bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2019-64-2-150-164bloodjour-135Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESХИМИОТЕРАПИЯ ПО ПРОГРАММЕ R-mNHL-BFM-90 В КОМБИНАЦИИ С ЛЕНАЛИДОМИДОМ КАК ТЕРАПИЯ ПЕРВОЙ ЛИНИИ У БОЛЬНЫХ MUM1-ПОЗИТИВНОЙ ДИФФУЗНОЙ В-КРУПНОКЛЕТОЧНОЙ ЛИМФОМОЙ И ФОЛЛИКУЛЯРНОЙ ЛИМФОМОЙ 3В ЦИТОЛОГИЧЕСКОГО ТИПАCHEMOTHERAPY ACCORDING TO THE R-mNHL-BFM-90 PROTOCOL IN COMBINATION WITH LENALIDOMIDE AS THE FIRST LINE THERAPY IN PATIENTS WITH MUM1-POSITIVE DIFFUSIVE LARGE B-CELL LYMPHOMA AND FOLLICULAR LYMPHOMA GRADE 3Bhttps://orcid.org/0000-0001-5171-0414ГабееваН. Г.GabeevaN. G.

Габеева Нэлли Георгиевна, кандидат медицинских наук, врачгематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным и дневным стационарами 

тел.:+7(495) 612-4382, доб. 16-97; 125167, г. Москва, Новый Зыковский проезд, 4. 

Nelli G. Gabeeva*, Cand. Sci. (Med.), Hematologist, Intensive High-dose Chemotherapy of Lymphomas Department with a 24-hour Hospital

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

Королева Дарья Александровна, врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным и дневным стационарами

Daria A. Koroleva, Hematologist, Intensive High-dose Chemotherapy of Lymphomas Department with a 24-hour Hospital

koroleva_12-12@mail.ruhttps://orcid.org/0000-0003-0591-2589СмольяниноваА. К.SmolyaninovaA. K.

Смольянинова Анна Константиновна, кандидат медицинских наук, врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным и дневным стационарами

Anna K. Smolyaninova, Cand. Sci. (Med.), Hematologist, Intensive High-dose Chemotherapy of Lymphomas Department with a 24-hour Hospital

anmo8@mail.ruhttps://orcid.org/0000-0002-4913-2245БеляеваА. В.BelyaevaA. V.

Беляева Анастасия Валерьевна, врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным и дневным стационарами

Anastasia V. Belyaeva, Hematologist, Intensive High-dose Chemotherapy of Lymphomas Department with a 24-hour Hospital

dr.belyaeva.a@gmail.comhttps://orcid.org/0000-0001-8803-1079ТатарниковаС. А.TatarnikovaC. A.

Татарникова Светлана Андреевна, врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным и дневным стационарами

Svetlana A. Tatarnikova, Hematologist, Intensive High-dose Chemotherapy of Lymphomas Department with a 24-hour Hospital

lana.tatarnikova.89@mail.ruhttps://orcid.org/0000-0002-8357-977XГемджянЭ. Г.GemdzhianE. G.

Гемджян Эдуард Георгиевич, старший научный сотрудник информационноаналитического отдела

Eduard G. Gemdzhyan, Senior Researcher, Information and Analytical Department

edstat@mail.ruhttps://orcid.org/0000-0003-1065-3702ЦыганковаС. В.TsygankovaS. V.

Цыганкова Светлана Валерьевна, кандидат биологических наук, старший научный сотрудник лаборатории палео- и этногенетики Курчатовского комплекса НБИКС-природоподобных технологий

Svetlana V. Tsygankova, Cand. Sci. (Biol.), Senior Researcher, Laboratory of Paleo- and Ethnogenetics, Nature-Like Technologies Kurchatov Complex

svetlana.tsygankova@gmail.comhttps://orcid.org/0000-0003-3795-0571БулыгинаЕ. С.BulyginaE. S.

Булыгина Евгения Станиславовна, кандидат биологических наук, ведущий научный сотрудник ресурсного центра молекулярно-клеточной биологии Курчатовского комплекса НБИКС-природоподобных технологий

Evgeniya S. Bulygina, Cand. Sci. (Biol.), Leading Researcher, Resource Centre of Molecular Cell Biology, Nature-Like Technologies Kurchatov Complex

eugenia.bulygina@gmail.comhttps://orcid.org/0000-0002-0095-0255РасторгуевС. М.RastorguevS. M.

Расторгуев Сергей Михайлович, кандидат биологических наук, старший научный сотрудник лаборатории палео- и этногенетики Курчатовского комплекса НБИКС — природоподобных технологий

Sergey M. Rastorguev, Cand. Sci. (Biol.), Senior Researcher, Laboratory of Paleo- and Ethnogenetics, Nature-Like Technologies Kurchatov Complex

rastorgueff@gmail.comhttps://orcid.org/0000-0001-7040-0892НедолужкоА. В.NedoluzhkoA. V.

Недолужко Артем Валерьевич, кандидат биологических наук, руководитель лаборатории палео- и этногенетики Курчатовского комплекса НБИКС — природоподобных технологий

Artyom V. Nedoluzhko, Cand. Sci. (Biol.), Head of the Laboratory of Paleo-and Ethnogenetics, Nature-Like Technologies Kurchatov Complex

nedoluzhko@gmail.comНарайкинО. С.NaraikinO. C.

Нарайкин Олег Степанович, доктор технических наук, профессор, членкорреспондент РАН, заместитель директора по научной работе и связям с органами государственной власти

Oleg S. Naraikin, Dr. Sci. (Tech.), Prof., RAS Corresponding Member, Deputy Director for Research and Relations with Government Agencies

https://orcid.org/0000-0002-6253-3334БидерманБ. В.BidermanB. V.

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

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

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

Судариков Андрей Борисович, доктор медицинских наук, заведующий лабораторией молекулярной генетики

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

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

Обухова Татьяна Никифоровна, кандидат медицинских наук, заведующая лабораторией кариологии

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

obukhova_t@mail.ruhttps://orcid.org/0000-0002-1082-8659КовригинаА. М.KovriginaA. M.

Ковригина Алла Михайловна, доктор биологических наук, заведующая патологоанатомическим отделением

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

kovrigina.alla@gmail.comhttps://orcid.org/0000-0002-2639-7419ЗвонковЕ. Е.ZvonkovE. E.

Звонков Евгений Евгеньевич, доктор медицинских наук, заведующий отделением интенсивной высокодозной химиотерапии лимфом с круглосуточным и дневным стационарами

Evgeny E. Zvonkov, Dr. Sci. (Med.), Head of the Department of Intensive Highdose Chemotherapy of Lymphomas with a 24-hour Hospital

dr.zvonkov@gmail.comФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationНациональный исследовательский центр «Курчатовский институт»РоссияNational Research Center «Kurchatov institute»Russian Federation201903102019642150164Copyright © Габеева Н.Г., Королева Д.А., Смольянинова А.К., Беляева А.В., Татарникова С.А., Гемджян Э.Г., Цыганкова С.В., Булыгина Е.С., Расторгуев С.М., Недолужко А.В., Нарайкин О.С., Бидерман Б.В., Судариков А.Б., Обухова Т.Н., Ковригина А.М., Звонков Е.Е., 20192019Габеева Н.Г., Королева Д.А., Смольянинова А.К., Беляева А.В., Татарникова С.А., Гемджян Э.Г., Цыганкова С.В., Булыгина Е.С., Расторгуев С.М., Недолужко А.В., Нарайкин О.С., Бидерман Б.В., Судариков А.Б., Обухова Т.Н., Ковригина А.М., Звонков Е.Е.Gabeeva N.G., Koroleva D.A., Smolyaninova A.K., Belyaeva A.V., Tatarnikova C.A., Gemdzhian E.G., Tsygankova S.V., Bulygina E.S., Rastorguev S.M., Nedoluzhko A.V., Naraikin O.C., Biderman B.V., Sudarikov A.B., Obukhova T.N., Kovrigina A.M., 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/135Введение

Введение. Диффузная В-крупноклеточная лимфома постгерминального происхождения (АВС-ДВККЛ) и фолликулярная лимфома 3В цитологического типа (ФЛ3В) отличаются агрессивным течением и резистентностью к химиотерапии (ХТ). Оба заболевания характеризуются активацией генов постгерминальной стадии дифференцировки В-клеток и высокой экспрессией транскрипционного белка MUM1. Леналидомид в комбинации с R-CHOP позволил улучшить результаты лечения больных АВС-ДВККЛ, однако около 40 % остаются резистентными к проводимой терапии.

Цель

Цель: оценить эффективность и токсичность программы R-mNHL-BFM-90 с леналидомидом (R2-mNHL-BFM-90), а также проанализировать возможные причины резистентности к ХТ больных АВС-ДВККЛ и ФЛ3В.

Больные и методы

Больные и методы. В период с октября 2016 по декабрь 2018 г. в исследование были включены 8 больных с MUM1-позитивной ДВККЛ и ФЛ3В. У всех больных проводили цитогенетическое исследование опухолевых образцов, определялся мутационный статус гена ТР53 методом секвенирования по Сэнгеру.

Результаты

Результаты. Больные получали комбинированную ХТ по программе R2-mNHL-BFM-90 с леналидомидом в дозе 25 мг/сут с 1 по 10 день каждого курса. Трем больным в качестве консолидации была проведена трансплантация аутологичных гемопоэтических стволовых клеток. После окончания ХТ у всех больных была достигнута полная ремиссия заболевания. Рецидив развился у 1 больного с мутацией в гене ТР53. При сроке наблюдения 11 месяцев (1–23) бессобытийная выживаемость составила 87 %.

Заключение

Заключение. Программа R2-mNHL-BFM-90 продемонстрировала высокую эффективность и приемлемую токсичность у больных АВС-ДВККЛ и ФЛ3В. Наличие мутации в гене ТР53 является фактором крайне неблагоприятного прогноза даже при применении интенсивных программ терапии и диктует необходимость разработки альтернативных подходов к лечению.

Introduction

Introduction. Diffuse large B-cell lymphoma of postgerminal origin (ABC-DLBCL) and follicular lymphoma grade 3B (FL3B) are characterised by an aggressive course and resistance to chemotherapy (CT). Both diseases are characterised by the activation of genes of the post-terminal stage of B-cell differentiation and high expression of the MUM1 transcriptional protein. Lenalidomide in combination with R-CHOP improved the results of treatment in patients with ABC-DLBCL; however, about 40 % of them remain resistant to the therapy.

Aim

Aim. The aim of the study was to evaluate the efficacy and toxicity of the R-mNHL-BFM-90 protocol with lenalidomide (R2-mNHL-BFM-90), as well as to analyse possible causes of CT resistance in patients with ABC-DLBCL and FL3B.

Patients and methods

Patients and methods. Over the period from October 2016 to December 2018, 8 patients with MUM1-positive DLBCL and FL3B were included in the research. All patients underwent a cytogenetic study of tumour samples. A mutational status of the TP53 gene was determined by Sanger sequencing.

Results

Results. Patients received combination chemotherapy according to the R2-mNHL-BFM-90 protocol with lenalidomide at a dose of 25 mg/day, from the 1st to the 10th day of each course. Autologous hematopoietic stem cell transplantation was performed as a consolidation in three patients. After the end of the chemotherapy, a complete remission of the disease was achieved in all patients. Relapse developed in 1 patient with a mutation in the TP53 gene. With a median follow-up period of 11 months (1–23), event-free survival was 87 %.

Conclusions

Conclusions. The R2-mNHL-BFM-90 protocol has demonstrated a high efficacy and acceptable toxicity in patients with ABC-DLBCL and FL3B. The presence of a mutation in the TP53 gene is established to be an extremely unfavourable prognostic factor even provided intensive treatment protocols, thus requiring the development of alternative approaches to the management of such patients.

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