bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2022-67-1-8-28bloodjour-334Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESТерапия Т-клетками с химерным антигенным рецептором взрослых больных В-клеточными лимфопролиферативными заболеваниямиChimeric antigen receptor T-cell therapy in adult patients with B-cell lymphoproliferative diseaseshttps://orcid.org/0000-0002-9969-8482ГаврилинаО. А.GavrilinaO. A.

Гаврилина Ольга Александровна, кандидат медицинских наук, заведующая обсервационным отделением 

125167, Москва

Olga A. Gavrilina, Cand. Sci. (Med.), Head of the Observational Department 

125167, Moscow

dr.gavrilina@mail.ruhttps://orcid.org/0000-0001-8818-8949ГалстянГ. М.GalstyanG. M.

Галстян Геннадий Мартинович, доктор медицинских наук, заведующий отделением реанимации и интенсивной терапии 

125167, Москва

Gennadiy M. Galstyan, Dr. Sci. (Med.), Head of the Department of Resuscitation and Intensive Care 

125167, Moscow

gengalst@gmail.comhttps://orcid.org/0000-0002-7916-2322ЩекинаА. Е.ShchekinaA. E.

Щекина Антонина Евгеньевна, аспирант, врач-реаниматолог отделения реанимации и интенсивной терапии 

125167, Москва

Antonina E. Shchekina, Postgraduate Student, Physician, Resuscitation and Intensive Care Unit 

125167, Moscow

shekina_ae@mail.ruhttps://orcid.org/0000-0002-7968-1923КотоваЕ. С.KotovaE. S.

Котова Екатерина Сергеевна, аспирант отделения интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения 

125167, Москва

Ekaterina S. Kotova, Postgraduate Researcher, Department of Intensive HighDose Chemotherary of Haemoblastosis and Hametopoiesis Depressions 

125167, Moscow

2017e.s.kotova@gmail.comhttps://orcid.org/0000-0003-1735-0093МасчанМ. А.MaschanM. A.

Масчан Михаил Александрович, доктор медицинских наук, заместитель генерального директора, директор Института молекулярной и экспериментальной медицины 

117997, Москва

Michail M. Maschan, Dr. Sci. (Med.), Deputy Director, Director of the Institute of Molecular and Experimental Medicine 

117997, Moscow

mmaschan@yandex.ruhttps://orcid.org/0000-0002-4827-8947ТроицкаяВ. В.TroitskayaV. V.

Троицкая Вера Витальевна, кандидат медицинских наук, первый заместитель директора по лечебной работе 

125167, Москва

Vera V. Troitskaya, Cand. Sci. (Med.), Deputy Director General for Medicine 

125167, Moscow

troitskaya.v@blood.ruhttps://orcid.org/0000-0001-5762-8294КоролеваД. А.KorolevaD. A.

Королева Дарья Александровна, кандидат медицинских наук, врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом 

125167, Москва

Daria A. Koroleva, Cand. Sci. (Med.), Hematologist, Department of Intensive High-dose Chemotherapy of Lymphomas 

125167, Moscow

koroleva_12-12@mail.ruhttps://orcid.org/0000-0002-2639-7419ЗвонковЕ. Е.ZvonkovE. E.

Звонков Евгений Евгеньевич, доктор медицинских наук, заведующий отделением интенсивной высокодозной химиотерапии лимфом 

125167, Москва

Evgeny E. Zvonkov, Dr. Sci. (Med.), Head of the Department of Intensive Highdose Chemotherapy of Lymphomas 

125167, Moscow

dr.zvonkov@gmail.comhttps://orcid.org/0000-0003-0934-6094ФидароваЗ. Т.FidarovaZ. T.

Фидарова Залина Таймуразовна, кандидат медицинских наук, заведующая отделением интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения 

125167, Москва

Zalina T. Fidarova, Cand. Sci. (Med.), Head of the Department of Intensive High-Dose Chemotherary of Haemoblastosis and Hametopoiesis Depressions  

125167, Moscow

zalinafidarova@mail.ruhttps://orcid.org/0000-0003-0904-7385ВасильеваВ. А.VasilyevaV. A.

Васильева Вера Алексеевна, кандидат медицинских наук, заведующая отделением иммунохимиотерапии с дневным стационаром для больных после ТКМ 

125167, Москва

Vera A. Vasilyeva, Cand. Sci. (Med.), Head of Immunochemotherapy Department for Patients after BMT, National Research Center for Hematology 

125167, Moscow

vasilievava4@mail.ruhttps://orcid.org/0000-0001-6177-3566ПаровичниковаЕ. Н.ParovichnikovaE. N.

Паровичникова Елена Николаевна, доктор медицинских наук, генеральный директор 

125167, Москва

Elena N. Parovichnikova, Dr. Sci. (Med.), CEO of the National Research Center for Hematology 

125167, Moscow

parovichnikova.e@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Министерства здравоохранения Российской ФедерацииРоссияDmitriy Rogachev Nation al Medical Research Center of Pediatric Hematology, Oncology and ImmunologyRussian Federation202207042022671828Copyright © Гаврилина О.А., Галстян Г.М., Щекина А.Е., Котова Е.С., Масчан М.А., Троицкая В.В., Королева Д.А., Звонков Е.Е., Фидарова З.Т., Васильева В.А., Паровичникова Е.Н., 20222022Гаврилина О.А., Галстян Г.М., Щекина А.Е., Котова Е.С., Масчан М.А., Троицкая В.В., Королева Д.А., Звонков Е.Е., Фидарова З.Т., Васильева В.А., Паровичникова Е.Н.Gavrilina O.A., Galstyan G.M., Shchekina A.E., Kotova E.S., Maschan M.A., Troitskaya V.V., Koroleva D.A., Zvonkov E.E., Fidarova Z.T., Vasilyeva V.A., Parovichnikova E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/334Введение

Введение. Внедрение в клиническую практику терапии Т-клетками с химерным антигенным рецептором (Chimeric Antigen Receptor T-cell — CAR-T) открывает новые перспективы лечения рефрактерных форм и рецидивов (Р/Р) Вклеточных лимфопролиферативных заболеваний (ЛПЗ).

Цель — представить результаты CAR-T-клеточной терапии взрослых больных В-клеточными ЛПЗ.

Материалы и методы

Материалы и методы. В рамках пилотного исследования ФГБУ «НМИЦ гематологии» Минздрава России, одобренного локальным этическим комитетом, выполнен анализ проведения CAR-T-клеточной терапии у взрослых больных с Р/Р течением или персистенцией минимальной остаточной болезни (МОБ) при В-клеточных ЛПЗ: — при остром В-лимфобластном лейкозе / лимфоме (В-ОЛЛ/ЛБЛ), диффузной В крупноклеточной лимфоме (ДВККЛ), лимфоме из клеток зоны мантии (ЛКЗМ), которые не имели альтернативных вариантов эффективного и безопасного лечения. Всем больным после подписания информированного согласия проводили лимфодеплецию флударабином и циклофосфамидом в течение 4 дней перед введением CAR-T-лимфоцитов, профилактику синдрома выброса цитокинов (СВЦ) тоцилизумабом в день введения CAR-T-лимфоцитов, трансфузию CAR-T-клеток в зависимости от экспрессии опухолевых антигенов на поверхности опухолевых клеток. Проводили оценку эффективности и безопасности применения CAR-T-терапии.

Результаты

Результаты. С 01.01.2020 по 01.01.2022 было выполнено 10 введений CAR-T-лимфоцитов 6 взрослым (возраст — 19–68 лет, медиана — 32 года) больным В-клеточными ЛПЗ: 4 — Р/Р B-ОЛЛ, 1 — Р/Р ДВККЛ, 1 — персистенция МОБ при ЛКЗМ. У всех больных с Р/Р течением до выполнения CAR-T-терапии было проведено от 2 до 5 (медиана — 4) линий химио- и/или иммунотерапии. Трем больным были введены CD19 СAR-T, двум — CD19/CD22 CAR-T, одной — CD19 СAR-T и СD20 CAR-T. Четырем (66 %) больным были введены аутологичные СAR-T-клетки, одному — аллогенные CAR-T-клетки, у одной больной было два введения CAR-T-клеток — 1 аутологичных и 1 aллогенных. Медиана введенных СAR-T-лимфоцитов составила 0,5 × 10 6/кг (от 0,1 × 10 6/кг до 3 × 10 6/кг). В 7 (87,5 %) из 8 случаев после введения CAR-T был достигнут общий ответ на терапию (полная или частичная ремиссия), а полная ремиссия была достигнута в 6 (75 %) случаях. Побочные эффекты отмечены после 8 из 10 трансфузий CAR-T-клеток, среди них: СВЦ — в 40 % случаев (СВЦ 1–10 %, СВЦ 2–20 %, СВЦ 3–10 %), иммунными клетками ассоциированный нейротоксический синдром — в 10 %, синдром распада опухоли — в 20 %, синдром полиорганной недостаточности — в 10 %. Летальных исходов от осложнений CAR-Т-терапии не было. Медиана периода наблюдения за больными составила 6 (1–16) месяцев. От рецидива и прогрессии основного заболевания умерли 2 (33 %) из 6 больных. Одна (17 %) больная умерла в полной ремиссии от инфекционных осложнений. Под наблюдением находятся трое (50 %) больных. Медиана циркуляции CAR-T-клеток составила 33 (6–60) дня.

Заключение

Заключение. CAR-T-клеточная терапия является перспективным методом лечения как при Р/Р течении В-клеточных лимфопролиферативных заболеваний, так и при персистенции МОБ после циторедуктивной терапии при агрессивных В-клеточных неходжкинских лимфомах высокого риска. Применение данного вида терапии требует мультидисциплинарного подхода.

Introduction

Introduction. The introduction of chimeric antigen receptor (CAR) T-cell therapy is a promising treatment of patients with relapsed or refractory (R/R) B-cell lymphoproliferative diseases (LPDs).

Aim — to present the results of CAR-T-cell therapy of 6 adult patients with B-cell LPDs.

Materials and methods

Materials and methods. This is a pilot study conducted in adult patients with R/R or persistent minimal residual disease B-cell LPDs treated with CAR-T-cells. The study was approved by a local ethical committee of National Research Center for Hematology. Patients did not have alternative options for effective and safe treatment. All patients signed an informed consent. All patients were lymphodeplated with fl udarabine and cyclophosphamide for 4 days before the introduction of CAR-T-lymphocytes. Cytokine release syndrome (CRS) was prevented by tocilizumab on the day of CAR-T-cell administration. The effi cacy and safety of CAR-T-cell therapy was evaluated.

Results

Results. From 01.01.2020 to 01.01.2022, 10 CAR-T-cell infusions were performed for 6 adult patients (age 19–68 years, median — 32 years) with B-cell LPDs: 4 — R/R B-acute lymphoblastic leukemia, 1 — R/R diffuse large B-cell lymphoma, 1 — persistence of MRD in mantle cell lymphoma. In all patients with a R/R, median — 4 (2–5) lines of chemotherapy and/ or immunotherapy were performed before CAR-T-cell therapy. CD19 CAR-T-cells received 3 patients, CD19/CD22 CAR-Tcells — 2 patients, CD19 and CD20 CAR-T-cells received 1 patient. Autologous CAR-T-cells received 4 (66 %) patients, allogeneic CAR-T-cells received 1 patient, and one patient had two CAR-T-cell administrations — 1 autologous and 1 allogeneic. The median number of CAR-T-cells was 0.5 × 106 /kg (from 0.1 × 106 /kg to 3 × 106 /kg). In 7 (87.5 %) of the 8 cases after CAR-T-cell administration, overall response to therapy (complete or partial remission) was achieved, and complete remission was achieved in 6 (75 %) cases. Side effects were noted after 8 of 10 CAR-T-cell transfusions: CRS in 40 % (CRS 1 — 10 %, CRS 2 — 20 %, CRS 3 — 10 %), ICANS in 10 %, tumor lysis syndrome in 20 %, multi-organ dysfunction syndrome in 10 %.  There were no lethal complications due to CAR-T-cell administrations. The median follow-up period was 6 (1–16) months. Of the 6 patients, 2 (33 %) died from relapses and progression of LPD. One (17 %) patient died in complete remission from infectious complications. Three (50 %) patients are observed till now. The median time of CAR-T-cell circulation was 33 (6– 60) days.

Conclusion

Conclusion. CAR-T-cell therapy is a promising treatment for R/R B-cell LPDs and LPDs with persistence of MRD after cytoreductive therapy. This type of therapy requires a multidisciplinary approach.

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The authors declare that there are no conflicts of interest present.