bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2022-67-3-441-452bloodjour-391Research ArticleКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯCASE REPORTSКомбинация ибрутиниба и венетоклакса с последующей терапией Т-клетками с химерным антигенным рецептором в первой линии лечения у пожилого больного лимфомой из клеток мантии с гиперлейкоцитозом и мутацией в гене ТР53Combination of ibrutinib and venetoclax followed by Chimeric Antigen Receptor T-cell therapy in the first line of treatment in an elderly patient with mantle cell lymphoma with hyperleukocytosis and mutation in the TP53 genehttps://orcid.org/0000-0002-2639-7419ЗвонковЕ. Е.ZvonkovE. E.

Евгений Евгеньевич Звонков, доктор медицинских наук, заведующий от- делением гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167, Москва

Evgene E. Zvonkov, Dr. Sci. (Med.), Head of the Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167, Moscow

dr.zvonkov@gmail.comhttps://orcid.org/0000-0001-5762-8294КоролеваД. А.KorolevaD. A.

Дарья Александровна Королева, кандидат медицинских наук, гематолог отделения гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167, Москва

Daria A. Koroleva, Cand. Sci. (Med.), Hematologist, Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167, Moscow

koroleva_12-12@mail.ruhttps://orcid.org/0000-0001-5171-0414ГабееваН. Г.GabeevaN. G.

Габеева Нелли Георгиевна, кандидат медицинских наук, старший научный сотрудник, врач-гематолог отделения гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167, Москва

Nelli G. Gabeeva, Cand. Sci. (Med.), Senior Researcher, Department of Hema- tology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167, Moscow

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

Щекина Антонина Евгеньевна, реаниматолог отделения реанимации и интенсивной терапии

125167, Москва

Antonina E. Shchekina, Postgraduate Researcher, Resuscitation and Intensive Care Unit

125167, Moscow

shekina_ae@mail.ruhttps://orcid.org/0000-0001-7053-7039ТеляшовМ. А.TelyashovM. A.

Теляшов Максим Александрович, трансфузиолог отделения забора гемопоэтических стволовых клеток, обработки и хранения костного мозга и гемопоэтических стволовых клеток

125167, Москва

Maksim A. Telyashov, Transfusiologist, Department for the Collection of Hematopoietic Stem Cells, Processing and Storage of Bone Marrow and Hematopoietic Stem Cells

125167, Moscow

ticktackkk@icloud.comhttps://orcid.org/0000-0002-9969-8482АлешинаО. А.AleshinaO. A.

Алешина Ольга Александровна, кандидат медицинских наук, заведующая обсервационным отделением

125167, Москва

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

125167, Moscow

dr.gavrilina@mail.ruhttps://orcid.org/0000-0002-6253-3334БидерманБ. В.BidermanB. V.

Бидерман Белла Вениаминовна, кандидат биологических наук, старший научный сотрудник лаборатории молекулярной гематологии

125167, Москва

Bella V. Biderman, Cand. Sci. (Biol.), Senior Researcher, Laboratory of Molecular Hematology

125167, Moscow

bella_biderman@mail.ruhttps://orcid.org/0000-0001-9463-9187СудариковА. Б.SudarikovA. B.

Судариков Андрей Борисович, доктор биологических наук, заведующий лабораторией молекулярной гематологии

125167, Москва

Andrey B. Sudarikov, Dr. Sci. (Biol.), Head of the Laboratory of Molecular Genetics

125167, Moscow

a.sudarikov@blood.ruhttps://orcid.org/0000-0003-1613-652XОбуховаТ. Н.ObukhovaT. N.

Обухова Татьяна Никифоровна, кандидат медицинских наук, заведующая лабораторией кариологии

125167, Москва

Tatiana N. Obukhova, Cand. Sci. (Med.), Head of the Karyology Laboratory

125167, Moscow

obukhova_t@mail.ruhttps://orcid.org/0000-0002-8490-6066ГальцеваИ. В.GaltsevaI. V.

Гальцева Ирина Владимировна, кандидат медицинских наук, заведующая лабораторией иммунофенотипирования клеток крови и костного мозга

125167, Москва

Irina V. Galtseva, Cand. Sci. (Med.), Head of the Scientific and Clinical Laboratory for Immunophenotyping of Blood and Bone Marrow Cells, Hematologist

125167, Moscow

galtseva.i@blood.ruhttps://orcid.org/0000-0002-9808-8519ДвирныкВ. Н.DvirnikV. N.

Двирнык Валентина Николаевна, кандидат медицинских наук, заведующая централизованной клинико-диагностической лабораторией

125167, Москва

Valentina N. Dvirnik, Cand. Sci. (Med.), Head of the Regional Clinical and Diagnostic Laboratory

125167, Moscow

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

Троицкая Вера Витальевна, кандидат медицинских наук, первый заместитель генерального директора

125167, Москва

Vera V. Troitskaya, Cand. Sci. (Med.), First Deputy CEO

125167, Moscow

troitskaya.v@blood.ruhttps://orcid.org/0000-0001-8818-8949ГалстянГ. М.GalstyanG. M.

Галстян Геннадий Мартинович, доктор медицинских наук, заведующий отделом 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/0000-0003-1735-0093МасчанМ. А.MaschanM. A.

Масчан Михаил Александрович, доктор медицинских наук, профессор, заместитель генерального директора института молекулярной и экспериментальной медицины

117997, Москва

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

117997, Moscow

mmaschan@yandex.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

125167, Moscow

parovichnikova@gmail.comФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for HematologyRussian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Министерства здравоохранения Российской ФедерацииРоссияNational Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology named after Dmitry RogachevRussian Federation202223102022673441452Copyright © Звонков Е.Е., Королева Д.А., Габеева Н.Г., Щекина А.Е., Теляшов М.А., Алешина О.А., Бидерман Б.В., Судариков А.Б., Обухова Т.Н., Гальцева И.В., Двирнык В.Н., Троицкая В.В., Галстян Г.М., Масчан М.А., Паровичникова Е.Н., 20222022Звонков Е.Е., Королева Д.А., Габеева Н.Г., Щекина А.Е., Теляшов М.А., Алешина О.А., Бидерман Б.В., Судариков А.Б., Обухова Т.Н., Гальцева И.В., Двирнык В.Н., Троицкая В.В., Галстян Г.М., Масчан М.А., Паровичникова Е.Н.Zvonkov E.E., Koroleva D.A., Gabeeva N.G., Shchekina A.E., Telyashov M.A., Aleshina O.A., Biderman B.V., Sudarikov A.B., Obukhova T.N., Galtseva I.V., Dvirnik V.N., Troitskaya V.V., Galstyan G.M., Maschan M.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/391Введение

Введение. Тактика терапии пожилых коморбидных больных лимфомой из клеток мантии (ЛКМ) с факторами неблагоприятного прогноза (ФНП) (комплексный кариотип, делеция 17р13, мутации в гене ТР53) не разработана. Использование интенсивных схем химиотерапии и трансплантации аллогенных гемопоэтических стволовых клеток (алло-ТГСК) часто невозможно из-за коморбидности пожилых больных. Рациональным подходом является применение комбинации ибрутиниба и венетоклакса. В качестве альтернативы алло-ТГСК новой опцией для пожилых больных с ФНП является терапия Т-клетками с химерным антигенным рецептором (Chimeric Antigen Receptor T-cells, CAR-T-клетки).

Цель — представить опыт применения комбинации ибрутиниба и венетоклакса с последующей CAR-T-клеточной терапией в первой линии лечения у пожилого больного ЛКМ, у которого было множество ФНП.

Основные сведения

Основные сведения. Больной М., 68 лет, был госпитализирован в октябре 2021 г. При обследовании были выявлены гиперлейкоцитоз (978 × 109/л), анемия (55 г/л), тромбоцитопения (30 × 109/л), спленомегалия (250 × 180 мм). По результатам лабораторных исследований была верифицирована ЛКМ с комплексным кариотипом, делецией 17р13, 13q14 и мутацией p.R248W в 7-м экзоне гена ТР53 (VAF = 26 %). С циторедуктивной целью проведено два сеанса лейкоцитафереза и предфаза циклофосфамидом (200 мг/м2) и дексаметазоном (10 мг/м2). С 3-го дня была начата терапия ибрутинибом в дозе 420 мг/сут. и венетоклаксом в дозе 100 мг/сут. Через 2 сут. количество лейкоцитов крови составило 0,7 × 109/л, уменьшились размеры селезенки, развился синдром лизиса опухоли. В результате интенсивной терапии, включавшей заместительную почечную терапию, состояние было стабилизировано, что позволило возобновить лечение. Через 7 сут. в анализе крови количество лейкоцитов стало 2,5 × 109/л, нейтрофилов — 70 %, тромбоцитов — 90 × 109/л, гемоглобин — 95 г/л. По данным иммунофенотипирования, популяция В-лимфоцитов составила 4 %. По данным секвенирования нового поколения аллельная нагрузка мутации в гене ТР53 — 0,8 %. Больному была проведена анти-CD19 CAR-T-клеточная терапия, достигнута полная ремиссия. Через 3 мес. после терапии сохраняется МОБ (минимальная остаточная болезнь) — негативная ремиссия и определяется персистенция CAR-T-клеток.

Introduction

Introduction. The tactics of therapy for elderly comorbid patients with mantle cell lymphoma with unfavorable prognosis factors (complex karyotype, 17p13 deletion, mutations in the TP53 gene) have not been developed. The use of intensive chemotherapy regimens and transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is impossible due to severe comorbidity in elderly patients. A rational approach is the use of a combination of ibrutinib and venetoclax. As an alternative to allo-HSCT, a new option for elderly patients with poor prognostic factors is Chimeric Antigen Receptor T-cell therapy (CAR-T) cell therapy.

Aim — to present the experience of using ibrutinib and venetoclax with CAR-T-cell therapy in the first line of treatment in an elderly patient with MCL with a mutation in the TP53 gene and hyperleukocytosis.

Main findings

Main findings. Patient M., 68 years old. The examination revealed hyperleukocytosis 978 × 109/L, anemia (55 g/L), thrombocytopenia (30 × 109/L), and splenomegaly 250 × 180 mm. According to the results of laboratory studies, the diagnosis of lymphoma from mantle cells with a complex karyotype, deletion 17p13, 13q14 and mutation p.R248W in exon 7 of the TP53 gene (VAF = 26 %) was verified. For cytoreductive purposes, two sessions of leukocytapheresis and prephase with cyclophosphamide (200 mg/m2) and dexamethasone (10 mg/m2) were performed. From day 3, therapy with ibrutinib 420 mg/day and venetoclax 100 mg/day was started. After 2 days, the leukocytes were 0.7 × 109/L, and the size of the spleen decreased, as a result of which the development of tumor lysis syndrome was noted. As a result of intensive therapy, the patient’s condition stabilized, which allowed him to resume treatment. After 7 days, the number of leukocytes was 2.5 × 109/L, neutrophils — 70 %, platelets — 90 × 109/L, hemoglobin — 95 g/L. According to immunophenotyping, the population of B-lymphocytes was 4 %. According to NGS data, the allelic load of the mutation in the TP53 gene is 0.8 %. The patient underwent anti-CD19 CAR-T-cell therapy and achieved complete remission. Three months after therapy, MRD remains-negative remission and the persistence of CAR-T cells is determined.

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