The New Algorithm for Second-Line Large B-Cell Lymphoma Treatment

Jason Westin, MD

New enhanced treatment options with prolonged overall survival are improving patient outcomes in diffuse large B-cell lymphoma (DLBCL), according to Jason Westin, MD, director of Lymphoma Clinical Research Program and section chief of Aggressive Lymphoma, Department of Lymphoma and Melanoma at The University of Texas MD Anderson Cancer Center in Houston, a speaker at the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023) who discussed the topic on Friday, September 8, 2023.

The first-line standard of care (SOC) has been R-CHOP [rituximab (Rituxan®; Genentech, Biogen)], plus cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone], which is curative in approximately two-thirds of patients.^1,2 Second-line SOC has been platinum chemotherapy followed by stem cell transplant. However, recent advances have changed the clinical practice: chimeric antigen receptor (CAR) T-cell therapy, bispecific antibody treatments, and Pola-R-CHP (polatuzumab vedotin-piiq; [Polivy®; Genentech], rituximab [Rituxan®; Genentech, Biogen], cyclophosphamide, doxorubicin, and prednisone) therapy. As a result, the DLBCL treatment landscape is evolving with Pola-R-CHP and CAR T-cell therapy moving into the frontline setting.³

“We have proposed a new algorithm…where the question asked is, ‘How long ago was initial therapy?’ If the answer is 1 year or less, which is true for the overwhelming majority of patients [with] relapsed DLBCL, the preferred approach is CAR T-cell therapy,” Westin said during an interview with The SOHO Daily News.

Several clinical practice–transforming studies have been reported in the frontline setting (POLARIX, NCT03274492), and in the early relapse (ZUMA-7, NCT03391466 and TRANSFORM, NCT03575351) and multiple recurrent stages (ZUMA-1, NCT02348216; JULIET, NCT02445248; TRANSCEND-NHL-001, NCT02631044; L-MIND, NCT02399085; and LOTIS-2, NCT03589469). The POLARIX study compared Pola-R-CHP vs R-CHOPefficacy in patients with previously untreated DLBCL.⁴ Pola-R-CHP treatment compared with R-CHOP demonstrated longer event-free survival (EFS, 86.6% vs 82.7%) and prolonged overall survival (OS), with a higher proportion of patients surviving beyond 2 years with Pola-R-CHP treatment.

Three CAR T-cell therapies, tisagenlecleucel (tisa-cel; Kymriah®; Novartis), axicabtagene ciloleucel (axi-cel; Yescarta®; Kite), and lisocabtagene maraleucel (liso-cel; Breyanzi®; Bristol Myers Squibb) are approved for use in the second-line setting in patients with relapsed or refractory DLBCL, and the latter 2 demonstrated superior outcomes compared with SOC. Axi-cel treatment compared with SOC demonstrated longer median EFS (8.3 months vs 2 months) and the OS rate was 63.5%.^5,6 Liso-cel treatment compared with SOC at limited follow-up of 6 months demonstrated longer median EFS (10.1 months vs 2.3 months) and the OS was not reached.⁷ However, limited access to leukapheresis and the long wait times involved with CAR T-cell production necessitates bridging therapies.

lymphoma cell © Dr_Microbe - stock.adobe.com

The DLBCL treatment landscape is evolving with CAR T-cell therapies moving into frontline therapy and the emergence of promising bispecific antibodies. The ZUMA-3 trial (NCT02614066) is evaluating axi-cel efficacy compared to SOC in patients with newly diagnosed DLBCL.⁸ The most advanced bispecific antibodies are glofitamab-gxbm (Columvi™; Genentech) and epcoritamab-bysp (Epkinly™; Genmab; AbbVie), which showed comparable efficacy in the next-line setting in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.^9,10 Thus, these therapies are promising for DLBCL treatment, and epcoritamab recently was approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after 2 or more lines of systemic therapy.¹¹

Despite the improved outcomes with Pola-R-CHP and CAR T-cell therapies, a limited number of patients remain ineligible for these treatments and stem cell transplant. Loncastuximab tesirine-lpyl (Zynlonta®; ADC Therapeutics) or tafasitamab-cxix (Monjuvi®; MorphoSys, Incyte) in combination with lenalidomide (Revlimid®; Bristol Myers Squibb) may represent potential therapeutic options in this population. Clinical trials evaluating loncastuximab tesirine-lpyl or tafasitamab-cxix plus lenalidomide efficacy in the next-line setting in patients with DLBCL demonstrated median PFS of 4.9 months and 11.6 months and median OS of 9.9 months and 33.5 months, respectively.^12,13

Acute CAR T-cell adverse effects (AEs) that require close monitoring are cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Early detection and intervention are critical as these treatments are moved into earlier lines of therapy. Grade 3 or greater treatment-related AEs were observed in 42% of patients with glofitamab. However, in both glofitamab and epcoritamab trials, less than 10% of patients discontinued treatment due to AEs, and the treatments are given in a stepped-up manner to reduce the risk of CRS and ICANS.

The promising DLBCL therapies emerging pose a challenge of how to select the most appropriate treatment for the patient, and how to combine or sequence therapies, according to Westin. “CAR T-cell therapy has changed the paradigm. If your patient has refractory DLBCL or relapses within 1 year, you should refer [them] immediately to a CAR T-cell center,” Westin said.

REFERENCES

1. 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. doi:10.1182/blood-2010-03-276246

2. Pfreundschuh M, Trümper L, Osterborg A, et al. 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. doi:10.1016/S1470-2045(06)70664-7

3. NCCN. Clinical practice guidelines in oncology. B-cell lymphomas, version 2.2023. Accessed July 6, 2023. https://bit.ly/3qihhKW

4. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304

5. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133

6. Bachy E, Le Gouill S, Di Blasi R, et al. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med. 2022;28(10):2145-2154. doi:10.1038/s41591-022-01969-y

7. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-2308. doi:10.1016/S0140-6736(22)00662-6

8. Westin J, Jacobson CA, Chavez JC, et al. ZUMA-23: A global, phase 3, randomized controlled study of axicabtagene ciloleucel versus standard of care as first-line therapy in patients with high-risk large B-cell lymphoma. J Clin Oncol. 2023;41(suppl 16):TPS7578. 10.1200/JCO.2023.41.16_suppl.TPS7578

9. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: pivotal phase II expansion results. J Clin Oncol. 2022;40(suppl 16):7500. doi:10.1200/JCO.2022.40.16_suppl.7500

10. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J Clin Oncol. 2023;41(12):2238-2247. doi:10.1200/JCO.22.01725

11. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. News release. FDA. Accessed August 5, 2023. https://bit.ly/3OKcAmz

12. Caimi PF, Ai W, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800. doi:10.1016/S1470-2045(21)00139-X

13. Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021;9(106):2417-2426. doi:10.3324/haematol.2020.275958