Vol 55, No 2 (2024)
Review article
Published online: 2024-03-07
Update on management of diffuse large B-cell lymphoma Richter's transformation
DOI: 10.5603/ahp.98365
Acta Haematol Pol 2024;55(2):97-107.
Abstract
Richter’s transformation (RT) is defined as the development of an aggressive lymphoma in 2–10% of patients with chronic lymphocytic leukemia (CLL). Despite significant advances in the last decade, there is currently no established standard of care for RT, making its management a significant challenge. Questions regarding patients’ treatment management in the era of novel agents and targeted therapies have yet to be answered. Nevertheless, several retrospective studies and clinical trials have emphasized the use of novel targeted agents to address this problem. In this review, we provide a summary of potential therapeutic options for RT.
Keywords: chronic lymphocytic leukemiatreatmentRichter's transformationimmunotherapy
References
- Soilleux EJ, Wotherspoon A, Eyre TA, et al. Diagnostic dilemmas of high-grade transformation (Richter's syndrome) of chronic lymphocytic leukaemia: results of the phase II National Cancer Research Institute CHOP-OR clinical trial specialist haemato-pathology central review. Histopathology. 2016; 69(6): 1066–1076.
- Jamroziak K, Tadmor T, Robak T, et al. Richter syndrome in chronic lymphocytic leukemia: updates on biology, clinical features and therapy. Leuk Lymphoma. 2015; 56(7): 1949–1958.
- Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013; 162(6): 774–782.
- Rossi D, Spina V, Gaidano G. Biology and treatment of Richter syndrome. Blood. 2018; 131(25): 2761–2772.
- Roncati L. Richter's syndrome of T-cell lineage (T rex lymphoma). Curr Med Res Opin. 2020; 36(3): 473–476.
- Ge H, Wu X, Shen J, et al. A case report of extranodal NK/T-cell lymphoma in patient with chronic lymphocytic leukemia. Medicine. 2018; 97(30): e11619.
- Klintman J, Appleby N, Stamatopoulos B, et al. Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia. Blood. 2021; 137(20): 2800–2816.
- Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med. 2013; 210(11): 2273–2288.
- Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol. 2007; 31(10): 1605–1614.
- Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011; 117(12): 3391–3401.
- Ryan CE, Davids MS. Practical management of Richter transformation in 2023 and beyond. Am Soc Clin Oncol Educ Book. 2023; 43: e390804.
- Sośnia O, Pruszczyk K, Danecki M, et al. Richter transformation - retrospective treatment outcomes analysis in Polish Adult Leukemia Study Group. Leuk Lymphoma. 2024; 65(2): 175–186.
- Wang Y, Tschautscher MA, Rabe KG, et al. Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center. Haematologica. 2020; 105(3): 765–773.
- Parry EM, Leshchiner I, Guièze R, et al. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome. Nat Med. 2023; 29(1): 158–169.
- Hampel P, Rabe KG, Wang Y, et al. Incidence of Richter transformation in patients with chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL): a cohort study evaluating different therapeutic eras. Blood. 2023; 142(Suplement 1): 3271.
- Tsimberidou AM, O'Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol . 2006; 24(15): 2343–2351.
- Woyach JA, Ruppert AS, Guinn D, et al. BTK-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017; 35(13): 1437–1443.
- Davids M, Huang Y, Rogers K, et al. Richter's syndrome (RS) in patients with chronic lymphocytic leukemia (CLL) on novel agent therapy. Journal of Clinical Oncology. 2017; 35(15_suppl): 7505.
- Tsimberidou AM, Keating MJ. Richter's transformation in chronic lymphocytic leukemia. Semin Oncol. 2006; 33(2): 250–256.
- Pfreundschuh M, Trümper L, Osterborg A, et al. MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006; 7(5): 379–391.
- Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010; 116(12): 2040–2045.
- Langerbeins P, Busch R, Anheier N, et al. Poor efficacy and tolerability of R-CHOP in relapsed/refractory chronic lymphocytic leukemia and Richter transformation. Am J Hematol. 2014; 89(12): E239–E243.
- Eyre TA, Schuh A. An update for Richter syndrome - new directions and developments. Br J Haematol. 2017; 178(4): 508–520.
- Tsimberidou AM, Wierda WG, Plunkett W, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone plus rituximab and granulocyte-macrophage-colony stimulating factor (GM-CSF) alternating with methotrexate and cytarabine plus rituximab and GM-CSF in patients with Richter syndrome or fludarabine-refractory chronic lymphocytic leukemia. Cancer. 2003; 97(7): 1711–1720.
- Dabaja bs, O'Brien SM, Kantarjian HM, et al. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's syndrome. Leuk Lymphoma. 2001; 42(3): 329–337.
- Puła B, Salomon-Perzyński A, Prochorec-Sobieszek M, et al. Immunochemotherapy for Richter syndrome: current insights. Immunotargets Ther. 2019; 8: 1–14.
- Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Lancet Oncol. 2022; 386(4): 351–363.
- Romano I, Condoluci A, Rossi D. SOHO State of the Art Updates and Next Questions | Treatment of Richter's Transformation. Clin Lymphoma Myeloma Leuk. 2023; 23(11): 786–799.
- Tsimberidou AM, O'Brien S, Khouri I, et al. Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol. 2006; 24(15): 2343–2351.
- Herrera AF, Ahn KW, Litovich C, et al. Autologous and allogeneic hematopoietic cell transplantation for diffuse large B-cell lymphoma-type Richter syndrome. Blood Adv. 2021; 5(18): 3528–3539.
- Barbanti MC, Appleby N, Kesavan M, et al. Cellular therapy in high-risk relapsed/refractory chronic lymphocytic leukemia and Richter syndrome. Front Oncol. 2022; 12: 888109.
- Cwynarski K, van Biezen A, de Wreede L, et al. Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia (Richter's syndrome): A retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012; 30(18): 2211–2217.
- Davids MS, Roberts AW, Kenkre VP, et al. Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol. 2017; 35(8): 826–833.
- Tsang M, Shanafelt TD, Call TG, et al. The efficacy of ibrutinib in the treatment of Richter syndrome. Blood. 2015; 125(10): 1676–1678.
- Eyre TA, Schuh A, Wierda WG, et al. Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study. Lancet Haematol. 2021; 8(12): e912–e921.
- Tam C, Munoz J, Cull G, et al. Zanubrutinib, alone and in combination with tislelizumab, for the treatment of richter transformation of chronic lymphocytic leukemia. Hemasphere. 2023; 7(4): e870.
- Wierda W, Lewis D, Ghia P, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: results from the phase 1/2 BRUIN study. Blood. 2022; 140(Supplement 1): 846–849.
- Woyach J, Stephens D, Flinn I, et al. Final results of phase 1, dose escalation study evaluating ARQ 531 in patients with relapsed or refractory B-cell lymphoid malignancies. Blood. 2019; 134(Supplement_1): 4298–4298.
- Davids MS, Rogers KA, Tyekucheva S, et al. Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Blood. 2022; 139(5): 686–689.
- Eyre TA. Richter transformation-is there light at the end of this tunnel? Hematology Am Soc Hematol Educ Program. 2023; 2023(1): 427–432.
- Davids MS, Rogers KA, Jain N, et al. Initial results of a multicenter phase 2 study of venetoclax in combination with R‐CHOP (VR‐CHOP) for patients with Richter Syndrome. Hematological Oncology. 2023; 41(S2): 466–468.
- Briski R, Taylor J. Treatment of Richter transformation of chronic lymphocytic leukemia in the modern era. Cancers (Basel). 2023; 15(6).
- Hampel P, Parikh S, Wierda W, et al. P651: venetoclax-based treatment of patients with Richter syndrome: outcomes from a multicenter retrospective study. HemaSphere. 2022; 6: 549–550.
- Appleby N, Eyre TA, Cabes M, et al. The STELLAR trial protocol: a prospective multicentre trial for Richter's syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease. BMC Cancer. 2019; 19(1): 471.
- Visentin A, Imbergamo S, Scomazzon E, et al. BCR kinase inhibitors, idelalisib and ibrutinib, are active and effective in Richter syndrome. Br J Haematol. 2019; 185(1): 193–197.
- Ryan C, Crombie J, Tyekucheva S, et al. Updated results from a phase I/II study of duvelisib and venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or Richter's syndrome (RS). Blood. 2022; 140(Supplement 1): 9871–9872.
- Davids MS, Deng J, Wiestner A, et al. Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia. Blood. 2012; 120(17): 3501–3509.
- Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood. 2017; 129(26): 3419–3427.
- Armand P, Murawski N, Molin D, et al. Pembrolizumab in relapsed or refractory Richter syndrome. Br J Haematol. 2020; 190(2): e117–e120.
- Jain N, Senapati J, Thakral B, et al. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL. Blood Adv. 2023; 7(10): 1958–1966.
- Tam C, Munoz J, Cull G, et al. Zanubrutinib, alone and in combination with tislelizumab, for the treatment of Richter transformation of chronic lymphocytic leukemia. Hemasphere. 2023; 7(4): e870.
- Shouse G, Siddiqi T, Popplewell L, et al. A phase i trial of pi3kαδ inhibitor copanlisib in combination with nivolumab in patients with richter's transformation (RT) or transformed non-hodgkin lymphoma (tnhl). Blood. 2021; 138(Supplement 1): 3558.
- Mato A, Svoboda J, Prak EL, et al. Phase I/II study of umbralisib (TGR-1202) in combination with ublituximab (TG-1101) and pembrolizumab in patients with relapsed/refractory CLL and Richter's transformation. Blood. 2018; 132(Supplement 1): 297.
- Frustaci AM, Montillo M, Rossi D, et al. Efficacy and safety of molto, a multicenter, open label, phase ii clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in Richter syndrome. Hematological Oncology. 2023; 41(S2): 62–63.
- Cruz CR, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013; 122(17): 2965–2973.
- Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015; 33(6): 540–549.
- Benjamini O, Shimoni A, Besser M, et al. Safety and efficacy of CD19-CAR t cells in Richter's transformation after targeted therapy for chronic lymphocytic leukemia. Blood. 2020; 136(Supplement 1): 40.
- Kittai AS, Bond DA, William B, et al. Clinical activity of axicabtagene ciloleucel in adult patients with Richter syndrome. Blood Adv. 2020; 4(19): 4648–4652.
- Long M, Beckwith K, Do P, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest. 2017; 127(8): 3052–3064.
- Fraietta JA, Beckwith KA, Patel PR, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016; 127(9): 1117–1127.
- Kittai A, Bond D, Huang Y, et al. Anti-CD19 chimeric antigen receptor t-cell therapy for Richter's transformation: an international multicenter retrospective study. Blood. 2023; 142(Suplement 1): 18.
- Ortiz-Maldonado V, Frigola G, Español-Rego M, et al. Results of ARI-0001 CART19 cells in patients with chronic lymphocytic leukemia and Richter's transformation. Front Oncol. 2022; 12: 828471.
- Liu E, Marin D, Banerjee P, et al. Use of CARr-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020; 382(6): 545–553.
- van de Donk NW, Zweegman S. T-cell-engaging bispecific antibodies in cancer. Lancet. 2023; 402(10396): 142–158.
- Guieze R, Ysebaert L, Roos-Weil D, et al. Blinatumomab for patients with Richter syndrome: final results of the phase 2 blinart trial from the Filo Group. Blood. 2022; 140(Supplement 1): 6631–6632.
- Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting T-cell-engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell lymphoma: a phase i trial. J Clin Oncol. 2021; 39(18): 1959–1970.
- Kater A, Ye J, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter's syndrome: early results from phase 1b/2 trial (EPCORE CLL-1). Blood. 2022; 140(Supplement 1): 850–851.
- Cheah Ch, Assouline S, Baker R, et al. Mosunetuzumab monotherapy demonstrates activity and a manageable safety profile in patients with relapsed or refractory Richter's transformation. Blood. 2023; 142(Suplement 1): 614.
- Wang ML, Barrientos JC, Furman RR, et al. Zilovertamab vedotin targeting of ROR1 as therapy for lymphoid cancers. NEJM Evid. 2022; 1(1): EVIDoa2100001.
- Kipps TJ. ROR1: an orphan becomes apparent. Blood. 2022; 140(14): 1583–1591.
- Spurgeon S, Mei M, Barr P, et al. Waveline-001: updated results from a phase 1 dose escalation and cohort expansion study of zilovertamab vedotin (MK-2140) in non-Hodgkin lymphoma. Blood. 2022; 140(Supplement 1): 6640–6641.
- Hus I, Giannopoulos K, Jamroziak K, et al. Diagnostic and therapeutic recommendations of the Polish Society of Haematologists and Transfusiologists, and Polish Adult Leukemia Group-CLL for chronic lymphocytic leukemia in 2023. Acta Haematol Pol. 2023; 54(6): 342–371.