The diffuse large B-cell lymphoma treatment landscape is evolving with Pola-R-CHP and CAR T-cell therapy moving into the frontline setting.
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.
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.