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Rituximab plus CHOP is not a suitable frontline treatment regimen for all patients with diffuse large B-cell lymphoma, explained Andre H. Goy, MD, who specified that patients with a high-risk International Prognostic Index, elderly patients, and patients with high-risk molecular subtypes require alternative treatment.
Rituximab (Rituxan) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is not a suitable frontline treatment regimen for all patients with diffuse large B-cell lymphoma (DLBCL), explained Andre H. Goy, MD, who specified that patients with a high-risk International Prognostic Index (IPI), elderly patients, and patients with high-risk molecular subtypes require alternative treatment.
“The old standard of R-CHOP, which was a great accomplishment and progress in large cell lymphoma, is no longer valid in over half of patients,” said Goy, Physician in Chief Hackensack Meridian Health Oncology Care Transformation Service, Chairman & Chief Physician Officer - John Theurer Cancer Center, Lydia Pfund Chair for Lymphoma, Academic Chairman Oncology - Hackensack Meridian School of Medicine, Professor of Medicine – Georgetown University, Hackensack, NJ, in a presentation during the 25th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, a program hosted by the Physicians Education Resource®, LCC.
Approximately 50% of patients with DLBCL are cured with R-CHOP induction therapy. However, 20% to 30% of patients will relapse and 10% to 15% represent primary failures.1,2
Patients with a high-risk IPI have particularly poor overall survival (OS) with R-CHOP compared with low- and intermediate-risk patients. In a real-world analysis, patients with a high IPI of 4 or 5 who received R-CHOP had a median OS of 4.5 years vs a median OS that had not been reached in patients with a low IPI of 0 or 1 at a median follow-up of 6 years.2
Patients with double-hit lymphoma (DHL) also do poorly with R-CHOP, said Goy. Typically, these patients are recommended for allogeneic stem cell transplant. However, findings from the phase 2 ZUMA-12 trial, which were presented at the 2020 ASH Annual Meeting and Exposition, demonstrated encouraging results with the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) as consolidation in patients with DHL or DLBCL with a high IPI of 3 or greater.
In the study, patients received 2 cycles of rituximab and chemotherapy, and if they were PET positive, they received axi-cel as consolidation. The objective response rate (ORR) with this approach was 85%, comprising a complete response (CR) rate of 74% (n = 20) and a partial response rate of 11% (n = 3).3
Other potential strategies for patients with DHL include the addition of venetoclax (Venclexta) to R-CHOP, particularly in patients with BCL-2 positivity or overexpression, said Goy. Such a strategy is based on a matched analysis of patients who received R-CHOP vs R-CHOP plus venetoclax in the phase 3 GOYA trial and phase 1/2 CAVALLI trial, respectively.4,5
According the analysis, 65% and 70% of patients with BCL-2 positivity and BCL-2 overexpression experienced a CR with R-CHOP/venetoclax, respectively, in the CAVALLI trial vs 60% and 48% of patients who received R-CHOP alone, respectively, in the GOYA trial.
These data served as the rationale for an ongoing phase 1 trial (NCT03036904), which is evaluating dose-adjusted R-EPOCH (R-CHOP plus etoposide) plus venetoclax or dose-adjusted R-EPOCH alone in patients with DHL.6 The study will also compare R-CHOP plus venetoclax with R-CHOP alone in patients with double expression.
Mutated TP53 is another high-risk feature that confers early resistance to frontline treatment, explained Goy. In a large cohort of patients with DLBCL who received R-CHOP, those with TP53 mutations had worse overall and progression-free survival compared with those without. The median OS of 395 patients with wild-type TP53 was 94.49 months vs 52.90 months in the 111 patients with TP53 mutations (HR, 0.5320; 95% CI, 0.37-0.76).7
To that end, another regimen that has been put forth as an alternative for patients with poor-risk features is that of rituximab plus lenalidomide (Revlimid; R2) and ibrutinib (Imbruvica). In the relapsed/refractory setting, the regimen led to an ORR of 44% and a CR rate of 28%.8 In the activated B-cell subtype, the ORR was 65%, and the CR rate was 41%. These findings led to a phase 2 trial (NCT02636322) in the frontline setting, which evaluated the same regimen plus chemotherapy in patients with the adverse prognostic variables of non-germinal center B-cell subtype, Ki-67 of greater than 80%, and double expression. The results demonstrated comparable outcomes with other patients, with an ORR of 86% and a CR rate of 36%.9
“This is interesting because you can potentially kill the clones that are P53 positive and then can use chemotherapy afterwards,” said Goy.
Other approaches that are under study as a way to build upon R-CHOP include combinations with targeted therapies, such as with copanlisib (Aliqopa) and selinexor (Xpovio), monoclonal antibodies, such as tafasitamab-cxic (Monjuvi), antibody drug-conjugates, such as polatuzumab vedotin-piiq (Polivy), as well as with checkpoint inhibitors and bispecific T-cell engagers, concluded Goy.