Immunotherapy of diffuse large B-cell lymphoma
- Authors: Filatova L.V1,2
-
Affiliations:
- N.N. Petrov National Medical Research Center of Oncology
- North-Western State Medical University n.a. I.I. Mechnikov
- Issue: Vol 27, No 7 (2020)
- Pages: 85-95
- Section: Articles
- URL: https://journals.eco-vector.com/2073-4034/article/view/312733
- DOI: https://doi.org/10.18565/pharmateca.2020.7.85-95
- ID: 312733
Cite item
Abstract
First-line CHOP-R immunochemotherapy provides long-term progression-free survival (PFS) in 33-96% of patients with diffuse large B-cell lymphoma (DLBCL) depending on the prognosis, but progression or relapse occurs in 30-40% of patients. When carrying out high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT with auto-HSCT) for patients with chemo-sen-sitive recurrence of DLBCL, 5-year event-free survival (EFS) reaches 46%, overall survival (OS) - 53%. To improve the results of HDCT with auto-HSCT, new “rescue" therapy regimens are being studied, as well as modes of supporting remission after HDCT with auto-HSCT. The effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with recurrence of DLBCL after HDCT with auto-HSCT was confirmed by high rates of 3-year PFS and OS - 41 and 53%. Modern ideas about the molecular biological characteristics of DLBCL justify the use of immunotherapy in the treatment of relapses and refractory forms. Modern “rescue" therapies for the DLBCL with high efficacy and low toxicity are especially relevant for patients who are not candidates for HDCT with auto-HSCT, as well as for relapses after HDCT with auto-HSCT. In June 2019, the FDA granted accelerated approval for the use of polatuzumab vedotin in combination with bendamustine and rituximab for the treatment of relapses and refractory forms of DLBCL after two or more lines of previous therapy. In June 2018, the FDA granted granted for pembrolizumab in the treatment of adults and children with relapses and refractory forms of primary mediastinal (thymic) B-cell lymphoma (PMBCL) after two or more lines of previous systemic therapy. The antitumor efficacy of the combination of nivolumab with brentuximab vedotin is significantly higher compared to that of monotherapy with nivolumab/pembrolizumab, brentuximab vedotin: the overall response (OR) rates are 73.0%, 48.0 and 13.3%, complete remissions (CR) - 37% , 13, 0% in PMVCL patients with relapses and refractory forms. In the Phase IIL-MIND study [NCT0239085], the efficacy of tafasitamab (OR - 60%, CR - 43%) is comparable to that of CAR-Tcell therapy in patients with relapses and refractory forms of DLBCL, while tafasitamab has significantly lower toxicity. In order to increase the antitumor effect of immunotherapy, combined modes are being studied, primarily with various mechanisms of action and possible synergistic antitumor activity. The identification of predictive biomarkers will allow to develop an optimal algorithm for the appointment of immunotherapy, which helps to determine the dose, regimen, effectiveness and duration of therapy. Promising areas of DLBCL therapy are associated with the further study of new targets for tumor cells and their signaling pathways.
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About the authors
L. V Filatova
N.N. Petrov National Medical Research Center of Oncology;North-Western State Medical University n.a. I.I. Mechnikov
Email: Larisa_Filatova@list.ru
Dr. Sci. (Med.), Leading Researcher at the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology; Professor at the Department of Oncology, North-Western Medical University n.a. I.I. Mechnikov 68, Leningradskaya str., Pesochny settlement, St. Petersburg 197758, Russian Federation
References
- Morton L.M., Wang S.S., Devesa S.S., et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107(1):265-76. doi: 10.1182/blood-2005-06-2508.
- Shipp M.A., Harrington D.P, Anderson J.R., et al. A predictive model for aggressive non-Hodgkin's lymphomaThe International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329(14):987-94. Doi: 10.1056/ NEJM199309303291402.
- Barrans S, Crouch S., Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360-65. Doi: 10.1200/ JCO.2009.26.3947.
- Savage K.J, Johnson N.A., Ben-Neriah S., et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;1 14( 1 7):3533-37. Doi. org/10.1182/blood-2009-05-220095.
- Johnson N.A, Savage K.J, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009;114(11):2273-79. doi: 10.1182/blood-2009-03-212191.
- Moskowitz C.H., Schoder H., Teruya-Feldstein J, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in Advanced-stage diffuse large B-Cell lymphoma. J Clin Oncol. 2010;28(11):1896-903. doi: 10.1200/JCO.2009.26.5942.
- Horning S.J., Juweid M.E., Schoder H., et al. Interim positron emission tomography scans in diffuse large B-cell lymphoma: an independent expert nuclear medicine evaluation of the Eastern Cooperative Oncology Group E3404 study. Blood. 2010;115(4):775-77. doi: 10.1182/blood-2009-08-234351.
- Chen Y.B., Hochberg E.P, Feng Y., et al. Characteristics and outcomes after autologous stem cell transplant for patients with relapsed or refractory diffuse large B-cell lymphoma who failed initial rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone therapy compared to patients who failed cyclophosphamide, adriamycin, vincristine, and prednisone. Leuk Lymphoma. 2010;51(5):789-96. doi: 10.3109/10428191003699852.
- Fenske T.S., Hari P.N., Carreras J., et al. Impact of pre-transplant rituximab on survival after autologous hematopoietic stem cell transplantation for diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2009;15(11):1455-64. doi: 10.1016/j.bbmt.2009.07.017.
- Philip T., Guglielmi C., Hagenbeek A., et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995;333(23):1540-45. doi: 10.1056/NEJM199512073332305.
- Johnston P.B., Wiseman G.A., Micallef I.N. Positron emission tomography using F-18 fluorodeoxyglucose pre-and post-autologous stem cell transplant in non-Hodgkin's lymphoma. Bone Marrow Transplant. 2008;41(11):919-25. doi: 10.1038/bmt.2008.82.
- Vose J.M., Bierman P.J., Anderson J.R., et al. Progressive disease after high-dose therapy and autologous transplantation for lymphoid malignancy: clinical course and patient follow-up. Blood. 1992;80(8):2142-48.
- van Kampen R.J., Canals C., Schouten H.C., et al. Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non - Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol. 2011;29(10):1342-8. Doi: 10.1200/ JCO.2010.30.2596.
- Wiernik P.H., Lossos I.S., Tuscano J.M., et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2008;26(30):4952-57. doi: 10.1200/JCO.2007.15.3429.
- Steidl C., Gascoyne R.D. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood. 2011;118(10):2659-69. doi: 10.1182/blood-2011-05-326538.
- Jacobsen E.D., Sharman J.P, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(9):1394-402. doi: 10.1182/blood- 2014-09-598763.
- Yasenchak C.A., Farber C.M., Budde L.E., et al. Brentuximab vedotin in combination with RCHOP as front-line therapy in patients with DLBCL: interim results from a phase 2 study. Blood. 2014;124(21):1745. doi: 10.1182/blood. V124.21.1745.1745.
- Budde L.E., Halwani A., Yasenchak C.A., et al. Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL). Blood. 2016;128(22):104. doi: 10.1182/blood. V128.22.104.104.
- Zinzani P.L, Pellegrini C., Chiappella A., et al. Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma: results from a phase 2 clinical trial. Blood. 2017;129(16):2328-30. doi: 10.1182/blood-2017-01-764258.
- Dornan D, Bennett F., Chen Y, et al. Therapeutic potential of an anti-CD79b antibody-drug conjugate, anti-CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma. Blood. 2009;114(13):2721-29. doi: 10.1182/blood-2009-02-205500.
- Sehn L.H., Herrera A.F., Matasar M.J., et al. Polatuzumab Vedotin (Pola) Plus Bendamustine (B) with Rituximab (R) or Obinutuzumab (G) in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Updated Results of a Phase lb/ll Study. Blood. 2018;132(1):1683. doi: 10.1182/blood-2018-99-118551.
- Sehn L.H., Matasar M.J., Flowers C.R., et al. Polatuzumab Vedotin Plus Bendamustine with Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Updated Results of a Phase lb/ ll Randomized Study. Blood. 2019;134(1):4081. doi: 10.1182/blood-2019-123449.
- Morschhauser F., Flinn l.W., Advani R., et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol. 2019;6(5):e254-65. Doi: 10.1016/ S2352-3026(19)30026-2.
- Tilly H, Sharman J., Bartlett N., et al. POLA-R-CHP: polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin,prednisone for patients with previouslyuntreated diffuse largeB-cell lymphoma. Hematol. Oncol. 2017;35(52):90-1. doi: 10.1002/hon.2437_79.
- Tilly H., Flowers C., Friedberg J.W., et al. POLARlX: A phase 3 study of polatuzumab vedotin (pola) plus R-CHP versus R-CHOP in patients (pts) with untreated DLBCL. Hematol. Oncol. 2019;35(52):68-70. Doi: 10.1002/ hon.36_2629.
- Ansell S.M., Hurvitz S.A., Koenig P.A., et al. Phase l study of ipilimumab, an anti-CTLA-4 monoclonal antibody,.in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin. Cancer Res. 2009;15(20):6446-53. doi: 10.1158/1078-0432.CCR-09-1339.
- Chu F, Neelapu S.S. Anti-PD-1 antibodies for the treatment of B-cell lymphoma: lmportance of PD-1+T-cell subsets. Oncoimmunol. 2014;3(1):е28101.
- Mahoney K.M., Freeman G.J., McDermott D.F. The next immune-checkpoint inhibitors: PD-1/ PD-L1 blockade in melanoma. Clin Ther. 2015; 37:764-82.
- Twa D.D.W., Chan F.C., Ben-Neriah S., et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014;123(13):2063-65. doi: 10.1182/blood-2013-10-535443.
- Georgiou K., Chen L., Berglund M., et al. Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. Blood. 2016;127(24):3026-34. doi: 10.1182/blood-2015-12-686550.
- Twa D.D., Chan F.C., Ben-Neriah S., et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014;123(13):2062-65. doi: 10.1182/blood-2013-10-535443.
- Chapuy B., Roemer M.G., Stewart C., et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869-81. Doi: 10.1182/ blood-2015-10-673236.
- Smith S.D., Till B.G., Lynch R.C., et al. Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy. Br J Haematol. 2020 Feb 6. Doi: 10.1111/ bjh.16494.
- Rieger M., Osterborg A., Pettengell R., et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: Results of the Mabthera lnternational Trial Group study. Ann Oncol. 2011;22(3):664-70. doi: 10.1093/annonc/mdq418.
- Giulino-Roth L., O'Donohue T., Chen Z., et al. Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Br J Haematol. 2017;179(5):739-47. doi: 10.1111/bjh.14951.
- Kuruvilla J., Pintilie M., Tsang R., et al. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma. Leuk. Lymphoma. 2008;49(7):1329-36. doi: 10.1080/10428190802108870.
- Zinzani P.L., Ribrag V, Moskowitz C.H., et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130(3):267-70. doi: 10.1182/blood-2016-12-758383.
- Armand P., Rodig S., Melnichenko V., et al. Pembrolizumab in patients with relapsed or refractory primary mediastinal large B-Cell lymphoma (PMBCL): Data from the Keynote-013 and Keynote-170 studies. Blood. 2018;132(1):228. doi: 10.1182/blood-2018-99-110220.
- Ansell S.M., Minnema M.C., Johnson P, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: A single-arm, phase ll study. J Clin Oncol. 2019;37(6):481-89. doi: 10.1200/JCO.18.00766.
- Zinzani P.L., Santoro A., Gritti G., et al. Nivolumab combined with brentuximab vedotin for relapsed/ refractory primary mediastinal B-cell lymphoma: efficacy and safety from the phase ll CheckMate 436 study. J Clin Oncol. 2019;37(33):3081-89. doi: 10.1200/JCO.19.01492.
- Quintanilla-Martinez L., de Jong D., de Mascarel A., et al. Gray zones around diffuse large B cell lymphoma. Conclusions based on the workshop of the XlV meeting of the European Association for Hematopathology and the Society of Hematopathology in Bordeaux, France. J. Hematopathol. 2009;2:211-36. Doi. org/10.1007/s12308-009-0053-9.
- Evens A.M., Kanakry J.A., Sehn L.H., et al. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. Am J Hematol. 2015;90(9):778-83. doi: 10.1002/ajh.24082.
- Wilson W.H., Pittaluga S., Nicolae A., et al. A prospective study of mediastinal gray-zone lymphoma. Blood. 2014;124(10):1563-69. doi: 10.1182/blood-2014-03-564906.
- Dunleavy K., Pittaluga S., Maeda L.S., et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N. Engl. J. Med. 2013;368(15):1408-16. Doi: 10.1056/ NEJMoa1214561.
- Bentz M., Barth T.F., Bruderlein S., et al. Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line. Genes, Chromosomes Cancer. 2001;30(4):393-401. doi: 10.1002/1098-2264(2001)9999:9999<::aid-gcc1105>3.0.co;2-i.
- Melzner l., Bucur A.J., Bruderlein S., et al. Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood. 2005;105(6):2535-42. doi: 10.1182/blood-2004-09-3701.
- Wessendorf S., Barth T.F.E., Viardot A., et al. Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas: an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH). Leukemia. 2007;21:2463-69.
- Shi M, Roemer M.G., Chapuy B., et al. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am J Surg Pathol. 2014;38(12):1715-23. Doi: 10.1097/ PAS.0000000000000297.
- Green M.R., Monti S., Rodig S.J., et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268-77. doi: 10.1182/blood-2010-05-282780.
- Steidl C., Gascoyne R.D. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood. 2011;118(10):2659-69. doi: 10.1182/blood-2011-05-326538.
- Green M.R., Monti S., Rodig S.J., et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116:3268-77.
- Green M.R., Rodig S., Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: Implications for targeted therapy. Clin Cancer. Res. 2012; 18:1611-18.
- Paydas S., Bagir E., Seydaoglu, G., et al. Programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and EBVencoded RNA (EBER) expression in Hodgkin lymphoma. Ann Hematol. 2015;94:1545-52. doi: 10.1007/s00277-015-2403-2.
- Chen B.J., Chapuy B., Ouyang J., et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res. 2013;19(13):3462-73. doi: 10.1158/1078-0432.CCR-13-0855.
- Younes A., Burke J.M., Cheson B.D., et al. Safety and Efficacy of Atezolizumab in Combination with Rituximab Plus CHOP in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Updated Analysis of a Phase I/II Study. Blood. 2019;134(1):2874. doi: 10.1182/blood-2019-123368.
- Hawkes E.A., Manos K., Smith C., et al. AvR-CHOP: Feasibility Study of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL). Blood. 2019;134(1):5332. doi: 10.1182/blood-2019-127858.
- Casulo C., Santoro A., Ando K., et al. Durvalumab (Anti PD-L1) As Monotherapy or in Combination Therapy for Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL): A Subgroup Analysis from the Phase 1/2 Fusion NHL-001 Global Multicenter Trial. Blood. 2019;134(1):5320. Doi: 10.1182/ blood-2019-124102.
- Jaeger U., Kalakonda N., Everaus H., et al. Phase II study of Durvalumab (anti-PD-L1) combined with either R-CHOP or Lenalidomide and R-CHOP in previously untreated, high-risk diffuse large Bcell lymphoma. Hematol Oncol. 2017;35(52):419-20. doi: 10.1002/hon.2440_1.
- Nowakowski G.S., Willenbacher W., Greil R., et al. Safety and efficacy of PD-L1 inhibitor durvalumab with R-CHOP or R2-CHOP in subjects with previously untreated, high-risk DLBCL. J Clin Oncol. 2019;37(15):7520.
- Maddocks K.J., Duell J., Gonzalez Barca E., et al. Update of the single-arm phase II L-MIND study of MOR208+lenalidomide (LEN) in relapsed/ refractory diffuse large B-cell lymphoma (R-R DLBCL): Response rates in patient subgroups with poor prognosis. J. Clin. Oncol. 2019;37(15):7521.
- Weber J.S., Yang J.C., Atkins M.B., et al. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol. 2015;33(18):2092-99. Doi: 10.1200/ JCO.2014.60.0379.
- Xu-Monette Z.Y, Zhou J., Young K.H. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas. Blood. 2018;131(1):68-83. doi: 10.1182/blood-2017-07-740993.
- Vetizou M., Pitt J.M., Daillere R., et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-84. doi: 10.1126/science.aad1329.
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