" ["SECTION_META_TITLE"]=> string(150) "Памяти 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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27542" ["VALUE"]=> array(2) { ["TEXT"]=> string(176) "<p> Александр Д. Кулагин, Рюдигер Хельманн, Роберт Питер Гэйл, Аксель Цандер, Борис Фезе </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(164) "

Александр Д. Кулагин, Рюдигер Хельманн, Роберт Питер Гэйл, Аксель Цандер, Борис Фезе

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Он был выдающимся врачом, ученым и исследователем, возглавлял Национальный медицинский исследовательский центр гематологии России, был главным внештатным гематологом министерства здравоохранения РФ, президентом Национального гематологического общества и академиком Российской академии наук. На протяжении многих лет он отвечал за развитие гематологии в СССР и, позже – в России. </p> <p style="text-align: justify;"> Валерий Григорьевич Савченко родился 8 января 1952 года на Украине. После окончания в 1969 году второй московской физико-математической школы при МГУ, он поступил в 1-й Московский медицинский институт им. И. М. Сеченова, который с отличием закончил в 1975 г. </p> <p style="text-align: justify;"> Его жизнь в медицине и науке была посвящена гематологии. В 1980 г. В. Г. Савченко окончил ординатуру и аспирантуру на кафедре гематологии и интенсивной терапии Центрального института усовершенствования врачей, защитив кандидатскую диссертацию на тему «Патогенез и лечение идиопатической тромбоцитопенической пурпуры», затем в течение 7 лет работал ассистентом кафедры. В 1988 г. В. Г. Савченко, со своим учителем, профессором А. И. Воробьевым перешел в гематологический научный центр Минздрава СССР, где был назначен заведующим отделением химиотерапии гемобластозов и трансплантации костного мозга. В 1993 г. защитил докторскую диссертацию по теме «Современная стратегия терапии острых лейкозов». Ученое звание профессора было присвоено ему в 1996 г. В 2011 г. В. Г. Савченко был назначен Генеральным директором ФГБУ «Гематологический научный центр» Минздрава России (ныне – ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России). В 2004 г. он был избран членом-корреспондентом академии медицинских наук, а в 2013 г. – академиком Российской академии наук. </p> <p style="text-align: justify;"> Его пытливый ум, энциклопедические знания и аналитическое мышление позволили ему добиться превосходных результатов во многих областях современной гематологии. В. Г. Савченко мог четко сформулировать конкретные научные задачи и решать их, подсказать направление диагностического поиска и разработку алгоритмов лечения. Он разрабатывал программы терапии острых лейкозов и депрессий кроветворения, руководил проведением первых в России многоцентровых исследований в этой области и, наряду с профессором Б. В. Афанасьевым, был у истоков внедрения и совершенствования трансплантации костного мозга в СССР и России. </p> <p style="text-align: justify;"> Профессор Савченко руководил многими исследованиями в области молекулярной генетики, биологии, физиологии кроветворения, цитогенетики и трансплантационной иммунологии. Под его руководством были разработаны национальные алгоритмы диагностики и лечения заболеваний системы крови. У него было множество учеников, некоторые из которых теперь являются лидерами российской гематологии. Под руководством В. Г. Савченко защищено 30 кандидатских и 14 докторских диссертаций. Он является соавтором 14 авторских свидетельств на изобретения. Уделяя большое внимание сохранению школы в подготовке врачей- гематологов, он постоянно занимался преподавательской деятельностью и участвовал в междисциплинарных консилиумах. </p> <p style="text-align: justify;"> В. Г. Савченко являлся главным редактором журнала «Гематология и трансфузиология», входил в состав редколлегии журналов «Терапевтический архив», «Гематология. Трансфузиология. Восточная Европа», членом редакционного совета журналов «Cellular Therapy and Transplantation», «Биопрепараты. Профилактика, диагностика, лечение». </p> <p style="text-align: justify;"> Профессор Савченко был членом Всемирного комитета Международной ассоциации сравнительного изучения лейкозов и родственных заболеваний (МАСИЛР), в которую он вошел в начале 1990-х гг. по приглашению профессора Рольфа Нета и представлял Россию во Всемирном комитете с 1997 по 2007 г. и далее – с 2015 г. В 2019 г. он был переизбран во Всемирный комитет по 2023 г. В 2021 г. он был приглашен в качестве президента 31-го симпозиума МАСИЛР в Москве (2023 г). </p> <p style="text-align: justify;"> В. Г. Савченко развивал участие своего Центра гематологии в работе European LeukemiaNet (ELN), его организация стала одним из 6 первых российских участников ELN. В 2011 г. он прочел основную лекцию об остром миелоидном лейкозе на конгрессе ELN. Его группа продолжает вносить весомый вклад в кооперативные исследования по лейкозам, проводимые ELN. </p> <p style="text-align: justify;"> Аналитический ум В. Г. Савченко, его мягкая речь и сдержанный юмор незабываемы. Мы выражаем соболезнования его жене и многолетнему соратнику – профессору Елене Паровичниковой, известному в мире гематологу, его сыну Павлу, дочери Софье, и внукам. </p> <p style="text-align: justify;"> Есть люди, которых трудно заменить, Валерий Григорьевич Савченко был одним из них. Пословица гласит: Смерть – великан, против которого даже цари должны обратить оружие. Эта утрата огромна. </p> <p> <b> Александр Д. Кулагин,</b> проф., директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, <br> Санкт-Петербургский государственный медицинский университет <br> им. И. П. Павлова, Санкт-Петербург, Россия<br> <b>Рюдигер Хельманн,</b> проф., почетный доктор, Медицинский факультет Манхайм, Гейдельбергский университет, Германия<br> <b>Роберт Питер Гэйл,</b> проф., доктор, приглашенный профессор, почетный доктор, Центр гематологических исследований, Имперский колледж, Лондон, Соединенное Королевство<br> <b>Аксель Цандер,</b> проф., почетный доктор, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия<br> <b>Борис Фезе,</b> проф., доктор, Гамбургский университет, Германия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(10415) "Savchenko-1.jpg

Российская гематология потеряла всеми уважаемого лидера – профессора Валерия Савченко, который скоропостижно скончался 25 июля 2021 г. Он был выдающимся врачом, ученым и исследователем, возглавлял Национальный медицинский исследовательский центр гематологии России, был главным внештатным гематологом министерства здравоохранения РФ, президентом Национального гематологического общества и академиком Российской академии наук. На протяжении многих лет он отвечал за развитие гематологии в СССР и, позже – в России.

Валерий Григорьевич Савченко родился 8 января 1952 года на Украине. После окончания в 1969 году второй московской физико-математической школы при МГУ, он поступил в 1-й Московский медицинский институт им. И. М. Сеченова, который с отличием закончил в 1975 г.

Его жизнь в медицине и науке была посвящена гематологии. В 1980 г. В. Г. Савченко окончил ординатуру и аспирантуру на кафедре гематологии и интенсивной терапии Центрального института усовершенствования врачей, защитив кандидатскую диссертацию на тему «Патогенез и лечение идиопатической тромбоцитопенической пурпуры», затем в течение 7 лет работал ассистентом кафедры. В 1988 г. В. Г. Савченко, со своим учителем, профессором А. И. Воробьевым перешел в гематологический научный центр Минздрава СССР, где был назначен заведующим отделением химиотерапии гемобластозов и трансплантации костного мозга. В 1993 г. защитил докторскую диссертацию по теме «Современная стратегия терапии острых лейкозов». Ученое звание профессора было присвоено ему в 1996 г. В 2011 г. В. Г. Савченко был назначен Генеральным директором ФГБУ «Гематологический научный центр» Минздрава России (ныне – ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России). В 2004 г. он был избран членом-корреспондентом академии медицинских наук, а в 2013 г. – академиком Российской академии наук.

Его пытливый ум, энциклопедические знания и аналитическое мышление позволили ему добиться превосходных результатов во многих областях современной гематологии. В. Г. Савченко мог четко сформулировать конкретные научные задачи и решать их, подсказать направление диагностического поиска и разработку алгоритмов лечения. Он разрабатывал программы терапии острых лейкозов и депрессий кроветворения, руководил проведением первых в России многоцентровых исследований в этой области и, наряду с профессором Б. В. Афанасьевым, был у истоков внедрения и совершенствования трансплантации костного мозга в СССР и России.

Профессор Савченко руководил многими исследованиями в области молекулярной генетики, биологии, физиологии кроветворения, цитогенетики и трансплантационной иммунологии. Под его руководством были разработаны национальные алгоритмы диагностики и лечения заболеваний системы крови. У него было множество учеников, некоторые из которых теперь являются лидерами российской гематологии. Под руководством В. Г. Савченко защищено 30 кандидатских и 14 докторских диссертаций. Он является соавтором 14 авторских свидетельств на изобретения. Уделяя большое внимание сохранению школы в подготовке врачей- гематологов, он постоянно занимался преподавательской деятельностью и участвовал в междисциплинарных консилиумах.

В. Г. Савченко являлся главным редактором журнала «Гематология и трансфузиология», входил в состав редколлегии журналов «Терапевтический архив», «Гематология. Трансфузиология. Восточная Европа», членом редакционного совета журналов «Cellular Therapy and Transplantation», «Биопрепараты. Профилактика, диагностика, лечение».

Профессор Савченко был членом Всемирного комитета Международной ассоциации сравнительного изучения лейкозов и родственных заболеваний (МАСИЛР), в которую он вошел в начале 1990-х гг. по приглашению профессора Рольфа Нета и представлял Россию во Всемирном комитете с 1997 по 2007 г. и далее – с 2015 г. В 2019 г. он был переизбран во Всемирный комитет по 2023 г. В 2021 г. он был приглашен в качестве президента 31-го симпозиума МАСИЛР в Москве (2023 г).

В. Г. Савченко развивал участие своего Центра гематологии в работе European LeukemiaNet (ELN), его организация стала одним из 6 первых российских участников ELN. В 2011 г. он прочел основную лекцию об остром миелоидном лейкозе на конгрессе ELN. Его группа продолжает вносить весомый вклад в кооперативные исследования по лейкозам, проводимые ELN.

Аналитический ум В. Г. Савченко, его мягкая речь и сдержанный юмор незабываемы. Мы выражаем соболезнования его жене и многолетнему соратнику – профессору Елене Паровичниковой, известному в мире гематологу, его сыну Павлу, дочери Софье, и внукам.

Есть люди, которых трудно заменить, Валерий Григорьевич Савченко был одним из них. Пословица гласит: Смерть – великан, против которого даже цари должны обратить оружие. Эта утрата огромна.

Александр Д. Кулагин, проф., директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой,
Санкт-Петербургский государственный медицинский университет
им. И. П. Павлова, Санкт-Петербург, Россия
Рюдигер Хельманн, проф., почетный доктор, Медицинский факультет Манхайм, Гейдельбергский университет, Германия
Роберт Питер Гэйл, проф., доктор, приглашенный профессор, почетный доктор, Центр гематологических исследований, Имперский колледж, Лондон, Соединенное Королевство
Аксель Цандер, проф., почетный доктор, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия
Борис Фезе, проф., доктор, Гамбургский университет, Германия

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Alexander D. Kulagin, Rüdiger Hehlmann, Robert Peter Gale, Axel R. Zander, Boris Fehse

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Savchenko who died suddenly on 25 July 2021. He was an outstanding physician, scientist and researcher. He headed the National Medical Research Center of Hematology, was Chief Hematologist of the Russian Health Ministry, President of National Hematology Society and Academician of the Russian Academy of Sciences. For many years he was responsible for advancing hematology in the USSR and later Russia.</p> <p style="text-align: justify;">Valery Savchenko was born in the Ukraine on 8 January, 1952. After graduation from the 2<sup>nd</sup> Moscow Physical and Mathematical School at Moscow University in 1969, he studied medicine at the 1<sup>st</sup> I. Sechenov Moscow Medical Institute graduating with distinction in 1975.</p> <p style="text-align: justify;">His life in medicine and research was devoted to hematology. In 1980, he completed his residency and postgraduate studies at the Department of Hematology and Intensive Care at the Central Institute of Postgraduate Education where he presented his MD thesis: <i>Pathogenesis and treatment of idiopathic thrombocytopenic purpura</i>. Thereafter, he joined the faculty as an Assistant Professor. In 1988, Dr. Savchenko moved with his mentor Prof. Andrei I. Vorobiov to the Research Centre for Hematology where he was appointed Head of the Hemoblastoses Chemotherapy and Bone Marrow Transplantation Department. In 1993, he presented his doctoral thesis: <i>Modern strategy for acute leukemia therapy</i>.</p> <p style="text-align: justify;">Dr. Savchenko was awarded the title of Full Professor in 1996. In 2011, he assumed the position of Director of the Hematology Research Centre, now National Medical Research Centre for Hematology of the Russian Ministry of Health. In 2004, he was elected a Corresponding Member of Academy of Medical Sciences, and in 2013 he became Academician of the Russian Academy of Sciences.</p> <p style="text-align: justify;">His inquiring mind, encyclopaedic knowledge and analytical thinking allowed him to excel in many areas of modern hematology. Prof. Savchenko was able to set forth distinct scientific tasks and resolve them, suggesting the direction of diagnostic evaluations and developing therapy algorithms.He evolved therapy protocols for acute leukemias and bone marrow failure disorders, headed the first Russian multi-centre studies, and, along with Prof. Boris Afanasyev, established and advanced hematopoietic cell transplants in the USSR and Russia.</p> <p style="text-align: justify;">Prof. Savchenko lead many studies in molecular genetics, biology, physiology of hematopoiesis, cytogenetics and transplant immunology and edited the Russian national guidelines for diagnosis and treatment of blood diseases. He had many pupils, several of whom are now leaders of hematology in Russia. Prof. Savchenko advised 30 PhD and 14 doctoral dissertations. He held or co-held 14 patents. He was very concerned with hematology education in Russia, was permanently engaged in educational activities and participated in interdisciplinary conferences.</p> <p style="text-align: justify;">Prof. Savchenko was Editor-in-Chief of <i>Hematology and Transfusiology</i> and on the Editorial Board of several academic journals including <i>Therapeutic Archive, Hematology. Transfusiology Eastern Europe, Cellular Therapy and Transplantation,</i> and <i>Biological Products. Prevention, Diagnosis, Treatment</i>. </p> <p style="text-align: justify;">Prof. Savchenko was a member of the World Committee of the International Association for Comparative Research on Leukemia and Related Diseases (IACRLRD) which he joined in the early 1990s on invitation by Prof. Rolf Neth and was on the World Committee as a Russian representative from 1997-2007 and again from 2015 onwards. In 2019, he was re-elected to serve on the World Committee until 2023. In 2021, he was invited to head as president the 31st IACRLRD symposium in Moscow in 2023.</p> <p style="text-align: justify;">Prof. Savchenko promoted participation of his Hematological Centre in the European LeukemiaNet (ELN); his institution becoming one of the six initial Russian ELN-participants. In 2011, he gave the ELN-keynote lecture on acute myeloid leukemia. His group continues to be a strong partner of cooperative leukemia research within ELN. </p> <p style="text-align: justify;">Analytical mind, soft speech and cautious humour of Prof. Savchenko’s are unforgettable. He is survived by his wife and long-term collaborator, Prof. Elena Parovichnikova, an internationally renowned hematologist, his son and daughter, Pavel and Sofia and grandchildren.</p> <p style="text-align: justify;">There are people that are hard to replace, and Savchenko was among them. We are reminded of the proverb: Death is a giant against whom even the Tsars must draw weapons. The loss is immense.</p> <p><b>Alexander D. Kulagin,</b> Prof., Director, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transpantation, Pavlov University, St. Petersburg, Russia<br> <b>Rüdiger Hehlmann,</b> Prof. Dr., Dr. h.c, Med. Fakultät Mannheim, Heidelberg University, Germany<br> <b>Robert Peter Gale,</b> Visiting Prof., Dr., DSc h.c., Hematology Research Centre, Imperial College London, London, UK<br> <b>Axel R. Zander,</b> Prof. Dr. Dr. h.c., University Medical Center Hamburg-Eppendorf, Germany<br> <b>Boris Fehse,</b> Prof. Dr., Hamburg University, Germany</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5647) "Savchenko-1.jpg

Russian hematology has lost an esteemed leader, Professor Valery G. Savchenko who died suddenly on 25 July 2021. He was an outstanding physician, scientist and researcher. He headed the National Medical Research Center of Hematology, was Chief Hematologist of the Russian Health Ministry, President of National Hematology Society and Academician of the Russian Academy of Sciences. For many years he was responsible for advancing hematology in the USSR and later Russia.

Valery Savchenko was born in the Ukraine on 8 January, 1952. After graduation from the 2nd Moscow Physical and Mathematical School at Moscow University in 1969, he studied medicine at the 1st I. Sechenov Moscow Medical Institute graduating with distinction in 1975.

His life in medicine and research was devoted to hematology. In 1980, he completed his residency and postgraduate studies at the Department of Hematology and Intensive Care at the Central Institute of Postgraduate Education where he presented his MD thesis: Pathogenesis and treatment of idiopathic thrombocytopenic purpura. Thereafter, he joined the faculty as an Assistant Professor. In 1988, Dr. Savchenko moved with his mentor Prof. Andrei I. Vorobiov to the Research Centre for Hematology where he was appointed Head of the Hemoblastoses Chemotherapy and Bone Marrow Transplantation Department. In 1993, he presented his doctoral thesis: Modern strategy for acute leukemia therapy.

Dr. Savchenko was awarded the title of Full Professor in 1996. In 2011, he assumed the position of Director of the Hematology Research Centre, now National Medical Research Centre for Hematology of the Russian Ministry of Health. In 2004, he was elected a Corresponding Member of Academy of Medical Sciences, and in 2013 he became Academician of the Russian Academy of Sciences.

His inquiring mind, encyclopaedic knowledge and analytical thinking allowed him to excel in many areas of modern hematology. Prof. Savchenko was able to set forth distinct scientific tasks and resolve them, suggesting the direction of diagnostic evaluations and developing therapy algorithms.He evolved therapy protocols for acute leukemias and bone marrow failure disorders, headed the first Russian multi-centre studies, and, along with Prof. Boris Afanasyev, established and advanced hematopoietic cell transplants in the USSR and Russia.

Prof. Savchenko lead many studies in molecular genetics, biology, physiology of hematopoiesis, cytogenetics and transplant immunology and edited the Russian national guidelines for diagnosis and treatment of blood diseases. He had many pupils, several of whom are now leaders of hematology in Russia. Prof. Savchenko advised 30 PhD and 14 doctoral dissertations. He held or co-held 14 patents. He was very concerned with hematology education in Russia, was permanently engaged in educational activities and participated in interdisciplinary conferences.

Prof. Savchenko was Editor-in-Chief of Hematology and Transfusiology and on the Editorial Board of several academic journals including Therapeutic Archive, Hematology. Transfusiology Eastern Europe, Cellular Therapy and Transplantation, and Biological Products. Prevention, Diagnosis, Treatment.

Prof. Savchenko was a member of the World Committee of the International Association for Comparative Research on Leukemia and Related Diseases (IACRLRD) which he joined in the early 1990s on invitation by Prof. Rolf Neth and was on the World Committee as a Russian representative from 1997-2007 and again from 2015 onwards. In 2019, he was re-elected to serve on the World Committee until 2023. In 2021, he was invited to head as president the 31st IACRLRD symposium in Moscow in 2023.

Prof. Savchenko promoted participation of his Hematological Centre in the European LeukemiaNet (ELN); his institution becoming one of the six initial Russian ELN-participants. In 2011, he gave the ELN-keynote lecture on acute myeloid leukemia. His group continues to be a strong partner of cooperative leukemia research within ELN.

Analytical mind, soft speech and cautious humour of Prof. Savchenko’s are unforgettable. He is survived by his wife and long-term collaborator, Prof. Elena Parovichnikova, an internationally renowned hematologist, his son and daughter, Pavel and Sofia and grandchildren.

There are people that are hard to replace, and Savchenko was among them. We are reminded of the proverb: Death is a giant against whom even the Tsars must draw weapons. The loss is immense.

Alexander D. Kulagin, Prof., Director, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transpantation, Pavlov University, St. Petersburg, Russia
Rüdiger Hehlmann, Prof. Dr., Dr. h.c, Med. Fakultät Mannheim, Heidelberg University, Germany
Robert Peter Gale, Visiting Prof., Dr., DSc h.c., Hematology Research Centre, Imperial College London, London, UK
Axel R. Zander, Prof. Dr. Dr. h.c., University Medical Center Hamburg-Eppendorf, Germany
Boris Fehse, Prof. Dr., Hamburg University, Germany

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Alexander D. Kulagin, Rüdiger Hehlmann, Robert Peter Gale, Axel R. Zander, Boris Fehse

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Alexander D. Kulagin, Rüdiger Hehlmann, Robert Peter Gale, Axel R. Zander, Boris Fehse

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Savchenko who died suddenly on 25 July 2021. He was an outstanding physician, scientist and researcher. He headed the National Medical Research Center of Hematology, was Chief Hematologist of the Russian Health Ministry, President of National Hematology Society and Academician of the Russian Academy of Sciences. For many years he was responsible for advancing hematology in the USSR and later Russia.</p> <p style="text-align: justify;">Valery Savchenko was born in the Ukraine on 8 January, 1952. After graduation from the 2<sup>nd</sup> Moscow Physical and Mathematical School at Moscow University in 1969, he studied medicine at the 1<sup>st</sup> I. Sechenov Moscow Medical Institute graduating with distinction in 1975.</p> <p style="text-align: justify;">His life in medicine and research was devoted to hematology. In 1980, he completed his residency and postgraduate studies at the Department of Hematology and Intensive Care at the Central Institute of Postgraduate Education where he presented his MD thesis: <i>Pathogenesis and treatment of idiopathic thrombocytopenic purpura</i>. Thereafter, he joined the faculty as an Assistant Professor. In 1988, Dr. Savchenko moved with his mentor Prof. Andrei I. Vorobiov to the Research Centre for Hematology where he was appointed Head of the Hemoblastoses Chemotherapy and Bone Marrow Transplantation Department. In 1993, he presented his doctoral thesis: <i>Modern strategy for acute leukemia therapy</i>.</p> <p style="text-align: justify;">Dr. Savchenko was awarded the title of Full Professor in 1996. In 2011, he assumed the position of Director of the Hematology Research Centre, now National Medical Research Centre for Hematology of the Russian Ministry of Health. In 2004, he was elected a Corresponding Member of Academy of Medical Sciences, and in 2013 he became Academician of the Russian Academy of Sciences.</p> <p style="text-align: justify;">His inquiring mind, encyclopaedic knowledge and analytical thinking allowed him to excel in many areas of modern hematology. Prof. Savchenko was able to set forth distinct scientific tasks and resolve them, suggesting the direction of diagnostic evaluations and developing therapy algorithms.He evolved therapy protocols for acute leukemias and bone marrow failure disorders, headed the first Russian multi-centre studies, and, along with Prof. Boris Afanasyev, established and advanced hematopoietic cell transplants in the USSR and Russia.</p> <p style="text-align: justify;">Prof. Savchenko lead many studies in molecular genetics, biology, physiology of hematopoiesis, cytogenetics and transplant immunology and edited the Russian national guidelines for diagnosis and treatment of blood diseases. He had many pupils, several of whom are now leaders of hematology in Russia. Prof. Savchenko advised 30 PhD and 14 doctoral dissertations. He held or co-held 14 patents. He was very concerned with hematology education in Russia, was permanently engaged in educational activities and participated in interdisciplinary conferences.</p> <p style="text-align: justify;">Prof. Savchenko was Editor-in-Chief of <i>Hematology and Transfusiology</i> and on the Editorial Board of several academic journals including <i>Therapeutic Archive, Hematology. Transfusiology Eastern Europe, Cellular Therapy and Transplantation,</i> and <i>Biological Products. Prevention, Diagnosis, Treatment</i>. </p> <p style="text-align: justify;">Prof. Savchenko was a member of the World Committee of the International Association for Comparative Research on Leukemia and Related Diseases (IACRLRD) which he joined in the early 1990s on invitation by Prof. Rolf Neth and was on the World Committee as a Russian representative from 1997-2007 and again from 2015 onwards. In 2019, he was re-elected to serve on the World Committee until 2023. In 2021, he was invited to head as president the 31st IACRLRD symposium in Moscow in 2023.</p> <p style="text-align: justify;">Prof. Savchenko promoted participation of his Hematological Centre in the European LeukemiaNet (ELN); his institution becoming one of the six initial Russian ELN-participants. In 2011, he gave the ELN-keynote lecture on acute myeloid leukemia. His group continues to be a strong partner of cooperative leukemia research within ELN. </p> <p style="text-align: justify;">Analytical mind, soft speech and cautious humour of Prof. Savchenko’s are unforgettable. He is survived by his wife and long-term collaborator, Prof. Elena Parovichnikova, an internationally renowned hematologist, his son and daughter, Pavel and Sofia and grandchildren.</p> <p style="text-align: justify;">There are people that are hard to replace, and Savchenko was among them. We are reminded of the proverb: Death is a giant against whom even the Tsars must draw weapons. The loss is immense.</p> <p><b>Alexander D. Kulagin,</b> Prof., Director, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transpantation, Pavlov University, St. Petersburg, Russia<br> <b>Rüdiger Hehlmann,</b> Prof. Dr., Dr. h.c, Med. Fakultät Mannheim, Heidelberg University, Germany<br> <b>Robert Peter Gale,</b> Visiting Prof., Dr., DSc h.c., Hematology Research Centre, Imperial College London, London, UK<br> <b>Axel R. Zander,</b> Prof. Dr. Dr. h.c., University Medical Center Hamburg-Eppendorf, Germany<br> <b>Boris Fehse,</b> Prof. Dr., Hamburg University, Germany</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5647) "Savchenko-1.jpg

Russian hematology has lost an esteemed leader, Professor Valery G. Savchenko who died suddenly on 25 July 2021. He was an outstanding physician, scientist and researcher. He headed the National Medical Research Center of Hematology, was Chief Hematologist of the Russian Health Ministry, President of National Hematology Society and Academician of the Russian Academy of Sciences. For many years he was responsible for advancing hematology in the USSR and later Russia.

Valery Savchenko was born in the Ukraine on 8 January, 1952. After graduation from the 2nd Moscow Physical and Mathematical School at Moscow University in 1969, he studied medicine at the 1st I. Sechenov Moscow Medical Institute graduating with distinction in 1975.

His life in medicine and research was devoted to hematology. In 1980, he completed his residency and postgraduate studies at the Department of Hematology and Intensive Care at the Central Institute of Postgraduate Education where he presented his MD thesis: Pathogenesis and treatment of idiopathic thrombocytopenic purpura. Thereafter, he joined the faculty as an Assistant Professor. In 1988, Dr. Savchenko moved with his mentor Prof. Andrei I. Vorobiov to the Research Centre for Hematology where he was appointed Head of the Hemoblastoses Chemotherapy and Bone Marrow Transplantation Department. In 1993, he presented his doctoral thesis: Modern strategy for acute leukemia therapy.

Dr. Savchenko was awarded the title of Full Professor in 1996. In 2011, he assumed the position of Director of the Hematology Research Centre, now National Medical Research Centre for Hematology of the Russian Ministry of Health. In 2004, he was elected a Corresponding Member of Academy of Medical Sciences, and in 2013 he became Academician of the Russian Academy of Sciences.

His inquiring mind, encyclopaedic knowledge and analytical thinking allowed him to excel in many areas of modern hematology. Prof. Savchenko was able to set forth distinct scientific tasks and resolve them, suggesting the direction of diagnostic evaluations and developing therapy algorithms.He evolved therapy protocols for acute leukemias and bone marrow failure disorders, headed the first Russian multi-centre studies, and, along with Prof. Boris Afanasyev, established and advanced hematopoietic cell transplants in the USSR and Russia.

Prof. Savchenko lead many studies in molecular genetics, biology, physiology of hematopoiesis, cytogenetics and transplant immunology and edited the Russian national guidelines for diagnosis and treatment of blood diseases. He had many pupils, several of whom are now leaders of hematology in Russia. Prof. Savchenko advised 30 PhD and 14 doctoral dissertations. He held or co-held 14 patents. He was very concerned with hematology education in Russia, was permanently engaged in educational activities and participated in interdisciplinary conferences.

Prof. Savchenko was Editor-in-Chief of Hematology and Transfusiology and on the Editorial Board of several academic journals including Therapeutic Archive, Hematology. Transfusiology Eastern Europe, Cellular Therapy and Transplantation, and Biological Products. Prevention, Diagnosis, Treatment.

Prof. Savchenko was a member of the World Committee of the International Association for Comparative Research on Leukemia and Related Diseases (IACRLRD) which he joined in the early 1990s on invitation by Prof. Rolf Neth and was on the World Committee as a Russian representative from 1997-2007 and again from 2015 onwards. In 2019, he was re-elected to serve on the World Committee until 2023. In 2021, he was invited to head as president the 31st IACRLRD symposium in Moscow in 2023.

Prof. Savchenko promoted participation of his Hematological Centre in the European LeukemiaNet (ELN); his institution becoming one of the six initial Russian ELN-participants. In 2011, he gave the ELN-keynote lecture on acute myeloid leukemia. His group continues to be a strong partner of cooperative leukemia research within ELN.

Analytical mind, soft speech and cautious humour of Prof. Savchenko’s are unforgettable. He is survived by his wife and long-term collaborator, Prof. Elena Parovichnikova, an internationally renowned hematologist, his son and daughter, Pavel and Sofia and grandchildren.

There are people that are hard to replace, and Savchenko was among them. We are reminded of the proverb: Death is a giant against whom even the Tsars must draw weapons. The loss is immense.

Alexander D. Kulagin, Prof., Director, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transpantation, Pavlov University, St. Petersburg, Russia
Rüdiger Hehlmann, Prof. Dr., Dr. h.c, Med. Fakultät Mannheim, Heidelberg University, Germany
Robert Peter Gale, Visiting Prof., Dr., DSc h.c., Hematology Research Centre, Imperial College London, London, UK
Axel R. Zander, Prof. Dr. Dr. h.c., University Medical Center Hamburg-Eppendorf, Germany
Boris Fehse, Prof. Dr., Hamburg University, Germany

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Russian hematology has lost an esteemed leader, Professor Valery G. Savchenko who died suddenly on 25 July 2021. He was an outstanding physician, scientist and researcher. He headed the National Medical Research Center of Hematology, was Chief Hematologist of the Russian Health Ministry, President of National Hematology Society and Academician of the Russian Academy of Sciences. For many years he was responsible for advancing hematology in the USSR and later Russia.

Valery Savchenko was born in the Ukraine on 8 January, 1952. After graduation from the 2nd Moscow Physical and Mathematical School at Moscow University in 1969, he studied medicine at the 1st I. Sechenov Moscow Medical Institute graduating with distinction in 1975.

His life in medicine and research was devoted to hematology. In 1980, he completed his residency and postgraduate studies at the Department of Hematology and Intensive Care at the Central Institute of Postgraduate Education where he presented his MD thesis: Pathogenesis and treatment of idiopathic thrombocytopenic purpura. Thereafter, he joined the faculty as an Assistant Professor. In 1988, Dr. Savchenko moved with his mentor Prof. Andrei I. Vorobiov to the Research Centre for Hematology where he was appointed Head of the Hemoblastoses Chemotherapy and Bone Marrow Transplantation Department. In 1993, he presented his doctoral thesis: Modern strategy for acute leukemia therapy.

Dr. Savchenko was awarded the title of Full Professor in 1996. In 2011, he assumed the position of Director of the Hematology Research Centre, now National Medical Research Centre for Hematology of the Russian Ministry of Health. In 2004, he was elected a Corresponding Member of Academy of Medical Sciences, and in 2013 he became Academician of the Russian Academy of Sciences.

His inquiring mind, encyclopaedic knowledge and analytical thinking allowed him to excel in many areas of modern hematology. Prof. Savchenko was able to set forth distinct scientific tasks and resolve them, suggesting the direction of diagnostic evaluations and developing therapy algorithms.He evolved therapy protocols for acute leukemias and bone marrow failure disorders, headed the first Russian multi-centre studies, and, along with Prof. Boris Afanasyev, established and advanced hematopoietic cell transplants in the USSR and Russia.

Prof. Savchenko lead many studies in molecular genetics, biology, physiology of hematopoiesis, cytogenetics and transplant immunology and edited the Russian national guidelines for diagnosis and treatment of blood diseases. He had many pupils, several of whom are now leaders of hematology in Russia. Prof. Savchenko advised 30 PhD and 14 doctoral dissertations. He held or co-held 14 patents. He was very concerned with hematology education in Russia, was permanently engaged in educational activities and participated in interdisciplinary conferences.

Prof. Savchenko was Editor-in-Chief of Hematology and Transfusiology and on the Editorial Board of several academic journals including Therapeutic Archive, Hematology. Transfusiology Eastern Europe, Cellular Therapy and Transplantation, and Biological Products. Prevention, Diagnosis, Treatment.

Prof. Savchenko was a member of the World Committee of the International Association for Comparative Research on Leukemia and Related Diseases (IACRLRD) which he joined in the early 1990s on invitation by Prof. Rolf Neth and was on the World Committee as a Russian representative from 1997-2007 and again from 2015 onwards. In 2019, he was re-elected to serve on the World Committee until 2023. In 2021, he was invited to head as president the 31st IACRLRD symposium in Moscow in 2023.

Prof. Savchenko promoted participation of his Hematological Centre in the European LeukemiaNet (ELN); his institution becoming one of the six initial Russian ELN-participants. In 2011, he gave the ELN-keynote lecture on acute myeloid leukemia. His group continues to be a strong partner of cooperative leukemia research within ELN.

Analytical mind, soft speech and cautious humour of Prof. Savchenko’s are unforgettable. He is survived by his wife and long-term collaborator, Prof. Elena Parovichnikova, an internationally renowned hematologist, his son and daughter, Pavel and Sofia and grandchildren.

There are people that are hard to replace, and Savchenko was among them. We are reminded of the proverb: Death is a giant against whom even the Tsars must draw weapons. The loss is immense.

Alexander D. Kulagin, Prof., Director, RM Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transpantation, Pavlov University, St. Petersburg, Russia
Rüdiger Hehlmann, Prof. Dr., Dr. h.c, Med. Fakultät Mannheim, Heidelberg University, Germany
Robert Peter Gale, Visiting Prof., Dr., DSc h.c., Hematology Research Centre, Imperial College London, London, UK
Axel R. Zander, Prof. Dr. Dr. h.c., University Medical Center Hamburg-Eppendorf, Germany
Boris Fehse, Prof. Dr., Hamburg University, Germany

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Александр Д. Кулагин, Рюдигер Хельманн, Роберт Питер Гэйл, Аксель Цандер, Борис Фезе

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Он был выдающимся врачом, ученым и исследователем, возглавлял Национальный медицинский исследовательский центр гематологии России, был главным внештатным гематологом министерства здравоохранения РФ, президентом Национального гематологического общества и академиком Российской академии наук. На протяжении многих лет он отвечал за развитие гематологии в СССР и, позже – в России. </p> <p style="text-align: justify;"> Валерий Григорьевич Савченко родился 8 января 1952 года на Украине. После окончания в 1969 году второй московской физико-математической школы при МГУ, он поступил в 1-й Московский медицинский институт им. И. М. Сеченова, который с отличием закончил в 1975 г. </p> <p style="text-align: justify;"> Его жизнь в медицине и науке была посвящена гематологии. В 1980 г. В. Г. Савченко окончил ординатуру и аспирантуру на кафедре гематологии и интенсивной терапии Центрального института усовершенствования врачей, защитив кандидатскую диссертацию на тему «Патогенез и лечение идиопатической тромбоцитопенической пурпуры», затем в течение 7 лет работал ассистентом кафедры. В 1988 г. В. Г. Савченко, со своим учителем, профессором А. И. Воробьевым перешел в гематологический научный центр Минздрава СССР, где был назначен заведующим отделением химиотерапии гемобластозов и трансплантации костного мозга. В 1993 г. защитил докторскую диссертацию по теме «Современная стратегия терапии острых лейкозов». Ученое звание профессора было присвоено ему в 1996 г. В 2011 г. В. Г. Савченко был назначен Генеральным директором ФГБУ «Гематологический научный центр» Минздрава России (ныне – ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России). В 2004 г. он был избран членом-корреспондентом академии медицинских наук, а в 2013 г. – академиком Российской академии наук. </p> <p style="text-align: justify;"> Его пытливый ум, энциклопедические знания и аналитическое мышление позволили ему добиться превосходных результатов во многих областях современной гематологии. В. Г. Савченко мог четко сформулировать конкретные научные задачи и решать их, подсказать направление диагностического поиска и разработку алгоритмов лечения. Он разрабатывал программы терапии острых лейкозов и депрессий кроветворения, руководил проведением первых в России многоцентровых исследований в этой области и, наряду с профессором Б. В. Афанасьевым, был у истоков внедрения и совершенствования трансплантации костного мозга в СССР и России. </p> <p style="text-align: justify;"> Профессор Савченко руководил многими исследованиями в области молекулярной генетики, биологии, физиологии кроветворения, цитогенетики и трансплантационной иммунологии. Под его руководством были разработаны национальные алгоритмы диагностики и лечения заболеваний системы крови. У него было множество учеников, некоторые из которых теперь являются лидерами российской гематологии. Под руководством В. Г. Савченко защищено 30 кандидатских и 14 докторских диссертаций. Он является соавтором 14 авторских свидетельств на изобретения. Уделяя большое внимание сохранению школы в подготовке врачей- гематологов, он постоянно занимался преподавательской деятельностью и участвовал в междисциплинарных консилиумах. </p> <p style="text-align: justify;"> В. Г. Савченко являлся главным редактором журнала «Гематология и трансфузиология», входил в состав редколлегии журналов «Терапевтический архив», «Гематология. Трансфузиология. Восточная Европа», членом редакционного совета журналов «Cellular Therapy and Transplantation», «Биопрепараты. Профилактика, диагностика, лечение». </p> <p style="text-align: justify;"> Профессор Савченко был членом Всемирного комитета Международной ассоциации сравнительного изучения лейкозов и родственных заболеваний (МАСИЛР), в которую он вошел в начале 1990-х гг. по приглашению профессора Рольфа Нета и представлял Россию во Всемирном комитете с 1997 по 2007 г. и далее – с 2015 г. В 2019 г. он был переизбран во Всемирный комитет по 2023 г. В 2021 г. он был приглашен в качестве президента 31-го симпозиума МАСИЛР в Москве (2023 г). </p> <p style="text-align: justify;"> В. Г. Савченко развивал участие своего Центра гематологии в работе European LeukemiaNet (ELN), его организация стала одним из 6 первых российских участников ELN. В 2011 г. он прочел основную лекцию об остром миелоидном лейкозе на конгрессе ELN. Его группа продолжает вносить весомый вклад в кооперативные исследования по лейкозам, проводимые ELN. </p> <p style="text-align: justify;"> Аналитический ум В. Г. Савченко, его мягкая речь и сдержанный юмор незабываемы. Мы выражаем соболезнования его жене и многолетнему соратнику – профессору Елене Паровичниковой, известному в мире гематологу, его сыну Павлу, дочери Софье, и внукам. </p> <p style="text-align: justify;"> Есть люди, которых трудно заменить, Валерий Григорьевич Савченко был одним из них. Пословица гласит: Смерть – великан, против которого даже цари должны обратить оружие. Эта утрата огромна. </p> <p> <b> Александр Д. Кулагин,</b> проф., директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, <br> Санкт-Петербургский государственный медицинский университет <br> им. И. П. Павлова, Санкт-Петербург, Россия<br> <b>Рюдигер Хельманн,</b> проф., почетный доктор, Медицинский факультет Манхайм, Гейдельбергский университет, Германия<br> <b>Роберт Питер Гэйл,</b> проф., доктор, приглашенный профессор, почетный доктор, Центр гематологических исследований, Имперский колледж, Лондон, Соединенное Королевство<br> <b>Аксель Цандер,</b> проф., почетный доктор, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия<br> <b>Борис Фезе,</b> проф., доктор, Гамбургский университет, Германия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(10415) "Savchenko-1.jpg

Российская гематология потеряла всеми уважаемого лидера – профессора Валерия Савченко, который скоропостижно скончался 25 июля 2021 г. Он был выдающимся врачом, ученым и исследователем, возглавлял Национальный медицинский исследовательский центр гематологии России, был главным внештатным гематологом министерства здравоохранения РФ, президентом Национального гематологического общества и академиком Российской академии наук. На протяжении многих лет он отвечал за развитие гематологии в СССР и, позже – в России.

Валерий Григорьевич Савченко родился 8 января 1952 года на Украине. После окончания в 1969 году второй московской физико-математической школы при МГУ, он поступил в 1-й Московский медицинский институт им. И. М. Сеченова, который с отличием закончил в 1975 г.

Его жизнь в медицине и науке была посвящена гематологии. В 1980 г. В. Г. Савченко окончил ординатуру и аспирантуру на кафедре гематологии и интенсивной терапии Центрального института усовершенствования врачей, защитив кандидатскую диссертацию на тему «Патогенез и лечение идиопатической тромбоцитопенической пурпуры», затем в течение 7 лет работал ассистентом кафедры. В 1988 г. В. Г. Савченко, со своим учителем, профессором А. И. Воробьевым перешел в гематологический научный центр Минздрава СССР, где был назначен заведующим отделением химиотерапии гемобластозов и трансплантации костного мозга. В 1993 г. защитил докторскую диссертацию по теме «Современная стратегия терапии острых лейкозов». Ученое звание профессора было присвоено ему в 1996 г. В 2011 г. В. Г. Савченко был назначен Генеральным директором ФГБУ «Гематологический научный центр» Минздрава России (ныне – ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России). В 2004 г. он был избран членом-корреспондентом академии медицинских наук, а в 2013 г. – академиком Российской академии наук.

Его пытливый ум, энциклопедические знания и аналитическое мышление позволили ему добиться превосходных результатов во многих областях современной гематологии. В. Г. Савченко мог четко сформулировать конкретные научные задачи и решать их, подсказать направление диагностического поиска и разработку алгоритмов лечения. Он разрабатывал программы терапии острых лейкозов и депрессий кроветворения, руководил проведением первых в России многоцентровых исследований в этой области и, наряду с профессором Б. В. Афанасьевым, был у истоков внедрения и совершенствования трансплантации костного мозга в СССР и России.

Профессор Савченко руководил многими исследованиями в области молекулярной генетики, биологии, физиологии кроветворения, цитогенетики и трансплантационной иммунологии. Под его руководством были разработаны национальные алгоритмы диагностики и лечения заболеваний системы крови. У него было множество учеников, некоторые из которых теперь являются лидерами российской гематологии. Под руководством В. Г. Савченко защищено 30 кандидатских и 14 докторских диссертаций. Он является соавтором 14 авторских свидетельств на изобретения. Уделяя большое внимание сохранению школы в подготовке врачей- гематологов, он постоянно занимался преподавательской деятельностью и участвовал в междисциплинарных консилиумах.

В. Г. Савченко являлся главным редактором журнала «Гематология и трансфузиология», входил в состав редколлегии журналов «Терапевтический архив», «Гематология. Трансфузиология. Восточная Европа», членом редакционного совета журналов «Cellular Therapy and Transplantation», «Биопрепараты. Профилактика, диагностика, лечение».

Профессор Савченко был членом Всемирного комитета Международной ассоциации сравнительного изучения лейкозов и родственных заболеваний (МАСИЛР), в которую он вошел в начале 1990-х гг. по приглашению профессора Рольфа Нета и представлял Россию во Всемирном комитете с 1997 по 2007 г. и далее – с 2015 г. В 2019 г. он был переизбран во Всемирный комитет по 2023 г. В 2021 г. он был приглашен в качестве президента 31-го симпозиума МАСИЛР в Москве (2023 г).

В. Г. Савченко развивал участие своего Центра гематологии в работе European LeukemiaNet (ELN), его организация стала одним из 6 первых российских участников ELN. В 2011 г. он прочел основную лекцию об остром миелоидном лейкозе на конгрессе ELN. Его группа продолжает вносить весомый вклад в кооперативные исследования по лейкозам, проводимые ELN.

Аналитический ум В. Г. Савченко, его мягкая речь и сдержанный юмор незабываемы. Мы выражаем соболезнования его жене и многолетнему соратнику – профессору Елене Паровичниковой, известному в мире гематологу, его сыну Павлу, дочери Софье, и внукам.

Есть люди, которых трудно заменить, Валерий Григорьевич Савченко был одним из них. Пословица гласит: Смерть – великан, против которого даже цари должны обратить оружие. Эта утрата огромна.

Александр Д. Кулагин, проф., директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой,
Санкт-Петербургский государственный медицинский университет
им. И. П. Павлова, Санкт-Петербург, Россия
Рюдигер Хельманн, проф., почетный доктор, Медицинский факультет Манхайм, Гейдельбергский университет, Германия
Роберт Питер Гэйл, проф., доктор, приглашенный профессор, почетный доктор, Центр гематологических исследований, Имперский колледж, Лондон, Соединенное Королевство
Аксель Цандер, проф., почетный доктор, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия
Борис Фезе, проф., доктор, Гамбургский университет, Германия

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Российская гематология потеряла всеми уважаемого лидера – профессора Валерия Савченко, который скоропостижно скончался 25 июля 2021 г. Он был выдающимся врачом, ученым и исследователем, возглавлял Национальный медицинский исследовательский центр гематологии России, был главным внештатным гематологом министерства здравоохранения РФ, президентом Национального гематологического общества и академиком Российской академии наук. На протяжении многих лет он отвечал за развитие гематологии в СССР и, позже – в России.

Валерий Григорьевич Савченко родился 8 января 1952 года на Украине. После окончания в 1969 году второй московской физико-математической школы при МГУ, он поступил в 1-й Московский медицинский институт им. И. М. Сеченова, который с отличием закончил в 1975 г.

Его жизнь в медицине и науке была посвящена гематологии. В 1980 г. В. Г. Савченко окончил ординатуру и аспирантуру на кафедре гематологии и интенсивной терапии Центрального института усовершенствования врачей, защитив кандидатскую диссертацию на тему «Патогенез и лечение идиопатической тромбоцитопенической пурпуры», затем в течение 7 лет работал ассистентом кафедры. В 1988 г. В. Г. Савченко, со своим учителем, профессором А. И. Воробьевым перешел в гематологический научный центр Минздрава СССР, где был назначен заведующим отделением химиотерапии гемобластозов и трансплантации костного мозга. В 1993 г. защитил докторскую диссертацию по теме «Современная стратегия терапии острых лейкозов». Ученое звание профессора было присвоено ему в 1996 г. В 2011 г. В. Г. Савченко был назначен Генеральным директором ФГБУ «Гематологический научный центр» Минздрава России (ныне – ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России). В 2004 г. он был избран членом-корреспондентом академии медицинских наук, а в 2013 г. – академиком Российской академии наук.

Его пытливый ум, энциклопедические знания и аналитическое мышление позволили ему добиться превосходных результатов во многих областях современной гематологии. В. Г. Савченко мог четко сформулировать конкретные научные задачи и решать их, подсказать направление диагностического поиска и разработку алгоритмов лечения. Он разрабатывал программы терапии острых лейкозов и депрессий кроветворения, руководил проведением первых в России многоцентровых исследований в этой области и, наряду с профессором Б. В. Афанасьевым, был у истоков внедрения и совершенствования трансплантации костного мозга в СССР и России.

Профессор Савченко руководил многими исследованиями в области молекулярной генетики, биологии, физиологии кроветворения, цитогенетики и трансплантационной иммунологии. Под его руководством были разработаны национальные алгоритмы диагностики и лечения заболеваний системы крови. У него было множество учеников, некоторые из которых теперь являются лидерами российской гематологии. Под руководством В. Г. Савченко защищено 30 кандидатских и 14 докторских диссертаций. Он является соавтором 14 авторских свидетельств на изобретения. Уделяя большое внимание сохранению школы в подготовке врачей- гематологов, он постоянно занимался преподавательской деятельностью и участвовал в междисциплинарных консилиумах.

В. Г. Савченко являлся главным редактором журнала «Гематология и трансфузиология», входил в состав редколлегии журналов «Терапевтический архив», «Гематология. Трансфузиология. Восточная Европа», членом редакционного совета журналов «Cellular Therapy and Transplantation», «Биопрепараты. Профилактика, диагностика, лечение».

Профессор Савченко был членом Всемирного комитета Международной ассоциации сравнительного изучения лейкозов и родственных заболеваний (МАСИЛР), в которую он вошел в начале 1990-х гг. по приглашению профессора Рольфа Нета и представлял Россию во Всемирном комитете с 1997 по 2007 г. и далее – с 2015 г. В 2019 г. он был переизбран во Всемирный комитет по 2023 г. В 2021 г. он был приглашен в качестве президента 31-го симпозиума МАСИЛР в Москве (2023 г).

В. Г. Савченко развивал участие своего Центра гематологии в работе European LeukemiaNet (ELN), его организация стала одним из 6 первых российских участников ELN. В 2011 г. он прочел основную лекцию об остром миелоидном лейкозе на конгрессе ELN. Его группа продолжает вносить весомый вклад в кооперативные исследования по лейкозам, проводимые ELN.

Аналитический ум В. Г. Савченко, его мягкая речь и сдержанный юмор незабываемы. Мы выражаем соболезнования его жене и многолетнему соратнику – профессору Елене Паровичниковой, известному в мире гематологу, его сыну Павлу, дочери Софье, и внукам.

Есть люди, которых трудно заменить, Валерий Григорьевич Савченко был одним из них. Пословица гласит: Смерть – великан, против которого даже цари должны обратить оружие. Эта утрата огромна.

Александр Д. Кулагин, проф., директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой,
Санкт-Петербургский государственный медицинский университет
им. И. П. Павлова, Санкт-Петербург, Россия
Рюдигер Хельманн, проф., почетный доктор, Медицинский факультет Манхайм, Гейдельбергский университет, Германия
Роберт Питер Гэйл, проф., доктор, приглашенный профессор, почетный доктор, Центр гематологических исследований, Имперский колледж, Лондон, Соединенное Королевство
Аксель Цандер, проф., почетный доктор, Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия
Борис Фезе, проф., доктор, Гамбургский университет, Германия

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Introduction

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell (HSC) disorder characterised by ineffective hematopoiesis accompanied by blood cytopenia and by common progression to acute myeloid leukemia (AML). MDS is mostly observed in the elderly persons [1-4]. The main clinical features of MDS are as follows:

Clonal hematopoietic stem-cell disease(s);
Abnormal differentiation, maturation, impaired apoptosis;
• Genetic (Immune) basis;
• Median age: 74 years;
• Incidence increases with age;
• 40-50 per 100 000 in > 70 yr;
Anemia (90%); Pancytopenia (50%);
AML Transformation (20%-60%).

The cytomorphological examination in MDS is based on detection of bi- or tri-lineage dysplasia in different hematopoietic lineages in the bone marrow and/or peripheral blood, and enumeration of blast cells in the samples (Fig. 1A, B).

Mittelman-fig01.jpg

Figure 1. General pattern of bone marrow in healthy person (A) and MDS patient (B). BM of MDS patients is characterized by altered (hyper or hypo-) cellularity, numerical (hyper or hypo-) changes, morphological abnormalities in one or more hematological lineages, and potential increased % of blasts

Classification

MDS patients are classified by International Prognostic Scoring System (IPSS):

Prognostic Parameters:
– FAB subtype: BM morphology – % blasts;
Cytogenetics;
– "good" vs "bad" types;
# Lineages affected.

IPSS:
– Low-risk; Intermediate-1 – Lower risk disease;
– Intermediate-2; High – Higher risk disease.

IPSS-R:
Very low; Low; Intermediate; High; Very high [5, 6].

Evaluation of Treatment Response – Not Blac & White:Thus, standard response criteria were proposed:

• International Working Group (IWG) 2000/2006 [5, 6]:
– Complete response (CR);
– Marrow CR (mCR); (Partial R);
– Cytogenetic response (Cyt R);
– Hematologic improvement (HI);
    - Erythroid (HI-E); Neutrophil (HI-N); Platelet (HI-P).

IWG 2018: HI-E – Erythroid response [7]:
Transfusion burden:
    - Non (0/16 wk), Low (3-7); High > 8;
    - Response: minor (50% less) or major (TI).

MDS treatment

General Strategy of MDS Treatment depends on the disease status (IPSS/R), by discerning lower-risk cases (IPSS: Low risk; Intermediate-I), and higher-risk MDS (IPSS: Intermediate-II; High risk cases).

Patient factors should be taken into account:
• Age; co-morbidities; functional status;
• Quality of life (QoL); Pt reported outcomes (PRO).

MDS treatment is often consistent with a general ‘Rule of Thumb’:
• Response of about 50%;
• Response duration about 2 yr.

This is true for the following therapeutic approaches:
• RBC Transfusions;
• Erythroid stimulating agents (ESAs);
• Lenalidomide;
• Hypomethylating agents (HMA);
• Stem Cell Transplant (SCT).

The remaining challenges include: increasing response rate and duration of response and, finally, achieving cure of this disorder.

Mittelman-fig02.jpg

Figure 2. Hematology research team at the George-Washington University (I am sitting, second on the right)

My experience with MDS could be traced from the Hematology-Oncology Fellowship – GW-NIH (USA) 1986-1989 at George Washington University Medical Center – Department of Hematology-Oncology (Fig. 2).

Recently, the European MDS Registry (EUMDS) is a prospective multicentre European registry for myelodysplastic syndromes (MDS), being the first international prospective, observational registry for newly diagnosed IPSS low- and intermediate-1 risk MDS patients. 18 countries participate in EUMDS activities, i.e., Austria, Chech Republic, France, Germany, Greece, Italy, Netherlands, Romania, Spain, Sweden, UK, Denmark, Portugal, Poland, Israel, Serbia, Croatia, Switzerland.

Appropriate Guidelines were issued by EUMDS (2019) (see MDS-Europe in the net).

Managing lower risk MDS

80% of MDS patients have a hemoglobin <10 g/dl at diagnosis, the majority become transfusion-dependent. Therefore, MDS treatment for anemia still includes multiple RBC transfusions. Most of these patients received MDS-specific supportive care, including RBC transfusions in 50% of the cases [8].

RBC Transfusions in MDS (I)

RBC transfusions are the mostly used (50%) in low-risk MDS. For those patients who were transfusion-independent at diagnosis, the mean interval between diagnosis and the first transfusion was 249 days [9]. For symptomatic anemia, however, limited evidence was shown.

Complications of RBC transfusions in MDS patients include the following events:
• Volume-related; TRALI (Transfusion-Related Acute Lung Injury); ABO incompatibility;
• RBC allo-immunization in 30% of cases [10]. Having MDS is suggested to be an independent risk factor contributing to production of RBC alloantibodies.

Iron overload due to multiple RBC transfusions is among complication of supportive therapy in MDS [11-12]. E.g., the transfusion dose density is associated with shorter progression-free survival (PFS) and worse quality of life. It showed an inverse correlation with PFS (P<1×10-4): the dose density had an increasing effect until 3 units/16 weeks [13].

RBC Transfusions in MDS (II): ELN-EUMDS 2019 Guidelines

The questions arising:
• Hb threshold for starting the transfusions?
– < 7 g/dl (most centers will transfuse if and when Hb < 7g/dl);
– Individualize (Grade B, level 1).
• Hb target levels?
– No target (Grade C, level 2) – recommendation – activate local policy.
• Transfusion frequency?
– Individualize (C-2).
• Prophylactic RBC Ag matching ? No (C-2)
• Symptomatic benefit vs toxicity?
– Individualize (C-2).

For reference see [14]: Bowen D, Mittelman M, ELN-EUMDS Guidelines (2019; online).

Effects of erythrocyte-stimulating agents (ESA) in low-risk MDS anemia were summarized for 2020. ESA were applied as first-line therapy (without RBC transfusions) and proved to be effective in a series of studies, as shown by Hb rise, fewer RBC transfused, improved QoL, with documented safety for the patients [15-19]. Hematological response was observed in a sufficient group of MDS patients (Table 1).

Table 1. Initial results on recombinant human Epo (rHuEPO) in MDS. The responding patients are shown in bold [20].

Mittelman-tab01.jpg

Therapeutic efficiency and safety of different erythrocyte-stimulating agents (ESAs) in LR-MDS was proven over 3 decades. E,g, darbopoietin A was tested in phase 3 trial (n=147), with ORR of 59% [21]. A randomized study of Epoetin-α (phase 3 trial) enrolled 130 cases, with 46% overall response rate [22]. A meta-analysis of different ESA in LR-MDS has shown an ORR of 45-73%, and, possibly, longer overall survival of MDS patients, with 50% response [23]. Finally, a large study by EUMDS included a cohort of LR-MDS patients, at median duration of ESA therapy for 27.5 months, delayed RBC transfusions (by 6 to 23 months), lower risk of death; similar risk of progression to AML, along with safety of such treatment [24].

A team from Denmark found only marginal effects (RR 1.1-1.9) of ESA upon risk of venous thromboembolism (VTE) and strokes in a cohort of 2114 patients [25]. In general, the response rate to ESA in MDS was 50% at the 2-year terms, and proven safety.

Mittelman-fig03.jpg

Figure 3. Comparative IL-6 levels in blood serum of heathy persons, in MM patients, and in Epo-treated MM patients [31]

EPO non-erythroid (immunologic) effects

Therapeutic efficiency of rhEPO was documented in myeloma-associated anemia [26]. Moreover, probable anti-neoplastic effects of erythropoietin were shown in experimental murine myeloma [27, 28].

Other events associated with erythropoietin therapy in patients with hematological disorders include a decreased glucose level [29], probable bone loss by targeting monocytes and osteoclastic activity in murine model [30], as well as decrease in serum IL-6 upon the EPO therapy [31], as seen in Fig. 3. In myelodysplastic syndrome, improvement of T cell immune functions was an additional positive effect observed after erythropoietin treatment [32].

ESA treatment may fail in sufficient part of MDS patients. Clinical outcomes in LR-MDS in the non-responsive cohort were studied by Park et al. [33].

The study represented a retrospective analysis of LR-MDS patients without 5q chromosome deletion. Of them, 653 experienced primary failure and 494 experienced relapse after a response. Median OS among ESA non-responders was 4.2 years in relapsing patients versus 3.7 years in primary failure. Second-line treatment was performed in 39% of them. Hypomethylating agents (HMA) were used in 336 patients, with 46% response, and lenalidomide, in 88 patients with 39% response rates. However, the five-year OS for patients receiving HMA, lenalidomide, or other therapies was 36.5%, 41.7%, and 51%, respectively (P = .21). In a multivariable analysis, there was no significant OS difference among the three groups. Yes, we need to do better…

Lenalidomide therapy

Several studies demonstrated efficiency of Lenalidomide in LR-MDS, either with or without 5q deletion. List et al. [34] have shown that transfusion demands were reduced in 76% of the treated patients with 5q chromosome deletion, and some of them did not longer require transfusions, regardless of the karyotype complexity. The response to lenalidomide occurred at the median time of 4.6 weeks and retained for a median of 2 years. In the meta-analysis by Lian et al. [35], overall rate of hematological erythrocyte response was 58%. The patients with 5q deletion had significantly higher rate of response, significantly prolonged overall survival and lower risk of AML progression. The drug showed a predictable and manageable safety profile in LR-MDS in terms of adverse effects [36]. P53 mutations with higher TP53 protein expression in BM progenitors of lenalidomide-treated patients proved to be associated with higher AML risk and shorter OS [37-39].

Below are main results of the MDS-004 study in Del (5q) MDS patients [38]:
– RRBC TI 56%; Cytogenetic response was observed in 50% at 10mg of Len daily
– Adverse effects: cytopenia, rash, gastrointestinal, thrombosis
– No effect on leukemic transformation
• Results with non-del (5q) patients: MDS-005 [39]
– Among a group of 239 pts (lenalidomide or placebo), transfusion independence was achieved in 27% (vs 2.5% with placebo) at 8 weeks of Len therapy.

Other therapeutic targets

TGF-binding drugs
Hence, anemia remains a sufficient problem in some LR-MDS patients. What can we offer when ESA, or Lenalidomide treatment fail? Newer drugs, e.g., activin analogues, may potentially improve erythropoiesis, by TGF-b binding, or Smad2/3 inhibition. E.g., Luspatercept was tested in a PACE-MDS Trial (ACE-536) at the Phase II, (s/c injections, every 3 wk; 58 pts; post ESA), as reported by Platzbecker et al. [40]. The drug caused a significant dose-dependent increase in blood Hb contents, and, after 4-mo treatment at a dose of 0.75-1.75 mg/kg, reduced demands for RBC transfusions.

The MEDALIST study was a phase 3, randomized, double-blind, placebo-controlled trial with transfusion-dependent MDS. Luspatercept therapy led to RBC transfusion independence in lower-risk MDS patients resistant to ESA [41]. Of the 229 patients, 153 were randomly assigned to receive luspatercept or placebo, s/c every 3 weeks, for ≥ 24 weeks. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in Luspatercept group versus 13% in the placebo group (P<0.001).

Sotatercept (ACE-011), a drug with similar action, was recently subject to phase 2 study carried out by Komrokji et al. [42]. 74 patients enrolled were ineligible for, or refractory to ESA therapy. Clinical response was documented in 40-50% (better outcomes in those with lower transfusion burden). Adverse effects manifested as diarrhea, bone pain, fatigue, GI, edema, lipase increase.

A special COMMANDS Trial aimed to compare Luspatercept versus erythropoietin is launched now [43].

Low Dose/Oral hypomethylating agents (HMA) in LR-MDS
A prospective trial (Phase 2) was performed using Azacitidine versus best supportive care (BSC). The primary endpoint was erythroid hematologic improvement which was achieved in 44.4% of cases after 9 treatment rounds, versus 5.5% of patients treated with BSC, as well as transfusion independence in all the drug responders for a median of 1 year [44].

Low-dose decitabine versus low-dose azacitidine (Aza) were applied in the phase II study [45]. A total of 113 patients were treated: 35% with Aza and 65% with Dec. The ORRs were 70% and 49% for Dec and Aza, respectively. Transfusion independence was achieved in 32 % of decitabine-trea-ted patients, and the treatment was well tolerated.

A meta-analysis performed by Komrokji et al. (2018) [46] concerning efficiency of Aza in a total sample of 233 patients with, mostly, non-del(5q) LR-MDS has shown that the RBC transfusion independence was achieved in 39% of the cases, at ≥6 azacitidine treatment cycles.

Several years ago, a report on clinical effects of peroral Aza (cc-486) in LR-MDS was published [47]. The study included 216 MDS patients. The disease status was assessed after cycle 6. The ORR was 40%, including hematologic improvement in 28% of patients, and transfusion independence lasted for 56 days in 47% of initially transfusion-dependent cases.

Therefore, QUAZAR study (AZA-MDS-003) was continued as randomized controlled trial (RCT), Phase 3, in LR-MDS patients with anemia and thrombocytopenia [48]. The patients received CC-486 or placebo. 31% and 11% of patients, respectively, achieved RBC-TI in the main and placebo group, which lasted, for, respectively, 11.1 and 5.0 months. Platelet improvement rate was also higher in the CC-486 arm (24.3% vs 6.5%).

Roxadustat (FG-4592)
Usage of oral prolyl hydroxylase (PH) inhibitors may be a promising tool of anemia treatment, since the PH inhibition may stabilize hypoxia-inducible factor (HIF). This factor induces erythropoietin production and decreases hepcidin, thus promoting iron mobilization [49]. Recently, this drug was shown to be safe and efficient in the patients with anemia caused by chronic renal failure – CRF [50].

Roxadustat is another PH inhibitor(Fibrogen) undergoes a clinical FGCL-4592-082 trial which is an open label study including 24 pts, achieving 38% TI if used at a dose of 2.5 mg/kg, ×3/wk [51]. Now this drug is under phase 3, randomized controlled trial, with 156 patients.

Telomerase inhibitors
Clinical trials with Imetelstat, a telomerase inhibitor, were performed in the patients with LR-MDS anemia [52-54]. Phase 2 trial is an open, single arm study, with the drug dose of 7.5 mg/kg I/V q 4 wk. A subgroup of 38 LR-MDS patients were selected with transfusion dependence, ESA relapse/resistance, non-del(5q), being hypomethylating agent and lenalidomide naïve. Of them, 16 patients (42%) achieved transfusion independence. This effect was durable (a median of 21 mo) and accompanied by reduced telomerase activit. Phase 3 (a placebo-controlled study) is ongoing.

Treatment of thrombocytopenia in MDS

Platelet transfusions (PLT) are made in MDS patients. However, there is no evidence on their efficiency. This procedure is indicated in cases of active bleeding and should be performed per local guidelines [14, 55]. In absence of active bleeding, the platelet transfusion cannot be routinely recommended!. One may consider "thrombostatics", e.g., Tranexamic acid, or Anti-fibrinolytic solutions, (Hexakapron).

Romiplostim in MDS
For the last decade, several groups study safety and efficacy of romiplostim, a synthetic protein, an analogue of thrombopoietin which increases platelet production, for treatment of MDS patients with thrombocytopenia. The phase I/II study by Kantarjan et al. [56] in 44 patients have shown a durable platelet response in 46% cases. After achieving platelet response (4 weeks) the patients were treated with romiplostim for up to 1 year. Serious adverse effects were registered in 11% of the cases, and 2 patients progressed to AML.

The Phase II study was arranged as a randomized, placebo-controlled trial which included a total of 250 LR-MDS patients randomized 2:1, to receive romiplostim or placebo weekly for 58 weeks [57]. The incidence of bleeding events was reduced in the romiplostim group, and platelet response rates proved to be higher in the patients who received romiplostim. However, study drug was stopped because of excess blasts and potential AML risk following this treatment. Later on, upon 5-year of this cohort, the percentages of patients with AML (12%) in romiplostim group were similar (11%) to those in placebo group, as shown by Kantarjian et al. [58]. In a special commentary, I emphasized that these long-term results were indeed reassuring, however, one has to bear in mind that treatment had been discontinued [59]. Thus, the long-term data reflect the outcome of a long-term follow up, while the drug exposure was relatively short.

Eltrombopag in MDS
Eltrombopag is an agonist of thrombopoietin receptor which promotes growth and differentiation of megakaryocytes. Since 2014, it was approved by FDA for treatment of aplastic anemia, stimulating production of platelets, RBC and leukocytes. In LR-MDS patients with thrombocytopenia, it has shown efficiency of 47% in terms of platelet responses, versus 3% in the placebo group (Oliva et al., 2017) [60].

The ASPIRE study (Part I) was an open-label, double-blind study of patients with advanced MDS treated for 8 weeks with Eltrombopag, and randomised at later terms [61]. Four patients of 17 achieved increased platelet counts following treatment, and ten had reduced platelet transfusion requirements. Serious adverse events were reported in 58% of eltrombopag-treated, and in 68% placebo-treated patients. In ASPIRE II, fewer adverse events were registered.

Combined effects of Eltrombopag and Azacytidin (AZA) were addressed in the SUPPORT Study [62]. The intermediate-1, intermediate-2, or high-risk MDS patients with low platelet counts were randomized 1:1 to eltrombopag, or placebo, plus azacitidine. The development of this study was, however, stopped due to efficacy outcomes, and for safety problems.

The French MDS group (GFM) have recently presented their experience using long-term eltrombopag, with encouraging clinical efficacy. These promising data might assist in lifting the embargo on thrombomimetic agnets [63].

Immunosuppressive therapy

Despite broad arsenal of novel therapeutic agents for MDS therapy, there are many LR-MDS patients with anemia who are resistant or have lost their response to such drugs. Therefore, immunosuppressive treatment (IST) in these cases is well justified, on the basis of similarity between severe aplastic anemia and hypoplastic MDS. Some experience in this field exists with ATG and/or cyclosporine treatment [64]. Clinical response, however, is dependent on the MDS patient’s age, transfusion history, and karyotype pattern, with erythroid response rate of 25-40%.

A large study published by Stahl et al. reported results of IST results obtained for cohort from 15 centers in Europe and USA, including 207 pts with MDS receiving IST [65].

The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). The overall response rate ORR 48.8%, with 11% reaching complete remission, and transfusion independence (RBC-TI) in 30% of the cases. Median overall survival (OS) was 47.4 mo, being longer for the patients with transfusion independence. The RBC-TI was associated with a bone marrow hypocellularity (<20%). Age, HLA-DR15 positivity did not predict clinical response to IST.

Iron Overload

Iron deposition in the patients occurs due to intrinsic mechanisms of MDS, and as a result of multiple RBC transfusion, causing damage of liver and other organs.

Iron chelator therapy is effective in these cases. A retrospective study based on the European MDS Registry data was recently published by Hoeks et al. [66]. The results of chelator treatment in MDS were compared with non-chelated patients. The propensity-score analysis has revealed improved OS for chelated patients, with erythroid response in up to 39% of the treated cohort. A similar TELESTO study (the only prospective) included 225 patients with high serum ferritin levels after multiple RBC transfusions treated with Deferasirox [67]. Following continuous treatment (0.5 to 3 years), median EFS was prolonged by ca. 1 year (1440 d vs 1091 d) with deferasirox vs placebo, at 36% reduction of events.

Several eligibility criteria are proposed for initiating the chelator therapy [14, 68] (Mittelman et al., 2008, current Guidelines 2019; MDS-EUROPE online [14]: 1. Patients classified as low or Int1, according to the International Prognostic Scoring System; 2. Patients with serum ferritin levels >1000 μg/Ll and those who received a total of 20-25 RBC units; 3. Patients whose blood transfusion requirement has increased significantly; 4. Patients with sufficient organ damage.

Summary and future prospects

Current treatment of the low-risk MDS includes the following:
• ESA +/- RBC transfusions;
• Lenalidomide (del 5q);
• 2nd Line:
  – Luspatercept; Roxadustat; Imetelstat; HMA (?)
Future prospectives:
• Combinations: ESA + other hematopoiesis-stimulating drugs;
• Novel agents;
• Low platelet counts in MDS patients:
  – Therapeutic approaches are still challenging.

Conflict of interest

Disclosures: Research funding: Celgene; Johnson & Johnson; Roche; Novartis; Gilead. Speakers’ bureau: Celgene; Johnson & Johnson; Novartis. Advisory boards (non-paid): Pfizer; Amgen; Roche; Novartis.

References

  1. Mittelman M. The myelodysplastic syndromes--1990. Isr J Med Sci. 1990;26(8):468-478. PMID: 2205597
  2. Malcovati L, Hellström-Lindberg E, Bowen D, Adès L, Cermak J, Del Cañizo C, Della Porta MG, Fenaux P, Gattermann N, Germing U, et al.; European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. doi: 10.1182/blood-2013-03-492884
  3. Adès L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet. 2014; 383(9936):2239-2252. doi: 10.1016/S0140-6736(13)61901-7
  4. Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, Edwards BK, List AF. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008; 112(1):45-52. doi: 10.1182/blood-2008-01-134858
  5. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, et al. ; WHO International working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000; 96(12):3671-3674. PMID: 11090046
  6. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 108(2):419-425. doi: 10.1182/blood-2005-10-4149
  7. Platzbecker U, Fenaux P, Adès L, Giagounidis A, Santini V, van de Loosdrecht AA, Bowen D, de Witte T, Garcia-Manero G, Hellström-Lindberg E, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019; 133(10):1020-1030. doi: 10.1182/blood-2018-06-857102
  8. Schanz J, Tüchler H, Solé F, Mallo M, Luno E, Cervera J, Granada I, Hildebrandt B, Slovak M, Ohyashiki K, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an International Database Merge. J Clin Oncol. 2012; 30(8):820-829. doi: 10.1200/JCO.2011.35.6394
  9. de Swart L, Smith A, Johnston TW, , Haase В, Droste J, Fenaux P, Symeonidis A, Sanz G, Hellström-Lindberg E, Čermák J, et al. Validation of the revised International Prognostic Scoring System (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. Br J Hematol. 2015;170:372-383. doi: 10.1111/bjh.13450
  10. Rozovski U, Ben-Tal O, Kirgner I, Mittelman M, Hareuveni M. Increased incidence of red blood cell alloantibodies in myelodysplastic syndrome. Isr Med Assoc J. 2015; 17(10): 624-627. PMID: 26665317
  11. Steensma DP, Heptinstall KV, Johnson VM, Novotny PJ, Sloan JA, Camoriano JK, Niblack J, Bennett JM, Mesa RA. Common troublesome symptoms and their impact on quality of life in patients with myelodysplastic syndromes (MDS): results of a large internet-based survey. Leuk Res. 2008; 32(5):691-698. doi: 10.1016/j.leukres.2007.10.015
  12. Platzbecker U, Fenaux P, Adès L, Giagounidis A, Santini V, van de Loosdrecht AA, Bowen D, de Witte T, Garcia-Manero G, Hellström-Lindberg E, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019;133(10):1020-1030. doi: 10.1182/blood-2018-06-857102
  13. de Swart L, Crouch S, Hoeks M, Smith A, Langemeijer S, Fenaux P, Symeonidis A, Cermâk J, Hellström-Lindberg E, Stauder R, et al. Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes. Haematologica. 2020; 105:632-639. doi: 10.3324/haematol.2018.212217
  14. Bowen D, Mittelman M, et al. ELN-EUMDS Guidelines (2019). https://mds-europe.org/
  15. Mittelman M. Recombinant erythropoietin in myelodysplastic syndromes: whom to treat and how? More questions than answers. Acta Haematol. 1993;90(2):53-57. doi: 10.1159/000204376
  16. Mittelman M, Lessin LS. Clinical application of recombinant erythropoietin in myelodysplasia. Hematol Oncol Clin North Am. 1994; 8(5):993-1009. PMID: 7852220
  17. Hellström-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, Ost A, Greenberg P. Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol. 1997; 99(2):344-351. doi: 10.1046/j.1365-2141.1997.4013211.x
  18. Cazzola M, Beguin Y, Kloczko J, Spicka I, Coiffier B. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol. 2003;122(3):386-393. doi: 10.1046/j.1365-2141.2003
  19. Gafter-Gvili A, Rozen-Zvi B, Vidal L, Leibovici L, Vansteenkiste J, Gafter U, Shpilberg O. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia – systematic review and meta-analysis of randomised controlled trials. Acta Oncol. 2013; 52(1):18-29. doi: 10.3109/0284186X.2012.702921
  20. Mittelman M, Floru S, Djaldetti M. Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Blood. 1992; 80(3):841-843. PMID: 1638033
  21. Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, Slama B, Badre S, Gasal E, Mehta B, Franklin J. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017; 31(9):1944-1950. doi: 10.1038/leu.2017.192
  22. Fenaux P, Santini V, Spiriti MAA, Giagounidis A, Schlag R, Radinoff A, Gercheva-Kyuchukova L, Anagnostopoulos A, Oliva EN, Symeonidis A, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018; 32(12):2648-2658. doi: 10.1038/s41375-018-0118-9
  23. Park S, Greenberg P, Yucel A, Farmer C, O'Neill F, De Oliveira Brandao C, Fenaux P. Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review. Br J Haematol. 2019; 184(2):134-160. doi: 10.1111/bjh.15707
  24. Garelius HK, Johnston WT, Smith AG, Park S, de Swart L, Fenaux P, Symeonidis A, Sanz G, Čermák J, Stauder R, et al. Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome. J Intern Med. 2017; 281(3):284-299. doi: 10.1111/joim.12579
  25. Horváth-Puhó E, Suttorp MM, Frederiksen H, Hoekstra T, Dekkers OM, Pedersen L, Cannegieter SC, Dekker FW, Sørensen HT. Erythropoiesis-stimulating agents and cardiovascular events in patients with myelodysplastic syndrome and multiple myeloma. Clin Epidemiol. 2018; 10:1371-1380. doi: 10.2147/CLEP.S172306
  26. Mittelman M, Zeidman A, Fradin Z, Magazanik A, Lewinski UH, Cohen A. Recombinant human erythropoietin in the treatment of multiple myeloma-associated anemia. Acta Haematol. 1997; 98(4):204-10. doi: 10.1159/000203625
  27. Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N. Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci U S A. 2001; 98(9):5181-5186. doi: 10.1073/pnas.081275298
  28. Mittelman M, Zeidman A, Kanter P, Katz O, Oster H, Rund D, Neumann D. Erythropoietin has an anti-myeloma effect – a hypothesis based on a clinical observation supported by animal studies. Eur J Haematol. 2004; 72(3):155-165. doi: 10.1046/j.0902-4441.2003.00190.x
  29. Oster HS, Gvili Perelman M, Kolomansky A, Neumann D, Mittelman M. Erythropoietin treatment is associated with decreased blood glucose levels in hematologic patients. Acta Haematol. 2021; 144(3):252-258. doi: 10.1159/000507974
  30. Hiram-Bab S, Liron T, Deshet-Unger N, Mittelman M, Gassmann M, Rauner M, Franke K, Wielockx B, Neumann D, Gabet Y. Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB J. 2015; 29(5):1890-1900. doi: 10.1096/fj.14-259085
  31. Prutchi-Sagiv S, Golishevsky N, Oster HS, Katz O, Cohen A, Naparstek E, Neumann D, Mittelman M. Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions: could it be beneficial in early disease? Br J Haematol. 2006; 135(5):660-672. doi: 10.1111/j.1365-2141.2006.06366.x
  32. Deshet-Unger N, Oster HS, Prutchi-Sagiv S, Maaravi N, Golishevski N, Neumann D, Mittelman M. Erythropoietin administration is associated with improved T-cell properties in patients with myelodysplastic syndromes. Leuk Res. 2017; 52:20-27. doi: 10.1016/j.leukres.2016.11.002
  33. Park S, Hamel JF, Toma A, Kelaidi C, Thépot S, Campelo MD, Santini V, Sekeres MA, Balleari E, Kaivers J, et al. Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents. J Clin Oncol. 2017; 35(14):1591-1597. doi: 10.1200/JCO.2016.71.3271
  34. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006; 355(14):1456-1465. doi: 10.1056/NEJMoa061292
  35. Lian XY, Zhang ZH, Deng ZQ, He PF, Yao DM, Xu ZJ, Wen XM, Yang L, Lin J, Qian J. Efficacy and safety of lenalidomide for treatment of low-/intermediate-1-risk myelodysplastic syndromes with or without 5q deletion: a systematic review and meta-analysis. PLoS One. 2016; 11(11):e0165948. doi: 10.1371/journal.pone.0165948
  36. Almeida A, Fenaux P, Garcia-Manero G, Goldberg SL, Gröpper S, Jonasova A, Vey N, Castaneda C, Zhong J, Beach CL, Santini V. Safety profile of lenalidomide in patients with lower-risk myelodysplastic syndromes without del(5q): results of a phase 3 trial. Leuk Lymphoma. 2018; 59(9):2135-2143. doi: 10.1080/10428194.2017.1421758
  37. Saft L, Karimi M, Ghaderi M, Matolcsy A, Mufti GJ, Kulasekararaj A, Göhring G, Giagounidis A, Selleslag D, Muus P. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica. 2014; 99(6):1041-1049. doi: 10.3324/haematol.2013.098103
  38. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011; 118(14):3765-3776. doi: 10.1182/blood-2011-01-330126
  39. Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, Mufti GJ, Buckstein R, Mittelman M, Platzbecker U, et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016;34(25):2988-2996. doi: 10.1200/JCO.2015.66.0118
  40. Platzbecker U, Germing U, Götze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, Sherman ML, Attie KM, Giagounidis A. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017; 18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0
  41. Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019; 133(8):790-794. doi: 10.1182/blood-2018-11-876888
  42. Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018; 5(2):e63-e72. doi: 10.1016/S2352-3026(18)30002-4
  43. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, M Cazzola, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. New Engl J Med. 2020; 382:140-151. doi: 10.1056/NEJMoa1908892
  44. Sanchez-Garcia J, Falantes J, Medina Perez A, Hernandez-Mohedo F, Hermosin L, Torres-Sabariego A, Bailen A, Hernandez-Sanchez JM, Solé Rodriguez M, Casaño FJ, et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma. 2018;59(5):1095-1104. doi: 10.1080/10428194.2017.1366998
  45. Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017;130(13):1514-1522. doi: 10.1182/blood-2017-06-788497
  46. Komrokji R, Swern AS, Grinblatt D, Lyons RM, Tobiasson M, Silverman LR, Sayar H, Vij R, Fliss A, Tu N, Sugrue MM. Azacitidine in lower-risk myelodysplastic syndromes: A meta-analysis of data from prospective studies. Oncologist. 2018; 23(2):159-170. doi: 10.1634/theoncologist.2017-0215
  47. Garcia-Manero G, Almeida A, Giagounidis A, Platzbecker U, Garcia R, Voso MT, Larsen SR, Valcarcel D, Silverman LR, Skikne B, Santini V. Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia. BMC Hematol. 2016;16:12. doi: 10.1186/s12878-016-0049-5
  48. Garcia-Manero G, Santini V, Almeida A, Platzbecker U, Jonasova A, Silverman LR, Falantes J, Reda G, Buccisano F, Fenaux P et al. Phase III, Randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2021: JCO2002619. doi: 10.1200/JCO.20.02619
  49. Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR. Prolyl hydroxylase inhibitors: a breakthrough in the therapy of anemia associated with chronic diseases. J Med. Chem. 2018, 61 (16): 6964-6982. doi: 10.1021/acs.jmedchem.7b01686
  50. Del Vecchio L, Locatelli F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018; 27(1):125-133. doi: 10.1080/13543784.2018.1417386
  51. Henry DH; Glaspy J, Harrup RA, Mittelman M, Zhou A, Carraway HE, Bradley C, Saha G, Bartels P, Leong R, et al. Oral Roxadustat demonstrates efficacy in anemia secondary to lower-risk myelodysplastic syndrome irrespective of ring sideroblasts and baseline erythropoietin levels. Blood. 2020,136, 29-30. ASH Meeting Abstract #1277, Dec 5, 2020.
  52. Fenaux P et al. Imetelstat provides durable transfusion independence in heavily transfused non-del(5q) LR-MDS R/R to ESAS. EHA 2019.
  53. Platzbecker U, Fenaux P, Steensma DP, Van Eygen K, Raza A, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, et al. Treatment with Imetelstat provides durable transfusion independence (TI) in heavily transfused non-del(5q) lower risk MDS (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). 2019. EHA Library. Platzbecker U. 06/12/20; 295003; S183.
  54. Steensma DP, Fenaux P, Van Eygen K, Raza A, Santini V, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a Phase II Study. J Clin Oncol. 2021; 39(1):48-56. doi: 10.1200/JCO.20.01895
  55. Malouf R, Ashraf A, Hadjinicolaou AV, Doree C, Hopewell S, Estcourt LJ. In people with bone marrow disorders, a comparison of giving platelet transfusions only when bleeding occurs to also giving them to prevent bleeding. Cochrane Database Syst Rev 2018 May 14; issue 5, art. CD012342.
  56. Kantarjian H, Fenaux P, Sekeres MA, Becker PS, Boruchov A, Bowen D, Hellstrom-Lindberg E, Larson RA, Lyons RM, Muus P, Shammo J, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010; 28(3):437-444. doi: 10.1200/JCO.2009.24.7999
  57. Giagounidis A, Mufti GJ, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Hu K, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014; 120(12): 1838-1846. doi: 10.1002/cncr.28663
  58. Kantarjian HM, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Carpenter N, Mehta B, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. Lancet Haematol. 2018; 5(3):e117-e126. doi: 10.1016/S2352-3026(18)30016-4
  59. Mittelman M. Good news for patients with myelodysplastic syndromes and thrombocytopenia. Lancet Haematol. 2018 Mar;5(3):e100-101. doi: 10.1016/S2352-3026(18)30017-6
  60. Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4(3):e127-e136. doi: 10.1016/S2352-3026(17)30012-1
  61. Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong R, Anagnostopoulos A, Brenner B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): A randomised, placebo-controlled, phase 2 trial. Lancet Haematology. 2018; 5(1); e34-e43. abstr 3822. doi: 10.1016/S2352-3026(17)30228-4
  62. Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U, et al. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018;132(25):2629-2638. doi: 10.1182/blood-2018-06-855221
  63. Mittelman M, Oster HS. Thrombocytopenia in myelodysplastic syndromes: time to lift the embargo on thrombomimetics? Br J Haematol 2021;194(2):231-233. doi: 10.1111/bjh.17538
  64. Mittelman M, Oster HS. Immunosuppressive therapy in myelodysplastic syndromes is still alive. Acta Haematol2015; 134:135-137. doi: 10.1159/000371833
  65. Stahl M, DeVeaux M, de Witte T, Neukirchen J, Sekeres MA, Brunner AM, Roboz GJ, Steensma DP, Bhatt VR, Platzbecker U, et al. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv. 2018; 2(14):1765-1772. doi: 10.1182/bloodadvances.2018019414
  66. Hoeks M, Yu G, Langemeijer S, Crouch S, de Swart L, Fenaux P, Symeonidis A, Čermák J, Hellström-Lindberg E, Sanz G, et al. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica. 2020;105(3): 640-651. doi: 10.3324/haematol.2018.212332
  67. Angelucci E, Li J, Greenberg P, Wu D, Hou M, Montano Figueroa EH, Rodriguez MG, Dong X, Ghosh J, Izquierdo M, Garcia-Manero G; TELESTO study investigators. iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes: A randomized trial. Ann Intern Med. 2020;172(8):513-522. doi: 10.7326/M19-0916
  68. Mittelman M, Lugassy G, Merkel D, Tamary H, Sarid N, Rachmilewitz E, Hershko C; MDS Israel Group; Israel Society of Hematology. Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines. Isr Med Assoc J. 2008;10: 374–376. PMID:18605364
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Introduction

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell (HSC) disorder characterised by ineffective hematopoiesis accompanied by blood cytopenia and by common progression to acute myeloid leukemia (AML). MDS is mostly observed in the elderly persons [1-4]. The main clinical features of MDS are as follows:

Clonal hematopoietic stem-cell disease(s);
Abnormal differentiation, maturation, impaired apoptosis;
• Genetic (Immune) basis;
• Median age: 74 years;
• Incidence increases with age;
• 40-50 per 100 000 in > 70 yr;
Anemia (90%); Pancytopenia (50%);
AML Transformation (20%-60%).

The cytomorphological examination in MDS is based on detection of bi- or tri-lineage dysplasia in different hematopoietic lineages in the bone marrow and/or peripheral blood, and enumeration of blast cells in the samples (Fig. 1A, B).

Mittelman-fig01.jpg

Figure 1. General pattern of bone marrow in healthy person (A) and MDS patient (B). BM of MDS patients is characterized by altered (hyper or hypo-) cellularity, numerical (hyper or hypo-) changes, morphological abnormalities in one or more hematological lineages, and potential increased % of blasts

Classification

MDS patients are classified by International Prognostic Scoring System (IPSS):

Prognostic Parameters:
– FAB subtype: BM morphology – % blasts;
Cytogenetics;
– "good" vs "bad" types;
# Lineages affected.

IPSS:
– Low-risk; Intermediate-1 – Lower risk disease;
– Intermediate-2; High – Higher risk disease.

IPSS-R:
Very low; Low; Intermediate; High; Very high [5, 6].

Evaluation of Treatment Response – Not Blac & White:Thus, standard response criteria were proposed:

• International Working Group (IWG) 2000/2006 [5, 6]:
– Complete response (CR);
– Marrow CR (mCR); (Partial R);
– Cytogenetic response (Cyt R);
– Hematologic improvement (HI);
    - Erythroid (HI-E); Neutrophil (HI-N); Platelet (HI-P).

IWG 2018: HI-E – Erythroid response [7]:
Transfusion burden:
    - Non (0/16 wk), Low (3-7); High > 8;
    - Response: minor (50% less) or major (TI).

MDS treatment

General Strategy of MDS Treatment depends on the disease status (IPSS/R), by discerning lower-risk cases (IPSS: Low risk; Intermediate-I), and higher-risk MDS (IPSS: Intermediate-II; High risk cases).

Patient factors should be taken into account:
• Age; co-morbidities; functional status;
• Quality of life (QoL); Pt reported outcomes (PRO).

MDS treatment is often consistent with a general ‘Rule of Thumb’:
• Response of about 50%;
• Response duration about 2 yr.

This is true for the following therapeutic approaches:
• RBC Transfusions;
• Erythroid stimulating agents (ESAs);
• Lenalidomide;
• Hypomethylating agents (HMA);
• Stem Cell Transplant (SCT).

The remaining challenges include: increasing response rate and duration of response and, finally, achieving cure of this disorder.

Mittelman-fig02.jpg

Figure 2. Hematology research team at the George-Washington University (I am sitting, second on the right)

My experience with MDS could be traced from the Hematology-Oncology Fellowship – GW-NIH (USA) 1986-1989 at George Washington University Medical Center – Department of Hematology-Oncology (Fig. 2).

Recently, the European MDS Registry (EUMDS) is a prospective multicentre European registry for myelodysplastic syndromes (MDS), being the first international prospective, observational registry for newly diagnosed IPSS low- and intermediate-1 risk MDS patients. 18 countries participate in EUMDS activities, i.e., Austria, Chech Republic, France, Germany, Greece, Italy, Netherlands, Romania, Spain, Sweden, UK, Denmark, Portugal, Poland, Israel, Serbia, Croatia, Switzerland.

Appropriate Guidelines were issued by EUMDS (2019) (see MDS-Europe in the net).

Managing lower risk MDS

80% of MDS patients have a hemoglobin <10 g/dl at diagnosis, the majority become transfusion-dependent. Therefore, MDS treatment for anemia still includes multiple RBC transfusions. Most of these patients received MDS-specific supportive care, including RBC transfusions in 50% of the cases [8].

RBC Transfusions in MDS (I)

RBC transfusions are the mostly used (50%) in low-risk MDS. For those patients who were transfusion-independent at diagnosis, the mean interval between diagnosis and the first transfusion was 249 days [9]. For symptomatic anemia, however, limited evidence was shown.

Complications of RBC transfusions in MDS patients include the following events:
• Volume-related; TRALI (Transfusion-Related Acute Lung Injury); ABO incompatibility;
• RBC allo-immunization in 30% of cases [10]. Having MDS is suggested to be an independent risk factor contributing to production of RBC alloantibodies.

Iron overload due to multiple RBC transfusions is among complication of supportive therapy in MDS [11-12]. E.g., the transfusion dose density is associated with shorter progression-free survival (PFS) and worse quality of life. It showed an inverse correlation with PFS (P<1×10-4): the dose density had an increasing effect until 3 units/16 weeks [13].

RBC Transfusions in MDS (II): ELN-EUMDS 2019 Guidelines

The questions arising:
• Hb threshold for starting the transfusions?
– < 7 g/dl (most centers will transfuse if and when Hb < 7g/dl);
– Individualize (Grade B, level 1).
• Hb target levels?
– No target (Grade C, level 2) – recommendation – activate local policy.
• Transfusion frequency?
– Individualize (C-2).
• Prophylactic RBC Ag matching ? No (C-2)
• Symptomatic benefit vs toxicity?
– Individualize (C-2).

For reference see [14]: Bowen D, Mittelman M, ELN-EUMDS Guidelines (2019; online).

Effects of erythrocyte-stimulating agents (ESA) in low-risk MDS anemia were summarized for 2020. ESA were applied as first-line therapy (without RBC transfusions) and proved to be effective in a series of studies, as shown by Hb rise, fewer RBC transfused, improved QoL, with documented safety for the patients [15-19]. Hematological response was observed in a sufficient group of MDS patients (Table 1).

Table 1. Initial results on recombinant human Epo (rHuEPO) in MDS. The responding patients are shown in bold [20].

Mittelman-tab01.jpg

Therapeutic efficiency and safety of different erythrocyte-stimulating agents (ESAs) in LR-MDS was proven over 3 decades. E,g, darbopoietin A was tested in phase 3 trial (n=147), with ORR of 59% [21]. A randomized study of Epoetin-α (phase 3 trial) enrolled 130 cases, with 46% overall response rate [22]. A meta-analysis of different ESA in LR-MDS has shown an ORR of 45-73%, and, possibly, longer overall survival of MDS patients, with 50% response [23]. Finally, a large study by EUMDS included a cohort of LR-MDS patients, at median duration of ESA therapy for 27.5 months, delayed RBC transfusions (by 6 to 23 months), lower risk of death; similar risk of progression to AML, along with safety of such treatment [24].

A team from Denmark found only marginal effects (RR 1.1-1.9) of ESA upon risk of venous thromboembolism (VTE) and strokes in a cohort of 2114 patients [25]. In general, the response rate to ESA in MDS was 50% at the 2-year terms, and proven safety.

Mittelman-fig03.jpg

Figure 3. Comparative IL-6 levels in blood serum of heathy persons, in MM patients, and in Epo-treated MM patients [31]

EPO non-erythroid (immunologic) effects

Therapeutic efficiency of rhEPO was documented in myeloma-associated anemia [26]. Moreover, probable anti-neoplastic effects of erythropoietin were shown in experimental murine myeloma [27, 28].

Other events associated with erythropoietin therapy in patients with hematological disorders include a decreased glucose level [29], probable bone loss by targeting monocytes and osteoclastic activity in murine model [30], as well as decrease in serum IL-6 upon the EPO therapy [31], as seen in Fig. 3. In myelodysplastic syndrome, improvement of T cell immune functions was an additional positive effect observed after erythropoietin treatment [32].

ESA treatment may fail in sufficient part of MDS patients. Clinical outcomes in LR-MDS in the non-responsive cohort were studied by Park et al. [33].

The study represented a retrospective analysis of LR-MDS patients without 5q chromosome deletion. Of them, 653 experienced primary failure and 494 experienced relapse after a response. Median OS among ESA non-responders was 4.2 years in relapsing patients versus 3.7 years in primary failure. Second-line treatment was performed in 39% of them. Hypomethylating agents (HMA) were used in 336 patients, with 46% response, and lenalidomide, in 88 patients with 39% response rates. However, the five-year OS for patients receiving HMA, lenalidomide, or other therapies was 36.5%, 41.7%, and 51%, respectively (P = .21). In a multivariable analysis, there was no significant OS difference among the three groups. Yes, we need to do better…

Lenalidomide therapy

Several studies demonstrated efficiency of Lenalidomide in LR-MDS, either with or without 5q deletion. List et al. [34] have shown that transfusion demands were reduced in 76% of the treated patients with 5q chromosome deletion, and some of them did not longer require transfusions, regardless of the karyotype complexity. The response to lenalidomide occurred at the median time of 4.6 weeks and retained for a median of 2 years. In the meta-analysis by Lian et al. [35], overall rate of hematological erythrocyte response was 58%. The patients with 5q deletion had significantly higher rate of response, significantly prolonged overall survival and lower risk of AML progression. The drug showed a predictable and manageable safety profile in LR-MDS in terms of adverse effects [36]. P53 mutations with higher TP53 protein expression in BM progenitors of lenalidomide-treated patients proved to be associated with higher AML risk and shorter OS [37-39].

Below are main results of the MDS-004 study in Del (5q) MDS patients [38]:
– RRBC TI 56%; Cytogenetic response was observed in 50% at 10mg of Len daily
– Adverse effects: cytopenia, rash, gastrointestinal, thrombosis
– No effect on leukemic transformation
• Results with non-del (5q) patients: MDS-005 [39]
– Among a group of 239 pts (lenalidomide or placebo), transfusion independence was achieved in 27% (vs 2.5% with placebo) at 8 weeks of Len therapy.

Other therapeutic targets

TGF-binding drugs
Hence, anemia remains a sufficient problem in some LR-MDS patients. What can we offer when ESA, or Lenalidomide treatment fail? Newer drugs, e.g., activin analogues, may potentially improve erythropoiesis, by TGF-b binding, or Smad2/3 inhibition. E.g., Luspatercept was tested in a PACE-MDS Trial (ACE-536) at the Phase II, (s/c injections, every 3 wk; 58 pts; post ESA), as reported by Platzbecker et al. [40]. The drug caused a significant dose-dependent increase in blood Hb contents, and, after 4-mo treatment at a dose of 0.75-1.75 mg/kg, reduced demands for RBC transfusions.

The MEDALIST study was a phase 3, randomized, double-blind, placebo-controlled trial with transfusion-dependent MDS. Luspatercept therapy led to RBC transfusion independence in lower-risk MDS patients resistant to ESA [41]. Of the 229 patients, 153 were randomly assigned to receive luspatercept or placebo, s/c every 3 weeks, for ≥ 24 weeks. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in Luspatercept group versus 13% in the placebo group (P<0.001).

Sotatercept (ACE-011), a drug with similar action, was recently subject to phase 2 study carried out by Komrokji et al. [42]. 74 patients enrolled were ineligible for, or refractory to ESA therapy. Clinical response was documented in 40-50% (better outcomes in those with lower transfusion burden). Adverse effects manifested as diarrhea, bone pain, fatigue, GI, edema, lipase increase.

A special COMMANDS Trial aimed to compare Luspatercept versus erythropoietin is launched now [43].

Low Dose/Oral hypomethylating agents (HMA) in LR-MDS
A prospective trial (Phase 2) was performed using Azacitidine versus best supportive care (BSC). The primary endpoint was erythroid hematologic improvement which was achieved in 44.4% of cases after 9 treatment rounds, versus 5.5% of patients treated with BSC, as well as transfusion independence in all the drug responders for a median of 1 year [44].

Low-dose decitabine versus low-dose azacitidine (Aza) were applied in the phase II study [45]. A total of 113 patients were treated: 35% with Aza and 65% with Dec. The ORRs were 70% and 49% for Dec and Aza, respectively. Transfusion independence was achieved in 32 % of decitabine-trea-ted patients, and the treatment was well tolerated.

A meta-analysis performed by Komrokji et al. (2018) [46] concerning efficiency of Aza in a total sample of 233 patients with, mostly, non-del(5q) LR-MDS has shown that the RBC transfusion independence was achieved in 39% of the cases, at ≥6 azacitidine treatment cycles.

Several years ago, a report on clinical effects of peroral Aza (cc-486) in LR-MDS was published [47]. The study included 216 MDS patients. The disease status was assessed after cycle 6. The ORR was 40%, including hematologic improvement in 28% of patients, and transfusion independence lasted for 56 days in 47% of initially transfusion-dependent cases.

Therefore, QUAZAR study (AZA-MDS-003) was continued as randomized controlled trial (RCT), Phase 3, in LR-MDS patients with anemia and thrombocytopenia [48]. The patients received CC-486 or placebo. 31% and 11% of patients, respectively, achieved RBC-TI in the main and placebo group, which lasted, for, respectively, 11.1 and 5.0 months. Platelet improvement rate was also higher in the CC-486 arm (24.3% vs 6.5%).

Roxadustat (FG-4592)
Usage of oral prolyl hydroxylase (PH) inhibitors may be a promising tool of anemia treatment, since the PH inhibition may stabilize hypoxia-inducible factor (HIF). This factor induces erythropoietin production and decreases hepcidin, thus promoting iron mobilization [49]. Recently, this drug was shown to be safe and efficient in the patients with anemia caused by chronic renal failure – CRF [50].

Roxadustat is another PH inhibitor(Fibrogen) undergoes a clinical FGCL-4592-082 trial which is an open label study including 24 pts, achieving 38% TI if used at a dose of 2.5 mg/kg, ×3/wk [51]. Now this drug is under phase 3, randomized controlled trial, with 156 patients.

Telomerase inhibitors
Clinical trials with Imetelstat, a telomerase inhibitor, were performed in the patients with LR-MDS anemia [52-54]. Phase 2 trial is an open, single arm study, with the drug dose of 7.5 mg/kg I/V q 4 wk. A subgroup of 38 LR-MDS patients were selected with transfusion dependence, ESA relapse/resistance, non-del(5q), being hypomethylating agent and lenalidomide naïve. Of them, 16 patients (42%) achieved transfusion independence. This effect was durable (a median of 21 mo) and accompanied by reduced telomerase activit. Phase 3 (a placebo-controlled study) is ongoing.

Treatment of thrombocytopenia in MDS

Platelet transfusions (PLT) are made in MDS patients. However, there is no evidence on their efficiency. This procedure is indicated in cases of active bleeding and should be performed per local guidelines [14, 55]. In absence of active bleeding, the platelet transfusion cannot be routinely recommended!. One may consider "thrombostatics", e.g., Tranexamic acid, or Anti-fibrinolytic solutions, (Hexakapron).

Romiplostim in MDS
For the last decade, several groups study safety and efficacy of romiplostim, a synthetic protein, an analogue of thrombopoietin which increases platelet production, for treatment of MDS patients with thrombocytopenia. The phase I/II study by Kantarjan et al. [56] in 44 patients have shown a durable platelet response in 46% cases. After achieving platelet response (4 weeks) the patients were treated with romiplostim for up to 1 year. Serious adverse effects were registered in 11% of the cases, and 2 patients progressed to AML.

The Phase II study was arranged as a randomized, placebo-controlled trial which included a total of 250 LR-MDS patients randomized 2:1, to receive romiplostim or placebo weekly for 58 weeks [57]. The incidence of bleeding events was reduced in the romiplostim group, and platelet response rates proved to be higher in the patients who received romiplostim. However, study drug was stopped because of excess blasts and potential AML risk following this treatment. Later on, upon 5-year of this cohort, the percentages of patients with AML (12%) in romiplostim group were similar (11%) to those in placebo group, as shown by Kantarjian et al. [58]. In a special commentary, I emphasized that these long-term results were indeed reassuring, however, one has to bear in mind that treatment had been discontinued [59]. Thus, the long-term data reflect the outcome of a long-term follow up, while the drug exposure was relatively short.

Eltrombopag in MDS
Eltrombopag is an agonist of thrombopoietin receptor which promotes growth and differentiation of megakaryocytes. Since 2014, it was approved by FDA for treatment of aplastic anemia, stimulating production of platelets, RBC and leukocytes. In LR-MDS patients with thrombocytopenia, it has shown efficiency of 47% in terms of platelet responses, versus 3% in the placebo group (Oliva et al., 2017) [60].

The ASPIRE study (Part I) was an open-label, double-blind study of patients with advanced MDS treated for 8 weeks with Eltrombopag, and randomised at later terms [61]. Four patients of 17 achieved increased platelet counts following treatment, and ten had reduced platelet transfusion requirements. Serious adverse events were reported in 58% of eltrombopag-treated, and in 68% placebo-treated patients. In ASPIRE II, fewer adverse events were registered.

Combined effects of Eltrombopag and Azacytidin (AZA) were addressed in the SUPPORT Study [62]. The intermediate-1, intermediate-2, or high-risk MDS patients with low platelet counts were randomized 1:1 to eltrombopag, or placebo, plus azacitidine. The development of this study was, however, stopped due to efficacy outcomes, and for safety problems.

The French MDS group (GFM) have recently presented their experience using long-term eltrombopag, with encouraging clinical efficacy. These promising data might assist in lifting the embargo on thrombomimetic agnets [63].

Immunosuppressive therapy

Despite broad arsenal of novel therapeutic agents for MDS therapy, there are many LR-MDS patients with anemia who are resistant or have lost their response to such drugs. Therefore, immunosuppressive treatment (IST) in these cases is well justified, on the basis of similarity between severe aplastic anemia and hypoplastic MDS. Some experience in this field exists with ATG and/or cyclosporine treatment [64]. Clinical response, however, is dependent on the MDS patient’s age, transfusion history, and karyotype pattern, with erythroid response rate of 25-40%.

A large study published by Stahl et al. reported results of IST results obtained for cohort from 15 centers in Europe and USA, including 207 pts with MDS receiving IST [65].

The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). The overall response rate ORR 48.8%, with 11% reaching complete remission, and transfusion independence (RBC-TI) in 30% of the cases. Median overall survival (OS) was 47.4 mo, being longer for the patients with transfusion independence. The RBC-TI was associated with a bone marrow hypocellularity (<20%). Age, HLA-DR15 positivity did not predict clinical response to IST.

Iron Overload

Iron deposition in the patients occurs due to intrinsic mechanisms of MDS, and as a result of multiple RBC transfusion, causing damage of liver and other organs.

Iron chelator therapy is effective in these cases. A retrospective study based on the European MDS Registry data was recently published by Hoeks et al. [66]. The results of chelator treatment in MDS were compared with non-chelated patients. The propensity-score analysis has revealed improved OS for chelated patients, with erythroid response in up to 39% of the treated cohort. A similar TELESTO study (the only prospective) included 225 patients with high serum ferritin levels after multiple RBC transfusions treated with Deferasirox [67]. Following continuous treatment (0.5 to 3 years), median EFS was prolonged by ca. 1 year (1440 d vs 1091 d) with deferasirox vs placebo, at 36% reduction of events.

Several eligibility criteria are proposed for initiating the chelator therapy [14, 68] (Mittelman et al., 2008, current Guidelines 2019; MDS-EUROPE online [14]: 1. Patients classified as low or Int1, according to the International Prognostic Scoring System; 2. Patients with serum ferritin levels >1000 μg/Ll and those who received a total of 20-25 RBC units; 3. Patients whose blood transfusion requirement has increased significantly; 4. Patients with sufficient organ damage.

Summary and future prospects

Current treatment of the low-risk MDS includes the following:
• ESA +/- RBC transfusions;
• Lenalidomide (del 5q);
• 2nd Line:
  – Luspatercept; Roxadustat; Imetelstat; HMA (?)
Future prospectives:
• Combinations: ESA + other hematopoiesis-stimulating drugs;
• Novel agents;
• Low platelet counts in MDS patients:
  – Therapeutic approaches are still challenging.

Conflict of interest

Disclosures: Research funding: Celgene; Johnson & Johnson; Roche; Novartis; Gilead. Speakers’ bureau: Celgene; Johnson & Johnson; Novartis. Advisory boards (non-paid): Pfizer; Amgen; Roche; Novartis.

References

  1. Mittelman M. The myelodysplastic syndromes--1990. Isr J Med Sci. 1990;26(8):468-478. PMID: 2205597
  2. Malcovati L, Hellström-Lindberg E, Bowen D, Adès L, Cermak J, Del Cañizo C, Della Porta MG, Fenaux P, Gattermann N, Germing U, et al.; European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964. doi: 10.1182/blood-2013-03-492884
  3. Adès L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet. 2014; 383(9936):2239-2252. doi: 10.1016/S0140-6736(13)61901-7
  4. Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, Edwards BK, List AF. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008; 112(1):45-52. doi: 10.1182/blood-2008-01-134858
  5. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg B, Beran M, de Witte TM, Stone RM, et al. ; WHO International working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000; 96(12):3671-3674. PMID: 11090046
  6. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 108(2):419-425. doi: 10.1182/blood-2005-10-4149
  7. Platzbecker U, Fenaux P, Adès L, Giagounidis A, Santini V, van de Loosdrecht AA, Bowen D, de Witte T, Garcia-Manero G, Hellström-Lindberg E, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019; 133(10):1020-1030. doi: 10.1182/blood-2018-06-857102
  8. Schanz J, Tüchler H, Solé F, Mallo M, Luno E, Cervera J, Granada I, Hildebrandt B, Slovak M, Ohyashiki K, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an International Database Merge. J Clin Oncol. 2012; 30(8):820-829. doi: 10.1200/JCO.2011.35.6394
  9. de Swart L, Smith A, Johnston TW, , Haase В, Droste J, Fenaux P, Symeonidis A, Sanz G, Hellström-Lindberg E, Čermák J, et al. Validation of the revised International Prognostic Scoring System (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. Br J Hematol. 2015;170:372-383. doi: 10.1111/bjh.13450
  10. Rozovski U, Ben-Tal O, Kirgner I, Mittelman M, Hareuveni M. Increased incidence of red blood cell alloantibodies in myelodysplastic syndrome. Isr Med Assoc J. 2015; 17(10): 624-627. PMID: 26665317
  11. Steensma DP, Heptinstall KV, Johnson VM, Novotny PJ, Sloan JA, Camoriano JK, Niblack J, Bennett JM, Mesa RA. Common troublesome symptoms and their impact on quality of life in patients with myelodysplastic syndromes (MDS): results of a large internet-based survey. Leuk Res. 2008; 32(5):691-698. doi: 10.1016/j.leukres.2007.10.015
  12. Platzbecker U, Fenaux P, Adès L, Giagounidis A, Santini V, van de Loosdrecht AA, Bowen D, de Witte T, Garcia-Manero G, Hellström-Lindberg E, et al. Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials. Blood. 2019;133(10):1020-1030. doi: 10.1182/blood-2018-06-857102
  13. de Swart L, Crouch S, Hoeks M, Smith A, Langemeijer S, Fenaux P, Symeonidis A, Cermâk J, Hellström-Lindberg E, Stauder R, et al. Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes. Haematologica. 2020; 105:632-639. doi: 10.3324/haematol.2018.212217
  14. Bowen D, Mittelman M, et al. ELN-EUMDS Guidelines (2019). https://mds-europe.org/
  15. Mittelman M. Recombinant erythropoietin in myelodysplastic syndromes: whom to treat and how? More questions than answers. Acta Haematol. 1993;90(2):53-57. doi: 10.1159/000204376
  16. Mittelman M, Lessin LS. Clinical application of recombinant erythropoietin in myelodysplasia. Hematol Oncol Clin North Am. 1994; 8(5):993-1009. PMID: 7852220
  17. Hellström-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, Ost A, Greenberg P. Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol. 1997; 99(2):344-351. doi: 10.1046/j.1365-2141.1997.4013211.x
  18. Cazzola M, Beguin Y, Kloczko J, Spicka I, Coiffier B. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol. 2003;122(3):386-393. doi: 10.1046/j.1365-2141.2003
  19. Gafter-Gvili A, Rozen-Zvi B, Vidal L, Leibovici L, Vansteenkiste J, Gafter U, Shpilberg O. Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia – systematic review and meta-analysis of randomised controlled trials. Acta Oncol. 2013; 52(1):18-29. doi: 10.3109/0284186X.2012.702921
  20. Mittelman M, Floru S, Djaldetti M. Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Blood. 1992; 80(3):841-843. PMID: 1638033
  21. Platzbecker U, Symeonidis A, Oliva EN, Goede JS, Delforge M, Mayer J, Slama B, Badre S, Gasal E, Mehta B, Franklin J. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017; 31(9):1944-1950. doi: 10.1038/leu.2017.192
  22. Fenaux P, Santini V, Spiriti MAA, Giagounidis A, Schlag R, Radinoff A, Gercheva-Kyuchukova L, Anagnostopoulos A, Oliva EN, Symeonidis A, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018; 32(12):2648-2658. doi: 10.1038/s41375-018-0118-9
  23. Park S, Greenberg P, Yucel A, Farmer C, O'Neill F, De Oliveira Brandao C, Fenaux P. Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review. Br J Haematol. 2019; 184(2):134-160. doi: 10.1111/bjh.15707
  24. Garelius HK, Johnston WT, Smith AG, Park S, de Swart L, Fenaux P, Symeonidis A, Sanz G, Čermák J, Stauder R, et al. Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in nontransfused patients with lower-risk myelodysplastic syndrome. J Intern Med. 2017; 281(3):284-299. doi: 10.1111/joim.12579
  25. Horváth-Puhó E, Suttorp MM, Frederiksen H, Hoekstra T, Dekkers OM, Pedersen L, Cannegieter SC, Dekker FW, Sørensen HT. Erythropoiesis-stimulating agents and cardiovascular events in patients with myelodysplastic syndrome and multiple myeloma. Clin Epidemiol. 2018; 10:1371-1380. doi: 10.2147/CLEP.S172306
  26. Mittelman M, Zeidman A, Fradin Z, Magazanik A, Lewinski UH, Cohen A. Recombinant human erythropoietin in the treatment of multiple myeloma-associated anemia. Acta Haematol. 1997; 98(4):204-10. doi: 10.1159/000203625
  27. Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N. Erythropoietin induces tumor regression and antitumor immune responses in murine myeloma models. Proc Natl Acad Sci U S A. 2001; 98(9):5181-5186. doi: 10.1073/pnas.081275298
  28. Mittelman M, Zeidman A, Kanter P, Katz O, Oster H, Rund D, Neumann D. Erythropoietin has an anti-myeloma effect – a hypothesis based on a clinical observation supported by animal studies. Eur J Haematol. 2004; 72(3):155-165. doi: 10.1046/j.0902-4441.2003.00190.x
  29. Oster HS, Gvili Perelman M, Kolomansky A, Neumann D, Mittelman M. Erythropoietin treatment is associated with decreased blood glucose levels in hematologic patients. Acta Haematol. 2021; 144(3):252-258. doi: 10.1159/000507974
  30. Hiram-Bab S, Liron T, Deshet-Unger N, Mittelman M, Gassmann M, Rauner M, Franke K, Wielockx B, Neumann D, Gabet Y. Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB J. 2015; 29(5):1890-1900. doi: 10.1096/fj.14-259085
  31. Prutchi-Sagiv S, Golishevsky N, Oster HS, Katz O, Cohen A, Naparstek E, Neumann D, Mittelman M. Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions: could it be beneficial in early disease? Br J Haematol. 2006; 135(5):660-672. doi: 10.1111/j.1365-2141.2006.06366.x
  32. Deshet-Unger N, Oster HS, Prutchi-Sagiv S, Maaravi N, Golishevski N, Neumann D, Mittelman M. Erythropoietin administration is associated with improved T-cell properties in patients with myelodysplastic syndromes. Leuk Res. 2017; 52:20-27. doi: 10.1016/j.leukres.2016.11.002
  33. Park S, Hamel JF, Toma A, Kelaidi C, Thépot S, Campelo MD, Santini V, Sekeres MA, Balleari E, Kaivers J, et al. Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents. J Clin Oncol. 2017; 35(14):1591-1597. doi: 10.1200/JCO.2016.71.3271
  34. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006; 355(14):1456-1465. doi: 10.1056/NEJMoa061292
  35. Lian XY, Zhang ZH, Deng ZQ, He PF, Yao DM, Xu ZJ, Wen XM, Yang L, Lin J, Qian J. Efficacy and safety of lenalidomide for treatment of low-/intermediate-1-risk myelodysplastic syndromes with or without 5q deletion: a systematic review and meta-analysis. PLoS One. 2016; 11(11):e0165948. doi: 10.1371/journal.pone.0165948
  36. Almeida A, Fenaux P, Garcia-Manero G, Goldberg SL, Gröpper S, Jonasova A, Vey N, Castaneda C, Zhong J, Beach CL, Santini V. Safety profile of lenalidomide in patients with lower-risk myelodysplastic syndromes without del(5q): results of a phase 3 trial. Leuk Lymphoma. 2018; 59(9):2135-2143. doi: 10.1080/10428194.2017.1421758
  37. Saft L, Karimi M, Ghaderi M, Matolcsy A, Mufti GJ, Kulasekararaj A, Göhring G, Giagounidis A, Selleslag D, Muus P. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica. 2014; 99(6):1041-1049. doi: 10.3324/haematol.2013.098103
  38. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011; 118(14):3765-3776. doi: 10.1182/blood-2011-01-330126
  39. Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, Mufti GJ, Buckstein R, Mittelman M, Platzbecker U, et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. 2016;34(25):2988-2996. doi: 10.1200/JCO.2015.66.0118
  40. Platzbecker U, Germing U, Götze KS, Kiewe P, Mayer K, Chromik J, Radsak M, Wolff T, Zhang X, Laadem A, Sherman ML, Attie KM, Giagounidis A. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017; 18(10):1338-1347. doi: 10.1016/S1470-2045(17)30615-0
  41. Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019; 133(8):790-794. doi: 10.1182/blood-2018-11-876888
  42. Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, Sekeres MA, Berdeja J, Savona MR, Beyne-Rauzy O, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018; 5(2):e63-e72. doi: 10.1016/S2352-3026(18)30002-4
  43. Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, M Cazzola, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. New Engl J Med. 2020; 382:140-151. doi: 10.1056/NEJMoa1908892
  44. Sanchez-Garcia J, Falantes J, Medina Perez A, Hernandez-Mohedo F, Hermosin L, Torres-Sabariego A, Bailen A, Hernandez-Sanchez JM, Solé Rodriguez M, Casaño FJ, et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma. 2018;59(5):1095-1104. doi: 10.1080/10428194.2017.1366998
  45. Jabbour E, Short NJ, Montalban-Bravo G, Huang X, Bueso-Ramos C, Qiao W, Yang H, Zhao C, Kadia T, Borthakur G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood. 2017;130(13):1514-1522. doi: 10.1182/blood-2017-06-788497
  46. Komrokji R, Swern AS, Grinblatt D, Lyons RM, Tobiasson M, Silverman LR, Sayar H, Vij R, Fliss A, Tu N, Sugrue MM. Azacitidine in lower-risk myelodysplastic syndromes: A meta-analysis of data from prospective studies. Oncologist. 2018; 23(2):159-170. doi: 10.1634/theoncologist.2017-0215
  47. Garcia-Manero G, Almeida A, Giagounidis A, Platzbecker U, Garcia R, Voso MT, Larsen SR, Valcarcel D, Silverman LR, Skikne B, Santini V. Design and rationale of the QUAZAR Lower-Risk MDS (AZA-MDS-003) trial: a randomized phase 3 study of CC-486 (oral azacitidine) plus best supportive care vs placebo plus best supportive care in patients with IPSS lower-risk myelodysplastic syndromes and poor prognosis due to red blood cell transfusion-dependent anemia and thrombocytopenia. BMC Hematol. 2016;16:12. doi: 10.1186/s12878-016-0049-5
  48. Garcia-Manero G, Santini V, Almeida A, Platzbecker U, Jonasova A, Silverman LR, Falantes J, Reda G, Buccisano F, Fenaux P et al. Phase III, Randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2021: JCO2002619. doi: 10.1200/JCO.20.02619
  49. Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR. Prolyl hydroxylase inhibitors: a breakthrough in the therapy of anemia associated with chronic diseases. J Med. Chem. 2018, 61 (16): 6964-6982. doi: 10.1021/acs.jmedchem.7b01686
  50. Del Vecchio L, Locatelli F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018; 27(1):125-133. doi: 10.1080/13543784.2018.1417386
  51. Henry DH; Glaspy J, Harrup RA, Mittelman M, Zhou A, Carraway HE, Bradley C, Saha G, Bartels P, Leong R, et al. Oral Roxadustat demonstrates efficacy in anemia secondary to lower-risk myelodysplastic syndrome irrespective of ring sideroblasts and baseline erythropoietin levels. Blood. 2020,136, 29-30. ASH Meeting Abstract #1277, Dec 5, 2020.
  52. Fenaux P et al. Imetelstat provides durable transfusion independence in heavily transfused non-del(5q) LR-MDS R/R to ESAS. EHA 2019.
  53. Platzbecker U, Fenaux P, Steensma DP, Van Eygen K, Raza A, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, et al. Treatment with Imetelstat provides durable transfusion independence (TI) in heavily transfused non-del(5q) lower risk MDS (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). 2019. EHA Library. Platzbecker U. 06/12/20; 295003; S183.
  54. Steensma DP, Fenaux P, Van Eygen K, Raza A, Santini V, Germing U, Font P, Diez-Campelo M, Thepot S, Vellenga E, et al. Imetelstat achieves meaningful and durable transfusion independence in high transfusion-burden patients with lower-risk myelodysplastic syndromes in a Phase II Study. J Clin Oncol. 2021; 39(1):48-56. doi: 10.1200/JCO.20.01895
  55. Malouf R, Ashraf A, Hadjinicolaou AV, Doree C, Hopewell S, Estcourt LJ. In people with bone marrow disorders, a comparison of giving platelet transfusions only when bleeding occurs to also giving them to prevent bleeding. Cochrane Database Syst Rev 2018 May 14; issue 5, art. CD012342.
  56. Kantarjian H, Fenaux P, Sekeres MA, Becker PS, Boruchov A, Bowen D, Hellstrom-Lindberg E, Larson RA, Lyons RM, Muus P, Shammo J, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010; 28(3):437-444. doi: 10.1200/JCO.2009.24.7999
  57. Giagounidis A, Mufti GJ, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Hu K, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014; 120(12): 1838-1846. doi: 10.1002/cncr.28663
  58. Kantarjian HM, Fenaux P, Sekeres MA, Szer J, Platzbecker U, Kuendgen A, Gaidano G, Wiktor-Jedrzejczak W, Carpenter N, Mehta B, et al. Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial. Lancet Haematol. 2018; 5(3):e117-e126. doi: 10.1016/S2352-3026(18)30016-4
  59. Mittelman M. Good news for patients with myelodysplastic syndromes and thrombocytopenia. Lancet Haematol. 2018 Mar;5(3):e100-101. doi: 10.1016/S2352-3026(18)30017-6
  60. Oliva EN, Alati C, Santini V, Poloni A, Molteni A, Niscola P, Salvi F, Sanpaolo G, Balleari E, Germing U, et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single-blind, randomised, controlled, phase 2 superiority trial. Lancet Haematol. 2017;4(3):e127-e136. doi: 10.1016/S2352-3026(17)30012-1
  61. Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong R, Anagnostopoulos A, Brenner B, et al. Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): A randomised, placebo-controlled, phase 2 trial. Lancet Haematology. 2018; 5(1); e34-e43. abstr 3822. doi: 10.1016/S2352-3026(17)30228-4
  62. Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U, et al. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018;132(25):2629-2638. doi: 10.1182/blood-2018-06-855221
  63. Mittelman M, Oster HS. Thrombocytopenia in myelodysplastic syndromes: time to lift the embargo on thrombomimetics? Br J Haematol 2021;194(2):231-233. doi: 10.1111/bjh.17538
  64. Mittelman M, Oster HS. Immunosuppressive therapy in myelodysplastic syndromes is still alive. Acta Haematol2015; 134:135-137. doi: 10.1159/000371833
  65. Stahl M, DeVeaux M, de Witte T, Neukirchen J, Sekeres MA, Brunner AM, Roboz GJ, Steensma DP, Bhatt VR, Platzbecker U, et al. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv. 2018; 2(14):1765-1772. doi: 10.1182/bloodadvances.2018019414
  66. Hoeks M, Yu G, Langemeijer S, Crouch S, de Swart L, Fenaux P, Symeonidis A, Čermák J, Hellström-Lindberg E, Sanz G, et al. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica. 2020;105(3): 640-651. doi: 10.3324/haematol.2018.212332
  67. Angelucci E, Li J, Greenberg P, Wu D, Hou M, Montano Figueroa EH, Rodriguez MG, Dong X, Ghosh J, Izquierdo M, Garcia-Manero G; TELESTO study investigators. iron chelation in transfusion-dependent patients with low- to intermediate-1-risk myelodysplastic syndromes: A randomized trial. Ann Intern Med. 2020;172(8):513-522. doi: 10.7326/M19-0916
  68. Mittelman M, Lugassy G, Merkel D, Tamary H, Sarid N, Rachmilewitz E, Hershko C; MDS Israel Group; Israel Society of Hematology. Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines. Isr Med Assoc J. 2008;10: 374–376. PMID:18605364
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"" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(42) "

Моше Миттельман

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, Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль

" ["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) "27555" ["VALUE"]=> array(2) { ["TEXT"]=> string(1967) "<p style="text-align: justify;">За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1911) "

За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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Moshe Mittelman            

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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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Moshe Mittelman            

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Moshe Mittelman            

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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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A significant progress has been made over the last couple of decades in understanding the biology and treatment of myelodysplastic syndromes. Based on several parameters (% blasts, cytogenteics, number of affected lineages) the patients are classified as having a lower-risk (LR) or higher risk disease. Here, we will focus on LR-MDS.

The patients with LR-MDS are treated with RBC transfusions as needed, with or without erythroid stimulating agents. Luspatercept, an activin analogue, is a reasonable second line agent. Among the investigational agents in this field we can mention ruxodustat (a HIF inhibitor) and imetelstat, a telomerase inhibitor. Treatment of thrombocytopenia remain challenging and an open question.

Keywords

Myelodysplastic syndrome, low-risk, diagnostics, management, targeted therapy.

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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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Tel Aviv Sourasky Medical Center; Tel Aviv University, Israel


Correspondence
Prof. Dr. Moshe Mittelman, Professor of Internal Medicine and Hematology; Past Chairman, Department of Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University; Past President, Israel Society of Hematology and Transfusion Medicine.
Tel Aviv Sourasky (Ichilov) Medical Center, 6 Weizmann St, 64239, Israel.
E-mail: moshemt@gmail.com


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Моше Миттельман

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Моше Миттельман

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За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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За последние десятилетия достигнут значительный прогресс в понимании биологии и лечении миелодиспластических синдромов (МДС). На основе нескольких клинико-лабораторных параметров (процент бластных клеток, цитогенетические данные, число нарушенных ростков кроветворения) таких пациентов классифицируют по степени риска заболевания (сниженный или высокий риск). Здесь мы обратим особое внимание на МДС низкого риска (НР-МДС). Пациентов с НР-МДС лечат посредством трансфузий эритроцитов (при необходимости), с применением эритропоэз-стимулирующих препаратов или без них. Луспатерсепт, активирующий аналог, является рациональным препаратом для второй линии терапии. Среди изучаемых препаратов в этой области можно упомянуть руксодустат (ингибитор фактора, идуцируемого гипоксией) и иметелстат – ингибитор геломеразы. Лечение тромбоцитопении остается проблемным и открытым вопросом.

Ключевые слова

Миелодиспластический синдром, низкая степень риска, диагностика, лечение, таргетная терапия.

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, Медицинский центр Сураски, Университ Тель-Авива, Тель-Авив, Израиль

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Introduction

Cell and gene therapy comprise a booming avenue in devising novel, emerging healthcare products during the last decade. One such approach with a variety of applications includes CAR-T therapy, which, owing to its innovative and effective approach, has leaped outstandingly fast from idea to clinical practice. Contrary to the prolonged procedure of FDA approval, as observed in case of conventional drugs, the anti-CD-19 CAR-T, KYMRIAH was approved by the FDA within a short span of 4 years in 2017 [1, 2]. This therapeutic was imminently bestowed with the title of the ASCO breakthrough of the year in January 2018 [3]. However, cell and gene therapies such as KYMRIAH are distinct from the "ordinary" drugs in most aspects, and such differences are commonly shared between most cell and gene therapies. In this review, we will focus on some distinct features of such therapies throughout their development, from the R&D bench to the patient bedside, including the regulatory and business aspects of such new therapies which are often overlooked in the reviews on this topic.

The journey of a new drug from labs to shelves is divided into five main areas: R&D, production, regulatory approval, business, and funding. If one of these aspects is missing or is defunct, the drug, irrespective of its efficacy or safety, fails to reach the clinic. The new cell and gene therapies are different from the common drugs in all these areas, as CAR-Ts vividly demonstrate or highlight such differences as well as features that are common to the cell and gene therapies, it is the focus of this review which emphasizes on each of these areas.

Area #1. R&D and emerging technologies

The most distinct feature of CAR-T is that it is based on the concept of personalized medicine which has completely shifted the healthcare ecosystem paradigm from the "one pill fits all" to "every pill made for one patient". The most fascinating aspect of this approach is that it can be effective, not only from a therapeutic but from a business perspective as well. Moreover, these personalized drugs do not disrupt the previous approach, since they can fit well together.

Although the CD-19 CAR-T therapies usher the prospect of long-lasting recovery from advanced stages of cancer which were previously thought incurable [4], its road to approval is fraught with the reports of patient deaths due to cytokine storm [5]. At present, researchers are exposed to new challenges to enable widespread application of this therapy in new areas like infectious diseases, to cure solid tumors, and to enhance its safety, efficacy as well as affordability. To accomplish these goals, the key role is being played by the R&D sector and academic research, which are advancing towards clinical trials with new technology (Table 1).

Table 1. Cell therapy production. Emerging models

Samsonov-tab01.jpg

Firstly, the process of development of personalized drugs shares numerous features with those of the new product development strategies from information technology (IT), or agile processes [6], involving 3 three-step cycle testing ideas like:
– Producing minimal viable product (MVP) as fast as possible.
– Measuring the performance with real-life patients (customers) and gaining knowledge about the improvements needed.
– Repeating [7], and application of agile development methodology.

In this process, every iteration adds some additional features, and fast testing with real-life data shows whether the ideas are right or wrong. One important feature of such products is that they must be very flexible, allowing changes in parts, but maintain the basic functional concept. The software-based products are the best fit for this since they usually utilize the same platform which is used to design the product. This is the case with platforms in biologics, cell, and gene therapies; it allows the use of a platform-based approach for development. Every drug that is based on introducing changes in the DNA or RNA is a kind of "reprogramming" or "genetic software development" suggesting that some effective approaches from IT can be transferred to drug development. This includes all gene and cell-based therapies such as CAR-Ts, or plasmid DNA, or several mRNA-based COVID vaccines, CRISPR-based therapies, etc.

Although there are differences in time frames and regulatory pathways, the approach utilized for personalized drug-development appears to be more similar to this iteration-based development strategy than the standard one-at-a-time perfect drug development strategy used in pharmaceutical industry in the previous as well as present times. Indeed, if we look at the most splendid example- how CAR-T technology developed into its present and future, we can see many similarities.

The first-generation CAR-T therapies were a breakthrough technology in the 1980s [9]; however, despite big hopes, its design was too simple to generate reliable outcomes in clinical trials [8, 10]. Technologically, the first generation of CARs included only the CD3ζ signaling endodomain fused to the extracellular scFv to act as an activator of the T cells. In terms of IT development, it fell exactly in the "minimal viable product" (MVP) category, the product that has the absolute minimum set of features to function. However, despite promising preclinical results, the clinical trials demonstrated caveats such as poor anti-tumor efficacy in patients, caused by low-level CAR-T cell activation. Therefore, the next 2nd generation was introduced, which included co-stimulatory domains for additional activation. This design was highly successful in the clinical trials in treating hematological malignancies, such as acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). This success was confirmed by the FDA approval of two CD-19 CAR-T drugs, KYMRIAH (Tisagenlecleucel) for r/r ALL and r/r large B cell lymphoma and YESCARTA (Axicabtagene ciloleucel) for r/r extent CLL.

In the process of successful clinical trials for both of these drugs, the core of the "agile development approach" was used to adapt for its clinical features and limitations. Additionally, various CAR-T cell-mediated toxicities were reported, such as tumor lysis syndrome [11], cytokine release syndrome (CRS), neurotoxicity [12], and on-target off-tumor toxicity [13], leading to a few patient deaths during the clinical trials.

The most frequent and dangerous feature of CAR-T therapy is cytokine release syndrome (CRS) [14], which leads to some lethal cases during the trials. The iteration product development cycle, which was at this point enabled by the FDA regulations for adaptive clinical trial design, allowed the identification of strategies to avert this risk by introducing several therapeutic options for CRS, such as anti-IL-6 therapy in case of CRS development, and tools to observe the patient, such as hospitalization for a week after CAR-T infusion to closely monitor for adverse reactions [12, 15].

However, the second CAR-T generation failed to show promising results in the case of solid tumors and had several limitations in treating hematological malignancies, such as antigen loss and consequent tumor escape. Such peculiarities of the second generation CAR-T limited the long-term success of CAR-T cell therapy for a quite large group of patients, leading to relapses or lack of tumor response [15, 16]. With further studies, new ideas emerged, leading to the third and fourth generation of CAR-T cells, comprising more receptor domains with different functions added to the chimeric receptor (Fig. 1).

Samsonov-fig01.jpg

Figure 1. Agile Development process and CAR-T (adapted from [7, 8])

The third-generation CAR-T cells combined the signaling potential of two costimulatory domains (CD28 and 4-1BB). To overcome the limitations of the third generation, the fourth generation of CAR-T assimilated various improvements in different parts of the chimeric construct, mostly linked with solid tumor therapies. The antitumor activity of the fourth-generation CAR-T cells was enhanced by features such as additional transgenes for cytokine secretion (e.g., IL-12) or additional costimulatory ligands. Based on the same principle, armored CAR-T cells and TRUCKs (T cells redirected for universal cytokine killing) are constructed i.e., they were modified to express not only CAR but also the inducible cytokine genes. The cytokine expression occurs only when antigen-binding activates the CAR-T cells [17, 18]. Other CAR-T approaches include the dual-receptor CAR-T cells, which are activated only in the presence of dual antigen tumor cells [19], and bi-epitope CARs [20], which fight antigen escape and loss.

With the increasing potency of CAR-T cells, more caution must be taken to ensure their safety. For solid tumors, the off-target activity becomes a limiting factor, since the target antigens are still expressed on some normal cells, and the cytotoxic activity toward these is not desirable. The first potential action is to adjust antibody affinity, thus mitigating on-target off-tumor toxicities related to low-level antigen expression in the normal tissues. The chimeric antibodies with middle or even low affinity to target can have sufficient potential to eradicate the antigen-overexpressing malignant cells, but not to damage normal tissues with low-level antigen expression [21]. Such situation is possible in case of solid tumors, which can even cause death during CAR-T therapy [22].

Another approach for reducing off-target activity is to fabricate short-lived CAR-T cells. This can be achieved via mRNA delivery with a chimeric construct instead of DNA incorporation into the T-cells. In this case, the T-cells express a CAR for up to several days at high efficiencies; however, the drawback of this approach is rapid loss of the transgenic construct and the T-cell activity associated with it, and a need for several dosages to obtain clinically relevant results [23]. This approach not only allows temporal control over the CAR-T pharmacokinetics but can also be applied with gene-editing tools such as TALEN, disrupting TCR and CD52 expression in the CAR-T cells, thus creating off-the-shelf CAR-Ts. In addition, this approach can expand the scope of therapy to treat hematological tumors. In this context, previous studies reported that by using mRNA-transduced anti-CD19 CAR-T cells targeted against the tumor microenvironment, promising results were obtained in the treatment of Hodgkin’s lymphoma [24]. The transient CAR-T production with mRNA delivery can be a potential option for future in vivo CAR-T therapy wherein, mRNA-loaded particles can be injected into specific T-cells within the patients [25].

Yet another approach to increase safety is via the on-off control of CAR-T cells. The most clinically advanced technology is the inducible suicide caspase-9 gene based on a modified human caspase-9 fused to the human FK506 binding protein (FKBP). This fusion protein, expressed in the T-cells, can form dimers when a chemical inducer of dimerization (AP1903 or Rimiducid) is administered to the patient. A single dose of the inducer drug causes rapid elimination of 85-90% of iC9-transduced T cells [26, 27]. Caspase-9-transduced T cells were used in the clinic as a tool to control graft-versus-host disease (GVHD) after haploidentical stem cell transplantation, and the GVHD-associated symptoms could be also quickly eliminated following the caspase switch activation [28].

With more than 600 ongoing clinical trials [29], there are a lot of features emerging continuously in the CAR-T field, similar to the software "add-ons", aimed to solve particular tasks within a particular setting (or overcome particular difficulties) with a combination of different targets and approaches to improve safety and efficacy, some of which were discussed above. Another important limitation concerns the costs and timing of production. Being completely personalized, the currently approved CAR-T relies solely on the patient’s T-cells for the CAR-T production. Therefore, apart from difficulties in logistics and lead times for therapy, the cost of such therapies becomes a huge burden to the patient and acts as a barrier to the widespread use of CAR-T therapies [30].

This issue has been addressed by off-the-shelf CAR-T and CAR-NK products in development. There are several approaches to treat GVHD which is the main challenge for off-the-shelf CAR–based therapies. One approach to solve this problem is to use other cells with the cytotoxic ability and not αβ T-cells. The NK cells fit this approach and have been used in phase 2 clinical trials. However, such off-the-shelf therapy seems to require fourth-generation CAR constructs including death switches and expression of stimulatory molecules to generate stable CAR-NK cell populations [31]. Gene-editing methods such as CRISPR/Cas9 and TALENs are used to disrupt genes encoding the endogenous TCR as well as human leukocyte antigen (HLA), thus creating universal CAR-T therapy. Apart from deleting human histocompatibility loci in CAR-introduced T-lymphocytes, gene editing and CRISPR-like technologies can be used to insert CAR constructs precisely into particular genome regions, instead of just delivering CAR-programming viral plasmids, which can improve the survival of modified T-cells [32, 33, 34]. Yet another promising option is that gene editing allows the deletion of T-cell suppressive receptors, thereby rendering the T-cells less susceptible to tumor-mediated immunosuppression [35].

The efficacy and safety of CAR-T cell therapy still have broad space for improvement, since not only increased safety but also higher efficacy is required. Notably, disease relapse can occur in up to 50% of patients within a year of therapy. Specific tumor biomarkers are widely used to choose and direct therapy with a growing variety of anti-cancer drugs [36]; therefore, the same approach is expected to benefit more complex CAR-T treatments, introducing the idea of individualized disease management as well as personalized therapy [37]. Safety is the first concern that can be managed with the help of biomarkers as cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) which cause up to 60% of life-threatening toxicities [38]. Response rate is also an important aspect that can be determined by biomarkers, especially the primary indications: if up to 90% response can be seen in ALL, according to a meta-analysis by Hou et al. [39], this figure drops to 9% (10-fold lower) in solid tumors.

CRS is caused by activation of T-cells after engagement of their CAR targets. Activated T-cells release various cytokines and chemokines, including interleukin (IL)-6, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and soluble IL-2Rα [40]. These cytokines activate monocytes, macrophages, and other immune cells, which in turn release inflammatory cytokines. However, only a few biomarkers have been identified as predictors in clinical trials: serum levels of IL-6 and IFN-γ in the first 24 h after CAR-T-cell infusion in B-ALL patients have been reported as robust biomarkers of severe CRS and CRES [41]. In NHL patients, increased serum IL-8, IL-10, and IL-15 levels, as well as decrease of transforming growth factor (TGF)-β could also predict severe CRS and potential neurotoxicity [42].

CAR-T efficacy prediction is still a challenging issue [43, 44]. Hence, there is a need to identify new biomarkers, especially with growing insights from the new genomic and transcriptomic analysis methods powered by next-generation sequencing, enabling TCR repertoire and lentiviral integration site analysis that allows for clone evolution of the CAR-T cells in the patient and its interaction with immune system [45].

We can see from the above discussion that the technical part of CAR-T development is open to a huge number of options and features, which can be combined into an optimal product to deliver the best possible combination of safety and efficacy for a wide variety of cancers in a personalized therapeutic manner. It is also clear that the diversity of combinations that is possible with CAR-T cells is huge and growing, along with the complexity and uncertainty of the result. This is similar to the current state of software development; thus, the transfer of effective approaches from this field into CAR-T’s development may benefit research and clinical development.

Area #2 Regulatory

As noted in the Harvard Business Review publication "Embracing Agile" [6], the type of innovation that will favor agile methodology is when "Problems are complex, solutions are unknown, and the scope is not clearly defined. Product specifications may change. Creative breakthroughs and the time to market are important. Cross-functional collaboration is vital".

The experience of drug regulation was just about the opposite: regulatory agencies and financial reimbursement bodies that set bottlenecks for fast drug development processes [46]. However, in recent decades, the most influential regulatory agencies, such as the FDA and EMA, have made huge steps toward flexibility, dialog, and increasing speed for innovations, especially in the field of gene and cell therapies. If we look at the history of changes in FDA regulations, the Orphan Drug Act, which loosens regulations for drugs aimed at conditions affecting less than 200,000 people in the USA (and personalized medicines can fit very well in that) was followed by the Accelerated Approval program that allows approval based on surrogate endpoints (with completion of post-approval Phase 4 trials to maintain approval) [47]. Next, the Fast Track designation allowed more frequent reviews with the FDA and expedited rolling reviews, allowing tighter contact between the regulator and developer [48]. The breakthrough therapy program added on top of it by the FDA allows drugs that fall within it to be approved based on clinical studies with alternative clinical designs that could be smaller in the number of subjects and use surrogate endpoints or biomarkers to determine efficacy [49]. The 21st Century Cures Act [50] has driven the FDA to maximize the use of these programs and supports the use of biomarkers as determinants of therapeutic efficacy rather than clinical outcomes alone. And most importantly for Gene and Cell therapies this act set a new Regenerative Medicine Advanced Therapies (RMAT) designation, that includes cell therapies, therapeutic tissue engineering products, human cell, and tissue products as well as certain human gene therapies and xenogeneic cell products aimed to treat serious disease.

It is important to note that drugs carrying an "orphan drug" designation can access the accelerated pathways mentioned above, requiring smaller trials (on average 3 times smaller vs common diseases), avoiding the need for randomization or double-blinding, and obtaining approval based on surrogate endpoints rather than stricter mortality or survival clinical endpoints.

Similar approaches are used by the European Medicinal Agency (EMA) and set in the number of directives [51, 52], which defines the special types of products-advanced therapy medicinal products. Such ATMPs can also be subject to orphan designation, which is different in the EU vs the USA- prevalence is not more than 5 in 10,000 [53]. Most of the activities and benefits that the developer obtains under ATMP, PRIME, and other expedited regimes are based first on extensive communication and obtaining advice and guidance from regulator experts on the development plans and regulatory strategies, including preclinical and clinical aspects. Again, the conditional approval option on the limited data of safety and efficacy (Phase II) is also possible.

The expedited reviews of new product development, readily available for gene and cell therapies, now provide unique opportunities for implementing the agile approach and increasing the efficiency of development for new therapeutics in this very demanding field. This is especially true when combined with therapy personalization, based not only on clinical diagnosis but also on specific biomarkers that enable particular therapeutic interventions. Since this itself opens the orphan pathway to approval, which is more frequently used, up to 25% of new approvals got an orphan designation [46].

New drugs are not only products to be developed for patients but are also products to be developed as regulators. The fate of the same drug candidate can differ dramatically with differences in clinical and pre-clinical data generation and presentation, in manufacturing and quality control processes and documentation [54], as well as the financial, organizational, and even behavioral characteristics of patients in clinical trials [55]. In this case, the ability to create a set of documents and approaches for approval as an "MVP for regulator" and test it during a face-to-face discussion in the iteration process can provide substantial benefits for the developer to make things faster and cheaper. Importantly, most advanced regulators such as FDA understand the uncertainty in development, which is reflected in recent and important for cell and gene therapy products CMC guidance [56] that of states about critical quality attributes (CQA). "We further acknowledge that understanding and defining product characteristics that are relevant to the clinical performance of the gene therapy may be challenging during early stages of product development, when product safety and quality may not be sufficiently understood".

Accelerated approval options (which not only allow approval of the drug based on the Phase II data but also requires tight communication with the regulator) according to some analysis may decrease R&D costs by up to 500 M$ and shorten the time to market for two years on average [57].

However, accelerated approval or conditioned approval in EMA forces developers to follow additional risk mitigation strategies, such as risk evaluation and mitigation strategies (REMS). The REMS program empowers the FDA to regulate post-market activities in exchange for pre-market approval. Under REMS, providers must continue to monitor and report patients with side effects. The CAR-T treatment sites needed to comply with REMS, approved by the FDA, for 15 years.

REMS for CAR-T includes a set of requirements before the site can start CAR-T treatments (such as having two doses of tocilizumab to prevent CRS and neurological toxicities per patient, requirements for medical staff training, and a system to report adverse effects). Fulfillment of the REMS (FDA) or risk management plan (EMA) requirements should be covered and controlled by the pharmaceutical company in partnership with the practicing clinicians.

Since the regulators understand well that cell and gene therapies are much different even from biologics, they are working intensively to create guidelines for this area. Currently, some guidelines cover areas from preclinical, manufacturing, clinical development, and follow-up [56, 58-65]. It is important to highlight new guidance for devices used in regenerative medicine advanced therapies in which CAR-T therapies are commonly included since it clearly defines the requirements for auxiliary devices used in the CAR-T production process [66].

CAR-T regulatory landscape in Russia

CAR-T in Russia falls into the category of biomedical cell products, which are regulated by the federal law # 180-FZ and all linked documents [67]. A full set of regulatory documents was completed in 2020, and real-life application for this law is in the early stage, there are no approved products and only one completely certified production site for cell therapy. Importantly, this law allows for written and even face-to-face consultations directly with experts of the regulator (Federal State Budgetary Institution "SCEEMP"), which is an important step to support the development of complex cell therapies.

Area #3. Production

The next step involved in making the therapy available to the patient is production. Since we are transitioning from the one-pill-fits-all to the one-pill-for-one patient model, the industry understands that big plants are not of much use in this new reality. CAR-T development not only opens issues that are specific to this field, but also provides some solutions to it [68]. New models of production start to emerge (see Table 1 "Cell therapy production. Emerging models", [69-71]). One of the most common strategies to produce in-house CAR-T cells is small-scale production volume, which is just fit to the number of patients in the clinic using cell-modifying equipment such as the CliniMACS Prodigy® system [67], which allows for the small-scale process of cell transformation and sorting for clinical applications.

The overall "agile-like" approach we have discussed above is used in personalized therapies like CAR-Ts such that the therapies are more effective and shorten the development cycle. If we can reduce the production duration and bring the product closer to the patient, it will bring several benefits to the entire system:
1. Benefits to the patient by shortening the duration of manufacturing and transportation. Better adjustment of therapy options due to faster response if the production site is in the clinics, enabling flexibility of regimes and targets.
2. The benefit to pharma companies – big investments in large production facilities are not needed.
3. The benefit to the regulator-better control of safety.

Such close-to-patient therapy production opens new possibilities for treatment adjustments, such as biomarker-assistant cell dosage, relapse, and tumor escape treatment with CARs aimed at different targets.

Academia in business

One feature of the agile approach towards product development is the non-hierarchical horizontal structure of teams of interdisciplinary experts. CAR-T is a product which requires tight collaboration between the pharmaceutical industry and clinics, that are most frequently vertically oriented; however, there are several examples of academia being an active part of the business. Some examples are:

Joint ventures | Startups
In 2013, the Fred Hutchinson Cancer Research Center (FHCRC), Memorial Sloan Kettering Cancer Center (MSKCC), and Seattle Children's Research initiated Juno Therapeutics company as a result of previous long collaboration in CAR-T development, and further started joint ventures with Juno Therapeutics for more than four clinical trials [73].

Academic institution networks, that unite researchers, developers, clinical centers, and companies for developing new therapy
The BioCanRx network (Canada immunotherapy network) is a pan-Canadian network of expertise and infrastructure for the development, manufacturing, and clinical testing of new immunotherapies. It was established in 2016 to boost infrastructure and manufacturing capacity to support bench-to-bedside research and to ultimately increase the access to CAR-T by increasing the number of clinical trials available to Canadian patients, as well as to empower innovations in the engineered T-cell area. It survived government financing cuts and delivered two CAR-T candidates in several clinical trials, including closed-cycle point-of-care CAR-T devices [74].

Multi-country consortia between the academic institutions and small companies allow bypassing big pharmaceutical companies or large investments in CAR-T development
The EURE-CART Alliance involved six academic centers from five countries, and three small and one medium-sized enterprise to conduct clinical trials of CAR-T candidates and to clinically develop CAR-T platforms. In 2020, the alliance started the first clinical trial of a CAR-T, CD44v6 candidate [75].

Crowdfunding consortia
The rare disease consortia started in 2008, uniting patients, charity, and academic research to develop a treatment for the Rett syndrome. In total, more than 60 M$ were collected to finance research or attract research teams in gene therapy and cell therapy dedicated towards curing this syndrome. Multiple collaborations of scientists covered different steps in therapy development. Enabling collaboration with AveXis made this company focus on Rett syndrome, develop AVXS-201 gene replacement therapy up to the preclinical phase, and even managed to keep it in the Novartis pipeline with a fixed date for IND application in 2021 [76]. The same community advanced other gene therapy candidates TSHA-102 with Taysha Therapeutics [77].

As we can see from these examples, forming [6] consortia can indeed deliver therapeutic products in this very complex and challenging field of gene and cell therapy due to advancements in collaboration and working in cross-functional teams, even though it lacks the power and experience of big pharmaceutical companies. However, this can be addressed by skillful application of agile processes technology giants.

Gene and cell technologies and new technology giants
An important point for the future of the healthcare sector, which was boosted in recent years, is the increased support from regulators, such as the US FDA, emerging and more effective technologies, decreasing time to market for them. Big data, genome-based personalization of treatments, and gene-editing are all included in the new focus of attention of regulators, which can possibly reduce the costs of treatment and drugs, and overall decrease the healthcare expenses [78, 79].

Since IT-born agile ideology can be applied to the development of personal therapeutics, they are sweet points of entry into the pharmaceutical market for tech giants who are experts in this development methodology.

One interesting example is the story of Jeff Bezos, Amazon, and Juno Therapeutics, which initiated a possible entry of Amazon into the CAR-T business with 7 years of approval, and possible changes in the US healthcare industry [80].

• 2013 – Juno Therapeutics spin-off from the Fred Hutchinson Cancer Research Center.
• 2014 – Bezos invests Juno 20M$ in 140M$ round.
• 2014 – Bezos family gifted the Fred Hutchinson Cancer Research Center 30M$ to create 1 in the USA clinic for immunotherapy treatment (Bezos Family immunotherapy clinic).
• 2018 – Celgene Juno was sold to Celgene, later to BMS.
• 2018 – Bezos (Amazon) enter the US drug market.
• 2019 – Juno ex-executives started company Sana, dedicated to the development of cell-based treatments ("ultimate next-gen cell engineering company with gene therapy and cell therapy").
• 2019 – Bezos (Amazon) enter the telemedicine and medical insurance markets.
• 2020 – Bezos and other VC invest 700M$ in Sana.
• 2020 – Seattle Cancer Care Alliance, including Bezos Family immunotherapy clinic, hosts 33 clinical trials of immunotherapies.
• 02.2021 – Approval of Juno CAR-T JCAR017 (BMS’ Liso-cel).

One interesting story to tell is Jeff Bezos's investments in the gene and cell therapies company, Juno back in 2014. From that time, Juno went through a series of M&As, starting from $6 billion ended up with $67 billion to BMS. Last year, Bezos again invested in the same Juno team, now gathered under the name Sana, to develop next-generation gene and cell therapies [81]. During these times, Amazon entered the drug delivery and medical insurance markets [82]. Some might infer that it was just smart investments, and it can be seen that Amazon now understands and is building a technology-oriented healthcare infrastructure, opening the existing bottlenecks for new, high-tech, and more efficient healthcare solutions. When the technology giants enter the field of healthcare, the market is destined to change dramatically.

Conclusion

When we look at the gene and cellular therapies, and, in particular, the CAR-T therapies as its most developed and effective segment, it vividly shows general approaches and challenges of this field, as well as features that are particular to the personal therapeutics. We can see that on the technological side, despite the common CAR-T platform, a variety of diseases and corresponding molecular targets, combined with the particularities of patient population groups, will require a diverse set of properties for such drugs, possibly with some features of opposite functions. In turn, to make the most of such flexible and programmable therapeutic platforms as CAR-T, an agile, iteration-based approach of product development can be used, and in fact, has already been used to bring the current flagship therapeutics like KYMRIAH to the market. Moreover, the current regulation for the cell- and gene-based therapeutics, new production technologies, methods of research, development, and clinical collaboration for such products can empower the agile approach, decreasing the costs and time to market such therapies, as well as bringing in new players from the IT and high technology industries to the pharmaceutical market.

Conflict of interest

No potential conflict of interest is reported.

References

  1. Loew A, Milone M C, Powell DJ, Zhao Y. Treatment of cancer using chimeric antigen receptor. WIPO Patent WO2015142675A2, 2015.
  2. FDA news release. FDA approval brings first gene therapy to the United States U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-st.... 30 Aug 2017. Accessed 22 Feb 2021.
  3. ASCO news releases. CAR T-cell immunotherapy named advance of the year in annual ASCO Report. ASCO. https://www.asco.org/about-asco/press-center/news-releases/car-t-cell-immunotherapy-named-advance-ye.... 30 Jan 2018. Accessed 22 Feb 2021.
  4. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi: 10.1056/NEJMoa1709866
  5. Seimetz D, Heller K, Richter J. Approval of First CAR-Ts: Have we solved all hurdles for ATMPs? Cell Med. 2019 Jan 22;11:2155179018822781. doi: 10.1177/2155179018822781
  6. Rigby, Darrell K., Sutherland J, Takeuchi H. Embracing Agile: How to master the process that's transforming management. Harvard Business Review. 2016;94 (5): 40-50.
  7. Ries E. The Lean Startup: How today's entrepreneurs use continuous innovation to create radically successful businesses. Crown Business, 2011.
  8. Subklewe M, von Bergwelt-Baildon M, Humpe A. Chimeric antigen receptor T cells: a race to revolutionize cancer therapy. Transfus Med Hemother. 2019;46(1):15-24. doi: 10.1159/000496870
  9. Hui K, Grosveld F, Festenstein H. Rejection of transplantable AKR leukaemia cells following MHC DNA-mediated cell transformation. Nature. 1984;311(5988):750-752. doi: 10.1038/311750a0
  10. Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181(5):1653–1659. doi: 10.1084/jem.181.5.1653
  11. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8): 725-733. doi: 10.1056/NEJMoa1103849
  12. Vairy S, Garcia JL, Teira P, Bittencourt H. CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Drug Des Devel Ther. 2018;12:3885-3898. doi: 10.2147/DDDT.S138765
  13. Hombach A, Hombach AA, Abken H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response. Gene Therapy. 2010;17(10):1206-1213. doi: 10.1038/gt.2010.91
  14. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS. M, et al. Cytokine release syndrome. J Immunother Cancer. 2018; 6(1):56. doi: 10.1186/s40425-018-0343-9
  15. Stoiber S, Cadilha BL, Benmebarek MR, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019;8(5):472. doi: 10.3390/cells8050472
  16. Li X, Chen W. Mechanisms of failure of chimeric antigen receptor T-cell therapy. Curr Opin Hematol. 2019;26(6):427-433. doi: 10.1097/MOH.0000000000000548
  17. Chmielewski M, Abken H. TRUCKS, the fourth generation CAR T cells: Current developments and clinical translation. Adv Cell Gene Ther. 2020; 3:e84. doi: 10.1517/14712598.2015.1046430
  18. Yeku OO, Purdon TJ, Koneru M, Spriggs D, Brentjens RJ. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci Rep 2017; 7:10541. doi: 10.1038/s41598-017-10940-8
  19. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA. Precision tumor recognition by T cells withcombinatorial antigen-sensing circuits. Cell. 2016; 164:770- 779. doi: 10.1016/j.cell.2016.01.011
  20. Xu J, Chen LJ, Yang SS, et al. Exploratory trial of a biepitopic CAR T- & targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci USA. 2019;116:9543-9551. doi: 10.1073/pnas.1819745116
  21. Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, Cogdill AP, Li N, Ramones M, Granda B. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75:3596-3607. doi: 10.1158/0008-5472.CAN-15-0159
  22. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 2010;18: 843-851. doi: 10.1038/mt.2010.24
  23. Foster JB, Barrett DM, Karikó K. The emerging role of in vitro-transcribed mRNA in adoptive T cell immunotherapy. Mol. Ther. 2019;27:747-756. doi: 10.1016/j.ymthe.2019.01.018
  24. Svoboda J, Rheingold SR, Gill SI, Grupp SA, Lacey SF, Kulikovskaya I et al. Nonviral RNA chimeric antigen receptor-modified T cells in patients with Hodgkin lymphoma. Blood. 2018;132:1022-1026. doi: 10.1182/blood-2018-03-837609
  25. Veiga N, Goldsmith M, Granot Y, Rosenblum D, Dammes N, Kedmi R, et al. Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. Nat. Commun. 2018;9:4493. 3. doi: 10.1038/s41467-018-06936-1
  26. Straathof KC, Pulè MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105:4247-4254. doi: 10.1182/blood-2004-11-4564
  27. Diaconu I, Ballard B, Zhang M, Chen Y, West J, Dotti G, et al. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T Cells. Mol. Ther. 2017;25:580-592. doi: 10.1016/j.ymthe.2017.01.011
  28. Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015;125:4103-4113. doi: 10.1182/blood-2015-02-628354
  29. Search list results. CAR-T | Recruiting, Not yet recruiting, Active, not recruiting, Enrolling by invitation Studies. https://clinicaltrials.gov/ct2/results?cond=&amp;term=CAR-T+&amp;cntry=&amp;state=&a.... Accessed 22 Feb 2021.
  30. Fiorenza S, Ritchie DS, Ramsey SD, Turtle CJ, Roth JA. Value and affordability of CAR T-cell therapy in the United States. Bone Marrow Transplant. 2020;55(9):1706-1715. doi: 10.1038/s41409-020-0956-8
  31. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020;382(6):545-553. doi: 10.1056/NEJMoa1910607
  32. Lee J, Sheen JH, Lim O, Lee Y, Ryu J, Shin D, et al. Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy. Sci Rep 2020; 10, 17753. doi: 10.1038/s41598-020-74772-9
  33. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19:185-199. doi: 10.1038/s41573-019-0051-2
  34. Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374):eaaj2013. doi: 10.1126/scitranslmed.aaj2013
  35. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR-T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255-2266. doi: 10.1158/1078-0432.CCR-16-1300
  36. Liu D. Cancer biomarkers for targeted therapy. Biomark Res. 2019;7:25. doi: 10.1186/s40364-019-0178-7
  37. Du M, Hari P, Hu Y, Mei H. Biomarkers in individualized management of chimeric antigen receptor T cell therapy. Biomark Res. 2020;8:13. doi: 10.1186/s40364-020-00190-8
  38. Wang Z, Han W. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res. 2018;6(22):4. doi: 10.1186/s40364-018-0116-0
  39. Hou B, Tang Y, Li W, Zeng Q, Chang D. Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis. Dis Markers. 2019;2019:3425291. doi: 10.1155/2019/3425291
  40. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664-679. doi: 10.1158/2159-8290.CD-16-0040
  41. Hay KA, Hanafi L, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295-2306. doi: 10.1182/blood-2017-06-793141
  42. Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):116r-355r. doi: 10.1126/scitranslmed.aaf8621
  43. Cahill KE, Leukam MJ, Riedell PA. Refining patient selection for CAR T-cell therapy in aggressive large B-cell lymphoma. Leuk Lymphoma. 2020;61(4):799-807. doi: 10.1080/10428194.2019.1691201
  44. Du M, Hari P, Hu Y, Mei H. Biomarkers in individualized management of chimeric antigen receptor T cell therapy. Biomark Res. 2020;8:13. doi: 10.1186/s40364-020-00190-8
  45. Sheih A, Voillet V, Hanafi LA, DeBerg HA, Yajima M, Hawkins R, et al. Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy. Nat Commun. 2020;11(1):219. doi: 10.1038/s41467-019-13880-1
  46. Van Norman GA. Update to drugs, devices, and the FDA: How recent legislative changes have impacted approval of new therapies. JACC Basic Transl Sci. 2020;5(8):831-839. doi: 10.1016/j.jacbts.2020.06.010
  47. Accelerated Approval Program. U.S. Food and Drug Administration. https://www.fda.gov/drugs/information-healthcare-professionals-drugs/accelerated-approval-program. Accessed 22 Feb 2021.
  48. Fast Track. U.S. Food and Drug Administration. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fa.... Accessed 22 Feb 2021.
  49. Breakthrough Therapy. U.S. Food and Drug Administration. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/br.... Accessed 22 Feb 2021.
  50. 21st Century Cures Act. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act. Accessed 22 Feb 2021.
  51. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 Off. J. Eur. Union, L324 (2007), pp. 121-137.
  52. Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products, Off. J. Eur. Union, L242 (2009), pp. 3-12.
  53. European Medicines Agency. Procedural advice for orphan medicinal product designation. Guidance for sponsors. 2020; EMA/420706/2018 Rev 91. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/procedural-advice-orphan-medi.... Accessed 22 Feb 2021.
  54. Carvalho M, Martins AP, Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European Marketing Authorization Applications. Drug Discov Today. 2019;24(3):823-828. doi: 10.1016/j.drudis.2018.12.007
  55. Fogel DB. Factors associated with clinical trials that as behavioral fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018;11:156-164. doi: 10.1016/j.conctc.2018.08.001
  56. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). U.S. Food and Drug Administration. https://www.fda.gov/media/113760/download. Accessed 22 Feb 2021.
  57. Prasad V, Mailankody S. Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval. JAMA Intern Med. 2017;177(11):1569-1575. doi: 10.1001/jamainternmed.2017.3601
  58. Long Term Follow-Up After Administration of Human Gene Therapy Products Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/113768/download. Accessed 22 Feb 2021.
  59. Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations Draft Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/134731/download. Accessed 22 Feb 2021.
  60. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/120267/download. Accessed 22 Feb 2021.
  61. Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products Guidance for Industry. U.S. Food and Drug Administration.https://www.fda.gov/media/89036/download. Accessed 22 Feb 2021.
  62. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/106369/download. Accessed 22 Feb 2021.
  63. Guidance for Industry. Preclinical Assessment of Investigational Cellular and Gene Therapy Products. U.S. Food and Drug Administration. https://www.fda.gov/media/87564/download. Accessed 22 Feb 2021.
  64. Guidance for Industry. Guidance for Human Somatic Cell Therapy and Gene Therapy. U.S. Food and Drug Administration. https://www.fda.gov/media/72402/download. Accessed 22 Feb 2021.
  65. Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/113790/download. Accessed 22 Feb 2021.
  66. Evaluation of Devices Used with Regenerative Medicine Advanced Therapies. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/120266/download. Accessed 22 Feb 2021.
  67. The Federal Law No. 180-FZ dated 23 June 2016 'On Biomedical Cell Products' (in Russian).
  68. Lulla P, Ramos CA. Expanding Accessibility to CD19-CAR T Cells: Commercializing a "Boutique" Therapy. Mol Ther. 2017;25(1):8-9. doi: 10.1016/j.ymthe.2016.12.002
  69. Bozenhardt EH, Bozenhardt HF. Repurposing An Aging Facility To Produce Cell & Gene Therapies: Layout & Design Considerations. Cell & Gene. https://www.cellandgene.com/doc/repurposing-an-aging-facility-to-produce-cell-gene-therapies-layout-.... August 24, 2020. Accessed 22 Feb 2021.
  70. Raper V. Crafting a More Efficient CAR T-Cell Industry. Genetic Engineering & Biotechnology News. 2019;39(5):24-26.
  71. Pharmaceutical & biotechnology industry update. August / September 2019. McIlvaine Company. http://www.mcilvainecompany.com/industryforecast/pharmaceutical/updates/2019%20updates/august.htm#Pl.... Accessed 22 Feb 2021.
  72. CliniMACS Prodigy Instrument. Miltenyi Biotec. https://www.miltenyibiotec.com/US-en/products/clinimacs-prodigy.html?countryRedirected=1#gref. Accessed 22 Feb 2021.
  73. Leading cancer research centers team up to launch biotech startup focused on cancer immunotherapy. Fred Hutchinson Cancer Research Center. https://www.fredhutch.org/en/news/releases/2013/11/biotech-startup-cancer-immunotherapy.html. Dec. 4, 2013. Accessed 22 Feb 2021.
  74. Made-in-Canada CAR T Therapy Timeline. BioCanRx, Canada’s Immunotherapy Network. https://biocanrx.com/research/made-canada-car-t-therapy-timeline. Accessed 22 Feb 2021.
  75. First Patient treated within EURE-CART Clinical Trial. EURE-CART. https://www.eure-cart.eu/news/news/news-detail/tx_news/first-patient-treated-within-eure-cart-clinic.... February 19 2020. Accessed 22 Feb 2021.
  76. Coenraads M. Novartis OAV201 Update. Rett Syndrome Research Trust. https://reverserett.org/novartis-oav201-update. February 9, 2021. Accessed 22 Feb 2021.
  77. Dear Rett Syndrome Community. Rett Syndrome Research Trust. https://reverserett.org/wp-content/uploads/2021/02/taysha-rett-community-letter-02-17-2021.pdf February 17, 2021. Accessed 22 Feb 2021.
  78. Statement from FDA Commissioner Scott Gottlieb, M.D., on proposed modernization of FDA’s drug review office. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-pro.... June 04, 2018. Accessed 22 Feb 2021.
  79. HEALTHY INNOVATION, SAFER FAMILIES: FDA’S 2018 STRATEGIC POLICY ROADMAP. U.S. Food and Drug Administration. https://www.fda.gov/media/110587/download. January 2018. Accessed 22 Feb 2021.
  80. Fred Hutch statement regarding the FDA approval of CD19 immunotherapy, lisocabtagene maraleucel. Fred Hutchinson Cancer Research Center. https://www.fredhutch.org/en/news/releases/2021/02/fred-hutch-statement-regarding-the-fda-approval-o.... Feb. 5, 2021. Accessed 22 Feb 2021.
  81. Thorne J. Former Juno execs unveil Sana, a new cell engineering biotech that’s reportedly raising more than $800M. GeekWire. https://www.geekwire.com/2019/led-former-juno-execs-sana-new-cell-engineering-biotech-thats-reported... January 7, 2019. Accessed 22 Feb 2021.
  82. Freedman DH. Do you trust Jeff Bezos with your life? Tech giants like Amazon are getting into the health care business. Newsweek. https://www.newsweek.com/amazon-health-care-jeff-bezos-telemedicine-1475154. December 3 2019, Accessed 22 Feb 2021.
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Introduction

Cell and gene therapy comprise a booming avenue in devising novel, emerging healthcare products during the last decade. One such approach with a variety of applications includes CAR-T therapy, which, owing to its innovative and effective approach, has leaped outstandingly fast from idea to clinical practice. Contrary to the prolonged procedure of FDA approval, as observed in case of conventional drugs, the anti-CD-19 CAR-T, KYMRIAH was approved by the FDA within a short span of 4 years in 2017 [1, 2]. This therapeutic was imminently bestowed with the title of the ASCO breakthrough of the year in January 2018 [3]. However, cell and gene therapies such as KYMRIAH are distinct from the "ordinary" drugs in most aspects, and such differences are commonly shared between most cell and gene therapies. In this review, we will focus on some distinct features of such therapies throughout their development, from the R&D bench to the patient bedside, including the regulatory and business aspects of such new therapies which are often overlooked in the reviews on this topic.

The journey of a new drug from labs to shelves is divided into five main areas: R&D, production, regulatory approval, business, and funding. If one of these aspects is missing or is defunct, the drug, irrespective of its efficacy or safety, fails to reach the clinic. The new cell and gene therapies are different from the common drugs in all these areas, as CAR-Ts vividly demonstrate or highlight such differences as well as features that are common to the cell and gene therapies, it is the focus of this review which emphasizes on each of these areas.

Area #1. R&D and emerging technologies

The most distinct feature of CAR-T is that it is based on the concept of personalized medicine which has completely shifted the healthcare ecosystem paradigm from the "one pill fits all" to "every pill made for one patient". The most fascinating aspect of this approach is that it can be effective, not only from a therapeutic but from a business perspective as well. Moreover, these personalized drugs do not disrupt the previous approach, since they can fit well together.

Although the CD-19 CAR-T therapies usher the prospect of long-lasting recovery from advanced stages of cancer which were previously thought incurable [4], its road to approval is fraught with the reports of patient deaths due to cytokine storm [5]. At present, researchers are exposed to new challenges to enable widespread application of this therapy in new areas like infectious diseases, to cure solid tumors, and to enhance its safety, efficacy as well as affordability. To accomplish these goals, the key role is being played by the R&D sector and academic research, which are advancing towards clinical trials with new technology (Table 1).

Table 1. Cell therapy production. Emerging models

Samsonov-tab01.jpg

Firstly, the process of development of personalized drugs shares numerous features with those of the new product development strategies from information technology (IT), or agile processes [6], involving 3 three-step cycle testing ideas like:
– Producing minimal viable product (MVP) as fast as possible.
– Measuring the performance with real-life patients (customers) and gaining knowledge about the improvements needed.
– Repeating [7], and application of agile development methodology.

In this process, every iteration adds some additional features, and fast testing with real-life data shows whether the ideas are right or wrong. One important feature of such products is that they must be very flexible, allowing changes in parts, but maintain the basic functional concept. The software-based products are the best fit for this since they usually utilize the same platform which is used to design the product. This is the case with platforms in biologics, cell, and gene therapies; it allows the use of a platform-based approach for development. Every drug that is based on introducing changes in the DNA or RNA is a kind of "reprogramming" or "genetic software development" suggesting that some effective approaches from IT can be transferred to drug development. This includes all gene and cell-based therapies such as CAR-Ts, or plasmid DNA, or several mRNA-based COVID vaccines, CRISPR-based therapies, etc.

Although there are differences in time frames and regulatory pathways, the approach utilized for personalized drug-development appears to be more similar to this iteration-based development strategy than the standard one-at-a-time perfect drug development strategy used in pharmaceutical industry in the previous as well as present times. Indeed, if we look at the most splendid example- how CAR-T technology developed into its present and future, we can see many similarities.

The first-generation CAR-T therapies were a breakthrough technology in the 1980s [9]; however, despite big hopes, its design was too simple to generate reliable outcomes in clinical trials [8, 10]. Technologically, the first generation of CARs included only the CD3ζ signaling endodomain fused to the extracellular scFv to act as an activator of the T cells. In terms of IT development, it fell exactly in the "minimal viable product" (MVP) category, the product that has the absolute minimum set of features to function. However, despite promising preclinical results, the clinical trials demonstrated caveats such as poor anti-tumor efficacy in patients, caused by low-level CAR-T cell activation. Therefore, the next 2nd generation was introduced, which included co-stimulatory domains for additional activation. This design was highly successful in the clinical trials in treating hematological malignancies, such as acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). This success was confirmed by the FDA approval of two CD-19 CAR-T drugs, KYMRIAH (Tisagenlecleucel) for r/r ALL and r/r large B cell lymphoma and YESCARTA (Axicabtagene ciloleucel) for r/r extent CLL.

In the process of successful clinical trials for both of these drugs, the core of the "agile development approach" was used to adapt for its clinical features and limitations. Additionally, various CAR-T cell-mediated toxicities were reported, such as tumor lysis syndrome [11], cytokine release syndrome (CRS), neurotoxicity [12], and on-target off-tumor toxicity [13], leading to a few patient deaths during the clinical trials.

The most frequent and dangerous feature of CAR-T therapy is cytokine release syndrome (CRS) [14], which leads to some lethal cases during the trials. The iteration product development cycle, which was at this point enabled by the FDA regulations for adaptive clinical trial design, allowed the identification of strategies to avert this risk by introducing several therapeutic options for CRS, such as anti-IL-6 therapy in case of CRS development, and tools to observe the patient, such as hospitalization for a week after CAR-T infusion to closely monitor for adverse reactions [12, 15].

However, the second CAR-T generation failed to show promising results in the case of solid tumors and had several limitations in treating hematological malignancies, such as antigen loss and consequent tumor escape. Such peculiarities of the second generation CAR-T limited the long-term success of CAR-T cell therapy for a quite large group of patients, leading to relapses or lack of tumor response [15, 16]. With further studies, new ideas emerged, leading to the third and fourth generation of CAR-T cells, comprising more receptor domains with different functions added to the chimeric receptor (Fig. 1).

Samsonov-fig01.jpg

Figure 1. Agile Development process and CAR-T (adapted from [7, 8])

The third-generation CAR-T cells combined the signaling potential of two costimulatory domains (CD28 and 4-1BB). To overcome the limitations of the third generation, the fourth generation of CAR-T assimilated various improvements in different parts of the chimeric construct, mostly linked with solid tumor therapies. The antitumor activity of the fourth-generation CAR-T cells was enhanced by features such as additional transgenes for cytokine secretion (e.g., IL-12) or additional costimulatory ligands. Based on the same principle, armored CAR-T cells and TRUCKs (T cells redirected for universal cytokine killing) are constructed i.e., they were modified to express not only CAR but also the inducible cytokine genes. The cytokine expression occurs only when antigen-binding activates the CAR-T cells [17, 18]. Other CAR-T approaches include the dual-receptor CAR-T cells, which are activated only in the presence of dual antigen tumor cells [19], and bi-epitope CARs [20], which fight antigen escape and loss.

With the increasing potency of CAR-T cells, more caution must be taken to ensure their safety. For solid tumors, the off-target activity becomes a limiting factor, since the target antigens are still expressed on some normal cells, and the cytotoxic activity toward these is not desirable. The first potential action is to adjust antibody affinity, thus mitigating on-target off-tumor toxicities related to low-level antigen expression in the normal tissues. The chimeric antibodies with middle or even low affinity to target can have sufficient potential to eradicate the antigen-overexpressing malignant cells, but not to damage normal tissues with low-level antigen expression [21]. Such situation is possible in case of solid tumors, which can even cause death during CAR-T therapy [22].

Another approach for reducing off-target activity is to fabricate short-lived CAR-T cells. This can be achieved via mRNA delivery with a chimeric construct instead of DNA incorporation into the T-cells. In this case, the T-cells express a CAR for up to several days at high efficiencies; however, the drawback of this approach is rapid loss of the transgenic construct and the T-cell activity associated with it, and a need for several dosages to obtain clinically relevant results [23]. This approach not only allows temporal control over the CAR-T pharmacokinetics but can also be applied with gene-editing tools such as TALEN, disrupting TCR and CD52 expression in the CAR-T cells, thus creating off-the-shelf CAR-Ts. In addition, this approach can expand the scope of therapy to treat hematological tumors. In this context, previous studies reported that by using mRNA-transduced anti-CD19 CAR-T cells targeted against the tumor microenvironment, promising results were obtained in the treatment of Hodgkin’s lymphoma [24]. The transient CAR-T production with mRNA delivery can be a potential option for future in vivo CAR-T therapy wherein, mRNA-loaded particles can be injected into specific T-cells within the patients [25].

Yet another approach to increase safety is via the on-off control of CAR-T cells. The most clinically advanced technology is the inducible suicide caspase-9 gene based on a modified human caspase-9 fused to the human FK506 binding protein (FKBP). This fusion protein, expressed in the T-cells, can form dimers when a chemical inducer of dimerization (AP1903 or Rimiducid) is administered to the patient. A single dose of the inducer drug causes rapid elimination of 85-90% of iC9-transduced T cells [26, 27]. Caspase-9-transduced T cells were used in the clinic as a tool to control graft-versus-host disease (GVHD) after haploidentical stem cell transplantation, and the GVHD-associated symptoms could be also quickly eliminated following the caspase switch activation [28].

With more than 600 ongoing clinical trials [29], there are a lot of features emerging continuously in the CAR-T field, similar to the software "add-ons", aimed to solve particular tasks within a particular setting (or overcome particular difficulties) with a combination of different targets and approaches to improve safety and efficacy, some of which were discussed above. Another important limitation concerns the costs and timing of production. Being completely personalized, the currently approved CAR-T relies solely on the patient’s T-cells for the CAR-T production. Therefore, apart from difficulties in logistics and lead times for therapy, the cost of such therapies becomes a huge burden to the patient and acts as a barrier to the widespread use of CAR-T therapies [30].

This issue has been addressed by off-the-shelf CAR-T and CAR-NK products in development. There are several approaches to treat GVHD which is the main challenge for off-the-shelf CAR–based therapies. One approach to solve this problem is to use other cells with the cytotoxic ability and not αβ T-cells. The NK cells fit this approach and have been used in phase 2 clinical trials. However, such off-the-shelf therapy seems to require fourth-generation CAR constructs including death switches and expression of stimulatory molecules to generate stable CAR-NK cell populations [31]. Gene-editing methods such as CRISPR/Cas9 and TALENs are used to disrupt genes encoding the endogenous TCR as well as human leukocyte antigen (HLA), thus creating universal CAR-T therapy. Apart from deleting human histocompatibility loci in CAR-introduced T-lymphocytes, gene editing and CRISPR-like technologies can be used to insert CAR constructs precisely into particular genome regions, instead of just delivering CAR-programming viral plasmids, which can improve the survival of modified T-cells [32, 33, 34]. Yet another promising option is that gene editing allows the deletion of T-cell suppressive receptors, thereby rendering the T-cells less susceptible to tumor-mediated immunosuppression [35].

The efficacy and safety of CAR-T cell therapy still have broad space for improvement, since not only increased safety but also higher efficacy is required. Notably, disease relapse can occur in up to 50% of patients within a year of therapy. Specific tumor biomarkers are widely used to choose and direct therapy with a growing variety of anti-cancer drugs [36]; therefore, the same approach is expected to benefit more complex CAR-T treatments, introducing the idea of individualized disease management as well as personalized therapy [37]. Safety is the first concern that can be managed with the help of biomarkers as cytokine release syndrome (CRS) and CAR-related encephalopathy syndrome (CRES) which cause up to 60% of life-threatening toxicities [38]. Response rate is also an important aspect that can be determined by biomarkers, especially the primary indications: if up to 90% response can be seen in ALL, according to a meta-analysis by Hou et al. [39], this figure drops to 9% (10-fold lower) in solid tumors.

CRS is caused by activation of T-cells after engagement of their CAR targets. Activated T-cells release various cytokines and chemokines, including interleukin (IL)-6, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and soluble IL-2Rα [40]. These cytokines activate monocytes, macrophages, and other immune cells, which in turn release inflammatory cytokines. However, only a few biomarkers have been identified as predictors in clinical trials: serum levels of IL-6 and IFN-γ in the first 24 h after CAR-T-cell infusion in B-ALL patients have been reported as robust biomarkers of severe CRS and CRES [41]. In NHL patients, increased serum IL-8, IL-10, and IL-15 levels, as well as decrease of transforming growth factor (TGF)-β could also predict severe CRS and potential neurotoxicity [42].

CAR-T efficacy prediction is still a challenging issue [43, 44]. Hence, there is a need to identify new biomarkers, especially with growing insights from the new genomic and transcriptomic analysis methods powered by next-generation sequencing, enabling TCR repertoire and lentiviral integration site analysis that allows for clone evolution of the CAR-T cells in the patient and its interaction with immune system [45].

We can see from the above discussion that the technical part of CAR-T development is open to a huge number of options and features, which can be combined into an optimal product to deliver the best possible combination of safety and efficacy for a wide variety of cancers in a personalized therapeutic manner. It is also clear that the diversity of combinations that is possible with CAR-T cells is huge and growing, along with the complexity and uncertainty of the result. This is similar to the current state of software development; thus, the transfer of effective approaches from this field into CAR-T’s development may benefit research and clinical development.

Area #2 Regulatory

As noted in the Harvard Business Review publication "Embracing Agile" [6], the type of innovation that will favor agile methodology is when "Problems are complex, solutions are unknown, and the scope is not clearly defined. Product specifications may change. Creative breakthroughs and the time to market are important. Cross-functional collaboration is vital".

The experience of drug regulation was just about the opposite: regulatory agencies and financial reimbursement bodies that set bottlenecks for fast drug development processes [46]. However, in recent decades, the most influential regulatory agencies, such as the FDA and EMA, have made huge steps toward flexibility, dialog, and increasing speed for innovations, especially in the field of gene and cell therapies. If we look at the history of changes in FDA regulations, the Orphan Drug Act, which loosens regulations for drugs aimed at conditions affecting less than 200,000 people in the USA (and personalized medicines can fit very well in that) was followed by the Accelerated Approval program that allows approval based on surrogate endpoints (with completion of post-approval Phase 4 trials to maintain approval) [47]. Next, the Fast Track designation allowed more frequent reviews with the FDA and expedited rolling reviews, allowing tighter contact between the regulator and developer [48]. The breakthrough therapy program added on top of it by the FDA allows drugs that fall within it to be approved based on clinical studies with alternative clinical designs that could be smaller in the number of subjects and use surrogate endpoints or biomarkers to determine efficacy [49]. The 21st Century Cures Act [50] has driven the FDA to maximize the use of these programs and supports the use of biomarkers as determinants of therapeutic efficacy rather than clinical outcomes alone. And most importantly for Gene and Cell therapies this act set a new Regenerative Medicine Advanced Therapies (RMAT) designation, that includes cell therapies, therapeutic tissue engineering products, human cell, and tissue products as well as certain human gene therapies and xenogeneic cell products aimed to treat serious disease.

It is important to note that drugs carrying an "orphan drug" designation can access the accelerated pathways mentioned above, requiring smaller trials (on average 3 times smaller vs common diseases), avoiding the need for randomization or double-blinding, and obtaining approval based on surrogate endpoints rather than stricter mortality or survival clinical endpoints.

Similar approaches are used by the European Medicinal Agency (EMA) and set in the number of directives [51, 52], which defines the special types of products-advanced therapy medicinal products. Such ATMPs can also be subject to orphan designation, which is different in the EU vs the USA- prevalence is not more than 5 in 10,000 [53]. Most of the activities and benefits that the developer obtains under ATMP, PRIME, and other expedited regimes are based first on extensive communication and obtaining advice and guidance from regulator experts on the development plans and regulatory strategies, including preclinical and clinical aspects. Again, the conditional approval option on the limited data of safety and efficacy (Phase II) is also possible.

The expedited reviews of new product development, readily available for gene and cell therapies, now provide unique opportunities for implementing the agile approach and increasing the efficiency of development for new therapeutics in this very demanding field. This is especially true when combined with therapy personalization, based not only on clinical diagnosis but also on specific biomarkers that enable particular therapeutic interventions. Since this itself opens the orphan pathway to approval, which is more frequently used, up to 25% of new approvals got an orphan designation [46].

New drugs are not only products to be developed for patients but are also products to be developed as regulators. The fate of the same drug candidate can differ dramatically with differences in clinical and pre-clinical data generation and presentation, in manufacturing and quality control processes and documentation [54], as well as the financial, organizational, and even behavioral characteristics of patients in clinical trials [55]. In this case, the ability to create a set of documents and approaches for approval as an "MVP for regulator" and test it during a face-to-face discussion in the iteration process can provide substantial benefits for the developer to make things faster and cheaper. Importantly, most advanced regulators such as FDA understand the uncertainty in development, which is reflected in recent and important for cell and gene therapy products CMC guidance [56] that of states about critical quality attributes (CQA). "We further acknowledge that understanding and defining product characteristics that are relevant to the clinical performance of the gene therapy may be challenging during early stages of product development, when product safety and quality may not be sufficiently understood".

Accelerated approval options (which not only allow approval of the drug based on the Phase II data but also requires tight communication with the regulator) according to some analysis may decrease R&D costs by up to 500 M$ and shorten the time to market for two years on average [57].

However, accelerated approval or conditioned approval in EMA forces developers to follow additional risk mitigation strategies, such as risk evaluation and mitigation strategies (REMS). The REMS program empowers the FDA to regulate post-market activities in exchange for pre-market approval. Under REMS, providers must continue to monitor and report patients with side effects. The CAR-T treatment sites needed to comply with REMS, approved by the FDA, for 15 years.

REMS for CAR-T includes a set of requirements before the site can start CAR-T treatments (such as having two doses of tocilizumab to prevent CRS and neurological toxicities per patient, requirements for medical staff training, and a system to report adverse effects). Fulfillment of the REMS (FDA) or risk management plan (EMA) requirements should be covered and controlled by the pharmaceutical company in partnership with the practicing clinicians.

Since the regulators understand well that cell and gene therapies are much different even from biologics, they are working intensively to create guidelines for this area. Currently, some guidelines cover areas from preclinical, manufacturing, clinical development, and follow-up [56, 58-65]. It is important to highlight new guidance for devices used in regenerative medicine advanced therapies in which CAR-T therapies are commonly included since it clearly defines the requirements for auxiliary devices used in the CAR-T production process [66].

CAR-T regulatory landscape in Russia

CAR-T in Russia falls into the category of biomedical cell products, which are regulated by the federal law # 180-FZ and all linked documents [67]. A full set of regulatory documents was completed in 2020, and real-life application for this law is in the early stage, there are no approved products and only one completely certified production site for cell therapy. Importantly, this law allows for written and even face-to-face consultations directly with experts of the regulator (Federal State Budgetary Institution "SCEEMP"), which is an important step to support the development of complex cell therapies.

Area #3. Production

The next step involved in making the therapy available to the patient is production. Since we are transitioning from the one-pill-fits-all to the one-pill-for-one patient model, the industry understands that big plants are not of much use in this new reality. CAR-T development not only opens issues that are specific to this field, but also provides some solutions to it [68]. New models of production start to emerge (see Table 1 "Cell therapy production. Emerging models", [69-71]). One of the most common strategies to produce in-house CAR-T cells is small-scale production volume, which is just fit to the number of patients in the clinic using cell-modifying equipment such as the CliniMACS Prodigy® system [67], which allows for the small-scale process of cell transformation and sorting for clinical applications.

The overall "agile-like" approach we have discussed above is used in personalized therapies like CAR-Ts such that the therapies are more effective and shorten the development cycle. If we can reduce the production duration and bring the product closer to the patient, it will bring several benefits to the entire system:
1. Benefits to the patient by shortening the duration of manufacturing and transportation. Better adjustment of therapy options due to faster response if the production site is in the clinics, enabling flexibility of regimes and targets.
2. The benefit to pharma companies – big investments in large production facilities are not needed.
3. The benefit to the regulator-better control of safety.

Such close-to-patient therapy production opens new possibilities for treatment adjustments, such as biomarker-assistant cell dosage, relapse, and tumor escape treatment with CARs aimed at different targets.

Academia in business

One feature of the agile approach towards product development is the non-hierarchical horizontal structure of teams of interdisciplinary experts. CAR-T is a product which requires tight collaboration between the pharmaceutical industry and clinics, that are most frequently vertically oriented; however, there are several examples of academia being an active part of the business. Some examples are:

Joint ventures | Startups
In 2013, the Fred Hutchinson Cancer Research Center (FHCRC), Memorial Sloan Kettering Cancer Center (MSKCC), and Seattle Children's Research initiated Juno Therapeutics company as a result of previous long collaboration in CAR-T development, and further started joint ventures with Juno Therapeutics for more than four clinical trials [73].

Academic institution networks, that unite researchers, developers, clinical centers, and companies for developing new therapy
The BioCanRx network (Canada immunotherapy network) is a pan-Canadian network of expertise and infrastructure for the development, manufacturing, and clinical testing of new immunotherapies. It was established in 2016 to boost infrastructure and manufacturing capacity to support bench-to-bedside research and to ultimately increase the access to CAR-T by increasing the number of clinical trials available to Canadian patients, as well as to empower innovations in the engineered T-cell area. It survived government financing cuts and delivered two CAR-T candidates in several clinical trials, including closed-cycle point-of-care CAR-T devices [74].

Multi-country consortia between the academic institutions and small companies allow bypassing big pharmaceutical companies or large investments in CAR-T development
The EURE-CART Alliance involved six academic centers from five countries, and three small and one medium-sized enterprise to conduct clinical trials of CAR-T candidates and to clinically develop CAR-T platforms. In 2020, the alliance started the first clinical trial of a CAR-T, CD44v6 candidate [75].

Crowdfunding consortia
The rare disease consortia started in 2008, uniting patients, charity, and academic research to develop a treatment for the Rett syndrome. In total, more than 60 M$ were collected to finance research or attract research teams in gene therapy and cell therapy dedicated towards curing this syndrome. Multiple collaborations of scientists covered different steps in therapy development. Enabling collaboration with AveXis made this company focus on Rett syndrome, develop AVXS-201 gene replacement therapy up to the preclinical phase, and even managed to keep it in the Novartis pipeline with a fixed date for IND application in 2021 [76]. The same community advanced other gene therapy candidates TSHA-102 with Taysha Therapeutics [77].

As we can see from these examples, forming [6] consortia can indeed deliver therapeutic products in this very complex and challenging field of gene and cell therapy due to advancements in collaboration and working in cross-functional teams, even though it lacks the power and experience of big pharmaceutical companies. However, this can be addressed by skillful application of agile processes technology giants.

Gene and cell technologies and new technology giants
An important point for the future of the healthcare sector, which was boosted in recent years, is the increased support from regulators, such as the US FDA, emerging and more effective technologies, decreasing time to market for them. Big data, genome-based personalization of treatments, and gene-editing are all included in the new focus of attention of regulators, which can possibly reduce the costs of treatment and drugs, and overall decrease the healthcare expenses [78, 79].

Since IT-born agile ideology can be applied to the development of personal therapeutics, they are sweet points of entry into the pharmaceutical market for tech giants who are experts in this development methodology.

One interesting example is the story of Jeff Bezos, Amazon, and Juno Therapeutics, which initiated a possible entry of Amazon into the CAR-T business with 7 years of approval, and possible changes in the US healthcare industry [80].

• 2013 – Juno Therapeutics spin-off from the Fred Hutchinson Cancer Research Center.
• 2014 – Bezos invests Juno 20M$ in 140M$ round.
• 2014 – Bezos family gifted the Fred Hutchinson Cancer Research Center 30M$ to create 1 in the USA clinic for immunotherapy treatment (Bezos Family immunotherapy clinic).
• 2018 – Celgene Juno was sold to Celgene, later to BMS.
• 2018 – Bezos (Amazon) enter the US drug market.
• 2019 – Juno ex-executives started company Sana, dedicated to the development of cell-based treatments ("ultimate next-gen cell engineering company with gene therapy and cell therapy").
• 2019 – Bezos (Amazon) enter the telemedicine and medical insurance markets.
• 2020 – Bezos and other VC invest 700M$ in Sana.
• 2020 – Seattle Cancer Care Alliance, including Bezos Family immunotherapy clinic, hosts 33 clinical trials of immunotherapies.
• 02.2021 – Approval of Juno CAR-T JCAR017 (BMS’ Liso-cel).

One interesting story to tell is Jeff Bezos's investments in the gene and cell therapies company, Juno back in 2014. From that time, Juno went through a series of M&As, starting from $6 billion ended up with $67 billion to BMS. Last year, Bezos again invested in the same Juno team, now gathered under the name Sana, to develop next-generation gene and cell therapies [81]. During these times, Amazon entered the drug delivery and medical insurance markets [82]. Some might infer that it was just smart investments, and it can be seen that Amazon now understands and is building a technology-oriented healthcare infrastructure, opening the existing bottlenecks for new, high-tech, and more efficient healthcare solutions. When the technology giants enter the field of healthcare, the market is destined to change dramatically.

Conclusion

When we look at the gene and cellular therapies, and, in particular, the CAR-T therapies as its most developed and effective segment, it vividly shows general approaches and challenges of this field, as well as features that are particular to the personal therapeutics. We can see that on the technological side, despite the common CAR-T platform, a variety of diseases and corresponding molecular targets, combined with the particularities of patient population groups, will require a diverse set of properties for such drugs, possibly with some features of opposite functions. In turn, to make the most of such flexible and programmable therapeutic platforms as CAR-T, an agile, iteration-based approach of product development can be used, and in fact, has already been used to bring the current flagship therapeutics like KYMRIAH to the market. Moreover, the current regulation for the cell- and gene-based therapeutics, new production technologies, methods of research, development, and clinical collaboration for such products can empower the agile approach, decreasing the costs and time to market such therapies, as well as bringing in new players from the IT and high technology industries to the pharmaceutical market.

Conflict of interest

No potential conflict of interest is reported.

References

  1. Loew A, Milone M C, Powell DJ, Zhao Y. Treatment of cancer using chimeric antigen receptor. WIPO Patent WO2015142675A2, 2015.
  2. FDA news release. FDA approval brings first gene therapy to the United States U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-st.... 30 Aug 2017. Accessed 22 Feb 2021.
  3. ASCO news releases. CAR T-cell immunotherapy named advance of the year in annual ASCO Report. ASCO. https://www.asco.org/about-asco/press-center/news-releases/car-t-cell-immunotherapy-named-advance-ye.... 30 Jan 2018. Accessed 22 Feb 2021.
  4. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi: 10.1056/NEJMoa1709866
  5. Seimetz D, Heller K, Richter J. Approval of First CAR-Ts: Have we solved all hurdles for ATMPs? Cell Med. 2019 Jan 22;11:2155179018822781. doi: 10.1177/2155179018822781
  6. Rigby, Darrell K., Sutherland J, Takeuchi H. Embracing Agile: How to master the process that's transforming management. Harvard Business Review. 2016;94 (5): 40-50.
  7. Ries E. The Lean Startup: How today's entrepreneurs use continuous innovation to create radically successful businesses. Crown Business, 2011.
  8. Subklewe M, von Bergwelt-Baildon M, Humpe A. Chimeric antigen receptor T cells: a race to revolutionize cancer therapy. Transfus Med Hemother. 2019;46(1):15-24. doi: 10.1159/000496870
  9. Hui K, Grosveld F, Festenstein H. Rejection of transplantable AKR leukaemia cells following MHC DNA-mediated cell transformation. Nature. 1984;311(5988):750-752. doi: 10.1038/311750a0
  10. Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181(5):1653–1659. doi: 10.1084/jem.181.5.1653
  11. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8): 725-733. doi: 10.1056/NEJMoa1103849
  12. Vairy S, Garcia JL, Teira P, Bittencourt H. CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Drug Des Devel Ther. 2018;12:3885-3898. doi: 10.2147/DDDT.S138765
  13. Hombach A, Hombach AA, Abken H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response. Gene Therapy. 2010;17(10):1206-1213. doi: 10.1038/gt.2010.91
  14. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS. M, et al. Cytokine release syndrome. J Immunother Cancer. 2018; 6(1):56. doi: 10.1186/s40425-018-0343-9
  15. Stoiber S, Cadilha BL, Benmebarek MR, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019;8(5):472. doi: 10.3390/cells8050472
  16. Li X, Chen W. Mechanisms of failure of chimeric antigen receptor T-cell therapy. Curr Opin Hematol. 2019;26(6):427-433. doi: 10.1097/MOH.0000000000000548
  17. Chmielewski M, Abken H. TRUCKS, the fourth generation CAR T cells: Current developments and clinical translation. Adv Cell Gene Ther. 2020; 3:e84. doi: 10.1517/14712598.2015.1046430
  18. Yeku OO, Purdon TJ, Koneru M, Spriggs D, Brentjens RJ. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci Rep 2017; 7:10541. doi: 10.1038/s41598-017-10940-8
  19. Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA. Precision tumor recognition by T cells withcombinatorial antigen-sensing circuits. Cell. 2016; 164:770- 779. doi: 10.1016/j.cell.2016.01.011
  20. Xu J, Chen LJ, Yang SS, et al. Exploratory trial of a biepitopic CAR T- & targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci USA. 2019;116:9543-9551. doi: 10.1073/pnas.1819745116
  21. Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, Cogdill AP, Li N, Ramones M, Granda B. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75:3596-3607. doi: 10.1158/0008-5472.CAN-15-0159
  22. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 2010;18: 843-851. doi: 10.1038/mt.2010.24
  23. Foster JB, Barrett DM, Karikó K. The emerging role of in vitro-transcribed mRNA in adoptive T cell immunotherapy. Mol. Ther. 2019;27:747-756. doi: 10.1016/j.ymthe.2019.01.018
  24. Svoboda J, Rheingold SR, Gill SI, Grupp SA, Lacey SF, Kulikovskaya I et al. Nonviral RNA chimeric antigen receptor-modified T cells in patients with Hodgkin lymphoma. Blood. 2018;132:1022-1026. doi: 10.1182/blood-2018-03-837609
  25. Veiga N, Goldsmith M, Granot Y, Rosenblum D, Dammes N, Kedmi R, et al. Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. Nat. Commun. 2018;9:4493. 3. doi: 10.1038/s41467-018-06936-1
  26. Straathof KC, Pulè MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105:4247-4254. doi: 10.1182/blood-2004-11-4564
  27. Diaconu I, Ballard B, Zhang M, Chen Y, West J, Dotti G, et al. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T Cells. Mol. Ther. 2017;25:580-592. doi: 10.1016/j.ymthe.2017.01.011
  28. Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015;125:4103-4113. doi: 10.1182/blood-2015-02-628354
  29. Search list results. CAR-T | Recruiting, Not yet recruiting, Active, not recruiting, Enrolling by invitation Studies. https://clinicaltrials.gov/ct2/results?cond=&amp;term=CAR-T+&amp;cntry=&amp;state=&a.... Accessed 22 Feb 2021.
  30. Fiorenza S, Ritchie DS, Ramsey SD, Turtle CJ, Roth JA. Value and affordability of CAR T-cell therapy in the United States. Bone Marrow Transplant. 2020;55(9):1706-1715. doi: 10.1038/s41409-020-0956-8
  31. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020;382(6):545-553. doi: 10.1056/NEJMoa1910607
  32. Lee J, Sheen JH, Lim O, Lee Y, Ryu J, Shin D, et al. Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy. Sci Rep 2020; 10, 17753. doi: 10.1038/s41598-020-74772-9
  33. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19:185-199. doi: 10.1038/s41573-019-0051-2
  34. Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374):eaaj2013. doi: 10.1126/scitranslmed.aaj2013
  35. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR-T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255-2266. doi: 10.1158/1078-0432.CCR-16-1300
  36. Liu D. Cancer biomarkers for targeted therapy. Biomark Res. 2019;7:25. doi: 10.1186/s40364-019-0178-7
  37. Du M, Hari P, Hu Y, Mei H. Biomarkers in individualized management of chimeric antigen receptor T cell therapy. Biomark Res. 2020;8:13. doi: 10.1186/s40364-020-00190-8
  38. Wang Z, Han W. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res. 2018;6(22):4. doi: 10.1186/s40364-018-0116-0
  39. Hou B, Tang Y, Li W, Zeng Q, Chang D. Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis. Dis Markers. 2019;2019:3425291. doi: 10.1155/2019/3425291
  40. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664-679. doi: 10.1158/2159-8290.CD-16-0040
  41. Hay KA, Hanafi L, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295-2306. doi: 10.1182/blood-2017-06-793141
  42. Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):116r-355r. doi: 10.1126/scitranslmed.aaf8621
  43. Cahill KE, Leukam MJ, Riedell PA. Refining patient selection for CAR T-cell therapy in aggressive large B-cell lymphoma. Leuk Lymphoma. 2020;61(4):799-807. doi: 10.1080/10428194.2019.1691201
  44. Du M, Hari P, Hu Y, Mei H. Biomarkers in individualized management of chimeric antigen receptor T cell therapy. Biomark Res. 2020;8:13. doi: 10.1186/s40364-020-00190-8
  45. Sheih A, Voillet V, Hanafi LA, DeBerg HA, Yajima M, Hawkins R, et al. Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy. Nat Commun. 2020;11(1):219. doi: 10.1038/s41467-019-13880-1
  46. Van Norman GA. Update to drugs, devices, and the FDA: How recent legislative changes have impacted approval of new therapies. JACC Basic Transl Sci. 2020;5(8):831-839. doi: 10.1016/j.jacbts.2020.06.010
  47. Accelerated Approval Program. U.S. Food and Drug Administration. https://www.fda.gov/drugs/information-healthcare-professionals-drugs/accelerated-approval-program. Accessed 22 Feb 2021.
  48. Fast Track. U.S. Food and Drug Administration. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fa.... Accessed 22 Feb 2021.
  49. Breakthrough Therapy. U.S. Food and Drug Administration. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/br.... Accessed 22 Feb 2021.
  50. 21st Century Cures Act. U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act. Accessed 22 Feb 2021.
  51. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 Off. J. Eur. Union, L324 (2007), pp. 121-137.
  52. Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products, Off. J. Eur. Union, L242 (2009), pp. 3-12.
  53. European Medicines Agency. Procedural advice for orphan medicinal product designation. Guidance for sponsors. 2020; EMA/420706/2018 Rev 91. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/procedural-advice-orphan-medi.... Accessed 22 Feb 2021.
  54. Carvalho M, Martins AP, Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European Marketing Authorization Applications. Drug Discov Today. 2019;24(3):823-828. doi: 10.1016/j.drudis.2018.12.007
  55. Fogel DB. Factors associated with clinical trials that as behavioral fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018;11:156-164. doi: 10.1016/j.conctc.2018.08.001
  56. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). U.S. Food and Drug Administration. https://www.fda.gov/media/113760/download. Accessed 22 Feb 2021.
  57. Prasad V, Mailankody S. Research and Development Spending to Bring a Single Cancer Drug to Market and Revenues After Approval. JAMA Intern Med. 2017;177(11):1569-1575. doi: 10.1001/jamainternmed.2017.3601
  58. Long Term Follow-Up After Administration of Human Gene Therapy Products Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/113768/download. Accessed 22 Feb 2021.
  59. Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations Draft Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/134731/download. Accessed 22 Feb 2021.
  60. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/120267/download. Accessed 22 Feb 2021.
  61. Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products Guidance for Industry. U.S. Food and Drug Administration.https://www.fda.gov/media/89036/download. Accessed 22 Feb 2021.
  62. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/106369/download. Accessed 22 Feb 2021.
  63. Guidance for Industry. Preclinical Assessment of Investigational Cellular and Gene Therapy Products. U.S. Food and Drug Administration. https://www.fda.gov/media/87564/download. Accessed 22 Feb 2021.
  64. Guidance for Industry. Guidance for Human Somatic Cell Therapy and Gene Therapy. U.S. Food and Drug Administration. https://www.fda.gov/media/72402/download. Accessed 22 Feb 2021.
  65. Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/113790/download. Accessed 22 Feb 2021.
  66. Evaluation of Devices Used with Regenerative Medicine Advanced Therapies. Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/120266/download. Accessed 22 Feb 2021.
  67. The Federal Law No. 180-FZ dated 23 June 2016 'On Biomedical Cell Products' (in Russian).
  68. Lulla P, Ramos CA. Expanding Accessibility to CD19-CAR T Cells: Commercializing a "Boutique" Therapy. Mol Ther. 2017;25(1):8-9. doi: 10.1016/j.ymthe.2016.12.002
  69. Bozenhardt EH, Bozenhardt HF. Repurposing An Aging Facility To Produce Cell & Gene Therapies: Layout & Design Considerations. Cell & Gene. https://www.cellandgene.com/doc/repurposing-an-aging-facility-to-produce-cell-gene-therapies-layout-.... August 24, 2020. Accessed 22 Feb 2021.
  70. Raper V. Crafting a More Efficient CAR T-Cell Industry. Genetic Engineering & Biotechnology News. 2019;39(5):24-26.
  71. Pharmaceutical & biotechnology industry update. August / September 2019. McIlvaine Company. http://www.mcilvainecompany.com/industryforecast/pharmaceutical/updates/2019%20updates/august.htm#Pl.... Accessed 22 Feb 2021.
  72. CliniMACS Prodigy Instrument. Miltenyi Biotec. https://www.miltenyibiotec.com/US-en/products/clinimacs-prodigy.html?countryRedirected=1#gref. Accessed 22 Feb 2021.
  73. Leading cancer research centers team up to launch biotech startup focused on cancer immunotherapy. Fred Hutchinson Cancer Research Center. https://www.fredhutch.org/en/news/releases/2013/11/biotech-startup-cancer-immunotherapy.html. Dec. 4, 2013. Accessed 22 Feb 2021.
  74. Made-in-Canada CAR T Therapy Timeline. BioCanRx, Canada’s Immunotherapy Network. https://biocanrx.com/research/made-canada-car-t-therapy-timeline. Accessed 22 Feb 2021.
  75. First Patient treated within EURE-CART Clinical Trial. EURE-CART. https://www.eure-cart.eu/news/news/news-detail/tx_news/first-patient-treated-within-eure-cart-clinic.... February 19 2020. Accessed 22 Feb 2021.
  76. Coenraads M. Novartis OAV201 Update. Rett Syndrome Research Trust. https://reverserett.org/novartis-oav201-update. February 9, 2021. Accessed 22 Feb 2021.
  77. Dear Rett Syndrome Community. Rett Syndrome Research Trust. https://reverserett.org/wp-content/uploads/2021/02/taysha-rett-community-letter-02-17-2021.pdf February 17, 2021. Accessed 22 Feb 2021.
  78. Statement from FDA Commissioner Scott Gottlieb, M.D., on proposed modernization of FDA’s drug review office. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-pro.... June 04, 2018. Accessed 22 Feb 2021.
  79. HEALTHY INNOVATION, SAFER FAMILIES: FDA’S 2018 STRATEGIC POLICY ROADMAP. U.S. Food and Drug Administration. https://www.fda.gov/media/110587/download. January 2018. Accessed 22 Feb 2021.
  80. Fred Hutch statement regarding the FDA approval of CD19 immunotherapy, lisocabtagene maraleucel. Fred Hutchinson Cancer Research Center. https://www.fredhutch.org/en/news/releases/2021/02/fred-hutch-statement-regarding-the-fda-approval-o.... Feb. 5, 2021. Accessed 22 Feb 2021.
  81. Thorne J. Former Juno execs unveil Sana, a new cell engineering biotech that’s reportedly raising more than $800M. GeekWire. https://www.geekwire.com/2019/led-former-juno-execs-sana-new-cell-engineering-biotech-thats-reported... January 7, 2019. Accessed 22 Feb 2021.
  82. Freedman DH. Do you trust Jeff Bezos with your life? Tech giants like Amazon are getting into the health care business. Newsweek. https://www.newsweek.com/amazon-health-care-jeff-bezos-telemedicine-1475154. December 3 2019, Accessed 22 Feb 2021.
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Самсонов<sup>1</sup>, Андрей М. Ломоносов<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(101) "

Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, 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) "27584" ["VALUE"]=> array(2) { ["TEXT"]=> string(1930) "<p style="text-align: justify;">За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1874) "

За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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Mikhail Yu. Samsonov1, Andrey M. Lomonosov2

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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The last decade has witnessed a significant advancement in medical science and technologies. The cell and gene therapies represent remarkable outcomes of such progress achieved in a very short timeframe. The COVID-19 pandemic has created roadblocks for patients to access hospitals for diagnosis and treatments since the onset of its first-wave. On the contrary, this one-year leap has witnessed unprecedented technological advances, especially in terms of mRNA-based therapies and their regulations. The present review focuses on CAR-T as a model with all key attributes and implications in complicated chains from early science to a variety of models and trends in clinical practice.

Keywords

Cell and gene therapy, CAR-T therapy, risk management plan, agile development approach.

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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1 RPharm JSC; Department of Pharmacology, Institute for Pharmacy, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 Healthnet Working Group of National Technology Initiative, Moscow, Russia


Correspondence
Dr. Mikhail Yu. Samsonov MD, PhD, RPharm. Leninsky prospect 111, Moscow, Russia
E-mail: samsonov@rpharm.ru

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Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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Михаил Ю. Самсонов1, Андрей М. Ломоносов2

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За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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За последнее десятилетие достигнуты значительные успехи в медицинской науке и прикладных технологиях. Клеточная и генная терапия позволили добиться выдающихся результатов этих разработок в течение очень коротких сроков. С начала первой волны заболеваемости, пандемия COVID-19 создала препятствия для пациентов в плане доступа к диагностике и лечению в госпитальных условиях. С другой стороны, этот годичный период был ознаменован беспрецедентными технологическими достижениями, особенно – в аспекте терапии, основанной на применении мРНК и ее законодательного регулирования. В настоящей обзорной статье обращается особое внимание на CAR-T-клетки в качестве клинической модели со всеми ключевыми атрибутами их внедрения в рамках сложных цепочек – от первичных научных исследований к многообразию моделей и тенденций их применения в клинической практике.

Ключевые слова

Клеточная и генная терапия, CAR-T–клеточная терапия, планирование управлением рисками, гибкое развитие.

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, Москва, Россия

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1 ООО Р-Фарм; Отдел фармакологии, институт фармации, Первый Московский государственный медицинский университет
им. И. Сеченова, Москва, Россия
2 Рабочая группа Хелснет Национальной технологической инициативы, Москва, Россия

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Introduction

Transplant-associated thrombotic microangiopathy (TA-TMA) was initially identified as a complication of allogeneic hematopoietic stem cell transplantation (HSCT) in the late 1980-s, primary as a complication of a graft-versus-host disease (GVHD) prophylaxis with cyclosporine [1, 2]. However, subsequently it was demonstrated that cyclosporine is not the only predisposing factor, and TA-TMA may be observed even after autologous HSCT [3] or high-dose chemotherapy [4]. Absence of diagnostic criteria for almost two decades precluded the appearance of any solid epidemiological data on the incidence of this complication. The reported incidence varied from 0.1% to 29%. Mean incidence across studies was 8.2%. Mortality in the majority of case series exceeded 50% [5-9]. In the modern era, the incidence varies from 3% in the registry studies in predominantly adult population [10] to 16% in the pediatric prospective studies [11]. This difference might represent identification and inclusion of mild TA-TMA cases in the prospective studies. In these recent studies TA-TMA was associated with additional 15% mortality when compared to patients without TA-TMA, also reflecting the spectrum of TA-TMA severity [9, 11].

Diagnostics of TA-TMA

Part of the diagnosis is assessment of TA-TMA probability in the particular HSCT patient. The major risk factors are transplantation from alternative donors, HLA-mismatched donors, non-myeloablative conditioning or intensified myeloablative conditioning, use of anti-lymphocyte globulin, GVHD prophylaxis with combination of calcineurin and mTOR inhibitors and prior HSCT [9,12,13]. Genetic predisposition include polymorphism in the complement pathway genes, including CFH, CFHR, CFI, CFB, C3 and several others. Certain HLA alleles in recipients were also reported to predispose to TA-TMA. Usually presence of several genetic variants and a triggering factor is required for development of TA-TMA [14]. Although TA-TMA may be not associated with additional complications of HSCT common, major clinical triggers are acute GVHD, particularly steroid-refractory form, viral reactivations, high concentrations of calcineurin inhibitors, or severe bacterial infections [15-17].

It should be admitted that currently there are no uniform criteria for TA-TMA. Primary TA-TMA was identified by the presence of microangiopatic hemolysis, fragmented cells (schistocytes), elevation of lactate dehydrogenase (LDH), thrombocytopenia, and organ damage due to microangiopathy, including renal failure or neurologic dysfunction [5, 6].

In 2005-2007, two consensus diagnostic criteria were developed, including Blood and Marrow Transplant Clinical Trials Network (BMT CTN) by Ho et al. [19] and International Working Group (IWG) by Ruutu T. et al. [20]. Analysis of the overlap between these criteria by Cho et al. has shown that twice less patients are diagnosed with TA-TMA using IWG criteria, while less than 10% of patients diagnosed with IWG criteria do not fall into the frame of BMT CTN criteria [21]. The "overall TMA" criteria were proposed on the basis on this analysis, i.e., ≥2% of schistocytes, elevation of LDH, decrease of hemoglobin and platelets. These "overall TMA" criteria are the most commonly used in the studies of novel agents (Table 1). Besides the differences with diagnostic criteria there is a technical problem with the key laboratory index of TA-TMA: schistocyte quantification, which is not standardized. Therefore, its morphological evaluation can provide various results from one laboratory to another [22].

Table 1. Overview of different diagnostic TA-TMA criteria

Moiseev-tab01.jpg

There are several reasons for the non-uniformity of accepted criteria. First, TA-TMA is a syndrome with endothelial dysfunction as the key pathogenetic feature. However, some degree of endothelial injury is present in all HSCT recipients [23]. Of note, the median level of schistocytes after allogeneic HSCT is around 1%, which is very close to the diagnostic level of BMT CTN criteria [24]. This difference could be easily alleviated by the differences in the morphological practices between transplantation centers. An autopsy study demonstrated 10% of patients who died from various causes had evidence of renal microangiopathy [25]. Other complications of HSCT that are also associated with significant endothelial injury can mimic TA-TMA. These are steroid-refractory GVHD, hemorrhagic viral enterocolitis, sepsis and hemorrhagic cystitis [25, 27, 28]. Thus, there is a spectrum of patients with various degrees of endothelial injury and complement activation after HSCT. In the absence of proven effective interventions it is hard to draw the border, where we can say that this degree of endothelial injury is TA-TMA. Emergence of novel therapies will drive the development of novel diagnostic criteria and this set of criteria will define the group of patients that will benefit from certain therapies.

On the other hand, TA-TMA is not only a syndrome with variable severity, but also a syndrome emerging due to a variety of etiological factors. In children, a clear relationship may exist between mutations in the complement – related genes, alterations in the complement pathway and evidence of complement activation that correlates with the clinical presentation. In pediatric cohort, the level of serum soluble membrane attack complex (C5b-9) was elevated in around 70% of TA-TMA patients. These patients had a more fulminate disease course and higher risk of mortality [29]. There are ethnic differences in the incidence of complement-associated TA-TMA. Hence, the exact percentage of this clinical entity may vary across countries [11]. However, in the adult population there is only limited data on complement activation after unmanipulated haploidentical transplantation [30], and In the general population of adult patients several relatively different entities can be distinguished: GVHD-related, drug-induced (primarily, calcineurin and mTOR inhibitors), infection-related (cytomegalovirus and herpes type 6 are most frequently reported viruses), and those associated with other HSCT toxicities. The same entity as in children with overt multiorgan failure and complement activation comprises only a minor subgroup of adult patients [13]. Vice versa 30% of children without complement activation, likely, have similar pathogenetic mechanisms to the adult population.

The large proportion of pediatric patients with complement activation led to the development of a diagnostic algorithm by Jodele S et al. [31]. It involves screening with serial measurement of LDH, proteinuria and blood pressure. If any of these parameters become abnormal, ADAMTS13-related TTP should be excluded and laboratory workout for TA-TMA should be performed. To confirm the diagnosis of TA-TMA, histological evidence of the organ involvement is sufficient. Alternatively, increased LDH, schistocytes on blood smear, de novo thrombocytopenia, or platelet transfusion dependence, arterial hypertension, proteinuria ≥30 mg/dL and elevation of soluble C5b-9 should be documented.

In clinical practice, local standards of TA-TMA diagnosis vary significantly due to above mentioned difficulties [9, 22], and it is hard to recommend one or another strategy. Before using certain diagnostic approach one should decide what will be an application of this approach.

Identification of patients with endothelial injury in the prospective clinical studies is one thing, selecting patients who will benefit from clinical interventions represents another task. However, several practical suggestions can be made to avoid under- and overdiagnosis of this complication. Regular screening of LDH and creatinine levels, proteinuria and blood pressure will identify potential patients at risk for TA-TMA. Further laboratory evaluation is required for the patients who have de novo grade 3-4 anemia or thrombocytopenia, never became transfusion-independent, or those who had acute kidney injury or neurologic dysfunction on the top of positive screening results. Other groups of patients without these key features are unlikely to require any interventions, even if TA-TMA evidence could be obtained from laboratory testing. Schistocyte evaluation is required to confirm the diagnosis, and Coombs test is required to rule out immune hemolytic anemia. When applying morphological criteria of TA-TMA, several rules were formulated for schistocyte quantification that allow to capture TMA-specific changes in the blood smears (Table 2) [22]. The patients with ≥2% schistocytes can be clinically considered having TA-TMA. Rising schistocyte and LDH levels on serial measurement additionally support the diagnosis. Although ADAMTS13 activity is included in the Jodele S et al. algorithm [31], but the incidence of this TMA mechanism in HSCT recipients is limited to single observations [32, 33]. Elevation of sC5b9 >300 ng/mL and angiopoietin-2 to >3 ng/mL can also provide evidence in favor of TMA diagnosis [33].

Table 2. Laboratory approach to the schistocyte quantification in TA-TMA

Moiseev-tab02.jpg

There is no well-established system for assessment of TA-TMA severity. Certain clinical features associated with higher mortality were reported, e.g., presence of neurological signs, acute kidney injury, LDH≥2 upper limits of normal (ULN), a need for ≥2 medications to control hypertension [29, 34]. The BMT CTN consensus proposed common toxicity criteria of severity, where grade 1 corresponded to absence of clinical consequences; grade 2 is assessed at elevated creatinine levels of ≤3 ULN; grade 3 corresponded to creatinine levels of >3 ULN not requiring dialysis, and grade 4 was characterized as renal failure requiring dialysis, and/or encephalopathy. Nonetheless, this severity system was not validated to predict survival of patients with TA-TMA and is rarely used during application of novel therapies.

Treatment of transplant-associated thrombotic microangiopathy

Currently, there are no established treatments of TA-TMA. Historically, therapeutic plasma exchange (TPE) was used, by analogy of thrombotic thrombocytopenic purpura, with a common standard of care. Despite early reports on its efficacy [35], the latest consensus established that average response rate, mostly defined by the subsided laboratory criteria, was 37% for 121 TPE-treated patients. Average mortality across all the patients was 79%, and the consensus stated that plasma exchange should not be considered a standard of care for TA-TMA [36]. The controversial results of TPE treatment may be related to very low frequency of ADAMTS-13-associated mechanism in TA-TMA [33].

Several other treatments were used outside clinical trials in TA-TMA. These included rituximab [37, 38, 39], defibrotide [40, 41, 42], and eculizumab [43, 44, 45, 46]. Clinical efficacy and mechanisms of rituximab in TA-TMA can be hardly assessed with only seven patients reported in the literature. On the other hand, 165 patients were treated with either defibrotide or eculizumab with a very comparable response rate of 73% and 58%, respectively. Nonetheless, overall mortality remained high with both treatments and was 40% across the studies. Particularly favorable results were reported by Jodele et al. with eculizumab in the pediatric cohort where large proportion of patients had mutations in complement-related genes and clear laboratory signs of complement activation [11, 12]. In this cohort, evaluation of eculizumab concentrations demonstrated higher drug clearance than in paroxysmal nocturnal hemoglobinuria as one of the mechanisms behind the lack of efficacy. Thus, Jodele et al. proposed the algorithm of weekly induction doses and additional induction doses based on daily CH50 activity [47]. Two small clinical trials also evaluated narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, also targeting complement pathway. Improvement of laboratory signs was observed in a proportion of patients and overall survival was 50% [48, 49] (Table 3). Looking at the response and survival rate of all these pharmacological treatments, it is clear that, if compared to PTE, they have merit in a proportion of patients. However, their administration was based on various indications and various diagnostic criteria. In the absence of severity criteria, it is also impossible to compare the groups of patients in these studies. Thus, it is difficult to recommend either approach as the first-line treatment. On the other hand, currently published data on the pharmacological treatments rather postulates the necessity for common criteria for severity and response based on empirical data.

Table 3. Results of clinical studies in transplant-associated thrombotic microangiopathy

Moiseev-tab03.jpg

Common first-line intervention for TA-TMA is to manipulate with immunosuppression regimens. The idea comes from early observations that inclusion of cyclosporine A in the prophylaxis regimens was associated with first documented TA-TMA cases [1, 2]. Further evidence for toxicity of calcineurin inhibitors (CNIs) towards endothelium [50] created the basis for tapering or discontinuation of CNIs in patients with TA-TMA [51]. Due to essential needs for GVHD control in the majority of these patients, glucocorticosteroids were historically administered in the most patients after CNIs discontinuation. Recent Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus supported discontinuation of CNIs as the primary intervention based on expert opinion [36]. Nonetheless, the large single-center analysis by Li et al. did not show any benefit in terms of overall survival, when tapering or discontinuing CNIs vs their continuation in all subgroups of TMA patients, irrespective of type of GVHD prophylaxis [52]. It seems that, like all other interventions in TMA, sole discontinuation of CNIs does not lead to resolution of symptoms in all the patients, but the time to resolution might be quicker. Also, the different centers are testing other type of agents for GVHD prophylaxis instead of CNIs, with effects on survival outcomes. In our single-center analysis, substitution of CNIs by sirolimus in severe GVHD proved to be superior to steroids [53]. Novel agents, like JAK inhibitors, might also facilitate sufficient GVHD control instead of CNIs without additional endothelial damage [54]. Further investigation of different substitution strategies are warranted. Even in continuation strategies, a pause before obtaining CNI concentration is a rational approach, because the majority of patients show a transitory reduction of CNIs clearance, and high concentrations are common at TMA diagnosis.

Conclusion

Along with clinical criteria, diagnostics of TA-TMA involves several laboratory tests, of which erythrocyte shistocytosis remain a less standardized criterion [22, 55]. Screening of LDH and creatinine levels, proteinuria and blood pressure, exclusion of autoimmune haemolysis should discern potential patients at risk for TA-TMA.

Further improvement of care in TA-TMA requires harmonization of definitions for mortality risk, response, outcome measures and indications for treatment. Since this is a relatively rare entity and even large centers rarely has information on more than 50-100 cases, cooperative effort to gather empirical data is crucial to formulate these definitions, only after that existing and novel therapies can be compared without bias in the multicenter studies. For current clinical practice, internal institutional guidelines should select one of the diagnostic criteria and adhere to them. Reduction or discontinuation of calcineurin inhibitors should be considered in all patients, but internal guidelines for substitution with active immunosuppressive agents should be developed for GVHD control. Novel treatments should be implemented in case of organ failure, or in patients not responding to immunosuppression manipulation.

Conflicts of interest

None reported.

References

  1. Myers BD. Cyclosporine nephrotoxicity. Kidney Int. 1986;30(6):964-974. doi: 10.1038/ki.1986.280
  2. Holler E, Kolb HJ, Hiller E, Mraz W, Lehmacher W, Gleixner B, Seeber C, Jehn U, Gerhartz HH, Brehm G, et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood. 1989;73(7):2018-2024. PMID: 2496776
  3. Wassmann B, Martin H, Elsner S, Bruecher J, Thaiss F, Stahl RA, Hoelzer D. Microangiopathic hemolytic anemia and renal impairment following autologous bone marrow transplantation: a case of hemolytic uremic syndrome? Bone Marrow Transplant. 1994;14(5):849-851. PMID: 7889019
  4. Fisher DC, Sherrill GB, Hussein A, Rubin P, Vredenburgh JJ, Elkordy M, Ross M, Petros W, Peters WP. Thrombotic microangiopathy as a complication of high-dose chemotherapy for breast cancer. Bone Marrow Transplant. 1996; 18(1):193-198. PMID: 8832014
  5. Iacopino P, Pucci G, Arcese W, Bosi A, Falda M, Locatelli F, Marenco P, Miniero R, Morabito F, Rossetti F, Sica S, Uderzo C, Bacigalupo A. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Gruppo Italiano Trapianto Midollo Osseo (GITMO). Bone Marrow Transplant. 1999; 24(1):47-51. doi: 10.1038/sj.bmt.1701830
  6. Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant. 1994;14:495-504.
  7. Kanamori H, Maruta A, Sasaki S, Yamazaki E, Ueda S, Katoh K, Tamura T, Otsuka-Aoba M, Taguchi J, Harano H, Ogawa K, Mohri H, Okubo T, Matsuzaki M, Watanabe S, Koharazawa H, Fujita H, Kodama F. Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 1998;21(7):705-709. doi: 10.1038/sj.bmt.1701151
  8. Platzbecker U, von Bonin M, Goekkurt E, Radke J, Binder M, Kiani A, Stoehlmacher J, Schetelig J, Thiede C, Ehninger G, Bornhäuser M. Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transplant. 2009;15(1):101-108. doi: 10.1016/j.bbmt.2008.11.004
  9. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44(2):294-304.
  10. Epperla N, Li A, Logan B, Fretham C, Chhabra S, Aljurf M, Chee L, Copelan E, Freytes CO, Hematti P, et al. Incidence, risk factors for and outcomes of transplant-associated thrombotic microangiopathy. Br J Haematol. 2020; 189(6):1171-1181. doi: 10.1111/bjh.16457
  11. Dandoy CE, Rotz S, Alonso PB, Klunk A, Desmond C, Huber J, Ingraham H, Higham C, Dvorak CC, Duncan C, et al. A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant. Blood Adv. 2021; 5(1):1-11. doi: 10.1182/bloodadvances.2020003455
  12. Jodele S, Dandoy CE, Myers K, Wallace G, Lane A, Teusink-Cross A, Weiss B, Davies SM. High-dose Carboplatin/Etoposide/Melphalan increases risk of thrombotic microangiopathy and organ injury after autologous stem cell transplantation in patients with neuroblastoma. Bone Marrow Transplant. 2018; 53(10):1311-1318. doi: 10.1038/s41409-018-0159-8
  13. Li A, Wu Q, Davis C, Kirtane KS, Pham PD, Sorror ML, Lee SJ, Gopal AK, Dong JF, Garcia DA, Weiss NS, R Hingorani S. Transplant-associated thrombotic microangiopathy is a multifactorial disease unresponsive to immunosuppressant withdrawal. Biol Blood Marrow Transplant. 2019; 25(3):570-576. doi: 10.1016/j.bbmt.2018.10.015
  14. Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, Medvedovic M, Chen J, Davies SM. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016; 127(8):989-996. doi: 10.1182/blood-2015-08-663435
  15. Balassa K, Andrikovics H, Remenyi P, Batai A, Bors A, Kiss KP, Szilvasi A, Rajczy K, Inotai D, Gopcsa L, et al. The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy. Bone Marrow Transplant. 2015; 50(10):1321-1325. doi: 10.1038/bmt.2015.161
  16. Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, Okamoto T, Kanamaru A, Kakishita E. Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant. 2003; 31(6):475-479. doi: 10.1038/sj.bmt.1703879
  17. Kraft S, Bollinger N, Bodenmann B, Heim D, Bucher C, Lengerke C, Kleber M, Tsakiris DA, Passweg J, Tzankov A, Medinger M. High mortality in hematopoietic stem cell transplant-associated thrombotic microangiopathy with and without concomitant acute graft-versus-host disease. Bone Marrow Transplant. 2019; 54(4):540-548. doi: 10.1038/s41409-018-0293-3
  18. Matsuda Y, Hara J, Miyoshi H, Osugi Y, Fujisaki H, Takai K, Ohta H, Tanaka-Taya K, Yamanishi K, Okada S. Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children. Bone Marrow Transplant. 1999; 24(8):919-923. doi: 10.1038/sj.bmt.1702003
  19. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005; 11(8):571-575. doi: 10.1016/j.bbmt.2005.06.001
  20. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lämmle B, et al.; European Group for Blood and Marrow Transplantation; European LeukemiaNet. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007; 92(1):95-100. doi: 10.3324/haematol.10699
  21. Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010; 90(8):918-926. doi: 10.1097/TP.0b013e3181f24e8d
  22. Moiseev IS, Tsvetkova T, Aljurf M, Alnounou RM, Bogardt J, Chalandon Y, Drokov MY, Dvirnyk V, Faraci M, Friis LS, et al. Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT. Bone Marrow Transplant. 2019; 54(7):1022-1028. doi: 10.1038/s41409-018-0374-3
  23. Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011; 46(12):1495-1502. doi: 10.1038/bmt.2011.65
  24. Lesesve JF, Alla F, Dugué F, Salignac S, Clément L, Lecompte T, Bordigoni P. Evaluation of schistocyte monitoring after haematopoietic stem cell transplantation. Int J Lab Hematol. 2011; 33(4):343-356. doi: 10.1111/j.1751-553X.2010.01292.x
  25. Girsberger M, Halter JP, Hopfer H, Dickenmann M, Menter T. Kidney pathology after hematologic cell transplantation-a single-center observation study of indication biopsies and autopsies. Biol Blood Marrow Transplant. 2018;24(3):571-580. doi: 10.1016/j.bbmt.2017.11.008
  26. Luft T, Dietrich S, Falk C, Conzelmann M, Hess M, Benner A, Neumann F, Isermann B, Hegenbart U, Ho AD, Dreger P. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood. 2011; 118(6):1685-1692. doi: 10.1182/blood-2011-02-334821
  27. Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, O'Reilly RJ, Papanicolaou GA. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007; 9(2):108-13. doi: 10.1111/j.1399-3062.2006.00184.x
  28. Kaphan E, Germi R, Bailly S, Bulabois CE, Carré M, Cahn JY, Thiebaut-Bertrand A. Risk factors of BK viral hemorrhagic cystitis in allogenic hematopoietic stem cell transplantation. Transpl Infect Dis. 2021: e13601. doi: 10.1111/tid.13601
  29. Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014; 124(4):645-653. doi: 10.1182/blood-2014-03-564997
  30. Qi J, Wang J, Chen J, Su J, Tang Y, Wu X, Ma X, Chen F, Ruan C, Zheng XL, et al. Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation. Ann Hematol. 2017; 96(11):1849-1855. doi: 10.1007/s00277-017-3092-9
  31. Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, Goebel J, Dixon BP. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015; 29(3):191-204. doi: 10.1016/j.blre.2014.11.001
  32. Peyvandi F, Siboni SM, Lambertenghi Deliliers D, Lavoretano S, De Fazio N, Moroni B, Lambertenghi Deliliers G, Mannuccio Mannucci P. Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation. Br J Haematol. 2006; 134(2):187-195. doi: 10.1111/j.1365-2141.2006.06126.x
  33. Li A, Bhatraju PK, Chen J, Chung DW, Hilton T, Houck K, Pao E, Weiss NS, Lee SJ, Davis C, et al. Prognostic biomarkers for thrombotic microangiopathy after acute graft-versus-host disease: a nested case-control study. Transplant Cell Ther. 2021; 27(4):308.e1-308.e8. doi: 10.1016/j.jtct.2020.12.010
  34. Schoettler M, Lehmann LE, Margossian S, Lee M, Kean LS, Kao PC, Ma C, Duncan CN. Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv. 2020; 4(11):2536-2547. doi: 10.1182/bloodadvances.2019001242
  35. Roy V, Rizvi MA, Vesely SK, George JN. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplant. 2001; 27(6):641-646. doi: 10.1038/sj.bmt.1702849
  36. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005; 11(8):571-575. doi: 10.1016/j.bbmt.2005.06.001
  37. Marr H, Mcdonald E, Merriman E, Smith M, Mangos H, Stoddart C, et al. Successful treatment of transplant-associated microangiopathy with rituximab. N Z Med J. 2009; 122:72-75.
  38. Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant-associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2012; 16(2):E39-42. doi: 10.1111/j.1399-3046.2010.01408.x
  39. Au WY, Ma ES, Lee TL, Ha SY, Fung AT, Lie AK, Kwong YL. Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab. Br J Haematol. 2007; 137(5):475-478. doi: 10.1111/j.1365-2141.2007.06588.x
  40. Martínez-Muñoz ME, Forés R, Lario A, Bautista G, Bueno JL, de Miguel C, Navarro B, De Laiglesia A, Sánchez-Guerrero A, Cabrera JR, Duarte RF. Use of defibrotide to treat adult patients with transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2019; 54(1):142-145. doi: 10.1038/s41409-018-0256-8
  41. Yeates L, Slatter MA, Bonanomi S, Lim FLWI, Ong SY, Dalissier A, Barberi W, Shulz A, Duval M, Heilmann C, et al. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant. 2017; 52(5):762-764. doi: 10.1038/bmt.2016.351
  42. Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, Balduzzi A. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2002; 29(6):542-543. doi: 10.1038/sj.bmt.1703414
  43. de Fontbrune FS, Galambrun C, Sirvent A, Huynh A, Faguer S, Nguyen S, Bay JO, Neven B, Moussi J, Simon L, et al. Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC. Transplantation. 2015; 99(9):1953-1959. doi: 10.1097/TP.0000000000000601
  44. Jodele S, Dandoy CE, Lane A, Laskin BL, Teusink-Cross A, Myers KC, Wallace G, Nelson A, Bleesing J, Chima RS, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049-1057. doi: 10.1182/blood.2019004218
  45. Vasu S, Wu H, Satoskar A, Puto M, Roddy J, Blum W, Klisovic R, Andritsos L, Hofmeister C, Benson DM, et al. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2016; 51(9):1241-1244. doi: 10.1038/bmt.2016.87
  46. Rudoni J, Jan A, Hosing C, Aung F, Yeh J. Eculizumab for transplant-associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients. Eur J Haematol. 2018; 101(3):389-398. doi: 10.1111/ejh.13127
  47. Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, Hirsch R, Teusink A, et al. Variable Eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016; 22(2):307-315. doi: 10.1016/j.bbmt.2015.10.002
  48. Rambaldi A, Khaled S, Smith M, Zecca M, Kwong YL, Claes K, et al. Improved survival following OMS721 treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy. In: The 23rd Congress of EHA. Stockholm, Sweden: European Hematology Association; 2018.
  49. Khaled SK, Kwong YL, Smith M et al. Early results of Phase II Study using OMS721 in patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HCT-TMA). Biol Blood Marrow Transplant 23 (2017) S18-S391.
  50. Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011; 46(12):1495-1502. doi: 10.1038/bmt.2011.65
  51. Worel N, Greinix HT, Leitner G, Mitterbauer M, Rabitsch W, Rosenmayr A, Höcker P, Kalhs P. ABO-incompatible allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning: close association with transplant-associated microangiopathy. Transfus Apher Sci. 2007; 36(3):297-304. doi: 10.1016/j.transci.2007.03.004
  52. Li A, Wu Q, Davis C, Kirtane KS, Pham PD, Sorror ML, Lee SJ, Gopal AK, Dong JF, Garcia DA, et al. Transplant-associated thrombotic microangiopathy is a multifactorial disease unresponsive to immunosuppressant withdrawal. Biol Blood Marrow Transplant. 2019; 25(3):570-576. doi: 10.1016/j.bbmt.2018.10.015
  53. Kanunnikov MM, Rakhmanova ZZ, Levkovsky NV, Vafina AI, Goloshapov OV, Shchegoleva TS, Vlasova JJ, Paina OV, Morozova EV, Zubarovskaya LS, Kulagin AD, Moiseev IS. Conversion from calcineurin inhibitors to sirolimus in transplant-associated thrombotic microangiopathy. Clin Transplant. 2021; 35(2):e14180. doi: 10.1111/ctr.14180
  54. Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020; 382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22. PMID: 32320566.
  55. Zini G. Laboratory diagnostics of HSCT complications: immature platelets and RBCs. Cell Ther Transplant. 2021; 10(1): 6-12. doi: 10.18620/ctt-1866-8836-2021-10-1-6-12
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Introduction

Transplant-associated thrombotic microangiopathy (TA-TMA) was initially identified as a complication of allogeneic hematopoietic stem cell transplantation (HSCT) in the late 1980-s, primary as a complication of a graft-versus-host disease (GVHD) prophylaxis with cyclosporine [1, 2]. However, subsequently it was demonstrated that cyclosporine is not the only predisposing factor, and TA-TMA may be observed even after autologous HSCT [3] or high-dose chemotherapy [4]. Absence of diagnostic criteria for almost two decades precluded the appearance of any solid epidemiological data on the incidence of this complication. The reported incidence varied from 0.1% to 29%. Mean incidence across studies was 8.2%. Mortality in the majority of case series exceeded 50% [5-9]. In the modern era, the incidence varies from 3% in the registry studies in predominantly adult population [10] to 16% in the pediatric prospective studies [11]. This difference might represent identification and inclusion of mild TA-TMA cases in the prospective studies. In these recent studies TA-TMA was associated with additional 15% mortality when compared to patients without TA-TMA, also reflecting the spectrum of TA-TMA severity [9, 11].

Diagnostics of TA-TMA

Part of the diagnosis is assessment of TA-TMA probability in the particular HSCT patient. The major risk factors are transplantation from alternative donors, HLA-mismatched donors, non-myeloablative conditioning or intensified myeloablative conditioning, use of anti-lymphocyte globulin, GVHD prophylaxis with combination of calcineurin and mTOR inhibitors and prior HSCT [9,12,13]. Genetic predisposition include polymorphism in the complement pathway genes, including CFH, CFHR, CFI, CFB, C3 and several others. Certain HLA alleles in recipients were also reported to predispose to TA-TMA. Usually presence of several genetic variants and a triggering factor is required for development of TA-TMA [14]. Although TA-TMA may be not associated with additional complications of HSCT common, major clinical triggers are acute GVHD, particularly steroid-refractory form, viral reactivations, high concentrations of calcineurin inhibitors, or severe bacterial infections [15-17].

It should be admitted that currently there are no uniform criteria for TA-TMA. Primary TA-TMA was identified by the presence of microangiopatic hemolysis, fragmented cells (schistocytes), elevation of lactate dehydrogenase (LDH), thrombocytopenia, and organ damage due to microangiopathy, including renal failure or neurologic dysfunction [5, 6].

In 2005-2007, two consensus diagnostic criteria were developed, including Blood and Marrow Transplant Clinical Trials Network (BMT CTN) by Ho et al. [19] and International Working Group (IWG) by Ruutu T. et al. [20]. Analysis of the overlap between these criteria by Cho et al. has shown that twice less patients are diagnosed with TA-TMA using IWG criteria, while less than 10% of patients diagnosed with IWG criteria do not fall into the frame of BMT CTN criteria [21]. The "overall TMA" criteria were proposed on the basis on this analysis, i.e., ≥2% of schistocytes, elevation of LDH, decrease of hemoglobin and platelets. These "overall TMA" criteria are the most commonly used in the studies of novel agents (Table 1). Besides the differences with diagnostic criteria there is a technical problem with the key laboratory index of TA-TMA: schistocyte quantification, which is not standardized. Therefore, its morphological evaluation can provide various results from one laboratory to another [22].

Table 1. Overview of different diagnostic TA-TMA criteria

Moiseev-tab01.jpg

There are several reasons for the non-uniformity of accepted criteria. First, TA-TMA is a syndrome with endothelial dysfunction as the key pathogenetic feature. However, some degree of endothelial injury is present in all HSCT recipients [23]. Of note, the median level of schistocytes after allogeneic HSCT is around 1%, which is very close to the diagnostic level of BMT CTN criteria [24]. This difference could be easily alleviated by the differences in the morphological practices between transplantation centers. An autopsy study demonstrated 10% of patients who died from various causes had evidence of renal microangiopathy [25]. Other complications of HSCT that are also associated with significant endothelial injury can mimic TA-TMA. These are steroid-refractory GVHD, hemorrhagic viral enterocolitis, sepsis and hemorrhagic cystitis [25, 27, 28]. Thus, there is a spectrum of patients with various degrees of endothelial injury and complement activation after HSCT. In the absence of proven effective interventions it is hard to draw the border, where we can say that this degree of endothelial injury is TA-TMA. Emergence of novel therapies will drive the development of novel diagnostic criteria and this set of criteria will define the group of patients that will benefit from certain therapies.

On the other hand, TA-TMA is not only a syndrome with variable severity, but also a syndrome emerging due to a variety of etiological factors. In children, a clear relationship may exist between mutations in the complement – related genes, alterations in the complement pathway and evidence of complement activation that correlates with the clinical presentation. In pediatric cohort, the level of serum soluble membrane attack complex (C5b-9) was elevated in around 70% of TA-TMA patients. These patients had a more fulminate disease course and higher risk of mortality [29]. There are ethnic differences in the incidence of complement-associated TA-TMA. Hence, the exact percentage of this clinical entity may vary across countries [11]. However, in the adult population there is only limited data on complement activation after unmanipulated haploidentical transplantation [30], and In the general population of adult patients several relatively different entities can be distinguished: GVHD-related, drug-induced (primarily, calcineurin and mTOR inhibitors), infection-related (cytomegalovirus and herpes type 6 are most frequently reported viruses), and those associated with other HSCT toxicities. The same entity as in children with overt multiorgan failure and complement activation comprises only a minor subgroup of adult patients [13]. Vice versa 30% of children without complement activation, likely, have similar pathogenetic mechanisms to the adult population.

The large proportion of pediatric patients with complement activation led to the development of a diagnostic algorithm by Jodele S et al. [31]. It involves screening with serial measurement of LDH, proteinuria and blood pressure. If any of these parameters become abnormal, ADAMTS13-related TTP should be excluded and laboratory workout for TA-TMA should be performed. To confirm the diagnosis of TA-TMA, histological evidence of the organ involvement is sufficient. Alternatively, increased LDH, schistocytes on blood smear, de novo thrombocytopenia, or platelet transfusion dependence, arterial hypertension, proteinuria ≥30 mg/dL and elevation of soluble C5b-9 should be documented.

In clinical practice, local standards of TA-TMA diagnosis vary significantly due to above mentioned difficulties [9, 22], and it is hard to recommend one or another strategy. Before using certain diagnostic approach one should decide what will be an application of this approach.

Identification of patients with endothelial injury in the prospective clinical studies is one thing, selecting patients who will benefit from clinical interventions represents another task. However, several practical suggestions can be made to avoid under- and overdiagnosis of this complication. Regular screening of LDH and creatinine levels, proteinuria and blood pressure will identify potential patients at risk for TA-TMA. Further laboratory evaluation is required for the patients who have de novo grade 3-4 anemia or thrombocytopenia, never became transfusion-independent, or those who had acute kidney injury or neurologic dysfunction on the top of positive screening results. Other groups of patients without these key features are unlikely to require any interventions, even if TA-TMA evidence could be obtained from laboratory testing. Schistocyte evaluation is required to confirm the diagnosis, and Coombs test is required to rule out immune hemolytic anemia. When applying morphological criteria of TA-TMA, several rules were formulated for schistocyte quantification that allow to capture TMA-specific changes in the blood smears (Table 2) [22]. The patients with ≥2% schistocytes can be clinically considered having TA-TMA. Rising schistocyte and LDH levels on serial measurement additionally support the diagnosis. Although ADAMTS13 activity is included in the Jodele S et al. algorithm [31], but the incidence of this TMA mechanism in HSCT recipients is limited to single observations [32, 33]. Elevation of sC5b9 >300 ng/mL and angiopoietin-2 to >3 ng/mL can also provide evidence in favor of TMA diagnosis [33].

Table 2. Laboratory approach to the schistocyte quantification in TA-TMA

Moiseev-tab02.jpg

There is no well-established system for assessment of TA-TMA severity. Certain clinical features associated with higher mortality were reported, e.g., presence of neurological signs, acute kidney injury, LDH≥2 upper limits of normal (ULN), a need for ≥2 medications to control hypertension [29, 34]. The BMT CTN consensus proposed common toxicity criteria of severity, where grade 1 corresponded to absence of clinical consequences; grade 2 is assessed at elevated creatinine levels of ≤3 ULN; grade 3 corresponded to creatinine levels of >3 ULN not requiring dialysis, and grade 4 was characterized as renal failure requiring dialysis, and/or encephalopathy. Nonetheless, this severity system was not validated to predict survival of patients with TA-TMA and is rarely used during application of novel therapies.

Treatment of transplant-associated thrombotic microangiopathy

Currently, there are no established treatments of TA-TMA. Historically, therapeutic plasma exchange (TPE) was used, by analogy of thrombotic thrombocytopenic purpura, with a common standard of care. Despite early reports on its efficacy [35], the latest consensus established that average response rate, mostly defined by the subsided laboratory criteria, was 37% for 121 TPE-treated patients. Average mortality across all the patients was 79%, and the consensus stated that plasma exchange should not be considered a standard of care for TA-TMA [36]. The controversial results of TPE treatment may be related to very low frequency of ADAMTS-13-associated mechanism in TA-TMA [33].

Several other treatments were used outside clinical trials in TA-TMA. These included rituximab [37, 38, 39], defibrotide [40, 41, 42], and eculizumab [43, 44, 45, 46]. Clinical efficacy and mechanisms of rituximab in TA-TMA can be hardly assessed with only seven patients reported in the literature. On the other hand, 165 patients were treated with either defibrotide or eculizumab with a very comparable response rate of 73% and 58%, respectively. Nonetheless, overall mortality remained high with both treatments and was 40% across the studies. Particularly favorable results were reported by Jodele et al. with eculizumab in the pediatric cohort where large proportion of patients had mutations in complement-related genes and clear laboratory signs of complement activation [11, 12]. In this cohort, evaluation of eculizumab concentrations demonstrated higher drug clearance than in paroxysmal nocturnal hemoglobinuria as one of the mechanisms behind the lack of efficacy. Thus, Jodele et al. proposed the algorithm of weekly induction doses and additional induction doses based on daily CH50 activity [47]. Two small clinical trials also evaluated narsoplimab, a mannan-binding lectin-associated serine protease-2 inhibitor, also targeting complement pathway. Improvement of laboratory signs was observed in a proportion of patients and overall survival was 50% [48, 49] (Table 3). Looking at the response and survival rate of all these pharmacological treatments, it is clear that, if compared to PTE, they have merit in a proportion of patients. However, their administration was based on various indications and various diagnostic criteria. In the absence of severity criteria, it is also impossible to compare the groups of patients in these studies. Thus, it is difficult to recommend either approach as the first-line treatment. On the other hand, currently published data on the pharmacological treatments rather postulates the necessity for common criteria for severity and response based on empirical data.

Table 3. Results of clinical studies in transplant-associated thrombotic microangiopathy

Moiseev-tab03.jpg

Common first-line intervention for TA-TMA is to manipulate with immunosuppression regimens. The idea comes from early observations that inclusion of cyclosporine A in the prophylaxis regimens was associated with first documented TA-TMA cases [1, 2]. Further evidence for toxicity of calcineurin inhibitors (CNIs) towards endothelium [50] created the basis for tapering or discontinuation of CNIs in patients with TA-TMA [51]. Due to essential needs for GVHD control in the majority of these patients, glucocorticosteroids were historically administered in the most patients after CNIs discontinuation. Recent Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus supported discontinuation of CNIs as the primary intervention based on expert opinion [36]. Nonetheless, the large single-center analysis by Li et al. did not show any benefit in terms of overall survival, when tapering or discontinuing CNIs vs their continuation in all subgroups of TMA patients, irrespective of type of GVHD prophylaxis [52]. It seems that, like all other interventions in TMA, sole discontinuation of CNIs does not lead to resolution of symptoms in all the patients, but the time to resolution might be quicker. Also, the different centers are testing other type of agents for GVHD prophylaxis instead of CNIs, with effects on survival outcomes. In our single-center analysis, substitution of CNIs by sirolimus in severe GVHD proved to be superior to steroids [53]. Novel agents, like JAK inhibitors, might also facilitate sufficient GVHD control instead of CNIs without additional endothelial damage [54]. Further investigation of different substitution strategies are warranted. Even in continuation strategies, a pause before obtaining CNI concentration is a rational approach, because the majority of patients show a transitory reduction of CNIs clearance, and high concentrations are common at TMA diagnosis.

Conclusion

Along with clinical criteria, diagnostics of TA-TMA involves several laboratory tests, of which erythrocyte shistocytosis remain a less standardized criterion [22, 55]. Screening of LDH and creatinine levels, proteinuria and blood pressure, exclusion of autoimmune haemolysis should discern potential patients at risk for TA-TMA.

Further improvement of care in TA-TMA requires harmonization of definitions for mortality risk, response, outcome measures and indications for treatment. Since this is a relatively rare entity and even large centers rarely has information on more than 50-100 cases, cooperative effort to gather empirical data is crucial to formulate these definitions, only after that existing and novel therapies can be compared without bias in the multicenter studies. For current clinical practice, internal institutional guidelines should select one of the diagnostic criteria and adhere to them. Reduction or discontinuation of calcineurin inhibitors should be considered in all patients, but internal guidelines for substitution with active immunosuppressive agents should be developed for GVHD control. Novel treatments should be implemented in case of organ failure, or in patients not responding to immunosuppression manipulation.

Conflicts of interest

None reported.

References

  1. Myers BD. Cyclosporine nephrotoxicity. Kidney Int. 1986;30(6):964-974. doi: 10.1038/ki.1986.280
  2. Holler E, Kolb HJ, Hiller E, Mraz W, Lehmacher W, Gleixner B, Seeber C, Jehn U, Gerhartz HH, Brehm G, et al. Microangiopathy in patients on cyclosporine prophylaxis who developed acute graft-versus-host disease after HLA-identical bone marrow transplantation. Blood. 1989;73(7):2018-2024. PMID: 2496776
  3. Wassmann B, Martin H, Elsner S, Bruecher J, Thaiss F, Stahl RA, Hoelzer D. Microangiopathic hemolytic anemia and renal impairment following autologous bone marrow transplantation: a case of hemolytic uremic syndrome? Bone Marrow Transplant. 1994;14(5):849-851. PMID: 7889019
  4. Fisher DC, Sherrill GB, Hussein A, Rubin P, Vredenburgh JJ, Elkordy M, Ross M, Petros W, Peters WP. Thrombotic microangiopathy as a complication of high-dose chemotherapy for breast cancer. Bone Marrow Transplant. 1996; 18(1):193-198. PMID: 8832014
  5. Iacopino P, Pucci G, Arcese W, Bosi A, Falda M, Locatelli F, Marenco P, Miniero R, Morabito F, Rossetti F, Sica S, Uderzo C, Bacigalupo A. Severe thrombotic microangiopathy: an infrequent complication of bone marrow transplantation. Gruppo Italiano Trapianto Midollo Osseo (GITMO). Bone Marrow Transplant. 1999; 24(1):47-51. doi: 10.1038/sj.bmt.1701830
  6. Pettitt AR, Clark RE. Thrombotic microangiopathy following bone marrow transplantation. Bone Marrow Transplant. 1994;14:495-504.
  7. Kanamori H, Maruta A, Sasaki S, Yamazaki E, Ueda S, Katoh K, Tamura T, Otsuka-Aoba M, Taguchi J, Harano H, Ogawa K, Mohri H, Okubo T, Matsuzaki M, Watanabe S, Koharazawa H, Fujita H, Kodama F. Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 1998;21(7):705-709. doi: 10.1038/sj.bmt.1701151
  8. Platzbecker U, von Bonin M, Goekkurt E, Radke J, Binder M, Kiani A, Stoehlmacher J, Schetelig J, Thiede C, Ehninger G, Bornhäuser M. Graft-versus-host disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transplant. 2009;15(1):101-108. doi: 10.1016/j.bbmt.2008.11.004
  9. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004;44(2):294-304.
  10. Epperla N, Li A, Logan B, Fretham C, Chhabra S, Aljurf M, Chee L, Copelan E, Freytes CO, Hematti P, et al. Incidence, risk factors for and outcomes of transplant-associated thrombotic microangiopathy. Br J Haematol. 2020; 189(6):1171-1181. doi: 10.1111/bjh.16457
  11. Dandoy CE, Rotz S, Alonso PB, Klunk A, Desmond C, Huber J, Ingraham H, Higham C, Dvorak CC, Duncan C, et al. A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant. Blood Adv. 2021; 5(1):1-11. doi: 10.1182/bloodadvances.2020003455
  12. Jodele S, Dandoy CE, Myers K, Wallace G, Lane A, Teusink-Cross A, Weiss B, Davies SM. High-dose Carboplatin/Etoposide/Melphalan increases risk of thrombotic microangiopathy and organ injury after autologous stem cell transplantation in patients with neuroblastoma. Bone Marrow Transplant. 2018; 53(10):1311-1318. doi: 10.1038/s41409-018-0159-8
  13. Li A, Wu Q, Davis C, Kirtane KS, Pham PD, Sorror ML, Lee SJ, Gopal AK, Dong JF, Garcia DA, Weiss NS, R Hingorani S. Transplant-associated thrombotic microangiopathy is a multifactorial disease unresponsive to immunosuppressant withdrawal. Biol Blood Marrow Transplant. 2019; 25(3):570-576. doi: 10.1016/j.bbmt.2018.10.015
  14. Jodele S, Zhang K, Zou F, Laskin B, Dandoy CE, Myers KC, Lane A, Meller J, Medvedovic M, Chen J, Davies SM. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016; 127(8):989-996. doi: 10.1182/blood-2015-08-663435
  15. Balassa K, Andrikovics H, Remenyi P, Batai A, Bors A, Kiss KP, Szilvasi A, Rajczy K, Inotai D, Gopcsa L, et al. The potential role of HLA-DRB1*11 in the development and outcome of haematopoietic stem cell transplantation-associated thrombotic microangiopathy. Bone Marrow Transplant. 2015; 50(10):1321-1325. doi: 10.1038/bmt.2015.161
  16. Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, Okamoto T, Kanamaru A, Kakishita E. Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant. 2003; 31(6):475-479. doi: 10.1038/sj.bmt.1703879
  17. Kraft S, Bollinger N, Bodenmann B, Heim D, Bucher C, Lengerke C, Kleber M, Tsakiris DA, Passweg J, Tzankov A, Medinger M. High mortality in hematopoietic stem cell transplant-associated thrombotic microangiopathy with and without concomitant acute graft-versus-host disease. Bone Marrow Transplant. 2019; 54(4):540-548. doi: 10.1038/s41409-018-0293-3
  18. Matsuda Y, Hara J, Miyoshi H, Osugi Y, Fujisaki H, Takai K, Ohta H, Tanaka-Taya K, Yamanishi K, Okada S. Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children. Bone Marrow Transplant. 1999; 24(8):919-923. doi: 10.1038/sj.bmt.1702003
  19. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005; 11(8):571-575. doi: 10.1016/j.bbmt.2005.06.001
  20. Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lämmle B, et al.; European Group for Blood and Marrow Transplantation; European LeukemiaNet. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007; 92(1):95-100. doi: 10.3324/haematol.10699
  21. Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010; 90(8):918-926. doi: 10.1097/TP.0b013e3181f24e8d
  22. Moiseev IS, Tsvetkova T, Aljurf M, Alnounou RM, Bogardt J, Chalandon Y, Drokov MY, Dvirnyk V, Faraci M, Friis LS, et al. Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT. Bone Marrow Transplant. 2019; 54(7):1022-1028. doi: 10.1038/s41409-018-0374-3
  23. Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011; 46(12):1495-1502. doi: 10.1038/bmt.2011.65
  24. Lesesve JF, Alla F, Dugué F, Salignac S, Clément L, Lecompte T, Bordigoni P. Evaluation of schistocyte monitoring after haematopoietic stem cell transplantation. Int J Lab Hematol. 2011; 33(4):343-356. doi: 10.1111/j.1751-553X.2010.01292.x
  25. Girsberger M, Halter JP, Hopfer H, Dickenmann M, Menter T. Kidney pathology after hematologic cell transplantation-a single-center observation study of indication biopsies and autopsies. Biol Blood Marrow Transplant. 2018;24(3):571-580. doi: 10.1016/j.bbmt.2017.11.008
  26. Luft T, Dietrich S, Falk C, Conzelmann M, Hess M, Benner A, Neumann F, Isermann B, Hegenbart U, Ho AD, Dreger P. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood. 2011; 118(6):1685-1692. doi: 10.1182/blood-2011-02-334821
  27. Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, O'Reilly RJ, Papanicolaou GA. Invasive adenoviral infections in T-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007; 9(2):108-13. doi: 10.1111/j.1399-3062.2006.00184.x
  28. Kaphan E, Germi R, Bailly S, Bulabois CE, Carré M, Cahn JY, Thiebaut-Bertrand A. Risk factors of BK viral hemorrhagic cystitis in allogenic hematopoietic stem cell transplantation. Transpl Infect Dis. 2021: e13601. doi: 10.1111/tid.13601
  29. Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014; 124(4):645-653. doi: 10.1182/blood-2014-03-564997
  30. Qi J, Wang J, Chen J, Su J, Tang Y, Wu X, Ma X, Chen F, Ruan C, Zheng XL, et al. Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation. Ann Hematol. 2017; 96(11):1849-1855. doi: 10.1007/s00277-017-3092-9
  31. Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, Goebel J, Dixon BP. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015; 29(3):191-204. doi: 10.1016/j.blre.2014.11.001
  32. Peyvandi F, Siboni SM, Lambertenghi Deliliers D, Lavoretano S, De Fazio N, Moroni B, Lambertenghi Deliliers G, Mannuccio Mannucci P. Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation. Br J Haematol. 2006; 134(2):187-195. doi: 10.1111/j.1365-2141.2006.06126.x
  33. Li A, Bhatraju PK, Chen J, Chung DW, Hilton T, Houck K, Pao E, Weiss NS, Lee SJ, Davis C, et al. Prognostic biomarkers for thrombotic microangiopathy after acute graft-versus-host disease: a nested case-control study. Transplant Cell Ther. 2021; 27(4):308.e1-308.e8. doi: 10.1016/j.jtct.2020.12.010
  34. Schoettler M, Lehmann LE, Margossian S, Lee M, Kean LS, Kao PC, Ma C, Duncan CN. Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv. 2020; 4(11):2536-2547. doi: 10.1182/bloodadvances.2019001242
  35. Roy V, Rizvi MA, Vesely SK, George JN. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes. Bone Marrow Transplant. 2001; 27(6):641-646. doi: 10.1038/sj.bmt.1702849
  36. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005; 11(8):571-575. doi: 10.1016/j.bbmt.2005.06.001
  37. Marr H, Mcdonald E, Merriman E, Smith M, Mangos H, Stoddart C, et al. Successful treatment of transplant-associated microangiopathy with rituximab. N Z Med J. 2009; 122:72-75.
  38. Jodele S, Bleesing JJ, Mehta PA, Filipovich AH, Laskin BL, Goebel J, Pinkard SL, Davies SM. Successful early intervention for hyperacute transplant-associated thrombotic microangiopathy following pediatric hematopoietic stem cell transplantation. Pediatr Transplant. 2012; 16(2):E39-42. doi: 10.1111/j.1399-3046.2010.01408.x
  39. Au WY, Ma ES, Lee TL, Ha SY, Fung AT, Lie AK, Kwong YL. Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab. Br J Haematol. 2007; 137(5):475-478. doi: 10.1111/j.1365-2141.2007.06588.x
  40. Martínez-Muñoz ME, Forés R, Lario A, Bautista G, Bueno JL, de Miguel C, Navarro B, De Laiglesia A, Sánchez-Guerrero A, Cabrera JR, Duarte RF. Use of defibrotide to treat adult patients with transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2019; 54(1):142-145. doi: 10.1038/s41409-018-0256-8
  41. Yeates L, Slatter MA, Bonanomi S, Lim FLWI, Ong SY, Dalissier A, Barberi W, Shulz A, Duval M, Heilmann C, et al. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant. 2017; 52(5):762-764. doi: 10.1038/bmt.2016.351
  42. Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, Balduzzi A. Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Bone Marrow Transplant. 2002; 29(6):542-543. doi: 10.1038/sj.bmt.1703414
  43. de Fontbrune FS, Galambrun C, Sirvent A, Huynh A, Faguer S, Nguyen S, Bay JO, Neven B, Moussi J, Simon L, et al. Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC. Transplantation. 2015; 99(9):1953-1959. doi: 10.1097/TP.0000000000000601
  44. Jodele S, Dandoy CE, Lane A, Laskin BL, Teusink-Cross A, Myers KC, Wallace G, Nelson A, Bleesing J, Chima RS, et al. Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood. 2020;135(13):1049-1057. doi: 10.1182/blood.2019004218
  45. Vasu S, Wu H, Satoskar A, Puto M, Roddy J, Blum W, Klisovic R, Andritsos L, Hofmeister C, Benson DM, et al. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2016; 51(9):1241-1244. doi: 10.1038/bmt.2016.87
  46. Rudoni J, Jan A, Hosing C, Aung F, Yeh J. Eculizumab for transplant-associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients. Eur J Haematol. 2018; 101(3):389-398. doi: 10.1111/ejh.13127
  47. Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, Hirsch R, Teusink A, et al. Variable Eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016; 22(2):307-315. doi: 10.1016/j.bbmt.2015.10.002
  48. Rambaldi A, Khaled S, Smith M, Zecca M, Kwong YL, Claes K, et al. Improved survival following OMS721 treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy. In: The 23rd Congress of EHA. Stockholm, Sweden: European Hematology Association; 2018.
  49. Khaled SK, Kwong YL, Smith M et al. Early results of Phase II Study using OMS721 in patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HCT-TMA). Biol Blood Marrow Transplant 23 (2017) S18-S391.
  50. Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011; 46(12):1495-1502. doi: 10.1038/bmt.2011.65
  51. Worel N, Greinix HT, Leitner G, Mitterbauer M, Rabitsch W, Rosenmayr A, Höcker P, Kalhs P. ABO-incompatible allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning: close association with transplant-associated microangiopathy. Transfus Apher Sci. 2007; 36(3):297-304. doi: 10.1016/j.transci.2007.03.004
  52. Li A, Wu Q, Davis C, Kirtane KS, Pham PD, Sorror ML, Lee SJ, Gopal AK, Dong JF, Garcia DA, et al. Transplant-associated thrombotic microangiopathy is a multifactorial disease unresponsive to immunosuppressant withdrawal. Biol Blood Marrow Transplant. 2019; 25(3):570-576. doi: 10.1016/j.bbmt.2018.10.015
  53. Kanunnikov MM, Rakhmanova ZZ, Levkovsky NV, Vafina AI, Goloshapov OV, Shchegoleva TS, Vlasova JJ, Paina OV, Morozova EV, Zubarovskaya LS, Kulagin AD, Moiseev IS. Conversion from calcineurin inhibitors to sirolimus in transplant-associated thrombotic microangiopathy. Clin Transplant. 2021; 35(2):e14180. doi: 10.1111/ctr.14180
  54. Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020; 382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22. PMID: 32320566.
  55. Zini G. Laboratory diagnostics of HSCT complications: immature platelets and RBCs. Cell Ther Transplant. 2021; 10(1): 6-12. doi: 10.18620/ctt-1866-8836-2021-10-1-6-12
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Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27570" ["VALUE"]=> array(2) { ["TEXT"]=> string(3185) "<p style="text-align: justify;">Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3129) "

Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27572" ["VALUE"]=> array(2) { ["TEXT"]=> string(142) "<p>Ivan S. Moiseev<sup>1</sup>, Tatyana G. Tsvetkova<sup>2</sup>, Tapani Ruutu<sup>3</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(94) "

Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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Ivan S. Moiseev1, Tatyana G. Tsvetkova2, Tapani Ruutu3

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation with an endothelial damage being the major cause of clinical signs. Currently, four major set of diagnostic criteria exist which capture different populations of patients with variable severity of endothelial dysfunction and target organ involvement. Absence of widely excepted criteria for TA-TMA severity, outcome and response measures complicate the comparison of different treatment approaches. Withdrawal or tapering of calcineurin inhibitors is a widely excepted intervention; however, there are studies that indicate no benefit of this intervention in improving overall survival. Different strategies of substituting calcineurin inhibitors with other immunosuppressive may also have impact on survival in TA-TMA patients. Novel approaches in treatment include oligonucleotides and complement inhibitors. Indications for these treatments according to different diagnostic criteria are still to be defined. Currently published evidence highlight the need for cooperative effort to gather empirical data and harmonize definitions required for comparative clinical studies of novel agents.

Keywords

Thrombotic microangiopathy, hematopoietic stem cell transplantation, diagnostic criteria, calcineurin inhibitors, defibrotide, eculizumab.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 Nikiforov Russian Center of Emergency and Radiation Medicine, St. Petersburg, Russia
3 Clinical Research Institute, Helsinki University Hospital, Helsinki, Finland


Correspondence
Ivan S. Moiseev, PhD, MD, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia

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Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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Иван С. Моисеев1, Татьяна Г. Цветкова2, Тапани Рууту3

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В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3129) "

Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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Посттрансплантационная тромботическая микроангиопатия (ПТ-ТМА) является редким осложнением трансплантации гемопоэтических стволовых клеток с повреждением эндотелия, которое лежит в основе клинических симптомов этого осложнения. В настоящее время существует четыре основных консенсуса в отношении диагностических критериев, которые охватывают различные популяции пациентов с различной степенью эндотелиального повреждения и поражения органов-мишеней. Отсутствие общепризнанных критериев тяжести, ответа и конечных целей терапии ПТ-ТМА затрудняет сравнение разных методов лечения. Отмена или снижение дозы ингибиторов кальциневрина – широко распространенная интервенция при ПТ-ТМА, однако опубликованы также и данные исследований, которые указывают на отсутствие улучшения общей выживаемости от манипуляций с иммуносупрессивной терапией. По-видимому, различные стратегии замены ингибиторов кальциневрина другими иммуносупрессивными препаратами могут влиять на выживаемость у пациентов с ТА-ТМА. Новые подходы к лечению включают олигонуклеотиды и ингибиторы комплемента, но показания для этих видов терапии в соответствии с различными диагностическими критериями еще предстоит определить в результате клинических исследований. Опубликованные в настоящее время данные подчеркивают необходимость совместных усилий для анализа эмпирических данных и утверждения клинических параметров, необходимых для сравнительных клинических исследований новых препаратов.

Ключевые слова

Тромботическая микроангиопатия, трансплантация гемопоэтических стволовых клеток, диагностические критерии, ингибиторы кальциневрина, дефибротид, экулизумаб.

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Всероссийский центр экстренной и радиационной медицины имени А. М. Никифорова, Санкт-Петербург, Россия
3 Клинический Исследовательский Институт, Клиника Университета Хельсинки, Хельсинки, Финляндия

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Introduction

Previous studies have shown heterogeneity of leukemia-producing cell populations in the patients with acute myeloid leukemia (AML) [1]. In model experiments with human leukemic cells transplanted into immunodeficient mice, the earlier CD34+CD38- human stem cells were responsible for leukemia induction and, moreover, were able to express a pan-specific Brain And Acute Leukemia Cytoplasmic (BAALC) gene [2, 3]. Moreover, similar experiments with acute promyelocytic leukemia (APL) cells revealed more mature leukemia-initiating precursors [4 Patel et al, 2012], which, along with blast cells, according to our hypothesis, might express WT1, another pan-specific gene [5-7]. Since mRNA of the both genes may be detected with quantitative real-time PCR (RT-qPCR), we attempted to evaluate the genes of interest by means of this standard approach [5-7]. Our works have yielded the following results: a) important role of BAALC expressing stem-cells in post-transplant relapses (PTR) of AML [5-6]; b) proven clinical effect of a targeted drug (Mylotarg) upon the levels of leukemic stem cells and precursors [7]; and c) possible presence of leukemic hematopoietic regulators causing transition from some immature stem cells in AML to more mature precursors [5, 7] as well as in APL [6]. To support this hypothesis, we have recently studied leukemic hematopoiesis in a mixed group of adult and pediatric patients with EVI1-positive AML. Chromosome aberrations at the 3q26 locus are considered common in adult patients, however, being virtually absent in pediatric cases. Meanwhile, EVI1-positive AML with presumable rearrangements of KMT2A gene was found in one-fourth of pediatric patients [8-10], thus also presenting essential age-dependent differences in responses to therapy and HSCT. At the same time, an excellent response to retinoid treatment has been recently revealed in all types of EVI1-positive AML [11], which seems to be associated with their direct action upon functional activity of stem cells [12].

The aim of our work was to test BAALC/WT1 molecular panel in the mixed pediatric and adult cohort of patients with of AML variants which are generally resistant to intensive therapy and HSCT.

Patients and methods

1.1. Patient cohort

Our retrospective study presents the data on BAALC and WT1 gene expression levels measured in parallel in the course of serial bone marrow sampling from fourteen EVI1-positive patients with different AML FAB-variants, who underwent allogeneic HSCT at R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2016 years. This group included 8 pediatric patients under 18 years and 6 adults with AML. In all the patients, BAALC and WT1 gene expression changes, as well as blast cell counts were serially monitored in the same bone marrow aspirates. Written informed consent was obtained from all patients, following the Declaration of Helsinki Recommendations.

1.2. Analysis of BAALC and WT1 gene expression levels

Total mRNA was extracted from fresh bone marrow samples, its reverse transcription and estimation of the BAALC gene expression level were performed by quantitative real-time PCR (RT-qPCR) as elsewhere described [13]. In brief, BAALC transcript copy numbers (CN) were determined by means of BAALC RQ-Kit (Inogene, Russia), including plasmid standards for plotting appropriate calibration curves for BAALC and ABL1 reference gene. Basic control time points for the bone marrow examination were as follows: at diagnosis (e.g., D-80), prior to conditioning (D0), and, as obligatory diagnostics, in post-transplant relapses (PTR). A median follow-up time after HSCT was 7 months (range, 0.6 to 52.5 months). Relative BAALC expression level was calculated as a ratio of CNBAALC to CNABL1 and expressed as a percent value. The expression level of 31% was chosen as a common cut-off value to study clinical significance of BAALC gene overexpression before and after HSCT. This value was shown to exceed maximal BAALC expression levels in the patients with pre-transplant cytological remission without any signs of the disease progression.

In parallel, the WT1 gene expression levels were determined in each sample at the same time points. The copy numbers of WT1 transcripts were evaluated by the similar RT-qPCR method, according to Recommendations of European LeukemiaNet Group [14]. The basal WT1 expression level of 250 copies per 104 copies of ABL1 reference gene was used to discriminate between low and high WT1 expression rates. Similarly, the 10 per cent expression level was considered a cut-off value when studying clinical significance of EVI1 overexpression.

1.3. Statistical analysis

Due to small numbers of patients in the tested groups, full-scale statistical analysis was not carried out. The data with asymmetric distribution were presented as extreme ranges and median values. Overall survival (OS) and relapse free-survival (RFS) were measured from D0 until the date of death, regardless of cause, or until the term of documented relapse, or last contact date. STATISTICA software was used for calculations. P< 0.05 was considered the statistically significant difference level, having been determined in every case.

Results

Basic clinical and laboratory data are presented in Table 1. They concern eight pediatric (lower 18 y. o.) and six adult patients. The common levels of EVI1 expression ranged from 0.3% to 130%, being the highest in 26 year-old female with M1 FAB-variant (#11) with complex karyotype. One should note that the cytogenetic changes in pediatric patients were not related to specific 3q26 locus, whereas this pattern of chromosome aberrations was found in 5 of 6 adult patients (83%). At the same time, one of pediatric patients (#5) showed KMT2A rearrangements which are more typical to this type of childhood AML. In general, the cytogenetic aberrations ranged from chromothripsis (#1) and highly complex karyotype to single reciprocal translocations (#8) or deletions (#6). Normal karyotype was registered only in one child (#3).

Table 1. Clinical and laboratory parameters of pediatric (#1-8) and adult (#9-14) variants of EVI1-positive acute myeloid leukemia, treated with hematopoietic stem cell transplantation

Mamaev-tab01.jpg

*, deceased patients; n/d, no data; rel, related; n/rel, nonrelated; haplo, haploidentical; overexpressed levels of BAALC expression and higher meanings of OV in children are noted by red and green colours, respectively

One should comment that primary diagnosis in most patients was assessed at regional hospitals, where precise molecular diagnostics was not available. Therefore, molecular markers at the early stages of disease are lacking in these patients.

Despite this drawback, elevated BAALC expression in EVI1-positive AML at primary diagnosis was demonstrated both in pediatric (#7) and adult (#9, 11) patients, being higher in adults.

Before HSCT, overexpression of BAALC was seen in three pediatric patients (#1, 6, 7), as well as in two adults (#9, 14) who, along with increased blast counts, showed insufficient response of these leukemic cells to pretransplant therapy. This pattern of response is also confirmed by common elevation of WT1 level expression prior to HSCT (6/13; 46%). Finally, upon emergence of post-transplant relapse (PTR) in 5/6 adult patients and 5/8 pediatric ones, the elevated BAALC expression was revealed in five cases (#4, 6, 9, 11 and 13), being the highest (389%) in a young female with secondary (from MDS) M4-FAB-variant of AML (# 9). WT1 gene expression at diagnosis, was enhanced in patients #7, #9 and #11 (11753, 867 and 10493 copies, respectively), with appropriate increase of blast numbers in bone marrow (resp., 88%, 17%, and 84%). At pre-transplant stage, the levels of WT1 expression were increased in the patients #3, #6, #8, #9 and #14 (up to 3693, 2048. 2957. 2025 and 2671 copies, respectively), showing only weak correlation with blast counts in their bone marrow samples (13.4, 7.2, 21, 38 and 7.6, respectively.) Comparison of these data argues for our earlier concept presuming an active participation of other cell populations in WT1 gene expression, for instance, of more mature precursors recently found in successful xenograft of APL samples in immunodeficient NOD/shi-SCID IL2Ry-/- mice [4].

Finally, at stage of PTR, increased WT1 expression levels were found in patients #1, 3, 4, 6, 8, 9, 11, 12, and 13 (respectively, 3315, 1049, 436. 120239. 32684, 1165, 6500, 4542 and 18872 copies) that also weakly correlated with number of blasts in tested bone marrows (60.4, 20.8, 29.8, 30.4, 24.4, 31.5, 51.2, 21, and 26%, respectively).

In conclusion, one should notice that the patients with M3 (#8) and M7 (#1 and 3) had lower levels of BAALC expression at all studied stages, which is explained simply by basic role in hematopoiesis with more mature precursors than BAALC-expressing stem cells. Further, one may conclude on opportunity for different variants of emerging PTR. Thus, in several cases (#4, 6, 9, 11, and 13), PTR were associated with activation of both BAALC-expressing stem cells and WT1-expressing mature precrsors. Meanwhile, PTR in patients with M3 (#8), M7 ( # 1 , 3 and single presenters of M5 (#12) FAB-variants were accompanied by WT1 expressing precursors only.

Discussion

Hence, despite different biological and cytogenetic characteristics of pediatric and adult EVI1-positive AML, they revealed relatively higher levels of BAALC-expressing precursors at diagnosis, as well as at pre- and posttransplant stages, which, in turn, may be related with great difficulties in preparative regimens for HSCT. The real difference between the age groups consisted only in more often relapse-free course of leukemia in children (n=3), than that was among adults (n=1). Therefore, median of overall survival in pediatric patients was longer than that in adults (999 vs 317 days, respectively) which is statistically significant (p<0.05). Presence of cases with AML FAB-variants of M7 (n=2) and M3 (n=1) in pediatric group among these patients may be another reason for absence of expected difference in OS. These patients, generally, do not show higher levels of BAALC expression, due to alternative nature of hematopoiesis precursors.

Conclusion

To reveal the expected difference in BAALC-expressing precursors between pediatric and adult EVI1-positive AML, further studies should be performed in larger cohorts of carefully chosen patients, with omission of M7 and M3 FAB- variants.

Our simultaneous measurements of BAALC and WT1-expressiong leukemic precursors by means of standardized RT-qPCR supported crucial role of BAALC-expressing stem cells in pathogenesis of EVI1-positive AML and relapses evolving in both tested groups.

Conflict of interest

None reported.

References

  1. Walter R, Appelbaum F, Estey E, Bernstein I. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 2012; 119: 6198-6208. doi: 10.1182/ blood-2011-11-325050
  2. Lapidot T, Siratd C, Vormoor J, et al. Z Cell initiating human acute myeloid leukemia after transplantation into SCID mice, Nature 1994;367(6464):645-8. doi: 10.1038/367645a0
  3. Morita R, Masamotyo Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 2015; 29(11): 2248-2256. doi: 10.1038/leu.2015.137
  4. Patel S, Zhang Y, Cassinat B, Zassadowski F, Ferré N, Cuccuini W, Cayuela JM, Fenaux P, Bonnet D, Chomienne C, Louache F. Successful xenografts of AML3 samples in immunodeficient NOD/shi-SCID IL2Rγ–/– mice. Leukemia 2012; 26(11):2432-2435. doi: 10.1038/leu.2012.154
  5. Mamaev NN, Shakirova AI, Barkhatov IM, et al. New opportunities for assay of leukemia initiating cells (LICs) participating in post-transplant relapse development in the patients with acute myeloid leukemia. 3rd Annual IACH Meeting, 1-3 October, 2020, Paris, report #12.
  6. Mamaev NN, Shakirova AI, Barkhatov IM, Gudozhnikova YV, Gindina TL, Kanunnikov MM, Kravtsova VM, Rakhmanova ZZ, Paina OV, Zubarovskaya LS. Crucial role of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses in patients with acute myeloid leukemias. Int J Hematol 2020; 8(6): 127-131. doi: 10.15406/htij.2020.08.00240
  7. Mamaev NN, Shakirova AI, Gindina TL, Bondarenko SN, Ayubova BI, Barkhatov IM, Gudozhnikova YaV, Kravtsova VM, Kanunnikov MM, Paina OV, Rakhmanova ZZ, Gracheva TYu, Zubarovskaya LS. Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamycin and hematopoietic stem cell transplantation. Cell Ther Transplant 2021; 10(1)):55-62. doi: 10.18620/ctt-1866-8836-2021-10-1-55-62
  8. Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters STJCM, van Wering ER, de Graaf SSN, et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 2010;24:942-949. doi:10.1038/leu.2010.47
  9. Ho PA, Alonzo TA, Gerbing RB, Pollard JA, Hirsch B, Raimondi SC, Cooper T, Gamis AS, Meshinchi S. High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in pediatric acute myeloid leukemia: a report from the children’s oncology group. Br J Haematol 2013;162(5): 670-677. doi: 10.1111/bjh.12444
  10. Sadaghian MH, Dezaki ZR. Prognostic value of EVI1 expression in pediatric acute myeloid leukemia: A systematic review. Iran J Pathol. 2018; 13(3):294-300. PMID: 30636951
  11. Pauebelle E, Piesa A, Hayette S, et al. Efficacy of ALL-TRANS-RETINOIC ACID in high riskacute myeloid leukemia with overexpression of EVI1. Oncol Ther 2019; 7(2): 121-130. doi: 10.1007/s40487-019-0095-9
  12. Mamaev NN, Shakirova AI, Morozova EV, Gindina TL. EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Practical Aspects (Literature Review). Clinical Oncohematol 2021;14(1): 103-117 (In Russian). doi: 10.21320/2500-2139-2021-14-1-103-117
  13. Shakirova A, Barkhatov I, Churkina A, Moiseev IS, Gindina TL, Bondarenko SN, Afanasyev BV. Prognostic significance of BAALC overexpression in patients with AML during the posttransplant period. Cell Ther Transplant 2018; 7(2):54-63. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63
  14. Cilloni D, Renneville A, Hermitte F, Hills R, Daly S, Jovanovic J, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van den Heijden A, van der Reijden B, Jansen J, van der Verlden V, Ommen H, Preudhomme C, Saglio G, Grimwade D. et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 2009; 27(31): 5195-5201. doi: 10.1200/JCO.2009.22.4865
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Introduction

Previous studies have shown heterogeneity of leukemia-producing cell populations in the patients with acute myeloid leukemia (AML) [1]. In model experiments with human leukemic cells transplanted into immunodeficient mice, the earlier CD34+CD38- human stem cells were responsible for leukemia induction and, moreover, were able to express a pan-specific Brain And Acute Leukemia Cytoplasmic (BAALC) gene [2, 3]. Moreover, similar experiments with acute promyelocytic leukemia (APL) cells revealed more mature leukemia-initiating precursors [4 Patel et al, 2012], which, along with blast cells, according to our hypothesis, might express WT1, another pan-specific gene [5-7]. Since mRNA of the both genes may be detected with quantitative real-time PCR (RT-qPCR), we attempted to evaluate the genes of interest by means of this standard approach [5-7]. Our works have yielded the following results: a) important role of BAALC expressing stem-cells in post-transplant relapses (PTR) of AML [5-6]; b) proven clinical effect of a targeted drug (Mylotarg) upon the levels of leukemic stem cells and precursors [7]; and c) possible presence of leukemic hematopoietic regulators causing transition from some immature stem cells in AML to more mature precursors [5, 7] as well as in APL [6]. To support this hypothesis, we have recently studied leukemic hematopoiesis in a mixed group of adult and pediatric patients with EVI1-positive AML. Chromosome aberrations at the 3q26 locus are considered common in adult patients, however, being virtually absent in pediatric cases. Meanwhile, EVI1-positive AML with presumable rearrangements of KMT2A gene was found in one-fourth of pediatric patients [8-10], thus also presenting essential age-dependent differences in responses to therapy and HSCT. At the same time, an excellent response to retinoid treatment has been recently revealed in all types of EVI1-positive AML [11], which seems to be associated with their direct action upon functional activity of stem cells [12].

The aim of our work was to test BAALC/WT1 molecular panel in the mixed pediatric and adult cohort of patients with of AML variants which are generally resistant to intensive therapy and HSCT.

Patients and methods

1.1. Patient cohort

Our retrospective study presents the data on BAALC and WT1 gene expression levels measured in parallel in the course of serial bone marrow sampling from fourteen EVI1-positive patients with different AML FAB-variants, who underwent allogeneic HSCT at R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg) from 2010 to 2016 years. This group included 8 pediatric patients under 18 years and 6 adults with AML. In all the patients, BAALC and WT1 gene expression changes, as well as blast cell counts were serially monitored in the same bone marrow aspirates. Written informed consent was obtained from all patients, following the Declaration of Helsinki Recommendations.

1.2. Analysis of BAALC and WT1 gene expression levels

Total mRNA was extracted from fresh bone marrow samples, its reverse transcription and estimation of the BAALC gene expression level were performed by quantitative real-time PCR (RT-qPCR) as elsewhere described [13]. In brief, BAALC transcript copy numbers (CN) were determined by means of BAALC RQ-Kit (Inogene, Russia), including plasmid standards for plotting appropriate calibration curves for BAALC and ABL1 reference gene. Basic control time points for the bone marrow examination were as follows: at diagnosis (e.g., D-80), prior to conditioning (D0), and, as obligatory diagnostics, in post-transplant relapses (PTR). A median follow-up time after HSCT was 7 months (range, 0.6 to 52.5 months). Relative BAALC expression level was calculated as a ratio of CNBAALC to CNABL1 and expressed as a percent value. The expression level of 31% was chosen as a common cut-off value to study clinical significance of BAALC gene overexpression before and after HSCT. This value was shown to exceed maximal BAALC expression levels in the patients with pre-transplant cytological remission without any signs of the disease progression.

In parallel, the WT1 gene expression levels were determined in each sample at the same time points. The copy numbers of WT1 transcripts were evaluated by the similar RT-qPCR method, according to Recommendations of European LeukemiaNet Group [14]. The basal WT1 expression level of 250 copies per 104 copies of ABL1 reference gene was used to discriminate between low and high WT1 expression rates. Similarly, the 10 per cent expression level was considered a cut-off value when studying clinical significance of EVI1 overexpression.

1.3. Statistical analysis

Due to small numbers of patients in the tested groups, full-scale statistical analysis was not carried out. The data with asymmetric distribution were presented as extreme ranges and median values. Overall survival (OS) and relapse free-survival (RFS) were measured from D0 until the date of death, regardless of cause, or until the term of documented relapse, or last contact date. STATISTICA software was used for calculations. P< 0.05 was considered the statistically significant difference level, having been determined in every case.

Results

Basic clinical and laboratory data are presented in Table 1. They concern eight pediatric (lower 18 y. o.) and six adult patients. The common levels of EVI1 expression ranged from 0.3% to 130%, being the highest in 26 year-old female with M1 FAB-variant (#11) with complex karyotype. One should note that the cytogenetic changes in pediatric patients were not related to specific 3q26 locus, whereas this pattern of chromosome aberrations was found in 5 of 6 adult patients (83%). At the same time, one of pediatric patients (#5) showed KMT2A rearrangements which are more typical to this type of childhood AML. In general, the cytogenetic aberrations ranged from chromothripsis (#1) and highly complex karyotype to single reciprocal translocations (#8) or deletions (#6). Normal karyotype was registered only in one child (#3).

Table 1. Clinical and laboratory parameters of pediatric (#1-8) and adult (#9-14) variants of EVI1-positive acute myeloid leukemia, treated with hematopoietic stem cell transplantation

Mamaev-tab01.jpg

*, deceased patients; n/d, no data; rel, related; n/rel, nonrelated; haplo, haploidentical; overexpressed levels of BAALC expression and higher meanings of OV in children are noted by red and green colours, respectively

One should comment that primary diagnosis in most patients was assessed at regional hospitals, where precise molecular diagnostics was not available. Therefore, molecular markers at the early stages of disease are lacking in these patients.

Despite this drawback, elevated BAALC expression in EVI1-positive AML at primary diagnosis was demonstrated both in pediatric (#7) and adult (#9, 11) patients, being higher in adults.

Before HSCT, overexpression of BAALC was seen in three pediatric patients (#1, 6, 7), as well as in two adults (#9, 14) who, along with increased blast counts, showed insufficient response of these leukemic cells to pretransplant therapy. This pattern of response is also confirmed by common elevation of WT1 level expression prior to HSCT (6/13; 46%). Finally, upon emergence of post-transplant relapse (PTR) in 5/6 adult patients and 5/8 pediatric ones, the elevated BAALC expression was revealed in five cases (#4, 6, 9, 11 and 13), being the highest (389%) in a young female with secondary (from MDS) M4-FAB-variant of AML (# 9). WT1 gene expression at diagnosis, was enhanced in patients #7, #9 and #11 (11753, 867 and 10493 copies, respectively), with appropriate increase of blast numbers in bone marrow (resp., 88%, 17%, and 84%). At pre-transplant stage, the levels of WT1 expression were increased in the patients #3, #6, #8, #9 and #14 (up to 3693, 2048. 2957. 2025 and 2671 copies, respectively), showing only weak correlation with blast counts in their bone marrow samples (13.4, 7.2, 21, 38 and 7.6, respectively.) Comparison of these data argues for our earlier concept presuming an active participation of other cell populations in WT1 gene expression, for instance, of more mature precursors recently found in successful xenograft of APL samples in immunodeficient NOD/shi-SCID IL2Ry-/- mice [4].

Finally, at stage of PTR, increased WT1 expression levels were found in patients #1, 3, 4, 6, 8, 9, 11, 12, and 13 (respectively, 3315, 1049, 436. 120239. 32684, 1165, 6500, 4542 and 18872 copies) that also weakly correlated with number of blasts in tested bone marrows (60.4, 20.8, 29.8, 30.4, 24.4, 31.5, 51.2, 21, and 26%, respectively).

In conclusion, one should notice that the patients with M3 (#8) and M7 (#1 and 3) had lower levels of BAALC expression at all studied stages, which is explained simply by basic role in hematopoiesis with more mature precursors than BAALC-expressing stem cells. Further, one may conclude on opportunity for different variants of emerging PTR. Thus, in several cases (#4, 6, 9, 11, and 13), PTR were associated with activation of both BAALC-expressing stem cells and WT1-expressing mature precrsors. Meanwhile, PTR in patients with M3 (#8), M7 ( # 1 , 3 and single presenters of M5 (#12) FAB-variants were accompanied by WT1 expressing precursors only.

Discussion

Hence, despite different biological and cytogenetic characteristics of pediatric and adult EVI1-positive AML, they revealed relatively higher levels of BAALC-expressing precursors at diagnosis, as well as at pre- and posttransplant stages, which, in turn, may be related with great difficulties in preparative regimens for HSCT. The real difference between the age groups consisted only in more often relapse-free course of leukemia in children (n=3), than that was among adults (n=1). Therefore, median of overall survival in pediatric patients was longer than that in adults (999 vs 317 days, respectively) which is statistically significant (p<0.05). Presence of cases with AML FAB-variants of M7 (n=2) and M3 (n=1) in pediatric group among these patients may be another reason for absence of expected difference in OS. These patients, generally, do not show higher levels of BAALC expression, due to alternative nature of hematopoiesis precursors.

Conclusion

To reveal the expected difference in BAALC-expressing precursors between pediatric and adult EVI1-positive AML, further studies should be performed in larger cohorts of carefully chosen patients, with omission of M7 and M3 FAB- variants.

Our simultaneous measurements of BAALC and WT1-expressiong leukemic precursors by means of standardized RT-qPCR supported crucial role of BAALC-expressing stem cells in pathogenesis of EVI1-positive AML and relapses evolving in both tested groups.

Conflict of interest

None reported.

References

  1. Walter R, Appelbaum F, Estey E, Bernstein I. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 2012; 119: 6198-6208. doi: 10.1182/ blood-2011-11-325050
  2. Lapidot T, Siratd C, Vormoor J, et al. Z Cell initiating human acute myeloid leukemia after transplantation into SCID mice, Nature 1994;367(6464):645-8. doi: 10.1038/367645a0
  3. Morita R, Masamotyo Y, Kataoka K, Koya J, Kagoya Y, Yashiroda H, Sato T, Murata S, Kurokawa M. BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 2015; 29(11): 2248-2256. doi: 10.1038/leu.2015.137
  4. Patel S, Zhang Y, Cassinat B, Zassadowski F, Ferré N, Cuccuini W, Cayuela JM, Fenaux P, Bonnet D, Chomienne C, Louache F. Successful xenografts of AML3 samples in immunodeficient NOD/shi-SCID IL2Rγ–/– mice. Leukemia 2012; 26(11):2432-2435. doi: 10.1038/leu.2012.154
  5. Mamaev NN, Shakirova AI, Barkhatov IM, et al. New opportunities for assay of leukemia initiating cells (LICs) participating in post-transplant relapse development in the patients with acute myeloid leukemia. 3rd Annual IACH Meeting, 1-3 October, 2020, Paris, report #12.
  6. Mamaev NN, Shakirova AI, Barkhatov IM, Gudozhnikova YV, Gindina TL, Kanunnikov MM, Kravtsova VM, Rakhmanova ZZ, Paina OV, Zubarovskaya LS. Crucial role of BAALC-expressing leukemic precursors in origin and development of posttransplant relapses in patients with acute myeloid leukemias. Int J Hematol 2020; 8(6): 127-131. doi: 10.15406/htij.2020.08.00240
  7. Mamaev NN, Shakirova AI, Gindina TL, Bondarenko SN, Ayubova BI, Barkhatov IM, Gudozhnikova YaV, Kravtsova VM, Kanunnikov MM, Paina OV, Rakhmanova ZZ, Gracheva TYu, Zubarovskaya LS. Quantitative study of BAALC- and WT1-expressing cell precursors in the patients with different cytogenetic and molecular AML variants treated with Gemtuzumab ozogamycin and hematopoietic stem cell transplantation. Cell Ther Transplant 2021; 10(1)):55-62. doi: 10.18620/ctt-1866-8836-2021-10-1-55-62
  8. Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters STJCM, van Wering ER, de Graaf SSN, et al. EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia. Leukemia 2010;24:942-949. doi:10.1038/leu.2010.47
  9. Ho PA, Alonzo TA, Gerbing RB, Pollard JA, Hirsch B, Raimondi SC, Cooper T, Gamis AS, Meshinchi S. High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in pediatric acute myeloid leukemia: a report from the children’s oncology group. Br J Haematol 2013;162(5): 670-677. doi: 10.1111/bjh.12444
  10. Sadaghian MH, Dezaki ZR. Prognostic value of EVI1 expression in pediatric acute myeloid leukemia: A systematic review. Iran J Pathol. 2018; 13(3):294-300. PMID: 30636951
  11. Pauebelle E, Piesa A, Hayette S, et al. Efficacy of ALL-TRANS-RETINOIC ACID in high riskacute myeloid leukemia with overexpression of EVI1. Oncol Ther 2019; 7(2): 121-130. doi: 10.1007/s40487-019-0095-9
  12. Mamaev NN, Shakirova AI, Morozova EV, Gindina TL. EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Practical Aspects (Literature Review). Clinical Oncohematol 2021;14(1): 103-117 (In Russian). doi: 10.21320/2500-2139-2021-14-1-103-117
  13. Shakirova A, Barkhatov I, Churkina A, Moiseev IS, Gindina TL, Bondarenko SN, Afanasyev BV. Prognostic significance of BAALC overexpression in patients with AML during the posttransplant period. Cell Ther Transplant 2018; 7(2):54-63. doi: 10.18620/ctt-1866-8836-2018-7-2-54-63
  14. Cilloni D, Renneville A, Hermitte F, Hills R, Daly S, Jovanovic J, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van den Heijden A, van der Reijden B, Jansen J, van der Verlden V, Ommen H, Preudhomme C, Saglio G, Grimwade D. et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 2009; 27(31): 5195-5201. doi: 10.1200/JCO.2009.22.4865
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string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["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) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> 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["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" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["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) "27618" ["VALUE"]=> array(2) { ["TEXT"]=> string(369) "<p>Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(357) "

Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская

" ["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) "27619" ["VALUE"]=> array(2) { ["TEXT"]=> string(367) "<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(355) "

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

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27620" ["VALUE"]=> array(2) { ["TEXT"]=> string(4710) "<p style="text-align: justify;"> Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при <i>EVI1</i>-позитивном (<i>EVI1<sup>+</sup></i>) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки <i>ВAALC/WT1</i>. Уровни экспрессии генов <i>BAALC, WT1</i> и <i>EVI1</i> определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с <i>EVI1<sup>+</sup></i> ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена <i>BAALC </i>в обеих группах на всех этапах исследования. Гиперэкспрессия <i>BAALC</i> перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия <i>BAALC </i>или <i>BAALC/WT1</i> была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли <i>BAALC</i>-экспрессирующих предшественников в развитии рецидива. </p> <p style="text-align: justify;"> Надо отметить, что гиперэкспрессия <i>BAALC</i> не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение <i>BAALC-</i> и <i>WT1</i>-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Острый миелобластный лейкоз, <i>EVI1</i>-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия <i>BAALC</i>, экспрессия <i>WT1</i>, экспрессия <i>EVI1</i>, предшественники лейкозных клеток, количественная ПЦР. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4392) "

Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1+) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1+ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.

Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

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


Correspondence
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamaev524@gmail.com

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Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1+) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1+ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.

Keywords

Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(214) "

Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

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Nikolay N. Mamaev, Alyena I. Shakirova, Ildar M. Barkhatov, Mikhail M. Kanunnikov, Tatiana L. Gindina, Zhamal Z. Rakhmanova, Olesya V. Paina, Maria V. Latypova, Tatiana Yu. Gracheva, Ludmila S. Zubarovskaya

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Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1+) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1+ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.

Keywords

Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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Some basic biological and cytogenetic characteristics of leukemic cells in EVI1-positive (EVI1+) acute myeloid leukemia (AML) are shown to be different for pediatric and adult patients, like as their response to chemotherapy and hematopoietic stem cell transplantation (HSCT). Hence, one may also expect different pathogenetic roles of leukemic precursors in these AML variants. Our aim was to check this opportunity, and we have quantitatively assessed mRNA expression by leukemic precursors using a recently proposed BAALC/WT1 molecular panel. The levels of BAALC, WT1 and EVI1 gene expression were determined simultaneously in bone marrow samples from 8 pediatric and 6 adult patients with EVI1+ AML by means of quantitative real-time polymerase reaction (RT-qPCR) at specified time-points: a) upon primary diagnosis, b) prior to HSCT, and c) during post-transplant relapse (PTR). Blast cell counts were also provided for these bone marrow samples. Our study showed BAALC gene overexpression in both groups at all the tested stages. Before hematopoietic stem cell transplantation (HSCT) BAALC overexpression was revealed in 6 of 14 patients which could be associated with real difficulties for chemotherapy preparation for HSCT in this category of patients. Moreover, BAALC, or combined BAALC/WT1 overexpression were revealed in most patients with posttransplant relapse (PTR), thus suggesting a crucial role of BAALC-expressing precursors for the emerging relapses. Worth of note, BAALC overexpression was absent at all the tested stages of M3 and M7 FAB-variants, probably, due to more mature nature of appropriate precursor cells. In general, determination of BAALC- and WT1-expressing precursors by means of RT-qPCR seems to be a promising approach to the studies of precise pathogenetic mechanisms in different AML variants, as well as to diagnostics of emerging relapses and, thus, it may be quite important for clinical practice.

Keywords

Acute myeloid leukemia, EVI1-positive, pediatric, adults, hematopoietic stem cell transplantation, relapses, BAALC expression, WT1 expression, EVI1 expression, leukemic cell precursors, quantitative PCR.

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


Correspondence
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamaev524@gmail.com

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


Correspondence
Prof. Nikolay N. Mamaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 12 Roentgen St, 197022, St. Petersburg, Russia
Phone: +7 (911) 760 5086
E-mail: nikmamaev524@gmail.com

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Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская

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Николай Н. Мамаев, Алена И. Шакирова, Ильдар М. Бархатов, Михаил М. Канунников, Татьяна Л. Гиндина, Джамал Ж. Рахманова, Олеся В. Паина, Мария В. Латыпова, Татьяна Ю. Грачева, Людмила С. Зубаровская

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Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки <i>ВAALC/WT1</i>. Уровни экспрессии генов <i>BAALC, WT1</i> и <i>EVI1</i> определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с <i>EVI1<sup>+</sup></i> ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена <i>BAALC </i>в обеих группах на всех этапах исследования. Гиперэкспрессия <i>BAALC</i> перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия <i>BAALC </i>или <i>BAALC/WT1</i> была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли <i>BAALC</i>-экспрессирующих предшественников в развитии рецидива. </p> <p style="text-align: justify;"> Надо отметить, что гиперэкспрессия <i>BAALC</i> не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение <i>BAALC-</i> и <i>WT1</i>-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Острый миелобластный лейкоз, <i>EVI1</i>-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия <i>BAALC</i>, экспрессия <i>WT1</i>, экспрессия <i>EVI1</i>, предшественники лейкозных клеток, количественная ПЦР. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4392) "

Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1+) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1+ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.

Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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Показано, что ряд основных биологических и цитогенетических характеристик лейкозных клеток при EVI1-позитивном (EVI1+) остром миелобластном лейкозе (ОМЛ) различен у пациентов детского возраста и взрослых, как и их ответ на химиотерапию и трансплантацию гемопоэтических стволовых клеток (ТГСК). Таким образом, можно ожидать и различную патогенетическую роль лейкозных клеток-предшественников при данных вариантах ОМЛ. Нашей целью была проверка этой возможности, и мы количественно определяли экспрессию мРНК лейкозными клетками-предшественниками с применением недавно предложенной молекулярной модели оценки ВAALC/WT1. Уровни экспрессии генов BAALC, WT1 и EVI1 определяли параллельно в образцах костного мозга у 8 пациентов детского возраста и 6 взрослых с EVI1+ ОМЛ с помощью количественной ПЦР в реальном режиме времени (РТ-кПЦР) в конкретные сроки: а) при первичной диагностике, б) перед ТГСК и в) на фоне посттрансплантационного рецидива (ПТР). Подсчет бластных форм проводили в этих же образцах костного мозга. Наши результаты показали наличие гиперэкспрессии гена BAALC в обеих группах на всех этапах исследования. Гиперэкспрессия BAALC перед проведением ТГСК выявлялась у 6 из 14 пациентов, что может быть связано с реальными сложностями химиотерапии для последующей ТГСК в этой категории больных. Кроме того, поскольку гиперэкспрессия BAALC или BAALC/WT1 была обнаружена у большинства пациентов с рецидивом после ТГСК, можно предполагать о ключевой роли BAALC-экспрессирующих предшественников в развитии рецидива.

Надо отметить, что гиперэкспрессия BAALC не выявлялась во всех исследованных этапах при M3- и M7-вариантах ОМЛ, возможно, благодаря большему уровню дифференцировки соответствующих клеток-предшественников. В целом, определение BAALC- и WT1-экспрессирующих предшественников посредством РТ-кПЦР представляется перспективным подходом к исследованиям конкретных патогенетических механизмов при различных вариантах ОМЛ, а также при диагностике возникающих рецидивов и может быть весьма важным для клинической практики.

Ключевые слова

Острый миелобластный лейкоз, EVI1-позитивный, дети, взрослые, трансплантация гемопоэтических стволовых клеток, рецидивы, экспрессия BAALC, экспрессия WT1, экспрессия EVI1, предшественники лейкозных клеток, количественная ПЦР.

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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

Multiple sclerosis (MS) is a severe inflammatory and demyelinating autoimmune disease of the central nervous system (CNS), which affects mainly young people and leads to progressive quality of life (QoL) deterioration due to progressive disability [1, 2]. Relapsing remitting MS (RRMS) evolves into secondary progressive disease in 70-80% of cases during 10-15 years [3, 4]. Hence, this relatively favorable variant of MS seems to be a very difficult condition with high risk of disability. Thus, the goal of treatment is to prevent MS progression and disability, to provide better control of the symptoms and to improve patient’s QoL [5]. Conventional DMT (Disease Modifying Therapies) does not provide satisfactory control of MS, due to inability to eradicate self-aggressive T- and B-cell clones. Immunosuppressive treatment including monoclonal antibodies, which are usually used as a second-line therapy, also have only partial beneficial effect [6, 7].

At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients [8-14]. The rationale for this method presumes that ablation of the impaired immune system followed by reconstitution of the new immune cell populations may alter the characteristics of the T – and B-cell responses and other immunological properties which can improve clinical course of MS [15, 16]. Previous studies demonstrated that AHSCT was associated with improvement in neurological disability and QoL in RRMS patients [17-21].

At the same time, in spite of promising clinical results, there are still several questions to be clarified before recommending AHSCT as a treatment choice for MS patients, especially for those with relapsing-remitting disease. For example, effectiveness and safety of different conditioning regimens (intermediate and low-intensity) should be analyzed carefully. Several clinical studies have addressed the issue of safety and effectiveness of AHSCT with BEAM as intermediate-intensity conditioning regimen in MS with certain promising results [22-25]. On the other side, it was shown recently, that low-intensity regimens (BEAM-like or Cyclophosphamide based) are associated with similar outcome results and less toxicity profile to compare with more intensive conditioning. Patients’ selection for AHSCT is another core issue [26, 27]. Additionally, comprehensive treatment outcomes assessment is very important in all variants of AHSCT [28, 29]. Both disease-free period and improvement of patient’s QoL are recognized as important treatment outcomes. Also, one of the key issues is the long-term follow-up and assessment of clinical and patient-reported outcomes [29-31].

Thus, we aimed to evaluate the effect of AHSCT with low-intensity conditioning regimens in patients with RRMS, in terms of clinical and patient-reported outcomes.

Patients and methods

All the patients underwent AHSCT in the Transplantation Unit, Department of Haematology and Cellular Therapy, Pirogov National Medical and Surgical Centre (Moscow) from October 2006 to October 2018. The study was conducted according to the principles of Helsinki Declaration, and was approved by the Institute Research Board and local Ethics Committee before initiation. All the patients had given their written informed consent. The patients were eligible if they were >15 years old and met the Poser and McDonald criteria for clinically defined MS [32]. Other criteria for patients’ selection included normal mental status and absence of severe concomitant diseases. The vast majority of patients was refractory to 2-4 different lines of conventional treatment including interferons, copaxone, mitoxantrone, cladribine, monoclonal antibodies therapy, azathioprine, intravenous immunoglobulin, glucocorticosteroids etc.

Hematopoietic stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF, 10 µg/kg) during 4-5 days. The mobilized cells were collected by apheresis after 4 days of stimulation until a yield of at least 2.0×106 CD34+ cells/kg.

Three low-intensity conditioning regimens were applied in the patients. Two regimens were based on reduced BEAM protocol: (1) BM schedule (BCNU 300 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion); (2) BEAM-like regimen (BCNU 300 mg/m2, Etoposide 100 mg/m2, Ara-C 100 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion). The third conditioning regimen included high-dose cyclophosphamide (200 mg/kg) + Rituximab (500 mg/m2) on D+11-12 (one infusion).

G-CSF (5 µg/kg) was administered on D+1 to D+2 until granulocyte recovery. For infection prophylaxis, oral levofloxacin, fluconazole, co-trimoxazole and acyclovir were used.

Toxicity of treatment was evaluated in accordance with National Cancer Institute Common Toxicity Criteria (version 2) [33]. The terms of posttransplant neutrophil engraftment were defined since the first day when absolute neutrophil count was >500 cells/mL. Platelet engraftment was registered since the first day when the platelet count was >20,000 platelets/mL (without platelet transfusions). Transplant-related mortality (TRM) included every death occurring within 100 days of transplantation [34].

The primary end point was disability level defined by the EDSS score [35]. Other studied end-points included safety, relapse-free survival (no acute relapses) and quality of life (QoL) changes. To evaluate clinical outcomes, neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and, later, at the annual basis. EDSS decrease of 1.0 or more was considered a significant improvement, and an increase of 1.0 or greater was viewed as significant worsening. MRI scans of brain and cervical spinal cord with gadolinium enhancement were performed at baseline, at 3, 6, and 12 months after transplantation, every 6 months up to 48 months, and then at yearly intervals. QoL was assessed using RAND SF-36 [36], common symptoms, by CSP-MS-42 [37]. The SF-36 is generic tool for QoL assessment widely used in patients with chronic diseases, including MS [38, 39]. The Comprehensive Symptom Profile-MS-42 (CSP-MS-42) was developed in 2007 by New Jersey Center for Quality of Life and Health Outcome Research (USA) and Multinational Center for QoL Research (Russia) to assess the severity of 42 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from "0" (no symptom) to "10" (most expressed symptom). The measurements were conducted before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and every 12 months after 2 years during 5 years after AHSCT.

For statistical evaluation, paired t-test, Wilcoxon test and ANOVA were used. Progression-free survival (PFS) and relapse-free survival (RFS) after AHSCT were evaluated using Kaplan-Meyer method. To compare survival rates, log-rank criterion and Tarone-Ware criterion were applied. Mc-Nemar’s test was used in order to compare the proportions of patients according to symptom prevalence before AHSCT and 12 months following transplant. P values of <0.05 will be used as a cut-off point for statistical significance, and all statistical tests will be two-sided.

Table 1. Characteristics of the patients with multiple sclerosis

Melnichenko-tab01.jpg

Melnichenko-fig01.jpg

Figure 1. EDSS medians in patients with RRMS before and at different time-points after AHSCT

Results

General characteristics

A total of 258 patients with RRMS were enrolled in the study. Mean age was 36.5 years old; male/female ratio, 73/185. Median EDSS value before transplantation was 2.0 (range 1.5-6.5). Mean duration of the disease was 4.9 years (median 3.0, range 0.5-24). Patients’ characteristics are shown in Table 1.

Safety

The procedure of autologous HSCT was well tolerated by the patients. There were no cases of transplantation-related mortality. Mobilization was successful in all cases with median number of 2.1×106/kg (range 2-10.9×106/kg) collected CD34+cells; no major clinical adverse events were observed during this phase.

The mean time of neutropenia (grade 4) was 8.0 days. The mean time of thrombocytopenia (grade 3-4) was 7.0 days. Neutrophil engraftment was registered on D+8- D+11. No differences in hematological toxicity between the three conditioning regimens were found (P>0.05).

Common adverse effects after AHSCT were as follows: hepatic toxicity (grade 2 and 3) – 20.5%; mucositis (grade 2), 1.6%; temporary neurological worsening, 6.4%; neutropenic fever, 27%; local infection, 6.2%; anemia (grade 3), 1.9%; allergic reactions, 2.3%. No differences in toxicity were observed among the patients who received different conditioning regimens. No deaths were registered throughout the entire follow-up period.

Сlinical outcomes

Median follow-up after AHSCT was 30 months (3.7-110.9). The vast majority of patients (99%) responded to treatment. The decrease of EDSS score from median 2.0 to 1.5 was observed at 12 months after AHSCT, and it remained at this level during the follow-up of more than 60 months (Fig. 1). The EDSS score improved significantly for the entire group (P <0.001) at all the time intervals, as compared with base-line. EDSS changes in patients with RRMS prior to and at different time-points after AHSCT are presented in Table 2. The proportion of patients with change of >1.0 in EDSS score was 36% (86 patients) with index of improvement at 12 months, and 0.4% (1 patient) with an index of the disease progression. At 2 years post-transplant, 47 (32%) patients showed improvement, 1 patient (0.7%) became worse, and others presented with stable disease. At 3 years posttransplant, improvement was observed in 23 (25%) patients, worsening – in 1 (1.1%) patient, the others were in stable clinical state. At 4 years posttransplant, the majority (83.1%) of patients were stable, there was no further worsening, and 10 patients (16.9%) exhibited improvement. Hence, the vast majority of patients was stable during the continuous follow-up; clinical deterioration took place in 6% of patients.

Table 2. EDSS changes in patients with RRMS before and at different time-points after AHSCT

Melnichenko-tab02.jpg

After AHSCT, the vast majority of patients with RRMS were relapse-free (245 out of 258). The mean term until relapse was 30.4 months (95% CI 18.24-42.52). Estimated relapse-free survival (RFS) at the median follow-up of 29.5 months was 95% (95% CI: 92.3-97.7) (Fig. 2A).

Estimated RFS at the follow-up of 36 months was 95.6% (95% CI: 92.4-98.8), at the follow-up of 60 months, 88.2% (95% CI: 80.2-96.2); at the follow-up of 84 months, 83.3% (95% CI: 71.3-95.3). Estimated progression-free survival (PFS) at the follow-up of 36 months was 98% (95% CI: 95.6-100.0), at the follow-up of 60 months, 91.2% (95% CI: 81.9-100.0), at the follow-up of 84 months, 86.2% (95% CI: 73.1-99.3), as seen from Fig. 2B.

Melnichenko-fig02.jpg

Figure 2. Relapse-free (a) and progression free (b) survival Kaplan-Meyer curves in RRMS patients after AHSCT

Melnichenko-fig03.jpg

Figure 3. Relapse-free survival Kaplan-Meyer curves for patients who received BEAM-like vs who received high-dose Cyclophosphamide+Rituximab

Separate analysis of RFS probability in the groups of patients with different conditioning regimen was also performed.Comparison was made between the conditioning regimens based on BEAM-like and Cyclophosphamide+Rituximab protocols. Previously, it was shown that the outcomes for mini-BEAM and BM were similar [24]. Thus, the BEAM-like group included mini-BEAM and BM conditioning regimens. No differences in RFS were found between patients who received BEAM-like and these who received high-dose cyclophosphamide+Rituximab (log-rank, P=0.92), as shown in Fig. 3.

Patient-reported outcomes

Mean QoL values in RRMS patients before AHSCT and 12 months after AHSCT (n=78) are presented in Table 3. QoL changes (Δ) of scores according to all the SF-36 scales in 12 mo after AHSCT were compared to the baseline levels (Fig. 4).

We have also performed analysis of QoL changes at long-term follow-up after AHSCT (≥18 months) as compared to baseline values (n=41). Median follow-up was 22.9 months (interquartile range: 16.8-35.7 mo; mean±SD, 23.9±5.05 mo;95% CI: 22.3 to 25.5 mo). The mean QoL values in RRMS patients before AHSCT and in the course of long-term follow-up after AHSCT are presented in Table 4. QoL changes (Δ) of scores for all SF-36 scales over long-term follow-up after AHSCT were compared to baseline scores (Fig. 5).

Table 3. Quality of life mean values in RRMS patients at baseline and 12 months after AHSCT

Melnichenko-tab03.jpg

Table 4. Mean values for QoL indexes in RRMS patients at baseline and in long-term follow-up after AHSCT

Melnichenko-tab04.jpg Melnichenko-fig04-05.jpg

Prevalence of the most common symptoms by CSP-MS42 in RRMS patients at 12 mo after ASCT against appropriate baseline values is shown in Fig. 6. Before AHSCT, the ten most common symptoms were present in more than half of the patients. Such symptoms as constant tiredness feeling, early exhaustion after physical activity, decreased energy, fatigue, heaviness in legs, loss of balance, lack of working coordination, difficulty walking and poor tolerance of hot water were reported by the vast majority of patients. As seen from the Fig. 6, their prevalence decreased 12 months post-transplant. The number of patients who experienced these symptoms except of heaviness in legs was significantly less after AHSCT as compared with baseline prevalence (P<0.05). The severity of all these symptoms also decreased after AHSCT (P<0.05).

Melnichenko-fig06.jpg

Figure 6. Prevalence of common MS symptoms before and at 12 months posttransplant

AHSCT was accompanied by a significant improvement in patient’s QoL and decrease of symptom burden. Improved QoL was preserved during the entire period of follow-up. AHSCT is beneficial in unfavorable group of MS patients, those with progressive MS, with high disability and long lasting disease.

Discussion

We have analyzed a cohort of 258 patients with RRMS undergoing AHSCT, with a median follow-up of 30 months. Low-intensity conditioning regimens based on BEAM and cyclophosphamide were applied. Outcomes of AHSCT were evaluated both from physician’s and patient’s perspective. Transplantation procedure was well tolerated by the patients. There were no cases of transplantation-related mortality. In our cohort, the vast majority of patients responded to treatment and exhibited clinical improvement, or were stable during the entire period of follow-up. Significant decrease of EDSS score was observed after transplantation; the EDSS score improved (decreased by ≥1.0 point), with 32% and 17% of patients demonstrating improvement at 2 years and 4 years, respectively. In our cohort, relapse-free survival and progression-free survival at 7-year follow-up were 83% and 86%, respectively. These results are in line with previously published data by R. Burt [18, 19].

Moreover, AHSCT was accompanied by significant improvement in patient’s QoL. The analysis of QoL demonstrated benefits of AHSCT with low-intensity conditioning regimens in this patient population. QoL is an important outcome of MS treatment and its assessment provides the patient’s perspective on the overall effect of treatment and allows evaluating patient benefits. Our results definitely show that AHSCT resulted in significant and sustained improvement of patient’s QoL. Also, prevalence and severity of common symptoms of MS decreased after transplantation. Thus, noticeble decrease of symptom burden after AHSCT was demonstrated.

For the first time to our knowledge, we report the AHSCT outcomes in MS patients after different low-intensity conditioning regimens and long-term follow-up. We did not find any differences in RFS between the patients who received BM/BEAM-like+ATG, and those who received high-dose cyclophosphamide+Rituximab. These data are in line with the results we have published previously [29]. Our study also demonstrated that RFS did not differ between various age groups, and between the groups with different duration of the disease.

On the contrary, disability status was an important factor influencing the outcomes of transplantation: RFS was dramatically better in patients with EDSS<4 as compared to patients with EDSS=4-6.5. This finding supports the idea that AHSCT is beneficial for patients with highly active relapsing-remitting MS and moderate disability.

This study has several important limitations. Firstly, the study was conducted at a single academic institution, which may introduce some bias. However, all patients had clinical continuity and were monitored for in terms of relapses or need for additional treatment. Secondly, a large number of patients were treated on a compassionate basis rather than within a study protocol. Thirdly, a long-term follow-up (i.e, for ≥4 years) was not available for a substantial proportion of patients. Fourth, this was an observational cohort lacking a control group. Therefore, any inferences about causal effects of AHSCT can’t be made.

Thus, the risk/benefit ratio of AHSCT with low-intensity conditioning regimens in our population of RRMS patients is rather favorable. The consistency of our clinical and QoL results, together with persistent improvement suggest clinical efficacy of AHSCT strategy in RRMS patients. In general, the results of our study support the feasibility of AHSCT with low-intensity conditioning in RRMS patients. To optimize the mentioned treatment protocols of AHSCT in RRMS, multicenter cooperative studies are necessary in future.

Conflicts of interest

None reported.

References

  1. Weinshenker BG. The natural history of multiple sclerosis. Neurol Clin. 1995; 13(1):119-146. PMID: 7739500
  2. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010; 9(5):520-532. doi: 10.1016/S1474-4422(10)70064-8
  3. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2
  4. Hafler DA. Multiple sclerosis. J Clin Invest. 2004; 113(6):788-794. doi: 10.1172/JCI21357
  5. Visser, LA, Louapre, C, Uyl-de Groot CA, Redekop WK. Health-related quality of life of multiple sclerosis patients: a European multi-country study. Arch Public Health 79, 39 (2021). doi: 10.1186/s13690-021-00561-z
  6. Lucchetta RC, Tonin FS, Borba HHL, Leonart LP, Ferreira VL, Bonetti AF, et al. Disease-modifying therapies for relapsing-remitting multiple sclerosis: A network meta-analysis. CNS Drugs. 2018;32(9):813-826. doi: 10.1007/s40263-018-0541-5
  7. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72(2):152-158. doi: 10.1001/jamaneurol.2014.3537
  8. Burt RK, Cohen B, Rose J, Petersen F, Oyama Y, Stefoski D et al. Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol. 2005; 62(6):860-864. doi: 10.1001/archneur.62.6.860
  9. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005
  10. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
  11. Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017; 23(2):201-204. doi: 10.1177/1352458516645670
  12. Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D et al. European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE). Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020;55(2):283-306. doi: 10.1038/s41409-019-0684-0
  13. Gavriilaki M, Sakellari I, Gavriilaki E, Kimiskidis VK, Anagnostopoulos A. Autologous hematopoietic cell transplantation in multiple sclerosis: Changing paradigms in the era of novel agents. Stem Cells Int. 2019; 2019:5840286. doi: 10.1155/2019/5840286
  14. Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A et al. Multiple sclerosis–autologous hematopoietic stem cell transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017; 74(4):459-469. doi: 10.1001/jamaneurol.2016.5867
  15. Miller AE, Chitnis T, Cohen BA, et al. Autologous hematopoietic stem cell transplant in multiple sclerosis: recommendations of the National Multiple Sclerosis Society. JAMA Neurol. 2021;78 (2):241-246. doi:10.1001/jamaneurol.2020.4025
  16. Tolf A, Fagius J, Carlson K, Åkerfeldt T, Granberg T, Larsson EM, Burman J. Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurol Scand. 2019; 140(5):320-327. doi:10.1111/ane.13147
  17. Cohen JA, Baldassari LE, Atkins HL, Bowen JD, Bredeson C, Carpenter PA et al. Autologous hematopoietic cell transplantation for treatment-refractory relapsing multiple sclerosis: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019; 25(5):845-854. doi: 10.1016/j.bbmt.2019.02.014
  18. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015; 313(3):275-284. doi: 10.1001/jama.2014.17986
  19. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: A randomized clinical trial. JAMA. 2019; 321(2):165-174. doi: 10.1001/jama.2018.18743
  20. Zhukovsky C, Sandgren S, Silfverberg T, Einarsdottir S, Tolf A, Landtblom A-M, et al. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study. J Neurol Neurosurg Psychiatry. 2020. doi: 10.1136/jnnp-2020-323992
  21. Bertolotto A, Martire S, Mirabile L, Capobianco M, De Gobbi M, Cilloni D. Autologous hematopoietic stem cell transplantation (AHSCT): standard of care for relapsing-remitting multiple sclerosis patients. Neurol Ther. 2020;9(2):197-203. doi:10.1007/s40120-020-00200-9
  22. Burt RK, Marmont A, Oyama Y, Slavin S, Arnold R, Hiepe F et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum. 2006; 54(12):3750-3760. doi: 10.1002/art.22256
  23. Muraro PA, McFarland HF, Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous hematopoietic stem cell transplantation.Stem Cell Therapy for Autoimmune Disease. 2004:277-283. doi:10.1201/9780367813895-33
  24. Rogojan C, Frederiksen JL. Hematopoietic stem cell transplantation in multiple sclerosis. Acta Neurol Scand. 2009; 120(6):371-382. doi: 10.1111/j.1600-0404.2009.01168.x
  25. Mohammadi R, Aryan A, Omrani MD, Ghaderian SMH, Fazeli Z. Autologous hematopoietic stem cell transplantation (AHSCT): An evolving treatment avenue in multiple sclerosis. Biologics. 2021;15:53-59. doi: 10.2147/BTT.S267277
  26. Ismail A, Sharrack B, Saccardi R, Moore JJ, Snowden JA. Autologous haematopoietic stem cell therapy for multiple sclerosis: a review for supportive care clinicians on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation. Curr Opin Support Palliat Care. 2019;13(4): 394-401. doi: 10.1097/SPC.0000000000000466
  27. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008; 7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
  28. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, Rykavicin OA, Ionova TI, Melnichenko VY, Fedorenko DA, Kulagin AD, Shamanski SV, Ivanov RA, Gorodokin G. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hematol. 2008; 36(8):922-928. doi: 10.1016/j.exphem.2008.03.001
  29. Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kartashov AV, Kurbatova KA, Gorodokin GI, Novik AA. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. 2012; 40(11):892-898. doi: 10.1016/j.exphem.2012.07.003
  30. Chen B, Zhou M, Ouyang J, Zhou R, Xu J, Zhang Q, Yang Y, Xu Y, Shao X, Meng L, Wang J, Xu Y, Ni X, Zhang X. Long-term efficacy of autologous haematopoietic stem cell transplantation in multiple sclerosis at a single institution in China. Neurol Sci. 2012; 33(4):881-886. doi: 10.1007/s10072-011-0859-y
  31. Saccardi R, Freedman MS, Sormani MP, Atkins H, Farge D, Griffith LM et al. European Blood and Marrow Transplantation Group; Center for International Blood and Marrow Research; HSCT in MS International Study Group. A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper. Mult Scler. 2012; 18(6):825-834. doi: 10.1177/1352458512438454
  32. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983; 13(3):227-231. doi: 10.1002/ana.410130302
  33. Common Toxicity Criteria. Version 2.0. Publish Date: April 30, 1999. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf
  34. Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E et al. Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation). Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002; 249(8):1088-1097. doi: 10.1007/s00415-002-0800-7
  35. Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology. 1984; 34(10):1368-1372. doi: 10.1212/wnl.34.10.1368
  36. Hays RD, Sherbourne CD, Mazel RM. User’s Manual for Medical Outcomes Study (MOS). Core measures of health-related quality of life. RAND Corporation, MR-162-RC. http://www.rand.org
  37. Ionova T, Value of patient-reported outcomes in multiple sclerosis patients undergoing autologous hematopoietic stem cell transplantation. Proc. Int. Conf. "Stem cell transplantation for treatment of autoimmune diseases", Moscow, 2019. P. 44-45
  38. Hobart J, Freeman J, Lamping D, Fitzpatrick R, Thompson A. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71(3):363-370. doi: 10.1136/jnnp.71.3.363
  39. Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Freeman JA, Jenkinson C, Peto V, Thompson AJ. Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles. J Neurol Neurosurg Psychiatry. 2003; 74(6):710-714. doi: 10.1136/jnnp.74.6.710
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Introduction

Multiple sclerosis (MS) is a severe inflammatory and demyelinating autoimmune disease of the central nervous system (CNS), which affects mainly young people and leads to progressive quality of life (QoL) deterioration due to progressive disability [1, 2]. Relapsing remitting MS (RRMS) evolves into secondary progressive disease in 70-80% of cases during 10-15 years [3, 4]. Hence, this relatively favorable variant of MS seems to be a very difficult condition with high risk of disability. Thus, the goal of treatment is to prevent MS progression and disability, to provide better control of the symptoms and to improve patient’s QoL [5]. Conventional DMT (Disease Modifying Therapies) does not provide satisfactory control of MS, due to inability to eradicate self-aggressive T- and B-cell clones. Immunosuppressive treatment including monoclonal antibodies, which are usually used as a second-line therapy, also have only partial beneficial effect [6, 7].

At present, high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (AHSCT) has been used with increasing frequency as a therapeutic option for MS patients [8-14]. The rationale for this method presumes that ablation of the impaired immune system followed by reconstitution of the new immune cell populations may alter the characteristics of the T – and B-cell responses and other immunological properties which can improve clinical course of MS [15, 16]. Previous studies demonstrated that AHSCT was associated with improvement in neurological disability and QoL in RRMS patients [17-21].

At the same time, in spite of promising clinical results, there are still several questions to be clarified before recommending AHSCT as a treatment choice for MS patients, especially for those with relapsing-remitting disease. For example, effectiveness and safety of different conditioning regimens (intermediate and low-intensity) should be analyzed carefully. Several clinical studies have addressed the issue of safety and effectiveness of AHSCT with BEAM as intermediate-intensity conditioning regimen in MS with certain promising results [22-25]. On the other side, it was shown recently, that low-intensity regimens (BEAM-like or Cyclophosphamide based) are associated with similar outcome results and less toxicity profile to compare with more intensive conditioning. Patients’ selection for AHSCT is another core issue [26, 27]. Additionally, comprehensive treatment outcomes assessment is very important in all variants of AHSCT [28, 29]. Both disease-free period and improvement of patient’s QoL are recognized as important treatment outcomes. Also, one of the key issues is the long-term follow-up and assessment of clinical and patient-reported outcomes [29-31].

Thus, we aimed to evaluate the effect of AHSCT with low-intensity conditioning regimens in patients with RRMS, in terms of clinical and patient-reported outcomes.

Patients and methods

All the patients underwent AHSCT in the Transplantation Unit, Department of Haematology and Cellular Therapy, Pirogov National Medical and Surgical Centre (Moscow) from October 2006 to October 2018. The study was conducted according to the principles of Helsinki Declaration, and was approved by the Institute Research Board and local Ethics Committee before initiation. All the patients had given their written informed consent. The patients were eligible if they were >15 years old and met the Poser and McDonald criteria for clinically defined MS [32]. Other criteria for patients’ selection included normal mental status and absence of severe concomitant diseases. The vast majority of patients was refractory to 2-4 different lines of conventional treatment including interferons, copaxone, mitoxantrone, cladribine, monoclonal antibodies therapy, azathioprine, intravenous immunoglobulin, glucocorticosteroids etc.

Hematopoietic stem cells were mobilized with granulocyte colony-stimulating factor (G-CSF, 10 µg/kg) during 4-5 days. The mobilized cells were collected by apheresis after 4 days of stimulation until a yield of at least 2.0×106 CD34+ cells/kg.

Three low-intensity conditioning regimens were applied in the patients. Two regimens were based on reduced BEAM protocol: (1) BM schedule (BCNU 300 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion); (2) BEAM-like regimen (BCNU 300 mg/m2, Etoposide 100 mg/m2, Ara-C 100 mg/m2, Melphalan 100 mg/m2 + horse ATG at the dose of 30 mg/kg on days 1 and 2 for in vivo T cell-depletion). The third conditioning regimen included high-dose cyclophosphamide (200 mg/kg) + Rituximab (500 mg/m2) on D+11-12 (one infusion).

G-CSF (5 µg/kg) was administered on D+1 to D+2 until granulocyte recovery. For infection prophylaxis, oral levofloxacin, fluconazole, co-trimoxazole and acyclovir were used.

Toxicity of treatment was evaluated in accordance with National Cancer Institute Common Toxicity Criteria (version 2) [33]. The terms of posttransplant neutrophil engraftment were defined since the first day when absolute neutrophil count was >500 cells/mL. Platelet engraftment was registered since the first day when the platelet count was >20,000 platelets/mL (without platelet transfusions). Transplant-related mortality (TRM) included every death occurring within 100 days of transplantation [34].

The primary end point was disability level defined by the EDSS score [35]. Other studied end-points included safety, relapse-free survival (no acute relapses) and quality of life (QoL) changes. To evaluate clinical outcomes, neurological assessment and MRI scans were performed. Neurological assessment using EDSS was performed at baseline, at discharge, at 3, 6, and 12 months after transplantation, every 6 months thereafter up to 48 months, and, later, at the annual basis. EDSS decrease of 1.0 or more was considered a significant improvement, and an increase of 1.0 or greater was viewed as significant worsening. MRI scans of brain and cervical spinal cord with gadolinium enhancement were performed at baseline, at 3, 6, and 12 months after transplantation, every 6 months up to 48 months, and then at yearly intervals. QoL was assessed using RAND SF-36 [36], common symptoms, by CSP-MS-42 [37]. The SF-36 is generic tool for QoL assessment widely used in patients with chronic diseases, including MS [38, 39]. The Comprehensive Symptom Profile-MS-42 (CSP-MS-42) was developed in 2007 by New Jersey Center for Quality of Life and Health Outcome Research (USA) and Multinational Center for QoL Research (Russia) to assess the severity of 42 symptoms which are common and most disturbing for MS patients. It consists of numerical analogous scales, scored from "0" (no symptom) to "10" (most expressed symptom). The measurements were conducted before AHSCT, at 6 and 12 months after AHSCT, then every 6 months during 2 years after AHSCT and every 12 months after 2 years during 5 years after AHSCT.

For statistical evaluation, paired t-test, Wilcoxon test and ANOVA were used. Progression-free survival (PFS) and relapse-free survival (RFS) after AHSCT were evaluated using Kaplan-Meyer method. To compare survival rates, log-rank criterion and Tarone-Ware criterion were applied. Mc-Nemar’s test was used in order to compare the proportions of patients according to symptom prevalence before AHSCT and 12 months following transplant. P values of <0.05 will be used as a cut-off point for statistical significance, and all statistical tests will be two-sided.

Table 1. Characteristics of the patients with multiple sclerosis

Melnichenko-tab01.jpg

Melnichenko-fig01.jpg

Figure 1. EDSS medians in patients with RRMS before and at different time-points after AHSCT

Results

General characteristics

A total of 258 patients with RRMS were enrolled in the study. Mean age was 36.5 years old; male/female ratio, 73/185. Median EDSS value before transplantation was 2.0 (range 1.5-6.5). Mean duration of the disease was 4.9 years (median 3.0, range 0.5-24). Patients’ characteristics are shown in Table 1.

Safety

The procedure of autologous HSCT was well tolerated by the patients. There were no cases of transplantation-related mortality. Mobilization was successful in all cases with median number of 2.1×106/kg (range 2-10.9×106/kg) collected CD34+cells; no major clinical adverse events were observed during this phase.

The mean time of neutropenia (grade 4) was 8.0 days. The mean time of thrombocytopenia (grade 3-4) was 7.0 days. Neutrophil engraftment was registered on D+8- D+11. No differences in hematological toxicity between the three conditioning regimens were found (P>0.05).

Common adverse effects after AHSCT were as follows: hepatic toxicity (grade 2 and 3) – 20.5%; mucositis (grade 2), 1.6%; temporary neurological worsening, 6.4%; neutropenic fever, 27%; local infection, 6.2%; anemia (grade 3), 1.9%; allergic reactions, 2.3%. No differences in toxicity were observed among the patients who received different conditioning regimens. No deaths were registered throughout the entire follow-up period.

Сlinical outcomes

Median follow-up after AHSCT was 30 months (3.7-110.9). The vast majority of patients (99%) responded to treatment. The decrease of EDSS score from median 2.0 to 1.5 was observed at 12 months after AHSCT, and it remained at this level during the follow-up of more than 60 months (Fig. 1). The EDSS score improved significantly for the entire group (P <0.001) at all the time intervals, as compared with base-line. EDSS changes in patients with RRMS prior to and at different time-points after AHSCT are presented in Table 2. The proportion of patients with change of >1.0 in EDSS score was 36% (86 patients) with index of improvement at 12 months, and 0.4% (1 patient) with an index of the disease progression. At 2 years post-transplant, 47 (32%) patients showed improvement, 1 patient (0.7%) became worse, and others presented with stable disease. At 3 years posttransplant, improvement was observed in 23 (25%) patients, worsening – in 1 (1.1%) patient, the others were in stable clinical state. At 4 years posttransplant, the majority (83.1%) of patients were stable, there was no further worsening, and 10 patients (16.9%) exhibited improvement. Hence, the vast majority of patients was stable during the continuous follow-up; clinical deterioration took place in 6% of patients.

Table 2. EDSS changes in patients with RRMS before and at different time-points after AHSCT

Melnichenko-tab02.jpg

After AHSCT, the vast majority of patients with RRMS were relapse-free (245 out of 258). The mean term until relapse was 30.4 months (95% CI 18.24-42.52). Estimated relapse-free survival (RFS) at the median follow-up of 29.5 months was 95% (95% CI: 92.3-97.7) (Fig. 2A).

Estimated RFS at the follow-up of 36 months was 95.6% (95% CI: 92.4-98.8), at the follow-up of 60 months, 88.2% (95% CI: 80.2-96.2); at the follow-up of 84 months, 83.3% (95% CI: 71.3-95.3). Estimated progression-free survival (PFS) at the follow-up of 36 months was 98% (95% CI: 95.6-100.0), at the follow-up of 60 months, 91.2% (95% CI: 81.9-100.0), at the follow-up of 84 months, 86.2% (95% CI: 73.1-99.3), as seen from Fig. 2B.

Melnichenko-fig02.jpg

Figure 2. Relapse-free (a) and progression free (b) survival Kaplan-Meyer curves in RRMS patients after AHSCT

Melnichenko-fig03.jpg

Figure 3. Relapse-free survival Kaplan-Meyer curves for patients who received BEAM-like vs who received high-dose Cyclophosphamide+Rituximab

Separate analysis of RFS probability in the groups of patients with different conditioning regimen was also performed.Comparison was made between the conditioning regimens based on BEAM-like and Cyclophosphamide+Rituximab protocols. Previously, it was shown that the outcomes for mini-BEAM and BM were similar [24]. Thus, the BEAM-like group included mini-BEAM and BM conditioning regimens. No differences in RFS were found between patients who received BEAM-like and these who received high-dose cyclophosphamide+Rituximab (log-rank, P=0.92), as shown in Fig. 3.

Patient-reported outcomes

Mean QoL values in RRMS patients before AHSCT and 12 months after AHSCT (n=78) are presented in Table 3. QoL changes (Δ) of scores according to all the SF-36 scales in 12 mo after AHSCT were compared to the baseline levels (Fig. 4).

We have also performed analysis of QoL changes at long-term follow-up after AHSCT (≥18 months) as compared to baseline values (n=41). Median follow-up was 22.9 months (interquartile range: 16.8-35.7 mo; mean±SD, 23.9±5.05 mo;95% CI: 22.3 to 25.5 mo). The mean QoL values in RRMS patients before AHSCT and in the course of long-term follow-up after AHSCT are presented in Table 4. QoL changes (Δ) of scores for all SF-36 scales over long-term follow-up after AHSCT were compared to baseline scores (Fig. 5).

Table 3. Quality of life mean values in RRMS patients at baseline and 12 months after AHSCT

Melnichenko-tab03.jpg

Table 4. Mean values for QoL indexes in RRMS patients at baseline and in long-term follow-up after AHSCT

Melnichenko-tab04.jpg Melnichenko-fig04-05.jpg

Prevalence of the most common symptoms by CSP-MS42 in RRMS patients at 12 mo after ASCT against appropriate baseline values is shown in Fig. 6. Before AHSCT, the ten most common symptoms were present in more than half of the patients. Such symptoms as constant tiredness feeling, early exhaustion after physical activity, decreased energy, fatigue, heaviness in legs, loss of balance, lack of working coordination, difficulty walking and poor tolerance of hot water were reported by the vast majority of patients. As seen from the Fig. 6, their prevalence decreased 12 months post-transplant. The number of patients who experienced these symptoms except of heaviness in legs was significantly less after AHSCT as compared with baseline prevalence (P<0.05). The severity of all these symptoms also decreased after AHSCT (P<0.05).

Melnichenko-fig06.jpg

Figure 6. Prevalence of common MS symptoms before and at 12 months posttransplant

AHSCT was accompanied by a significant improvement in patient’s QoL and decrease of symptom burden. Improved QoL was preserved during the entire period of follow-up. AHSCT is beneficial in unfavorable group of MS patients, those with progressive MS, with high disability and long lasting disease.

Discussion

We have analyzed a cohort of 258 patients with RRMS undergoing AHSCT, with a median follow-up of 30 months. Low-intensity conditioning regimens based on BEAM and cyclophosphamide were applied. Outcomes of AHSCT were evaluated both from physician’s and patient’s perspective. Transplantation procedure was well tolerated by the patients. There were no cases of transplantation-related mortality. In our cohort, the vast majority of patients responded to treatment and exhibited clinical improvement, or were stable during the entire period of follow-up. Significant decrease of EDSS score was observed after transplantation; the EDSS score improved (decreased by ≥1.0 point), with 32% and 17% of patients demonstrating improvement at 2 years and 4 years, respectively. In our cohort, relapse-free survival and progression-free survival at 7-year follow-up were 83% and 86%, respectively. These results are in line with previously published data by R. Burt [18, 19].

Moreover, AHSCT was accompanied by significant improvement in patient’s QoL. The analysis of QoL demonstrated benefits of AHSCT with low-intensity conditioning regimens in this patient population. QoL is an important outcome of MS treatment and its assessment provides the patient’s perspective on the overall effect of treatment and allows evaluating patient benefits. Our results definitely show that AHSCT resulted in significant and sustained improvement of patient’s QoL. Also, prevalence and severity of common symptoms of MS decreased after transplantation. Thus, noticeble decrease of symptom burden after AHSCT was demonstrated.

For the first time to our knowledge, we report the AHSCT outcomes in MS patients after different low-intensity conditioning regimens and long-term follow-up. We did not find any differences in RFS between the patients who received BM/BEAM-like+ATG, and those who received high-dose cyclophosphamide+Rituximab. These data are in line with the results we have published previously [29]. Our study also demonstrated that RFS did not differ between various age groups, and between the groups with different duration of the disease.

On the contrary, disability status was an important factor influencing the outcomes of transplantation: RFS was dramatically better in patients with EDSS<4 as compared to patients with EDSS=4-6.5. This finding supports the idea that AHSCT is beneficial for patients with highly active relapsing-remitting MS and moderate disability.

This study has several important limitations. Firstly, the study was conducted at a single academic institution, which may introduce some bias. However, all patients had clinical continuity and were monitored for in terms of relapses or need for additional treatment. Secondly, a large number of patients were treated on a compassionate basis rather than within a study protocol. Thirdly, a long-term follow-up (i.e, for ≥4 years) was not available for a substantial proportion of patients. Fourth, this was an observational cohort lacking a control group. Therefore, any inferences about causal effects of AHSCT can’t be made.

Thus, the risk/benefit ratio of AHSCT with low-intensity conditioning regimens in our population of RRMS patients is rather favorable. The consistency of our clinical and QoL results, together with persistent improvement suggest clinical efficacy of AHSCT strategy in RRMS patients. In general, the results of our study support the feasibility of AHSCT with low-intensity conditioning in RRMS patients. To optimize the mentioned treatment protocols of AHSCT in RRMS, multicenter cooperative studies are necessary in future.

Conflicts of interest

None reported.

References

  1. Weinshenker BG. The natural history of multiple sclerosis. Neurol Clin. 1995; 13(1):119-146. PMID: 7739500
  2. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010; 9(5):520-532. doi: 10.1016/S1474-4422(10)70064-8
  3. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2
  4. Hafler DA. Multiple sclerosis. J Clin Invest. 2004; 113(6):788-794. doi: 10.1172/JCI21357
  5. Visser, LA, Louapre, C, Uyl-de Groot CA, Redekop WK. Health-related quality of life of multiple sclerosis patients: a European multi-country study. Arch Public Health 79, 39 (2021). doi: 10.1186/s13690-021-00561-z
  6. Lucchetta RC, Tonin FS, Borba HHL, Leonart LP, Ferreira VL, Bonetti AF, et al. Disease-modifying therapies for relapsing-remitting multiple sclerosis: A network meta-analysis. CNS Drugs. 2018;32(9):813-826. doi: 10.1007/s40263-018-0541-5
  7. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015;72(2):152-158. doi: 10.1001/jamaneurol.2014.3537
  8. Burt RK, Cohen B, Rose J, Petersen F, Oyama Y, Stefoski D et al. Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol. 2005; 62(6):860-864. doi: 10.1001/archneur.62.6.860
  9. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262. doi: 10.1016/j.beha.2004.04.005
  10. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008;7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
  11. Sormani MP, Muraro PA, Saccardi R, Mancardi G. NEDA status in highly active MS can be more easily obtained with autologous hematopoietic stem cell transplantation than other drugs. Mult Scler. 2017; 23(2):201-204. doi: 10.1177/1352458516645670
  12. Sharrack B, Saccardi R, Alexander T, Badoglio M, Burman J, Farge D et al. European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE). Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020;55(2):283-306. doi: 10.1038/s41409-019-0684-0
  13. Gavriilaki M, Sakellari I, Gavriilaki E, Kimiskidis VK, Anagnostopoulos A. Autologous hematopoietic cell transplantation in multiple sclerosis: Changing paradigms in the era of novel agents. Stem Cells Int. 2019; 2019:5840286. doi: 10.1155/2019/5840286
  14. Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A et al. Multiple sclerosis–autologous hematopoietic stem cell transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017; 74(4):459-469. doi: 10.1001/jamaneurol.2016.5867
  15. Miller AE, Chitnis T, Cohen BA, et al. Autologous hematopoietic stem cell transplant in multiple sclerosis: recommendations of the National Multiple Sclerosis Society. JAMA Neurol. 2021;78 (2):241-246. doi:10.1001/jamaneurol.2020.4025
  16. Tolf A, Fagius J, Carlson K, Åkerfeldt T, Granberg T, Larsson EM, Burman J. Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation. Acta Neurol Scand. 2019; 140(5):320-327. doi:10.1111/ane.13147
  17. Cohen JA, Baldassari LE, Atkins HL, Bowen JD, Bredeson C, Carpenter PA et al. Autologous hematopoietic cell transplantation for treatment-refractory relapsing multiple sclerosis: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019; 25(5):845-854. doi: 10.1016/j.bbmt.2019.02.014
  18. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015; 313(3):275-284. doi: 10.1001/jama.2014.17986
  19. Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: A randomized clinical trial. JAMA. 2019; 321(2):165-174. doi: 10.1001/jama.2018.18743
  20. Zhukovsky C, Sandgren S, Silfverberg T, Einarsdottir S, Tolf A, Landtblom A-M, et al. Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study. J Neurol Neurosurg Psychiatry. 2020. doi: 10.1136/jnnp-2020-323992
  21. Bertolotto A, Martire S, Mirabile L, Capobianco M, De Gobbi M, Cilloni D. Autologous hematopoietic stem cell transplantation (AHSCT): standard of care for relapsing-remitting multiple sclerosis patients. Neurol Ther. 2020;9(2):197-203. doi:10.1007/s40120-020-00200-9
  22. Burt RK, Marmont A, Oyama Y, Slavin S, Arnold R, Hiepe F et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum. 2006; 54(12):3750-3760. doi: 10.1002/art.22256
  23. Muraro PA, McFarland HF, Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous hematopoietic stem cell transplantation.Stem Cell Therapy for Autoimmune Disease. 2004:277-283. doi:10.1201/9780367813895-33
  24. Rogojan C, Frederiksen JL. Hematopoietic stem cell transplantation in multiple sclerosis. Acta Neurol Scand. 2009; 120(6):371-382. doi: 10.1111/j.1600-0404.2009.01168.x
  25. Mohammadi R, Aryan A, Omrani MD, Ghaderian SMH, Fazeli Z. Autologous hematopoietic stem cell transplantation (AHSCT): An evolving treatment avenue in multiple sclerosis. Biologics. 2021;15:53-59. doi: 10.2147/BTT.S267277
  26. Ismail A, Sharrack B, Saccardi R, Moore JJ, Snowden JA. Autologous haematopoietic stem cell therapy for multiple sclerosis: a review for supportive care clinicians on behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation. Curr Opin Support Palliat Care. 2019;13(4): 394-401. doi: 10.1097/SPC.0000000000000466
  27. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol. 2008; 7(7):626-636. doi: 10.1016/S1474-4422(08)70138-8
  28. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, Rykavicin OA, Ionova TI, Melnichenko VY, Fedorenko DA, Kulagin AD, Shamanski SV, Ivanov RA, Gorodokin G. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hematol. 2008; 36(8):922-928. doi: 10.1016/j.exphem.2008.03.001
  29. Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kartashov AV, Kurbatova KA, Gorodokin GI, Novik AA. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. 2012; 40(11):892-898. doi: 10.1016/j.exphem.2012.07.003
  30. Chen B, Zhou M, Ouyang J, Zhou R, Xu J, Zhang Q, Yang Y, Xu Y, Shao X, Meng L, Wang J, Xu Y, Ni X, Zhang X. Long-term efficacy of autologous haematopoietic stem cell transplantation in multiple sclerosis at a single institution in China. Neurol Sci. 2012; 33(4):881-886. doi: 10.1007/s10072-011-0859-y
  31. Saccardi R, Freedman MS, Sormani MP, Atkins H, Farge D, Griffith LM et al. European Blood and Marrow Transplantation Group; Center for International Blood and Marrow Research; HSCT in MS International Study Group. A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper. Mult Scler. 2012; 18(6):825-834. doi: 10.1177/1352458512438454
  32. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983; 13(3):227-231. doi: 10.1002/ana.410130302
  33. Common Toxicity Criteria. Version 2.0. Publish Date: April 30, 1999. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf
  34. Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E et al. Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation). Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002; 249(8):1088-1097. doi: 10.1007/s00415-002-0800-7
  35. Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology. 1984; 34(10):1368-1372. doi: 10.1212/wnl.34.10.1368
  36. Hays RD, Sherbourne CD, Mazel RM. User’s Manual for Medical Outcomes Study (MOS). Core measures of health-related quality of life. RAND Corporation, MR-162-RC. http://www.rand.org
  37. Ionova T, Value of patient-reported outcomes in multiple sclerosis patients undergoing autologous hematopoietic stem cell transplantation. Proc. Int. Conf. "Stem cell transplantation for treatment of autoimmune diseases", Moscow, 2019. P. 44-45
  38. Hobart J, Freeman J, Lamping D, Fitzpatrick R, Thompson A. The SF-36 in multiple sclerosis: why basic assumptions must be tested. J Neurol Neurosurg Psychiatry. 2001;71(3):363-370. doi: 10.1136/jnnp.71.3.363
  39. Riazi A, Hobart JC, Lamping DL, Fitzpatrick R, Freeman JA, Jenkinson C, Peto V, Thompson AJ. Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles. J Neurol Neurosurg Psychiatry. 2003; 74(6):710-714. doi: 10.1136/jnnp.74.6.710
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В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.</p> <p style="text-align: justify;">В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(334) "Аутологичная трансплантация гемопоэтических стволовых клеток с режимом сниженной интенсивности при ремиттирующем рассеянном склерозе: клиническая эффективность и качество жизни" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(334) "Аутологичная трансплантация гемопоэтических стволовых клеток с режимом сниженной интенсивности при ремиттирующем рассеянном склерозе: клиническая эффективность и качество жизни" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(334) "Аутологичная трансплантация гемопоэтических стволовых 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Мельниченко<sup>1</sup>, Денис А. Федоренко<sup>1</sup>, Татьяна П. Никитина<sup>2</sup>, Наталья М. Порфирьева<sup>3</sup>, Илья С. Николаев<sup>1</sup>, Татьяна И. Ионова<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(299) "

Владимир Я. Мельниченко1, Денис А. Федоренко1, Татьяна П. Никитина2, Наталья М. Порфирьева3, Илья С. Николаев1, Татьяна И. Ионова2

" ["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) "27607" ["VALUE"]=> array(2) { ["TEXT"]=> string(667) "<p><sup>1</sup> Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия<br> <sup>2</sup> Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова, <br>Санкт-Петербург, Россия<br> <sup>3</sup> Межнациональный центр исследования качества жизни, 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(601) "

1 Национальный медико-хирургический центр им. Н. И. Пирогова Минздрава РФ, Москва, Россия
2 Санкт-Петербургский государственный университет, Клиника высоких медицинских технологий им. Н. И. Пирогова,
Санкт-Петербург, Россия
3 Межнациональный центр исследования качества жизни, Санкт-Петербург, Россия

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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ+ТГСК) – новый эффективный метод лечения рассеянного склероза (РС). В данной публикации представлены результаты комплексной оценки клинической эффективности и оценок, данных пациентом, у больных с ремиттирующим вариантом течения РС до и в разные сроки после ВИСТ+ТГСК с использованием режимов кондиционирования сниженной интенсивности (две программы на основе BEAM и одна на основе циклофосфамида). В исследование включены 258 пациентов, средний возраст – 36,5 лет, мужчины/женщины – 71/185. Медиана индекса инвалидизации по шкале EDSS до трансплантации – 2,0 балла. Средняя длительность периода наблюдения составила 4,9 года. Для оценки клинической эффективности использовались динамика индекс EDSS и данные МРТ. Также проводился анализ безрецидивной выживаемости и выживаемости без прогрессирования заболевания. Для оценки качества жизни использовали общий опросник RAND SF-36 и опросник оценки симптомов CSP-MS-42. Процедура мобилизации и трансплантации хорошо переносилась больными. Безрецидивная выживаемость и выживаемость без прогрессирования заболевания составила 83% и 86%, соответственно, в течение 7 лет после ТГСК.

В результате исследования не было выявлено различий в эффективности и токсичности при применении режимов кондиционирования сниженной интенсивности на основе BEAM с АТГ и циклофосфамида с ритуксимабом. После ТГСК отмечено значительное улучшение параметров качества жизни и снижение выраженности симптомов у подавляющего большинства пациентов. Таким образом, с помощью оценки клинического ответа и параметров качества жизни, продемонстрирована высокая эффективность и безопасность режимов кондиционирования сниженной интенсивности у пациентов с ремиттирующим РС.

Ключевые слова

Аутологичная трансплантация гемопоэтических стволовых клеток, режим кондиционирования, рассеянный склероз, клинический ответ, качество жизни.

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Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatiana P. Nikitina2, Natalia M. Porfirieva3, Ilya S. Nikolaev1, Tatiana I. Ionova2

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1 Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia
2 Saint Petersburg State University Hospital, St. Petersburg, Russia
3 Multinational Center for Quality of Life Research, St. Petersburg, Russia


Correspondence
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103, St. Petersburg, Russia
Phone: +7 (962) 710-17-11
E-mail: tation16@gmail.com

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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.

The vast majority of patients exhibited clinical improvement, or were in stable condition during the entire follow-up period. The estimated proportions of RFS and PFS were 83% and 86%, respectively, at 7 years after AHSCT. No differences in RFS were found between the patients who received reduced BEAM±ATG and high-dose cyclophosphamide+rituximab conditioning regimens. AHSCT resulted in significant and sustained QoL improvement, as well as decrease of symptom burden.The results of our study support feasibility of autologous HSCT with low-intensity conditioning regimens in RRMS. Multicentre cooperative studies should be done to optimize the treatment protocol of mini-AHSCT.

Keywords

Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27610" ["VALUE"]=> array(2) { ["TEXT"]=> string(288) "<p>Vladimir Y. Melnichenko<sup>1</sup>, Denis A. Fedorenko<sup>1</sup>, Tatiana P. Nikitina<sup>2</sup>, Natalia M. Porfirieva<sup>3</sup>, Ilya S. Nikolaev<sup>1</sup>, Tatiana I. Ionova<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(204) "

Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatiana P. Nikitina2, Natalia M. Porfirieva3, Ilya S. Nikolaev1, Tatiana I. Ionova2

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Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatiana P. Nikitina2, Natalia M. Porfirieva3, Ilya S. Nikolaev1, Tatiana I. Ionova2

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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.

The vast majority of patients exhibited clinical improvement, or were in stable condition during the entire follow-up period. The estimated proportions of RFS and PFS were 83% and 86%, respectively, at 7 years after AHSCT. No differences in RFS were found between the patients who received reduced BEAM±ATG and high-dose cyclophosphamide+rituximab conditioning regimens. AHSCT resulted in significant and sustained QoL improvement, as well as decrease of symptom burden.The results of our study support feasibility of autologous HSCT with low-intensity conditioning regimens in RRMS. Multicentre cooperative studies should be done to optimize the treatment protocol of mini-AHSCT.

Keywords

Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.

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The effect of autologous hematopoietic stem cell transplantation (AHSCT) with low-intensity conditioning regimens, in terms of clinical and patient-reported outcomes, was studied in patients with relapsing-remitting multiple sclerosis (RRMS). In total, 258 RRMS patients were enrolled in a single-center study. The median follow-up duration was 30 months. Low-intensity conditioning regimens (two based on reduced BEAM and one on cyclophosphamide) were applied. Outcomes of AHSCT were evaluated from both the physicians’ and patients’ perspectives. Reversal of the disability progression, relapse-free survival (RFS), progression-free survival (PFS), as well as changes in quality of life (QoL), and severity of symptoms were analyzed. Transplantation procedure was well tolerated by the patients, and there were no cases of transplantation-related mortality. In addition, no deaths were registered throughout the follow-up period.

The vast majority of patients exhibited clinical improvement, or were in stable condition during the entire follow-up period. The estimated proportions of RFS and PFS were 83% and 86%, respectively, at 7 years after AHSCT. No differences in RFS were found between the patients who received reduced BEAM±ATG and high-dose cyclophosphamide+rituximab conditioning regimens. AHSCT resulted in significant and sustained QoL improvement, as well as decrease of symptom burden.The results of our study support feasibility of autologous HSCT with low-intensity conditioning regimens in RRMS. Multicentre cooperative studies should be done to optimize the treatment protocol of mini-AHSCT.

Keywords

Autologous hematopoietic stem cell transplantation, conditioning regimen, multiple sclerosis, clinical outcomes, quality of life.

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1 Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia
2 Saint Petersburg State University Hospital, St. Petersburg, Russia
3 Multinational Center for Quality of Life Research, St. Petersburg, Russia


Correspondence
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103, St. Petersburg, Russia
Phone: +7 (962) 710-17-11
E-mail: tation16@gmail.com

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1 Pirogov National Medical and Surgical Center of The Ministry of Healthcare of Russian Federation, Moscow, Russia
2 Saint Petersburg State University Hospital, St. Petersburg, Russia
3 Multinational Center for Quality of Life Research, St. Petersburg, Russia


Correspondence
Professor Tatyana I. Ionova, Saint Petersburg State University Hospital, 154 Fontanka embankment, 190103, St. Petersburg, Russia
Phone: +7 (962) 710-17-11
E-mail: tation16@gmail.com

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Владимир Я. Мельниченко1, Денис А. Федоренко1, Татьяна П. Никитина2, Наталья М. Порфирьева3, Илья С. Николаев1, Татьяна И. Ионова2

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