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New Agents and Regimens for Diffuse Large B Cell Lymphoma

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New Agents and Regimens for Diffuse Large B Cell Lymphoma Wang et al. J Hematol Oncol (2020) 13:175 https://doi.org/10.1186/s13045-020-01011-z REVIEW Open Access New agents and regimens for difuse large B cell lymphoma Liang Wang1,2*, Lin‑rong Li3 and Ken H. Young4* Abstract As a widely recognized standard regimen, R‑CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is able to cure two‑thirds patients with difuse large B cell lymphoma (DLBCL), and the remaining patients sufer from refractory or relapsed disease due to resistance to R‑CHOP and fare poorly. Unsatisfed outcomes for those relapsed/refractory patients prompted eforts to discover new treatment approaches for DLBCL, including chimeric antigen receptor T cells, bispecifc T cell engagers, immunomodulatory drugs, immune checkpoint inhibitors, mono‑ clonal antibodies, antibody–drug conjugates, molecular pathway inhibitors, and epigenetic‑modifying drugs. Herein, up‑to‑date data about the most promising treatment approaches for DLBCL are recapitulated, and novel genetic clas‑ sifcation systems are introduced to guide individualized treatment for DLBCL. Keywords: Difuse large B cell lymphoma, Chimeric antigen receptor T cells, Immunotherapy, Chemoresistance, Novel agents, Genetic classifcation Introduction treated with R-CHOP [3]. In recent years, several ran- Difuse large B cell lymphoma (DLBCL) is the most com- domized clinical trials have been conducted by add- mon subtype of lymphoma in adults worldwide, compos- ing novel targeted agents to R-CHOP (the so-called ing about one-third of non-Hodgkin lymphomas (NHLs) R-CHOP + X mode) in order to improve outcomes for diagnosed each year [1], and it represents a consider- patients with non-GCB or activated B-cell-like (ABC) able socioeconomic burden afecting millions of people subtype of DLBCL, such as bortezomib [4], lenalidomide [2]. CHOP (cyclophosphamide, doxorubicin, vincristine, [5], or ibrutinib [6]. However, none of these targeted and prednisone) regimen has been used for more than agents have been found to confer benefts in these trials. 40 years, and rituximab was approved by the US Food Moreover, dose-adjusted EPOCH (etoposide, prednisone, and Drug Administration (FDA) in 2006 for use as frst- vincristine, cyclophosphamide, and doxorubicin) plus line treatment of patients with DLBCL in combination rituximab (DA-EPOCH-R) also failed to show improve- with CHOP. Tereafter, R-CHOP regimen has become ment in survival outcomes for patients with DLBCL in a the standard of care for patients with newly diagnosed phase III randomized study (CALGB 50303) [7]. Stand- DLBCL, even though patients with non-germinal center ard R-CHOP regimen is able to cure two-thirds patients B cell (non-GCB) subtype of DLBCL have signifcantly of DLBCL, and the remaining patients sufer from refrac- inferior outcomes than their GCB subtype counterparts tory or relapsed disease due to resistance to R-CHOP and fare poorly [8]. Te international SCHOLAR-1 study reported the median overall survival (OS) to be only *Correspondence: [email protected]; [email protected] 6.3 months for patients who were refractory to frst-line 1 Department of Hematology, Beijing TongRen Hospital, Capital Medical University, Beijing 100730, China treatment [9]. 4 Division of Hematopathology, Department of Pathology, Duke Poor outcomes for patients who failed R-CHOP University Medical Center and Cancer Institute, Durham, NC 27710, USA regimen prompted eforts to discover new treatment Full list of author information is available at the end of the article approaches for DLBCL, both up-front and at the time © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. J Hematol Oncol (2020) 13:175 Page 2 of 23 of relapse. With hundreds of clinical trials under- marketed as Yescarta) [10], lisocabtagene maraleucel way, the landscape for DLBCL treatments has become (liso-cel) [11], and tisagenlecleucel (marketed as Kym- increasingly crowded. In recent years, several agents or riah) [12] has been demonstrated in the context of approaches have received the FDA approval for DLBCL, CD19-directed CAR T cell therapy. In ZUMA-1 study, including polatuzumab vedotin, selinexor, tafasitamab, 101 patients of refractory aggressive B cell NHL with tisagenlecleucel, and axicabtagene ciloleucel (Table 1). a median of three prior lines of treatment received at 6 Together, the therapeutics targeting immune check- least 1.0 × 10 CAR-positive T cells/kg, and the investi- points, tumor microenvironment, molecular signaling gator-assessed ORR was 83%, and CR rate was 54% [10]. pathways, and epigenetic aberrations, as well as cellular Te 2-year follow-up data from ZUMA-1 indicated that immunotherapy, constitute the new landscape of treat- axi-cel could obtain durable responses and signifcantly ments for DLBCL. Tis review focuses on available data improve the OS with a manageable long-term safety about the most promising and potent agents now in profle in patients with r/r DLBCL [13]. Another 93 clinical testing and provides expertise on individualized patients who were ineligible or had disease progression treatment for DLBCL according to novel genetic and after ASCT received tisagenlecleucel, and the best ORR molecular classifcations. was 52%, with a CR rate of 40%. At 1 year after initial response, the estimated relapse-free survival rate was Immunotherapy 65%, indicating a durable response with tisagenlecleu- Chimeric antigen receptor T cells and natural killer (NK) cel [12]. Compared with historic data, these CAR T cell cells products have ofered unexpected durable responses Anti‑CD19 CAR T cells in patients with heavily pretreated DLBCL [14], which Chimeric antigen receptor (CAR) T cells are rapidly promoted the approval of Yescarta and Kymriah by emerging as a promising cellular immunotherapy in FDA. With improved access to these CAR T cell prod- relapsed/refractory (r/r) DLBCL (Figs. 1, 2). Te potent ucts, patients of r/r DLBCL may be treated with CAR T therapeutic efcacy of axicabtagene ciloleucel (axi-cel, Table 1 FDA-approved agents for the treatment of difuse large B cell lymphoma Agent Approved date Study Dose schedulea Number Efcacya of patientsa Tafasitamab‑cxix (Monjuvi) July 31, 2020 NCT02399085 12 mg/kg as an intravenous infu‑ 80 ORR: 55%; CR: 37% sion according to the following dosing schedule Cycle 1: Days 1, 4, 8, 15, and 22 of the 28‑day cycle Cycles 2 and 3: Days 1, 8, 15, and 22 of each 28‑day cycle Cycle 4 and beyond: Days 1 and 15 of each 28‑day cycle Selinexor (XPOVIO) June 22, 2020 NCT02227251 60 mg orally on days 1 and 3 of 134 CR: 13%; ORR: 29% each week Polatuzumab vedotin‑piiq (Polivy) June 10, 2019 NCT02257567 1.8 mg/kg for six 21‑day cycle with 80 CR: 40%; ORR: 63% bendamustine and a rituximab product Tisagenlecleucel (Kymriah) May 1, 2018 NCT02445248 0.6–6.0 108 CAR‑positive viable 68 CR: 32%; ORR: 50% T cells× Axicabtagene ciloleucel (Yescarta) October 18, 2017 NCT02348216 2.0 106 /kg CAR‑positive viable T 108 CR: 51%; ORR: 72% cells× (maximum 2 108) × Hyaluronidase human and rituxi‑ June 22, 2017 NCT01649856 1400 mg subcutaneous rituximab 381 CR: 51%; ORR: 83% mab (RITUXAN HYCELA) and 23,400 units hyaluronidase human, with CHOP Rituximab (Rituxan) February 10, 2006 LNH 98–5/GELA rituximab 375 mg/m2 with CHOP 399 CR:75%; 2‑y OS: 69% E4494 rituximab 375 mg/m2 with CHOP 632 2‑y OS: 74%; PFS: 3.1 years MInT rituximab 375 mg/mm2 with 823 2‑y OS: 95% CHOP/CHOP‑like regimens CR complete response, ORR objective response rate, EFS event-free survival, 2-y OS overall survival at 2 years, PFS progression-free survival, CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone, CAR chimeric antigen receptor a Refers to the FDA approval data posted on http://www.fda.gov/drugs Wang et al. J Hematol Oncol (2020) 13:175 Page 3 of 23 T cell Radiolabeled ADC mAb ADC mAb ADC T cell CD3 mAb BiTE CD79b CD20 CD19 BiTE CD3 CD20 CD19 mAb CD20 T cell CD20 CD19 PD-L1 PD-1 Tumor cell CD22 CAR T mAb CD19 CD47 CD22 CD20 CD22 CD74 mAb CD30 CAR T cell ADC CAR NK cell mAb Macrophage ADC ADC CAR T cell Fig. 1 Novel agents and strategies targeting DLBCL cell surface antigens. mAb monoclonal antibody, ADC antibody–drug conjugate, BiTE bispecifc T cell engager, CAR chimeric antigen receptor, NK natural killer, PD-1 programmed cell death protein 1 Antitumor activities Immunotherapy resistance Bispecific T cell engager CAR Monoclonal antibody Immune checkpoint inhibitor Radioimmunotherapy Antibody-drug conjugates Immune cell DLBCL cell Immune checkpoint DLBCL cell Surface antigens Cytotoxicity/tumor killing Fig. 2 Illustration of antitumor activities of various immunotherapies and potential resistance in DLBCL Wang et al. J Hematol Oncol (2020) 13:175 Page 4 of 23 cell therapy at second-line scenario, or even as frst-line CAR T cell therapy [20].
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