bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2019-64-3-256-273bloodjour-146Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESНЕГАТИВНОЕ ВЛИЯНИЕ МУТАЦИЙ В ГЕНЕ ТР53 НА ЭФФЕКТИВНОСТЬ ТЕРАПИИ ЛИМФОМЫ ИЗ КЛЕТОК МАНТИИ. ПРОМЕЖУТОЧНЫЕ РЕЗУЛЬТАТЫ ПРОТОКОЛА «ЛКМ-2016»NEGATIVE IMPACT OF THE TP53 GENE MUTATIONS ON THE EFFICACY OF THE THERAPY OF MANTLE CELL LYMPHOMA. INTERIM RESULTS OF THE MCL-2016 PROTOCOLhttps://orcid.org/0000-0001-5762-8294КоролеваД. А.KorolevaD. A.

врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным стационаром,

125167, г. Москва, Новый Зыковский проезд, 4

Hematologist, Intensive High-dose Chemotherapy of Lymphomas Department with a 24-hour Hospital,

125167, Moscow

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

кандидат медицинских наук, врач-гематолог отделения интенсивной высокодозной химиотерапии лимфом с круглосуточным стационаром,

125167, Москва

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

125167, Moscow

dr.gabeeva@gmail.comhttps://orcid.org/0000-0001-6201-6276КузьминаЛ. А.KuzminaL. A.

кандидат медицинских наук, заведующая отделением интенсивной высокодозной химиотерапии и трансплантации костного мозга с круглосуточным стационаром,

125167, Москва

Cand. Sci. (Med.), Head of the Department of Intensive High-Dose Chemotherapy and Bone Marrow Transplantation,

125167, Moscow

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

кандидат биологических наук, старший научный сотрудник лаборатории палео- и этногенетики Курчатовского комплекса НБИКС-природноподобных технологий,

123182, Москва

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

123182, Moscow

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

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

123182, Москва

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

123182, Moscow

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

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

123182, Москва

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

123182, Moscow

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

кандидат биологических наук, руководитель лаборатории палео- и этногенетики Курчатовского комплекса НБИКС-природоподобных технологий,

123182, Москва

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

123182, Moscow

nedoluzhko@gmail.comСаенкоС. С.SaenkoS. S.

лаборант-исследователь в лаборатории палео- и этногенетики Курчатовского комплекса НБИКС-природноподобных технологий,

123182, Москва

Research Assistant, Laboratory for Paleo- and Ethnogenetics, Kurchatov Complex of NBICS Nature-Like Technologies,

123182, Moscow

saenko@phystech.eduНарайкинО. С.NaraikinO. S.

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

123182, Москва

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

123182, Moscow

ГаврилинаО. А.GavrilinaO. A.

кандидат медицинских наук, старший научный сотрудник отдела химиотерапии гемобластозов, депрессий кроветворения и трансплантации костного мозга,

125167, Москва

Cand. Sci. (Med.), Senior Researcher, of the Department of Chemotherapy of Hematological malignancies and Hematopoietic Depressions and Bone Marrow Transplantation, 

125167, Moscow

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

кандидат биологических наук, старший научный сотрудник лаборатории молекулярной гематологии,

125167, Москва

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

125167, Moscow

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

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

125167, Москва

Cand. Sci. (Med.), Head of the Laboratory for Immunophenotyping Blood and Bone Marrow Cells, 

125167, Moscow

galtseva.i@blood.ruhttps://orcid.org/0000-0002-1082-8659КовригинаА. М.KovriginaA. M.

доктор биологических наук, заведующая патологоанатомическим отделением,

125167, Москва

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

125167, Moscow

kovrigina.alla@gmail.comhttps://orcid.org/0000-0003-1613-652XОбуховаТ. Н.ObukhovaT. N.

кандидат медицинских наук, заведующая лабораторией кариологии,

125167, Москва

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

125167, Moscow

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

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

125167, Москва

Dr. Sci. (Med.), Head of the Department of Intensive Highdose Chemotherapy of Lymphomas with a in-patient & out-patient Hospital,

125167, Moscow

dr.zvonkov@gmail.comФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской Федерации 125167, МоскваРоссияNational Research Center for HematologyRussian FederationФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian FederationНациональный исследовательский центр «Курчатовский институт»РоссияNational Research Center “Kurchatov institute”Russian FederationНациональный исследовательский центр «Курчатовский институтРоссияNational Research Center “Kurchatov institute”Russian Federation201908112019643256273Copyright © Королева Д.А., Габеева Н.Г., Кузьмина Л.А., Цыганкова С.В., Булыгина Е.С., Расторгуев С.М., Недолужко А.В., Саенко С.С., Нарайкин О.С., Гаврилина О.А., Бидерман Б.В., Гальцева И.В., Ковригина А.М., Обухова Т.Н., Звонков Е.Е., 20192019Королева Д.А., Габеева Н.Г., Кузьмина Л.А., Цыганкова С.В., Булыгина Е.С., Расторгуев С.М., Недолужко А.В., Саенко С.С., Нарайкин О.С., Гаврилина О.А., Бидерман Б.В., Гальцева И.В., Ковригина А.М., Обухова Т.Н., Звонков Е.Е.Koroleva D.A., Gabeeva N.G., Kuzmina L.A., Tsygankova S.V., Bulygina E.S., Rastorguev S.M., Nedoluzhko A.V., Saenko S.S., Naraikin O.S., Gavrilina O.A., Biderman B.V., Galtseva I.V., Kovrigina A.M., 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/146Введение

Введение. Прогноз лимфомы из клеток мантии (ЛКМ) определяется не только интенсификацией первой линии терапии, но и биологическими характеристиками опухоли.

Цель

Цель: оценить частоту встречаемости и выживаемость больных ЛКМ с мутациями в гене TP53.

Материалы и методы

Материалы и методы. В рамках проспективного исследования «ЛКМ-2016» с января 2016 г. по декабрь 2018 г. проведено исследование по определению мутации гена TP53 у 24 больных с ЛКМ. Скрининг мутаций гена ТР53 проводили с помощью секвенирования ДНК по Сэнгеру (экзоны 1(2)–11). Идентифицировали 20 больных без мутаций в гене TP53 (20 mut p53–) и 4 — с мутацией TP53 (4 mut p53+).

Результаты

Результаты. 17 больным ЛКМ (mut p53–) было проведено два цикла R-BAC (ритуксимаб, бендамустин, цитарабин) и два цикла R-HA (ритуксимаб, цитарабин 12 г/м2 ) с последующей трансплантацией аутологичных гемопоэтических стволовых клеток (ауто-ТГСК). После окончания терапии у всех 17 больных минимальная остаточная болезнь (МОБ) не определялась, у 3 больных продолжается терапия. Все больные, которые полностью завершили терапию, остаются в полной ремиссии с медианой наблюдения пять месяцев после ауто-ТГСК (от 1 до 17 месяцев). У больных ЛКМ с мутациями TP53 прогноз был хуже. Несмотря на использование интенсивной терапии, 2 больных с мутациями TP53 в данном исследовании умерли от прогрессии ЛКМ. Двум больным с мутацией TP53 была выполнена трансплантация аллогенных гемопоэтических стволовых клеток (алло-ТГСК) от неродственных полностью идентичных доноров. При сроках наблюдения 3 и 27 месяцев после алло-ТГСК больные живы, сохраняется полная ремиссия.

Заключение

Заключение. Программа R-BAC/R-HA позволила достичь полной клинической и МОБ-негативной ремиссии у всех больных в группе mut p53–, с приемлемым профилем токсичности. Для больных ЛКМ с мутациями гена TP53 аллоТГСК является единственным вариантом излечения. 

Introduction

Introduction. The prognosis of mantle cell lymphoma (MCL) is determined by both the intensification of the first-line therapy and the biological characteristics of the tumour.

Aim

Aim. To assess the MCL incidence rate, as well as the survival rate of MCL patients with TP53 gene mutations.

Materials and methods

Materials and methods. The prospective study MCL-2016 aimed at identifying TP53 gene mutations was carried out among 24 MCL patients from January 2016 to December 2018. TP53 gene mutations were screened using Sanger sequencing (exons 1(2)–11). No TP53 gene mutations were identified in 20 patients (20 mutp53-), with TP53 gene mutations (4 mutp53 +) being observed in 4 patients.

Results

Results. 17 MCL patients (mut p53-) underwent two cycles of R-BAC (rituximab, bendamustine, cytarabine) and two cycles of R-HA (rituximab, cytarabine 12 g/m2 ) with the subsequent transplantation of autologous hematopoietic stem cells. Following therapy, minimum residual disease (MRD) was undetected in all 17 patients, with 3 patients still undergoing therapy. All patients, who completed the therapy, remain in complete remission with a median follow-up of 5 months following the transplantation of autologous hematopoietic stem cells (from 1 to 17 the months). The prognosis in MCL patients with TP53 gene mutations was worse. In the course of this study, two patients with TP53 gene mutations died of progressing MCL in spite of intensive therapy. In two patients with TP53 gene mutation, allogeneic hematopoietic stem cells were transplanted from unrelated completely identical donors. After undergoing the transplantation, the patients are alive and remain in complete remission (observation periods of 3 and 27 months).

Conclusion

Conclusion. Following R-BAC/R-HA therapy, all patients from the mutp53- group reached complete clinical and MRDnegative remission, with an acceptable toxicity profile. For MCL patients with TP53 gene mutations, the transplantation of allogeneic hematopoietic stem cells constitutes the only effective treatment. 

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