bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2023-68-3-344-362bloodjour-477Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВысокодозная химиотерапия с трансплантацией аутологичных гемопоэтических стволовых клеток в первой линии терапии фолликулярной лимфомыHigh-dose chemotherapy with transplantation of autologous hematopoietic stem cells in the first line of follicular lymphoma therapyhttps://orcid.org/0000-0003-0591-2589СмольяниноваА. К.SmolyaninovaA. K.

Анна Константиновна Смольянинова, кандидат медицинских наук, научный сотрудник, гематолог

отделение гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Anna K. Smolianinova, Cand. Sci. (Med.), Hematologist

Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

annmo8@mail.ruhttps://orcid.org/0000-0001-8256-8801БеляеваА. В.BelyayevaA. V.

Анастасия Валерьевна Беляева, гематолог

отделение гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Anastasia V. Beliaeva, Hematologist

Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

dr.belyaeva.a@gmail.comhttps://orcid.org/0000-0003-1936-0084СидороваЮ. В.SidorovaYu. V.

Юлия Владимировна Сидорова, кандидат медицинских наук, старшийнаучный сотрудник

лаборатория молекулярной гематологии

125167

Москва

Yulia V. Sidorova, Researcher

Laboratory of Molecular Hematology

125167

Moscow

sidorova.y@blood.ruhttps://orcid.org/0000-0001-5171-0414ГабееваН. Г.GabeevaN. G.

Нелли Георгиевна Габеева, кандидат медицинских наук, научный сотрудник, гематолог

отделение гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Nelli G. Gabeeva, Cand. Sci. (Med.), Hematologist

Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

dr.gabeeva@gmail.comhttps://orcid.org/0000-0001-8803-1079ТатарниковаС. А.TatarnikovaS. A.

Светлана Андреевна Татарникова, гематолог

отделение гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Svetlana A. Tatarnikova, Hematologist

Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

lana.tatarnikova.89@mail.ruhttps://orcid.org/0000-0002-4223-2366БадмажаповаД. С.BadmazhapovaD. S.

Дарима Сэмункоевна Бадмажапова, кандидат медицинских наук, гематолог

отделение гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Darima S. Badmajapova, Cand. Sci. (Med.), Hematologist

Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

darima-doctor@mail.ruhttps://orcid.org/0000-0001-5762-8294КоролеваД. А.KorolevaD. A.

Дарья Александровна Королева, кандидат медицинских наук, гематолог

отделение 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/0000-0002-8357-977XГемджянЭ. Г.GemdzhianE. G.

Эдуард Георгиевич Гемджян, научный сотрудник

лаборатория по изучению психических и неврологических расстройств при заболеваниях системы крови

125167

Москва

Eduard G. Gemdzhian, Senior Researcher

125167

Moscow

edst-t@ma-l.ruhttps://orcid.org/0000-0002-1082-8659КовригинаА. М.KovriginaA. M.

Алла Михайловна Ковригина, доктор биологических наук, заведующаяотделением

патологоанатомическое отделение

125167

Москва

Alla M. Kovrigina, Dr. Sci. (Biol.), Head of the Department

Department of pathological department

125167

Moscow

kovrigina.a@blood.ruhttps://orcid.org/0000-0001-9463-9187СудариковА. Б.SudarikovA. B.

Андрей Борисович Судариков, доктор биологических наук, заведующий лабораторией

лаборатория молекулярной гематологии

125167

Москва

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

Laboratory of Molecular Genetics

125167

Moscow

a.sudarikov@blood.ruhttps://orcid.org/0000-0003-3914-8611НикулинаЕ. Е.NiculinaE. E.

Елена Евгеньевна Никулина, научный сотрудник

лаборатория молекулярной гематологии 

125167

Москва

Elena E. Nikulina, Researcher

Laboratory of Molecular Hematology

125167

Moscow

nikulina.e@blood.ruhttps://orcid.org/0000-0002-6035-9547НестероваЕ. С.NesterovaE. S.

Екатерина Сергеевна Нестерова, кандидат медицинских наук, научныйсотрудник, гематолог

отделение химиотерапии лимфатических опухолей с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Ekaterina S. Nesterova, Cand. Sci. (Med.), Hematologist

Department of Chemotherapy of Lymphatic tumors with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

nest.ek@yandex.ruhttps://orcid.org/0000-0003-1613-652XОбуховаТ. Н.ObukhovaT. N.

Татьяна Никифоровна Обухова, кандидат медицинских наук, заведующая лабораторией

125167

Москва

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

Karyology Laboratory

125167

Moscow

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

Евгений Евгеньевич Звонков, доктор медицинских наук, заведующий отделением

отделение гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167

Москва

Evgeny E. Zvonkov, Dr. Sci. (Med), Head of the Department

Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167

Moscow

zvonkov@blood.ruФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for HematologyRussian Federation202316112023683344362Copyright © Смольянинова А.К., Беляева А.В., Сидорова Ю.В., Габеева Н.Г., Татарникова С.А., Бадмажапова Д.С., Королева Д.А., Гемджян Э.Г., Ковригина А.М., Судариков А.Б., Никулина Е.Е., Нестерова Е.С., Обухова Т.Н., Звонков Е.Е., 20232023Смольянинова А.К., Беляева А.В., Сидорова Ю.В., Габеева Н.Г., Татарникова С.А., Бадмажапова Д.С., Королева Д.А., Гемджян Э.Г., Ковригина А.М., Судариков А.Б., Никулина Е.Е., Нестерова Е.С., Обухова Т.Н., Звонков Е.Е.Smolyaninova A.K., Belyayeva A.V., Sidorova Y.V., Gabeeva N.G., Tatarnikova S.A., Badmazhapova D.S., Koroleva D.A., Gemdzhian E.G., Kovrigina A.M., Sudarikov A.B., Niculina E.E., Nesterova E.S., Obukhova T.N., Zvonkov E.E.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/477   Введение

   Введение. При фолликулярной лимфоме (ФЛ) в большинстве случаев наблюдается высокая чувствительность опухоли к иммунохимиотерапии. Несмотря на продолжительную общую выживаемость (ОВ), течение заболевания характеризуется множественными рецидивами. Высокодозную химиотерапию (ВДХТ) с трансплантацией аутологичных гемопоэтических стволовых клеток (ауто-ТГСК) применяют при рецидиве ФЛ.

   Цель

   Цель: оценить эффективность и безопасность ВДХТ с ауто-ТГСК в первой линии терапии ФЛ и выявить факторы риска прогрессии и рефрактерности заболевания.

   Материалы и методы

   Материалы и методы. В проспективное одноцентровое исследование, проведенное с мая 2015 по январь 2023 г., включены 35 больных 18–65 лет (медиана 43 года) ФЛ 1–3 А градации t (14;18)+ с III–IV стадиями или II стадией с большим (> 6 см) размером опухоли. Проводили лечение по протоколу «ФЛ-2015»: 4 «R-CHOP», 2 «R-DHAP» и «BeEAM» с ауто-ТГСК. Статистический анализ (по намерению лечить) выполнен по состоянию данных на 12 января 2023 г.

   Результаты

   Результаты. У 86 % больных была IV стадия опухоли, у 79 % имелись 3–5 факторов Международного прогностического индекса ФЛ (Follicular Lymphoma International Prognostic Index, FLIPI). После окончания лечения частота общего ответа (ОО) и полной ремиссии (ПР) составили 90 и 90 %, частота прогрессии заболевания в течение 24 мес. (ПЗ24) — 3 %. После окончания индукции негативность по минимальной остаточной болезни (МОБ) была достигнута у 77 %. После полного завершения протокола МОБ-негативность достигнута у 96 % больных. Трехлетние ОВ, безрецидивная выживаемость, выживаемость без прогрессии и бессобытийная выживаемость составили 90, 90, 95 и 85 % (с одной и той же стандартной ошибкой в 9 %) при медиане наблюдения (оценка обратным методом Каплана — Мейера) 19 мес. (диапазон: от 1 до 91 мес.). Смертей из-за ранней токсичности в течение 100 дней после ауто-ТГСК не было. Прогностически неблагоприятными независимыми статистически значимыми (р < 0,01; критерий Вальда; отношение рисков > 1) предикторами прогрессии и рефрактерности по результатам многофакторного анализа по модели конкурирующих рисков Fine-Grey (р = 0,052 для модели) оказались: поражение костного мозга, высокий риск по ECOG, возраст больного > 50 лет, 4-я стадия заболевания, повышенная сывороточная концентрация лактатдегидрогеназы и В-симптомы.

   Заключение

   Заключение. Применение ВДХТ с ауто-ТГСК в первой линии у больных ФЛ эффективно и позволяет существенно снизить частоту ПЗ24 и ранней летальности.

   Introduction

   Introduction. The follicular lymphoma (FL) is the most common indolent lymphatic tumor with high sensitivity to immunochemotherapy un most cases. Although overall survival (OS) is generally long, the disease is characterized by multiple relapses. High-dose chemotherapy (HDCT) with transplantation of autologous hematopoietic stem cells (auto-HSCT) is used for recurrent FL.

   Aim

   Aim: to evaluate the efficacy and safety of HDCT with aHSCT in the first line of FL therapy; identify risk factors for disease progression and refractoriness.

   Material and methods

   Material and methods. A prospective single-center study (conducted from May 2015 to January 2023) included 35 patients aged 18–65 years (median 43) with PL 1–3A grade t(14;18)+ with stages III–IV or stage II with bulky, having at least one criterion for the need to start therapy (according to GELF). Patients were treated according to the FL-2015 protocol: 4 R-CHOP, 2 R-DHAP and BeEAM with auto-HSCT. The primary endpoint was the rate of overall response (OR) and/or complete remission (CR) at the end of chemotherapy. Secondary end points were 3-year survival rates: OS, relapse-free survival (RFS), progression-free survival (PFS), and event-free survival (EFS). Minimal residual disease (MRD) in blood and/or bone marrow was assessed by PCR based on immunoglobulin heavy chain (IGH) gene rearrangements and/or BCL2::IGH rearrangements. Statistical analysis (by intent to treat) was performed on January 12, 2023.

   Results

   Results. 86 % of patients had stage IV tumor and 79 % had 3–5 FLIPI factors. After the end of treatment, OR and PR were 90 % and 90 %, the incidence of POD24 was 3 %. After the end of induction (4 courses of R-CHOP), MRD-negativity was achieved in 77 % and 53 % of patients as determined by PCR-IGH and BCL2::IGH. After the full completion of the FL-2015 protocol, MRD was not detected in 96 % of patients (according to PCR-IGH). Three-year overall survival, disease-free survival, progression-free survival and event-free survival were respectively: 90 %, 90 %, 95 % and 85 % (with the same standarderror of 9 %) at a median follow-up (by inverse Kaplan-Meier estimate) of 19 months (range: from 1 to 91 months) There were no deaths due to early toxicity within 100 days of auto-HSCT. Prognostically unfavorable independent statistically significant (р < 0.01; Wald test; hazard ratio > 1) predictors of progression and refractoriness according to the results of multivariate analysis using the Fine-Grey competing risk model (р = 0.052 for the model) were: bone marrow disease, ECOG high risk, patient age > 50 years, stage 4 disease, elevated serum lactate dehydrogenase and B-symptoms.

   Conclusion

   Conclusion. The use of HDCT with auto-HSCT in the first line in patients with FL is highly effective and can significantly reduce the incidence of POD24 and early mortality from the tumor. The study is ongoing.

фолликулярная лимфоматрансплантация аутологичных гемопоэтических стволовых клетокминимальная резидуальная болезньанализ выживаемостиконкурирующие рискимодель Fine-Greyfollicular lymphomaautologous hematopoietic stem cell transplantationminimal residual diseasesurvival analysiscompeting risksFine and Gray modelИсследование не имело спонсорской поддержкиThis study had no sponsorshipReferencesCahill K.E., Smith S.M. Follicular Lymphoma: a Focus on Current and Emerging Therapies. Oncology (Williston Park). 2022; 36(2): 97–106. DOI: 10.46883/2022.25920946.Cahill K.E., Smith S.M. Follicular Lymphoma: a Focus on Current and Emerging Therapies. Oncology (Williston Park). 2022; 36(2): 97–106. DOI: 10.46883/2022.25920946.https://cr.minzdrav.gov.ru/clin_recomendhttps://cr.minzdrav.gov.ru/clin_recomendZelenetz A.D., Gordon L.I., Chang J.E., et al. NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021. J Natl Compr Cancer Netw. 2021; 19(11): 1218–30. 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The authors declare that there are no conflicts of interest present.