oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2023-22-2-34-42oncotomsk-2527Research ArticleКЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯCLINICAL STUDIESЭкспрессия LAG-3 на В-лимфоцитах как маркер прогноза ответа на терапию у больных хроническим лимфолейкозомExpression of LAG-3 on B-lymphocytes as a marker for prediction of response to therapy in patients with chronic lymphocytic leukemiahttps://orcid.org/0000-0001-6762-0835СелютинаО. Н.SelyutinaO. N.

Селютина Олеся Николаевна, биолог клинико-диагностической лаборатории, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Olesya N. Selyutina, Biologist, Clinical and Diagnostic Laboratory,

63, 14-th Liniya St., 344037, Rostov-on-Don

selyutinalesya@yandex.ruhttps://orcid.org/0000-0003-4457-3815ЛысенкоИ. Б.LysenkoI. B.

Лысенко Ирина Борисовна, доктор медицинских наук, профессор, заведующая отделением онкогематологии, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Irina B. Lysenko, MD, Professor, Head of the Department of Hematology/Oncology,

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0002-4222-1579ГуськоваН. К.GuskovaN. K.

Гуськова Наиля Катифовна, кандидат биологических наук, заведующая клинико-диагностической лабораторией, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Nailya K. Guskova, PhD, Head of Clinical and Diagnostic Laboratory,

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0002-6496-9641НовиковаИ. А.NovikovaI. A.

Новикова Инна Арнольдовна, кандидат медицинских наук, заместитель генерального директора по науке, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Inna A. Novikova, MD, PhD, Deputy General Director for Science, 

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0002-1410-122XЗлатникЕ. Ю.ZlatnikE. Yu.

Златник Елена Юрьевна, доктор медицинских наук, профессор, главный научный сотрудник лаборатории иммунофенотипирования опухолей, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Elena Yu. Zlatnik, MD, Professor, Chief Researcher of Laboratory of Immunophenotyping of Tumors,

63, 14-th Liniya St., 344037, Rostov-on-Don

ПушкареваТ. Ф.PushkarevaT. F.

Пушкарева Татьяна Федоровна, врач-онколог клинико-диагностического отделения, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Tatyana F. Pushkareva, MD, Oncologist, Clinical Diagnostic Department, 

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0001-7224-3106НиколаеваН. В.NikolaevaN. V.

Николаева Надежда Владимировна, доктор медицинских наук, врач-гематолог отделения онкогематологии, ведущий научный сотрудник отдела лекарственного лечения опухолей, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Nadezhda V. Nikolaeva, MD, DSc, Hematologist, Department of Oncology/Hematology, Leading Researcher, Department of Drug Treatment of Tumors, 

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0003-3001-0675КамаеваИ. А.KamaevaI. A.

Камаева Инна Анатольевна, кандидат медицинских наук, врач-онколог отделения онкогематологии, младший научный сотрудник отдела лекарственного лечения опухолей, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Inna A. Kamaeva, MD, PhD, Junior Researcher, Department of Drug Treatment of Tumors, 

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0003-0843-6012СаманеваН. Ю.SamanevaN. Yu.

Саманева Наталья Юрьевна, кандидат медицинских наук, младший научный сотрудник отдела лекарственного лечения опухолей, врач-онколог отделения онкогематологии, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Natalya Yu. Samaneva, MD, PhD, Junior Researcher, Department of Drug Treatment of Tumors, Oncologist, Department of Oncology/Hematology, 

63, 14-th Liniya St., 344037, Rostov-on-Don

https://orcid.org/0000-0002-0761-2486КапузаЕ. А.KapuzaE. A.

Капуза Елена Анатольевна, врач-онколог отделения онкогематологии, 

344037, г. Ростов-на-Дону, 14-я линия, 63

Elena A. Kapuza, MD, Oncologist, Department of Oncology/Hematology,

63, 14-th Liniya St., 344037, Rostov-on-Don

ФГБУ «Национальный медицинский исследовательский центр онкологии» Минздрава РоссииРоссияNational Medical Research Institute of Oncology of the Ministry of Health of the RussiaRussian Federation2023290420232223442Copyright © Селютина О.Н., Лысенко И.Б., Гуськова Н.К., Новикова И.А., Златник Е.Ю., Пушкарева Т.Ф., Николаева Н.В., Камаева И.А., Саманева Н.Ю., Капуза Е.А., 20232023Селютина О.Н., Лысенко И.Б., Гуськова Н.К., Новикова И.А., Златник Е.Ю., Пушкарева Т.Ф., Николаева Н.В., Камаева И.А., Саманева Н.Ю., Капуза Е.А.Selyutina O.N., Lysenko I.B., Guskova N.K., Novikova I.A., Zlatnik E.Y., Pushkareva T.F., Nikolaeva N.V., Kamaeva I.A., Samaneva N.Y., Kapuza E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/2527

Цель исследования ‒ изучить уровень экспрессии LAG-3 на В-лимфоцитах и возможность его применения в качестве маркера прогноза ответа на терапию у больных хроническим лимфолейкозом (ХЛЛ).

Материал и методы

Материал и методы. В исследование включены 40 больных с впервые установленным диагнозом ХЛЛ. Пациенты были разделены на две группы: I – ХЛЛ стадии A по Binet, которым не требовалось проведение терапии, II – ХЛЛ стадии С, которым проводилась иммунохимиотерапия в режимах RB и FCR. В зависимости от схемы лечения и гематологического ответа больных на терапию выделены 4 подгруппы: IIА-RB, IIА-FCR, IIБ-RB, IIБ-FCR. В контрольную группу, сопоставимую по возрасту и полу, вошли 20 человек без злокачественных заболеваний. Исходно во всех группах методом проточной цитофлюориметрии определены иммунофенотип и уровень В-лимфоцитов, экспрессия LAG-3, а также минимальная остаточная болезнь в группе II после 6-го курса иммунохимиотерапии. Данные оценены в программе Statistica 13.0.

Результаты

Результаты. Во всех группах больных ХЛЛ до лечения обнаружена экспрессия LAG-3 на В-лимфоцитах в отличие от контрольной группы. Более высокий уровень экспрессии отмечен у больных ХЛЛ стадии С по Binet по сравнению с пациентами с ХЛЛ стадии А. Данные демонстрируют отличия в уровне экспрессии LAG-3 у больных с разным ответом на проводимую терапию. Так, исходно более высокий уровень экспрессии LAG-3 на В-лимфоцитах наблюдается у больных ХЛЛ стадии С по Binet с неудовлетворительным ответом на терапию. Установлено, что при уровне экспрессии LAG-3 на В-лимфоцитах в пределах 14,57 ± 0,66 % можно предполагать хороший гематологический ответ независимо от схемы проводимой терапии, а при значениях 41,95 ± 1,62 % – неудовлетворительный ответ на лечение.

Заключение

Заключение. Исходный уровень экспрессии LAG-3 на B-лимфоцитах у больных хроническим лимфолейкозом может быть использован в качестве маркера для прогнозирования и мониторинга ответа на лечение независимо от используемого режима иммунохимиотерапии.

Purpose

Purpose: to study the level of LAG-3 expression on B-lymphocytes and the feasibility of using it as a marker for predicting response to therapy in patients with chronic lymphocytic leukemia (CLL).

Material and Methods

Material and Methods. The study included 40 patients with newly diagnosed CLL. All patients were divided into two groups: group I: patients with Binet stage A, who did not receive therapy and group II: patients with Binet stage C, who received immunochemotherapy in RB and FCR regimes. According to the treatment regimen and hematological response to therapy, 4 subgroups were distinguished: IIA-RB, IIA-FCR, IIB-RB, and IIB-FCR. The control group consisted of 20 people matched in age and gender without cancer. The immunophenotype, level of B-lymphocytes, LAG-3 expression, and the minimal residual disease in group II after the 6th course of immunochemotherapy were initially determined in all groups by flow cytometry. The data were evaluated using Statistica 13.0.

Results

Results. Compared to the control group, the LAG-3 expression on B-lymphocytes was found in all groups of CLL patients before treatment. The expression level was higher in patients with Binet stage C than in patients with Binet stage. The data demonstrated differences in the level of LAG-3 expression in patients with different hematological responses to therapy. The initially higher level of LAG-3 expression on B-lymphocytes was observed in patients with Binet stage C CLL with an unfavorable response to therapy. A good hematological response was found can be achieved at the level of LAG-3 expression within 14.57 ± 0.66 % regardless of the therapy regimen, and unfavorable response to therapy at the level of 41.95 ± 1.62 %.

Conclusion

Conclusion. The initial level of LAG-3 expression on B-lymphocytes in patients with CLL can be used as a marker for predicting and monitoring response to treatment, regardless of the immunochemotherapy regimen used. 

хронический лимфолейкозпроточная цитофлуориметрияLAG-3минимальная остаточная болезньиммунофенотипические прогностические маркерыиммунохимиотерапияchronic lymphocytic leukemiaflow cytometryLAG-3minimal residual diseaseimmunophenotypic prognostic markersimmunochemotherapyReferencesKipps T.J., Stevenson F.K., Wu C.J., Croce C.M., Packham G., Wierda W.G., O’Brien S., Gribben J., Rai K. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017; 3: 1–22. doi: 10.1038/nrdp.2016.96.Kipps T.J., Stevenson F.K., Wu C.J., Croce C.M., Packham G., Wierda W.G., O’Brien S., Gribben J., Rai K. Chronic lymphocytic leukaemia. Nat Rev Dis Primers. 2017; 3: 1–22. doi: 10.1038/nrdp.2016.96.Chiorazzi N., Rai K.R., Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005; 352(8): 804–15. doi: 10.1056/NEJMra041720.Chiorazzi N., Rai K.R., Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005; 352(8): 804–15. doi: 10.1056/NEJMra041720.Yosifov D.Y., Wolf C., Stilgenbauer S., Mertens D. From Biology to Therapy: The CLL Success Story. Hemasphere. 2019; 3(2). doi: 10.1097/HS9.0000000000000175.Yosifov D.Y., Wolf C., Stilgenbauer S., Mertens D. From Biology to Therapy: The CLL Success Story. Hemasphere. 2019; 3(2). doi: 10.1097/HS9.0000000000000175.Кравченко Д.В., Свирновский А.И. Хронический лимфоцитарный лейкоз: клиника, диагностика, лечение. Гомель, 2017. 117 с.Kravchenko D.V., Svirnovsky A.I. Chronic lymphocytic leukemia: clinic, diagnosis, treatment. Gomel, 2017. 117 p. (in Russian).Craig F.E., Foon K.A. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008; 111(8): 3941–67. doi: 10.1182/blood-2007-11-120535.Craig F.E., Foon K.A. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008; 111(8): 3941–67. doi: 10.1182/blood-2007-11-120535.Гуськова Н.К., Селютина О.Н., Новикова И.А., Максимов А.Ю., Ноздричева А.С., Абакумова С.В. Морфологические и иммунофенотипические особенности моноклональной популяции В-лимфоцитов при хроническом лимфолейкозе. Южно-Российский онкологический журнал. 2020; 1(3): 27–35. doi: 10.37748/2687-0533-2020-1-3-3.Guskova N.K., Selyutina O.N., Novikova I.A., Maksimov A.Yu., Nozdricheva A.S., Abakumova S.V. Morphological and immunofenotypic features of the monoclonal population of B-lymphocytes in chronic lymphocytic leukemia. South Russian Journal of Cancer. 2020; 1(3): 27–35. (in Russian). doi: 10.37748/2687-0533-2020-1-3-3.Rodríguez-Vicente A.E., Díaz M.G., Hernández-Rivas J.M. Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease. Cancer Genet. 2013; 206(3): 49–62. doi: 10.1016/j.cancergen.2013.01.003.Rodríguez-Vicente A.E., Díaz M.G., Hernández-Rivas J.M. Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease. Cancer Genet. 2013; 206(3): 49–62. doi: 10.1016/j.cancergen.2013.01.003.Eichhorst B., Robak T., Montserrat E., Ghia P., Niemann C.U., Kater A.P., Gregor M., Cymbalista F., Buske C., Hillmen P., Hallek M., Mey U.; ESMO Guidelines Committee. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(1): 23–33. doi: 10.1016/j.annonc.2020.09.019.Eichhorst B., Robak T., Montserrat E., Ghia P., Niemann C.U., Kater A.P., Gregor M., Cymbalista F., Buske C., Hillmen P., Hallek M., Mey U.; ESMO Guidelines Committee. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(1): 23–33. doi: 10.1016/j.annonc.2020.09.019.Baliakas P., Mattsson M., Stamatopoulos K., Rosenquist R. Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed? J Intern Med. 2016; 279(4): 347–57. doi: 10.1111/joim.12455.Baliakas P., Mattsson M., Stamatopoulos K., Rosenquist R. Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed? J Intern Med. 2016; 279(4): 347–57. doi: 10.1111/joim.12455.Brown J.R., Hillmen P., O’Brien S., Barrientos J.C., Reddy N.M., Coutre S.E., Tam C.S., Mulligan S.P., Jaeger U., Barr P.M., Furman R.R., Kipps T.J., Cymbalista F., Thornton P., Caligaris-Cappio F., Delgado J., Montillo M., DeVos S., Moreno C., Pagel J.M., Munir T., Burger J.A., Chung D., Lin J., Gau L., Chang B., Cole G., Hsu E., James D.F., Byrd J.C. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018; 32(1): 83–91. doi: 10.1038/leu.2017.175.Brown J.R., Hillmen P., O’Brien S., Barrientos J.C., Reddy N.M., Coutre S.E., Tam C.S., Mulligan S.P., Jaeger U., Barr P.M., Furman R.R., Kipps T.J., Cymbalista F., Thornton P., Caligaris-Cappio F., Delgado J., Montillo M., DeVos S., Moreno C., Pagel J.M., Munir T., Burger J.A., Chung D., Lin J., Gau L., Chang B., Cole G., Hsu E., James D.F., Byrd J.C. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018; 32(1): 83–91. doi: 10.1038/leu.2017.175.Taghiloo S., Allahmoradi E., Ebadi R., Tehrani M., HosseiniKhah Z., Janbabaei G., Shekarriz R., Asgarian-Omran H. Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia. Asian Pac J Cancer Prev. 2017; 18(8): 2269–74. doi: 10.22034/APJCP.2017.18.8.2269.Taghiloo S., Allahmoradi E., Ebadi R., Tehrani M., HosseiniKhah Z., Janbabaei G., Shekarriz R., Asgarian-Omran H. Upregulation of Galectin-9 and PD-L1 Immune Checkpoints Molecules in Patients with Chronic Lymphocytic Leukemia. Asian Pac J Cancer Prev. 2017; 18(8): 2269–74. doi: 10.22034/APJCP.2017.18.8.2269.Mohammed Basabaeen A.A., Abdelgader E.A., Babekir E.A., Abdelrahim S.O., Eltayeb N.H., Altayeb O.A., Fadul E.A., Sabo A., Ibrahim I.K. TP53 Gene 72 Arg/Pro (rs1042522) Single Nucleotide Polymorphism Contribute to Increase the Risk of B-Chronic Lymphocytic Leukemia in the Sudanese Population. Asian Pac J Cancer Prev. 2019; 20(5): 1579–85. doi: 10.31557/APJCP.2019.20.5.1579.Mohammed Basabaeen A.A., Abdelgader E.A., Babekir E.A., Abdelrahim S.O., Eltayeb N.H., Altayeb O.A., Fadul E.A., Sabo A., Ibrahim I.K. TP53 Gene 72 Arg/Pro (rs1042522) Single Nucleotide Polymorphism Contribute to Increase the Risk of B-Chronic Lymphocytic Leukemia in the Sudanese Population. Asian Pac J Cancer Prev. 2019; 20(5): 1579–85. doi: 10.31557/APJCP.2019.20.5.1579.Joshi N.S., Cui W., Chandele A., Lee H.K., Urso D.R., Hagman J., Gapin L., Kaech S.M. Inflammation directs memory precursor and short-lived efector CD8(+) T cell fates via the graded expression of Tbet transcription factor. Immunity. 2007; 27(2): 281–95. doi: 10.1016/j.immuni.2007.07.010.Joshi N.S., Cui W., Chandele A., Lee H.K., Urso D.R., Hagman J., Gapin L., Kaech S.M. Inflammation directs memory precursor and short-lived efector CD8(+) T cell fates via the graded expression of Tbet transcription factor. Immunity. 2007; 27(2): 281–95. doi: 10.1016/j.immuni.2007.07.010.Fischer K., Bahlo J., Fink A.M., Goede V., Herling C.D., Cramer P., Langerbeins P., von Tresckow J., Engelke A., Maurer C., Kovacs G., Herling M., Tausch E., Kreuzer K.A., Eichhorst B., Böttcher S., Seymour J.F., Ghia P., Marlton P., Kneba M., Wendtner C.M., Döhner H., Stilgenbauer S., Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2): 208–15. doi: 10.1182/blood-2015-06-651125.Fischer K., Bahlo J., Fink A.M., Goede V., Herling C.D., Cramer P., Langerbeins P., von Tresckow J., Engelke A., Maurer C., Kovacs G., Herling M., Tausch E., Kreuzer K.A., Eichhorst B., Böttcher S., Seymour J.F., Ghia P., Marlton P., Kneba M., Wendtner C.M., Döhner H., Stilgenbauer S., Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2): 208–15. doi: 10.1182/blood-2015-06-651125.Fischer K., Cramer P., Busch R., Böttcher S., Bahlo J., Schubert J., Pfüger K.H., Schott S., Goede V., Isfort S., von Tresckow J., Fink A.M., Bühler A., Winkler D., Kreuzer K.A., Staib P., Ritgen M., Kneba M., Döhner H., Eichhorst B.F., Hallek M., Stilgenbauer S., Wendtner C.M. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012; 30(26): 3209–16. doi: 10.1200/JCO.2011.39.2688.Fischer K., Cramer P., Busch R., Böttcher S., Bahlo J., Schubert J., Pfüger K.H., Schott S., Goede V., Isfort S., von Tresckow J., Fink A.M., Bühler A., Winkler D., Kreuzer K.A., Staib P., Ritgen M., Kneba M., Döhner H., Eichhorst B.F., Hallek M., Stilgenbauer S., Wendtner C.M. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012; 30(26): 3209–16. doi: 10.1200/JCO.2011.39.2688.Eichhorst B., Fink A.M., Bahlo J., Busch R., Kovacs G., Maurer C., Lange E., Köppler H., Kiehl M., Sökler M., Schlag R., Vehling-Kaiser U., Köchling G., Plöger C., Gregor M., Plesner T., Trneny M., Fischer K., Döhner H., Kneba M., Wendtner C.M., Klapper W., Kreuzer K.A., Stilgenbauer S., Böttcher S., Hallek M.; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016; 17(7): 928–42. doi: 10.1016/S1470-2045(16)30051-1.Eichhorst B., Fink A.M., Bahlo J., Busch R., Kovacs G., Maurer C., Lange E., Köppler H., Kiehl M., Sökler M., Schlag R., Vehling-Kaiser U., Köchling G., Plöger C., Gregor M., Plesner T., Trneny M., Fischer K., Döhner H., Kneba M., Wendtner C.M., Klapper W., Kreuzer K.A., Stilgenbauer S., Böttcher S., Hallek M.; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016; 17(7): 928–42. doi: 10.1016/S1470-2045(16)30051-1.Al-Sawaf O., Hallek M., Fischer K. The role of minimal residual disease in chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2022; 20(2): 97–103.Al-Sawaf O., Hallek M., Fischer K. The role of minimal residual disease in chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2022; 20(2): 97–103.Böttcher S., Ritgen M., Fischer K., Stilgenbauer S., Busch R.M., Fingerle-Rowson G., Fink A.M., Bühler A., Zenz T., Wenger M.K., Men-dila M., Wendtner C.M., Eichhorst B.F., Döhner H., Hallek M.J., Kneba M. Minimal residual disease quantifcation is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012; 30(9): 980–8. doi: 10.1200/JCO.2011.36.9348.Böttcher S., Ritgen M., Fischer K., Stilgenbauer S., Busch R.M., Fingerle-Rowson G., Fink A.M., Bühler A., Zenz T., Wenger M.K., Men-dila M., Wendtner C.M., Eichhorst B.F., Döhner H., Hallek M.J., Kneba M. Minimal residual disease quantifcation is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012; 30(9): 980–8. doi: 10.1200/JCO.2011.36.9348.Goede V., Fischer K., Busch R., Engelke A., Eichhorst B., Wendtner C.M., Chagorova T., de la Serna J., Dilhuydy M.S., Illmer T., Opat S., Owen C.J., Samoylova O., Kreuzer K.A., Stilgenbauer S., Döhner H., Langerak A.W., Ritgen M., Kneba M., Asikanius E., Humphrey K., Wenger M., Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12): 1101–10. doi: 10.1056/NEJMoa1313984.Goede V., Fischer K., Busch R., Engelke A., Eichhorst B., Wendtner C.M., Chagorova T., de la Serna J., Dilhuydy M.S., Illmer T., Opat S., Owen C.J., Samoylova O., Kreuzer K.A., Stilgenbauer S., Döhner H., Langerak A.W., Ritgen M., Kneba M., Asikanius E., Humphrey K., Wenger M., Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014; 370(12): 1101–10. doi: 10.1056/NEJMoa1313984.Kovacs G., Robrecht S., Fink A.M., Bahlo J., Cramer P., von Tresckow J., Maurer C., Langerbeins P., Fingerle-Rowson G., Ritgen M., Kneba M., Döhner H., Stilgenbauer S., Klapper W., Wendtner C.M., Fischer K., Hallek M., Eichhorst B., Böttcher S. Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group. J Clin Oncol. 2016; 34(31): 3758–65. doi: 10.1200/JCO.2016.67.1305.Kovacs G., Robrecht S., Fink A.M., Bahlo J., Cramer P., von Tresckow J., Maurer C., Langerbeins P., Fingerle-Rowson G., Ritgen M., Kneba M., Döhner H., Stilgenbauer S., Klapper W., Wendtner C.M., Fischer K., Hallek M., Eichhorst B., Böttcher S. Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group. J Clin Oncol. 2016; 34(31): 3758–65. doi: 10.1200/JCO.2016.67.1305.Dimier N., Delmar P., Ward C., Morariu-Zamfr R., Fingerle-Rowson G., Bahlo J., Fischer K., Eichhorst B., Goede V., van Dongen J.J.M., Ritgen M., Böttcher S., Langerak A.W., Kneba M., Hallek M. A model for predicting efect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018; 131(9): 955–62. doi: 10.1182/blood-2017-06-792333.Dimier N., Delmar P., Ward C., Morariu-Zamfr R., Fingerle-Rowson G., Bahlo J., Fischer K., Eichhorst B., Goede V., van Dongen J.J.M., Ritgen M., Böttcher S., Langerak A.W., Kneba M., Hallek M. A model for predicting efect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018; 131(9): 955–62. doi: 10.1182/blood-2017-06-792333.Molica S., Giannarelli D., Montserrat E. Minimal Residual Disease and Survival Outcomes in Patients With Chronic Lymphocytic Leukemia: A Systematic Review and Meta-analysis. Clin Lymphoma Myeloma Leuk. 2019; 19(7): 423–30. doi: 10.1016/j.clml.2019.03.014.Molica S., Giannarelli D., Montserrat E. Minimal Residual Disease and Survival Outcomes in Patients With Chronic Lymphocytic Leukemia: A Systematic Review and Meta-analysis. Clin Lymphoma Myeloma Leuk. 2019; 19(7): 423–30. doi: 10.1016/j.clml.2019.03.014.Huard B., Tournier M., Hercend T., Triebel F., Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994; 24(12): 3216–21. doi: 10.1002/eji.1830241246.Huard B., Tournier M., Hercend T., Triebel F., Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994; 24(12): 3216–21. doi: 10.1002/eji.1830241246.Shapiro M., Herishanu Y., Katz B.Z., Dezorella N., Sun C., Kay S., Polliack A., Avivi I., Wiestner A., Perry C. Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia. Haematologica. 2017; 102(5): 874–82. doi: 10.3324/haematol.2016.148965.Shapiro M., Herishanu Y., Katz B.Z., Dezorella N., Sun C., Kay S., Polliack A., Avivi I., Wiestner A., Perry C. Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia. Haematologica. 2017; 102(5): 874–82. doi: 10.3324/haematol.2016.148965.Kotaskova J., Tichy B., Trbusek M., Francova H.S., Kabathova J., Malcikova J., Doubek M., Brychtova Y., Mayer J., Pospisilova S. High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival. J Mol Diagn. 2010; 12(3): 328–34. doi: 10.2353/jmoldx.2010.090100.Kotaskova J., Tichy B., Trbusek M., Francova H.S., Kabathova J., Malcikova J., Doubek M., Brychtova Y., Mayer J., Pospisilova S. High expression of lymphocyte-activation gene 3 (LAG3) in chronic lymphocytic leukemia cells is associated with unmutated immunoglobulin variable heavy chain region (IGHV) gene and reduced treatment-free survival. J Mol Diagn. 2010; 12(3): 328–34. doi: 10.2353/jmoldx.2010.090100.Никитин Е.А., Бялик Т.Е., Зарицкий А.Ю., Исебер Л., Капланов К.Д., Лопаткина Т.Н., Луговская С.А., Мухортова О.В., Османов Е.А., Поддубная И.В., Самойлова О.С., Стадник Е.А., Фалалеева Н.А., Байков В.В., Ковригина А.М., Невольских А.А., Иванов С.А., Хайлова Ж.В., Геворкян Т.Г. Хронический лимфоцитарный лейкоз/лимфома из малых лимфоцитов. Клинические рекомендации. Современная Онкология. 2020; 22(3): 24–44. doi: 10.26442/18151434.2020.3.200385.Nikitin E.A., Bialik T.E., Zaritskii A.I., Iseber L., Kaplanov K.D., Lopatkina T.N., Lugovskaia S.A., Mukhortova O.V., Osmanov E.A., Poddubnaya I.V., Samoilova O.S., Stadnik E.A., Falaleeva N.A., Baikov V.V., Kovrigina A.M., Nevol’skikh A.A., Ivanov S.A., Khailova Z.V., Gevorkian T.G. Chronic lymphocytic leukemia/small lymphocytic lymphoma. Journal of Modern Oncology. 2020; 22 (3): 24–44. (in Russian). doi: 10.26442/18151434.2020.3.200385.Rawstron A.C., Villamor N., Ritgen M., Böttcher S., Ghia P., Zehnder J.L., Lozanski G., Colomer D., Moreno C., Geuna M., Evans P.A., Natkunam Y., Coutre S.E., Avery E.D., Rassenti L.Z., Kipps T.J., CaligarisCappio F., Kneba M., Byrd J.C., Hallek M.J., Montserrat E., Hillmen P. International standardized approach for fow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007; 21(5): 956–64. doi: 10.1038/sj.leu.2404584.Rawstron A.C., Villamor N., Ritgen M., Böttcher S., Ghia P., Zehnder J.L., Lozanski G., Colomer D., Moreno C., Geuna M., Evans P.A., Natkunam Y., Coutre S.E., Avery E.D., Rassenti L.Z., Kipps T.J., CaligarisCappio F., Kneba M., Byrd J.C., Hallek M.J., Montserrat E., Hillmen P. International standardized approach for fow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007; 21(5): 956–64. doi: 10.1038/sj.leu.2404584.Кит О.И., Тимофеева С.В., Ситковская А.О., Новикова И.А., Колесников Е.Н. Биобанк ФГБУ «НМИЦ онкологии» Минздрава России как ресурс для проведения исследований в области персонифицированной медицины. Современная онкология. 2022; 24(1): 6–11. doi: 10.26442/18151434.2022.1.201384.Kit O.I., Timofeeva S.V., Sitkovskaya A.O., Novikova I.A., Kolesnikov E.N. The Biobank of the National Medical Research Centre for Oncology as a resource for research in the feld of personalized medicine: A review. Modern Oncology. 2022; 24(1): 6–11. (in Russian). doi: 10.26442/18151434.2022.1.201384.Wierz M., Pierson S., Guyonnet L., Viry E., Lequeux A., Oudin A., Niclou S.P., Ollert M., Berchem G., Janji B., Guérin C., Paggetti J., Moussay E. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018; 131(14): 1617–21. doi: 10.1182/blood-2017-06-792267.Wierz M., Pierson S., Guyonnet L., Viry E., Lequeux A., Oudin A., Niclou S.P., Ollert M., Berchem G., Janji B., Guérin C., Paggetti J., Moussay E. Dual PD1/LAG3 immune checkpoint blockade limits tumor development in a murine model of chronic lymphocytic leukemia. Blood. 2018; 131(14): 1617–21. doi: 10.1182/blood-2017-06-792267.Sordo-Bahamonde C., Lorenzo-Herrero S., González-Rodríguez A.P., Payer Á.R., González-García E., López-Soto A., Gonzalez S. LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia. Cancers (Basel). 2021; 13(9): 2112. doi: 10.3390/cancers13092112.Sordo-Bahamonde C., Lorenzo-Herrero S., González-Rodríguez A.P., Payer Á.R., González-García E., López-Soto A., Gonzalez S. LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia. Cancers (Basel). 2021; 13(9): 2112. doi: 10.3390/cancers13092112.Woo S.R., Turnis M.E., Goldberg M.V., Bankoti J., Selby M., Nirschl C.J., Bettini M.L., Gravano D.M., Vogel P., Liu C.L., Tangsombatvisit S., Grosso J.F., Netto G., Smeltzer M.P., Chaux A., Utz P.J., Workman C.J., Pardoll D.M., Korman A.J., Drake C.G., Vignali D.A. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012; 72(4): 917–27. doi: 10.1158/0008-5472.CAN-11-1620.Woo S.R., Turnis M.E., Goldberg M.V., Bankoti J., Selby M., Nirschl C.J., Bettini M.L., Gravano D.M., Vogel P., Liu C.L., Tangsombatvisit S., Grosso J.F., Netto G., Smeltzer M.P., Chaux A., Utz P.J., Workman C.J., Pardoll D.M., Korman A.J., Drake C.G., Vignali D.A. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012; 72(4): 917–27. doi: 10.1158/0008-5472.CAN-11-1620.Grosso J.F., Kelleher C.C., Harris T.J., Maris C.H., Hipkiss E.L., De Marzo A., Anders R., Netto G., Getnet D., Bruno T.C., Goldberg M.V., Pardoll D.M., Drake C.G. LAG-3 regulates CD8+ T cell accumulation and efector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007; 117(11): 3383–92. doi: 10.1172/JCI31184.Grosso J.F., Kelleher C.C., Harris T.J., Maris C.H., Hipkiss E.L., De Marzo A., Anders R., Netto G., Getnet D., Bruno T.C., Goldberg M.V., Pardoll D.M., Drake C.G. LAG-3 regulates CD8+ T cell accumulation and efector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007; 117(11): 3383–92. doi: 10.1172/JCI31184.Qi Y., Chen L., Liu Q., Kong X., Fang Y., Wang J. Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Efective Immunotherapy Strategy. Front Immunol. 2021; 11. doi: 10.3389/fmmu.2020.563258.Qi Y., Chen L., Liu Q., Kong X., Fang Y., Wang J. Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Efective Immunotherapy Strategy. Front Immunol. 2021; 11. doi: 10.3389/fmmu.2020.563258.Liu D. Cancer biomarkers for targeted therapy. Biomark Res. 2019; 7: 25. doi: 10.1186/s40364-019-0178-7.Liu D. Cancer biomarkers for targeted therapy. Biomark Res. 2019; 7: 25. doi: 10.1186/s40364-019-0178-7.Grzywnowicz M., Karabon L., Karczmarczyk A., Zajac M., Skorka K., Zaleska J., Wlasiuk P., Chocholska S., Tomczak W., BojarskaJunak A., Dmoszynska A., Frydecka I., Giannopoulos K. The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia. Leuk Lymphoma. 2015; 56(10): 2908–13. doi: 10.3109/10428194.2015.1017820.Grzywnowicz M., Karabon L., Karczmarczyk A., Zajac M., Skorka K., Zaleska J., Wlasiuk P., Chocholska S., Tomczak W., BojarskaJunak A., Dmoszynska A., Frydecka I., Giannopoulos K. The function of a novel immunophenotype candidate molecule PD-1 in chronic lymphocytic leukemia. Leuk Lymphoma. 2015; 56(10): 2908–13. doi: 10.3109/10428194.2015.1017820.Li M., Sun X.H., Zhu X.J., Jin S.G., Zeng Z.J., Zhou Z.H., Yu Z., Gao Y.Q. HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitisB-infected patients. Lab Invest. 2012; 92(2): 295–304. doi: 10.1038/labinvest.2011.157.Li M., Sun X.H., Zhu X.J., Jin S.G., Zeng Z.J., Zhou Z.H., Yu Z., Gao Y.Q. HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitisB-infected patients. Lab Invest. 2012; 92(2): 295–304. doi: 10.1038/labinvest.2011.157.McClanahan F., Riches J.C., Miller S., Day W.P., Kotsiou E., Neuberg D., Croce C.M., Capasso M., Gribben J.G. Mechanisms of PDL1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model. Blood. 2015; 126(2): 212–21. doi: 10.1182/blood-2015-02-626754.McClanahan F., Riches J.C., Miller S., Day W.P., Kotsiou E., Neuberg D., Croce C.M., Capasso M., Gribben J.G. Mechanisms of PDL1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model. Blood. 2015; 126(2): 212–21. doi: 10.1182/blood-2015-02-626754.Ramsay A.G., Clear A.J., Fatah R., Gribben J.G. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012; 120(7): 1412–21. doi: 10.1182/blood-2012-02-411678.Ramsay A.G., Clear A.J., Fatah R., Gribben J.G. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012; 120(7): 1412–21. doi: 10.1182/blood-2012-02-411678.Табаков Д.В., Заботина Т.Н., Чантурия Н.В., Захарова Е.Н., Воротников И.К., Сельчук В.Ю., Соколовский В.В., Петровский А.В. Взаимосвязь экспрессии GITR, Lag-3 и PD-1 с основными показателями системного и локального иммунитета у больных раком молочной железы. Современная онкология. 2021; 23(3): 457–65. doi: 10.26442/18151434.2021.3.200809.Tabakov D.V., Zabotina T.N., Chanturia N.V., Zakharova E.N., Vorotnikov I.K., Selchuk V.Yu., Sokolovskiy V.V., Petrovsky A.V. The relationship of GITR, Lag-3 and PD-1 expression with the main indicators of systemic and local immunity in patients with breast cancer. Modern Oncology. 2021; 23(3): 457–65. (in Russian). doi: 10.26442/18151434.2021.3.200809.Wang Q., Zhang J., Tu H., Liang D., Chang D.W., Ye Y., Wu X. Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients. J Immunother Cancer. 2019; 7(1): 334. doi: 10.1186/s40425-019-0810-y.Wang Q., Zhang J., Tu H., Liang D., Chang D.W., Ye Y., Wu X. Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients. J Immunother Cancer. 2019; 7(1): 334. doi: 10.1186/s40425-019-0810-y.He Y., Wang Y., Zhao S., Zhao C., Zhou C., Hirsch F.R. sLAG-3 in non-small-cell lung cancer patients’ serum. Onco Targets Ther. 2018; 11: 4781–4. doi: 10.2147/OTT.S164178.He Y., Wang Y., Zhao S., Zhao C., Zhou C., Hirsch F.R. sLAG-3 in non-small-cell lung cancer patients’ serum. Onco Targets Ther. 2018; 11: 4781–4. doi: 10.2147/OTT.S164178.Eichhorst B., Fink A.M., Busch R., Kovacs G., Maurer C., Lange E., Köppler H., Kiehl M.G., Soekler M., Schlag R., Vehling-Kaiser U., Köchling G.R.A., Plöger C., Gregor M., Plesner T., Trneny M., Fischer K., Döhner H., Kneba M., Wendtner C.M., Klapper W., Kreuzer K.A., Stilgenbauer S., Böttcher S., Hallek M. Frontline chemoimmunotherapy with fudarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efcacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically ft patients (pts) with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 study). Blood. 2014; 124 (21): 19. doi: 10.1182/blood.V124.21.19.19.Eichhorst B., Fink A.M., Busch R., Kovacs G., Maurer C., Lange E., Köppler H., Kiehl M.G., Soekler M., Schlag R., Vehling-Kaiser U., Köchling G.R.A., Plöger C., Gregor M., Plesner T., Trneny M., Fischer K., Döhner H., Kneba M., Wendtner C.M., Klapper W., Kreuzer K.A., Stilgenbauer S., Böttcher S., Hallek M. Frontline chemoimmunotherapy with fudarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efcacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically ft patients (pts) with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 study). Blood. 2014; 124 (21): 19. doi: 10.1182/blood.V124.21.19.19.

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