bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2022-67-3-328-350bloodjour-382Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESПромежуточные результаты терапии первичной медиастинальной В-крупноклеточной лимфомы по протоколам «ПМЛ-16» и «ПМЛ-19»Interim results of the PML-16, PML-19 protocols for primary mediastinal large B-cell lymphoma therapyhttps://orcid.org/0000-0001-5171-0414ГабееваН. Г.GabeevaN. G.

Габеева Нелли Георгиевна, кандидат медицинских наук, старший научный сотрудник, гематолог отделения 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/0000-0001-5762-8294КоролеваД. А.KorolevaD. A.

Королева Дарья Александровна, 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

https://orcid.org/0000-0001-8803-1079ТатарниковаС. А.TatarnikovaS. A.

Татарникова Светлана Андреевна, гематолог отделения 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/0000-0003-0591-2589СмольяниноваА. К.SmolianinovaA. K.

Смольянинова Анна Константиновна, кандидат медицинских наук, гематолог отделения 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

https://orcid.org/0000-0002-4223-2366БадмажаповаД. С.BadmazhapovaD. S.

Бадмажапова Дарима Сэмункоевна, кандидат медицинских наук, гематолог отделения гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167, Москва

Darima S. Badmazhapova, Cand. Sci. (Med.), Hematologist, Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and He- matopoietic Stem Cell Transplantation Unit

125167, Moscow

darima-doctor@mail.ruhttps://orcid.org/0000-0001-6220-8868СмирноваС. Ю.SmirnovaS. Yu.

Смирнова Светлана Юрьевна, кандидат медицинских наук, научный сотрудник лаборатории молекулярной гематологии

125167, Москва

Svetlana Yu. Smirnova, Cand. Sci. (Med.), Researcher, Laboratory of Molecular Hematology

125167, Moscow

smirnova-s-ju@yandex.ruhttps://orcid.org/0000-0003-3914-8611НикулинаЕ. Е.NikulinaE. E.

Никулина Елена Евгеньевна, научный сотрудник лаборатории молекулярной гематологии

125167, Москва

Elena E. Nikulina, Researcher, Laboratory of Molecular Hematology

125167, Moscow

https://orcid.org/0000-0001-8256-8801БеляеваА. В.BelyaevaA. V.

Беляева Анастасия Валерьевна, гематолог отделения гематологии и химиотерапии лимфом с блоком трансплантации костного мозга и гемопоэтических стволовых клеток

125167, Москва

Anastasiya V. Belyaeva, Hematologist, Department of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Trans- plantation Unit

125167, Moscow

dr.belyaeva.a@gmail.comhttps://orcid.org/0000-0002-8357-977XГемджянЭ. Г.GemdzhianE. G.

Гемджян Эдуард Георгиевич, научный сотрудник лаборатории по изучению психических и неврологических расстройств при заболеваниях системы крови

125167, Москва

Eduard G. Gemdzhian, Researcher, Laboratory for Mental and Neurological Disorders in Hematological Malignancies

125167, Moscow

https://orcid.org/0000-0001-5085-5187ЛапинВ. А.LapinV. A.

Лапин Валерий Альбертович, главный внештатный специалист-гематолог Департамента здравоохранения и фармации Ярославской области, гематолог

150062, Ярославль

Valeriy A. Lapin, Chief Hematologist of the Department of Healthcare and Pharmacy of Yaroslavl region

150062, Yaroslavl

valapin0409@mail.ruhttps://orcid.org/0000-0002-0164-2422МоскалецЭ. Р.MoskaletsE. R.

Москалец Элина Рашитовна, радиолог

129090, Москва

Elina R. Moskalets, Radiologist, JSC

129090, Moscow

https://orcid.org/0000-0003-4683-4118КостинаИ. Э.KostinaI. E.

Костина Ирина Эдуардовна, кандидат медицинских наук, заведующая рентгеновским отделением

125167, Москва

Irina E. Kostina, Cand. Sci. (Med.), Head of Radiology Department

125167, Moscow

ikost@list.ruhttps://orcid.org/0000-0002-5522-7531МангасароваЯ. К.MangasarovaY. K.

Мангасарова Яна Константиновна, кандидат медицинских наук, заведующая отделением химиотерапии лимфатических опухолей с блоком трансплантации костного мозга и гемопоэтических стволовых клеток с дневным стационаром

125167, Москва

Yiana K. Mangasarova, Cand. Sci. (Med.), Head of the Department of Chemotherapy of Lymphatic tumors with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167, Moscow

https://orcid.org/0000-0002-5347-2947ШутовС. А.ShutovS. A.

Шутов Сергей Александрович, доктор медицинских наук, ведущий научный сотрудник отделения хирургии

125167, Москва

Sergei A. Shutov, Dr. Sci. (Med.), Leading Researcher of the Department of Surgery

125167, Moscow

shutov.s@blood.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/0000-0002-1082-8659КовригинаА. М.KovriginaA. M.

Ковригина Алла Михайловна, доктор биологических наук, заведующая патологоанатомическим отделением

125167, Москва

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

125167, Moscow

kovrigina.a@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

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

125167, Moscow

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

Евгений Евгеньевич Звонков, доктор медицинских наук, заведующий отделением 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 of Hematology and Chemotherapy of Lymphomas with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit

125167, Moscow

dr.zvonkov@gmail.comФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Center for HematologyRussian FederationГБУЗ ЯО «Областная клиническая больница»РоссияYaroslavl Regional Clinical HospitalRussian FederationАО «Европейский медицинский центр»РоссияJSC «European Medical Center»Russian Federation202222102022673328350Copyright © Габеева Н.Г., Королева Д.А., Татарникова С.А., Смольянинова А.К., Бадмажапова Д.С., Смирнова С.Ю., Никулина Е.Е., Беляева А.В., Гемджян Э.Г., Лапин В.А., Москалец Э.Р., Костина И.Э., Мангасарова Я.К., Шутов С.А., Бидерман Б.В., Судариков А.Б., Обухова Т.Н., Ковригина А.М., Галстян Г.М., Звонков Е.Е., 20222022Габеева Н.Г., Королева Д.А., Татарникова С.А., Смольянинова А.К., Бадмажапова Д.С., Смирнова С.Ю., Никулина Е.Е., Беляева А.В., Гемджян Э.Г., Лапин В.А., Москалец Э.Р., Костина И.Э., Мангасарова Я.К., Шутов С.А., Бидерман Б.В., Судариков А.Б., Обухова Т.Н., Ковригина А.М., Галстян Г.М., Звонков Е.Е.Gabeeva N.G., Koroleva D.A., Tatarnikova S.A., Smolianinova A.K., Badmazhapova D.S., Smirnova S.Y., Nikulina E.E., Belyaeva A.V., Gemdzhian E.G., Lapin V.A., Moskalets E.R., Kostina I.E., Mangasarova Y.K., Shutov S.A., Biderman B.V., Sudarikov A.B., Obukhova T.N., Kovrigina A.M., Galstyan G.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/382Введение

Введение. Первичная медиастинальная лимфома (ПМЛ) — агрессивная В-крупноклеточная лимфоидная опухоль, успех лечения которой определяется индукционной терапией. Применение ни одной из существующих схем химиотерапии (ХТ) не показало преимуществ в эффективности. Интенсивные программы терапии сопряжены с высокой токсичностью.

Цель — оценить эффективность применения двух пилотных проспективных протоколов лечения ПМЛ («ПМЛ-16» и «ПМЛ-19»), а также возможность использования анализа свободно циркулирующей опухолевой ДНК (соДНК) для оценки минимально остаточной болезни у больных ПМЛ.

Материалы и методы

Материалы и методы. С января 2016 г. по январь 2022 г. в исследование были последовательно включены 34 больных ПМЛ, ранее не получавших лечение; средний возраст — 32 года; стадия > I — у 60 %; экстрамедиастинальные очаги поражения — у 14,7 %; массивное поражение лимфатических узлов средостения (bulky disease) — у 73,5 % больных. Для оценки полноты ремиссии выполняли позитронно-эмиссионную томографию, совмещенную с компьютерной томографией (ПЭТ-КТ), определяли соДНК.

Результаты

Результаты. 18 больных получили лечение по протоколу «ПМЛ-16» (6 курсов ХТ; 2 блока «R-mNHL-BFM-90» + 4 курса «R-EPOCH»). После окончания терапии у всех 18 больных была достигнута ПЭТ-КТ-негативная ремиссия. Следующие 16 больных получили лечение по протоколу «ПМЛ-19» (4 курса ХТ; 2 блока «R-mNHL-BFM-90» + 2 курса «R-EPOCH») в комбинации с леналидомидом. После окончания терапии у 9 (56 %) больных была достигнута ПЭТ-негативная ремиссия; у 7 (44 %) сохранялась патологическая активность (D4–5 баллов). Через 3 и 6 мес. у 15 (94 %) больных достигнута нормализация метаболической активности. Учитывая высокую частоту ложнопозитивных результатов у больных ПМЛ, для определения глубины ремиссии у 15 больных было выполнено исследование соДНК. После окончания терапии у всех 15 больных произошла полная элиминация соДНК. Из них у 5 (33 %) после лечения сохранялась ПЭТ-КТ-позитивность. При дальнейшем наблюдении через 3–6 мес. у 4 больных метаболическая активность снизилась до физиологического уровня без применения консолидирующей терапии. Одна больная после окончания терапии перенесла новую коронавирусную инфекцию. Через месяц у нее в средостении сохранялось остаточное образование (стандартизированный уровень накопления — standardized uptake value, SUV) — SUVmax 14,2; больная находится под наблюдением. При медиане наблюдения 39 мес. (95%-ный доверительный интервал (95% ДИ): 26–47) для общей, беспрогрессивной и бессобытийной выживаемости и медиане наблюдения 36 мес. (95% ДИ: 22–43) для безрецидивной выживаемости все 34 больных живы, у них сохраняется ремиссия заболевания.

Заключение

Заключение. Эффективность «ПМЛ-16» позволила отказаться от проведения консолидирующей терапии и опровергла представление о необходимости проведения 6 курсов ХТ. Сочетание программ, основанных на применении принципа высокодозной коротко-импульсной индукции ремиссии (R-mNHL-BFM-90) в сочетании с продленным введением средних доз (R-EPOCH), имело решающее значение для достижения успешного результата. Включение леналидомида в программу «ПМЛ-19» позволило достичь ремиссии в 100 % случаев после 4 курсов. Показана возможность использования анализа соДНК для оценки МОБ у больных ПМЛ.

Introduction

Introduction. Primary mediastinal lymphoma (PML) is an aggressive lymphoid tumor treatment success of which is determined by induction therapy. To date, none of the standard chemotherapy regimens (CT) have demonstrated an advantage in efficacy. Intensive therapy programs are associated with high toxicity.

Aim — to evaluate the efficacy and toxicity of two pilot prospective treatment protocols PML-16 and PML-19 as well as the possibility of using the analysis of freely circulating tumor DNA (ctDNA) to assess MRD in patients with PML.

Materials and methods

Materials and methods. From January 2016 to January 2022, 34 previously untreated PML patients were included in the study; average age — 32; stage > I — in 60 %; extramediastinal lesions — in 14.7 %; bulky disease — in 73.5 % of patients. Positron emission tomography combined with computed tomography (PET-CT) was performed; ctDNA was determined to assess the completeness of remission.

Results

Results. Eighteen patients received treatment according to the PML-16 protocol (6 courses of chemotherapy; 2 blocks of RmNHL-BFM-90 + 4 courses of R-EPOCH). After the end of therapy, all 18 patients achieved PET-negative remission. The next 16 patients received treatment according to the PML-19 protocol (4 courses of chemotherapy; 2 blocks of R-mNHL-BFM-90 + 2 courses of R-EPOCH) in combination with lenalidomide. After the end of therapy, 9 (56 %) patients achieved PET-negative remission; 7 (44 %) retained pathological activity (D4–5 points). After 3 and 6 months 15 (94 %) patients achieved normalization of metabolic activity. Considering the high frequency of false-positive results in patients with PML, a ctDNA study was performed to determine the depth of remission in 15 patients. After the end of therapy, all 15 patients had complete elimination of ctDNA. Of these, 5 (33 %) remained PET-positive at the end of treatment. During further observation, after 3–6 months, in 4 patients the level of metabolic activity decreased to physiological without the use of consolidating therapy. After the end of therapy, one patient suffered the new coronavirus infection, COVID-19. A month later, residual formation of SUVmax 14.2 remained in the mediastinum. The patient is currently under observation. With a median follow-up of 36 months (9 to 76 months) all 34 patients are in remission.

Conclusion

Conclusion. The effectiveness of PML-16 made it possible to abandon the consolidation therapy and refuted the idea of the need for 6 courses of CT. The combination of programs based on the application of the principle of high-dose shortpulse induction of remission (R-mNHL-BFM-90) in combination with the prolonged administration of medium doses (R-EPOCH) was crucial in achieving a successful result. The inclusion of lenalidomide in the “PML-19” program made it possible to achieve complete remission in 100 % of cases after 4 courses. The possibility of using DNA analysis to assess MRD in patients with PML was shown.

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