Вызовы и перспективы 1-й линии терапии пациентов с диффузной В-клеточной крупноклеточной лимфомой

Бабичева Л.Г., Поддубная И.В. Вызовы и перспективы 1-й линии терапии пациентов с диффузной
В-клеточной крупноклеточной лимфомой. Современная Онкология. 2023;25(2):178–184.
DOI: 10.26442/18151434.2023.2.202238

© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.

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Babicheva LG, Poddubnaya IV. Challenges and perspectives of first-line therapy in patients with diffuse B-cell lymphoma: A review. Journal of Modern Oncology. 2023;25(2):178–184.
DOI: 10.26442/18151434.2023.2.202238

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Аннотация

Новообразование, которое мы называем диффузной В-клеточной крупноклеточной лимфомой (ДВККЛ), состоит из множества различных по течению подтипов, которые не должны подвергаться единому стандартизованному лечению. Критически важным на этапе диагностики является выделение редких (5–10%), но крайне агрессивных вариантов – В-клеточных крупноклеточных лимфом высокой степени злокачественности с двойной (DH) или тройной (TH) перестройкой генов MYC и BCL2 и/или BCL6, при которых должны применяться интенсивные программы химиоиммунотерапии. Основным и наиболее частым вариантом гетерогенной группы В-клеточных крупноклеточных лимфом, о котором пойдет речь в публикации, является ДВККЛ неспецифицированная (NOS). Согласно клеточному происхождению ДВККЛ NOS делится на подтип из В-клеток герминального/зародышевого центра (GCB) и активированных В-лимфоцитов (ABC), а также неклассифицированный (U) подтип. Иммуногистохимические алгоритмы позволяют разделить ДВККЛ NOS на подтипы GCB и non-GCB. Кроме того, в эту категорию входит лимфома с коэкспрессией MYC/BCL2 (double-expressor лимфома – DEL), которая не является уникальной биологической единицей и встречается как при подтипе GCB, так и non-GCB и ассоциируется с худшим прогнозом. За последние два десятилетия ДВККЛ NOS, на долю которой приходится более 80% всех случаев, стала объектом растущего числа молекулярных исследований, которые позволили идентифицировать прогностические факторы, активно внедряемые в реальную клиническую практику. С начала столетия наиболее частым подходом 1-й линии терапии ДВККЛ NOS считается режим R-CHOP, который позволяет достичь длительных ремиссий у 60–70% пациентов. Неудовлетворительная эффективность при использовании R-CHOP фиксируется в группах высокого риска раннего прогрессирования согласно Международному прогностическому индексу (IPI – 3–5), а также при неблагоприятных молекулярно-генетических характеристиках опухоли, например DEL или подтипе ABC ДВККЛ NOS. Именно эти популяции пациентов получили наибольшую выгоду от включения полатузумаба ведотина в режим инициальной терапии (схема Pola-R-CHP). Такой подход позволил снизить риск прогрессирования и смерти у пациентов с ДВККЛ высокого риска (IPI 3-5) на 30%, сократив на 34% потребность в назначении 2-й линии терапии, что можно считать прорывом последних 20 лет в поиске повышения эффективности «золотого стандарта» 1-й линии терапии и потенциального определения нового стандарта терапии первичных пациентов с ДВККЛ высокого риска раннего прогрессирования.

Ключевые слова: ДВККЛ, диффузная В-клеточная крупноклеточная лимфома, неходжкинская лимфома, R-CHOP, Pola-R-CHP, неспецифицированная лимфома, ДВККЛ NOS, коэкспрессия, DEL

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The neoplasm we refer to as diffuse large B-cell lymphoma (DLBCL) consists of many different subtypes that should not be subject to a single standardized treatment. Critical at the diagnostic stage is the identification of rare (5–10%) but extremely aggressive variants – high grade B-cell lymphomas with MYC and BCL2 and/or BCL6 double-hit (DH) or triple-hit (TH) rearrangement, in which intensive chemoimmunotherapy programs should be applied. The main and most frequent variant of the heterogeneous group of B-cell lymphomas discussed in this publication is diffuse large B-cell lymphoma, not otherwise specified (NOS). Two immunohistochemical subtypes of DLBCL NOS are distinguished, GCB and non-GCB. According to cell of origin, the DLBCL NOS is divided into GCB, ABC, and an unclassified (U) subtypes. In addition, DLBCL NOS includes MYC and BCL2 double-expressor lymphoma (DEL), which is not a unique biological entity, occurs in both GCB and non-GCB subtypes of DLBCL, and is associated with a worse prognosis. Over the past two decades, DLBCL NOS, which accounts for more than 80% of all cases, has been the subject of a growing number of molecular studies that have identified prognostic factors that are being actively introduced into real-world clinical practice. Since the turn of the century, the R-CHOP regimen has been considered the most frequent first line therapy approach for DLBCL NOS, achieving long-term remissions in 60–70% of patients. The worst outcomes when using R-CHOP are recorded in groups at high risk of progression according to the International Prognostic Index (IPI – 3–5), as well as in the presence of unfavorable molecular genetic characteristics of the tumor, such as DEL or ABC subtype of DLBCL NOS. These patient populations benefited the most from the inclusion of polatuzumab vedotin in the initial therapy regimen (Pola-R-CHP). This approach reduced the risk of progression and death in patients with high-risk DLBCL by 30%, reducing the need for second-line therapy by 34%, which can
be considered a breakthrough in the last 20 years of searching for improving the "gold standard" of first-line therapy and potentially defining a new standard of therapy for primary patients with high-risk DLBCL.

Keywords: DLBCL, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, R-CHOP, Pola-R-CHP, not otherwise specified lymphoma, DLBCL NOS, double-expressor lymphoma, DEL

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1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.
DOI:10.1182/blood-2016-01-643569
2. Wan M, Hong H, Li X, et al. Prognosis Evaluation of the Progression of Diffuse Large B-Cell Lymphoma within 24 Months. Ann Hematol Oncol. 2022;9(3):1398.
3. Maurer MJ, Habermann TM, Shi Q, et al. Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials. Ann Oncol. 2018;29(8):1822-7. DOI:10.1093/annonc/mdy203
4. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-68. DOI:10.1200/JCO.2013.54.8800
5. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Guidelines insights: B-cell lymphomas, Version 3.2019. J Natl Compr Canc Netw. 2019;17(6):650-61. DOI:10.6004/jnccn.2019.0029
6. Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452-9. DOI:10.1200/JCO.2011.41.0985
7. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503‑11. DOI:10.1038/35000501
8. Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-82. DOI:10.1182/blood-2003-05-1545
9. Khan AB, Barrington SF, Mikhaeel NG, et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013;122(1):61-7. DOI:10.1182/blood-2012-12-473389
10. Alzahrani M, El-Galaly TC, Hutchings M, et al. The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT: a Danish-Canadian study. Ann Oncol. 2016;27(6):1095-9. DOI:10.1093/annonc/mdw137
11. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1993;329(14):987-94. DOI:10.1056/NEJM199309303291402
12. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857-61. DOI:10.1182/blood-2006-08-038257
13. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837-42. DOI:10.1182/blood-2013-09-524108
14. Shi X, Liu X, Li X, et al. Risk Stratification for Diffuse Large B-Cell Lymphoma by Integrating Interim Evaluation and International Prognostic Index: A Multicenter Retrospective Study. Front Oncol. 2021;11:754964. DOI:10.3389/fonc.2021.754964
15. Tilly H, Gomes da Silva M, Vitolo U, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl. 5):v116-25. DOI:10.1093/annonc/mdv304
16. Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34(26):3150-6. DOI:10.1200/JCO.2015.65.6520
17. Lin Z, Chen X, Liu L, et al. The role of central nervous system (CNS) prophylaxis in preventing DLBCL patients from CNS relapse: A network meta-analysis. Crit Rev Oncol Hematol. 2022;176:103756. DOI:10.1016/j.critrevonc.2022.103756
18. Hutchings M, Ladetto M, Buske C, et al. ESMO Consensus Conference on malignant lymphoma: management of ‘ultra-high-risk’ patients. Ann Oncol. 2018;29(8):1687-700. DOI:10.1093/annonc/mdy167
19. Poddubnaya IV, Parovichnikova EN, Kaprin AD, Varfolomeeva SR. Klinicheskie rekomendatsii Agressivnye nefollikuliarnye limfomy – diffuznaia krupnokletochnaia V-kletochnaia limfoma, pervichnaia mediastinal'naia V-kletochnaia limfoma, limfoma Berkitta 2022 g. (in Russian).
20. Park S, Hong J, Hwang I, et al. Comprehensive geriatric assessment in elderly patients with newly diagnosed aggressive non-Hodgkin lymphoma treated with multi-agent chemotherapy. J Geriatr Oncol. 2015;6(6):470-8. DOI:10.1016/j.jgo.2015.10.183
21. Merli F, Luminari S, Tucci A, et al. Simplified geriatric assessment in older patients with diffuse large B-cell lymphoma: the prospective Elderly Project of the Fondazione Italiana Linfomi. J Clin Oncol. 2021;39(11):1214-22. DOI:10.1200/JCO.20.02465
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Авторы

Л.Г. Бабичева*, И.В. Поддубная

ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*lalibabicheva@mail.ru

________________________________________________

Lali G. Babicheva*, Irina V. Poddubnaya

Russian Medical Academy of Continuous Professional Education, Moscow, Russia
*lalibabicheva@mail.ru

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