BOVen Regimen is Safe and Effective in First-Line TP53-Mutated MCL

Zanubrutinib (Brukinsa) in combination with obinutuzumab (Gazyva) and venetoclax (Venclexta; BOVen) was active with a well-tolerated safety profile in the frontline treatment of patients with TP53-mutated mantle cell lymphoma (MCL), according to findings from a phase 2 study (NCT03824483) published in Blood.1

Patients with untreated TP53-mutated MCL who received BOVen in the intention-to-treat population (n = 25) achieved a best overall response rate (ORR) of 96%, including an 88% complete response (CR) rate. At a median follow-up of 28.2 months (range, 7.2-44.6), the median progression-free survival (PFS) was not yet reached (NR); the 2-year PFS rate was 72% (95% CI, 56%-92%). The median overall survival (OS) and disease-specific survival (DSS) were also NR. The 2-year DSS and OS rates were 91% (95% CI, 79%-100%) and 76% (95% CI, 61%-95%), respectively, which investigators noted can be attributed to deaths related to COVID-19.

Notably, all patients who completed 24 cycles of therapy (n = 18) achieved a CR.

“BOVen was well tolerated and [the study] met its primary efficacy end point in TP53-mutant MCL. These data support its use and ongoing evaluation,” Anita Kumar, MD, and her coauthors wrote. Kumar is a lymphoma specialist and associate attending physician at Memorial Sloan Kettering Cancer Center in Basking Ridge, New Jersey.

Treatment Regimen, Inclusion Criteria, and Baseline Characteristics

In the MCL cohort, the open-label, multicenter study enrolled adult patients with histologically confirmed previously untreated MCL. Patients were required to meet 1 of the following criteria for therapy to be initiated: significant constitutional symptoms, cytopenias, symptomatic splenomegaly, progressive or symptomatic nodal enlargement, or evidence of clinically significant organ compression or involvement. A Clinical Laboratory Improvement Amendments-approved next-generation sequencing or polymerase chain reaction assay was used to confirm the presence of a TP53 mutation.

The BOVen regimen was administered via 28-day cycles. Oral zanubrutinib was given twice daily at a dose of 160 mg starting on day 1 of cycle 1. Patients also received 1000 mg of intravenous obinutuzumab on day 1 of cycle 1, as well as on days 8 and 15, then on day 1 of cycles 2 through 8. Obinutuzumab was administered via a split dose over days 1 (100 mg) and 2 (900 mg) if patients had an absolute lymphocyte count above 25 ×109 L/μL or if the lymph node diameter was at least 5 cm. On day 1 of cycle 3, patients received venetoclax via a 5-week ramp-up period from 20 mg to 400 mg, then the agent was given at 400 mg daily.

Patients were treated for at least 24 cycles; those who achieved a CR with undetectable minimal residual disease (uMRD) at a sensitivity of 1 × 10–6 (uMRD6) in peripheral blood and bone marrow after 24 cycles discontinued therapy. If uMRD results were indeterminate at the 1 × 10–6 sensitivity level, a sensitivity of 1 × 10–5 (uMRD5) was used to inform treatment discontinuation decisions.

The primary end point was 2-year PFS rate to facilitate comparison with the outcomes of patients with TP53-mutated MCL from the phase 2 Nordic MCL2 (ISRCTN 87866680) and MCL3 (NCT00514475) studies. If at least 11 patients were progression free at 2 years, BOVen would be deemed worthy of further exploration. Levels of peripheral blood uMRD and response rates were also described in the study.

At baseline, the median age was 68 years (range, 29-82) and all patients had stage IV MCL. Most patients were male (76%), had classic MCL histology (68%), had Mantle Cell Lymphoma International Prognostic Index high-risk disease (68%), had bone marrow involvement (88%), had peripheral blood involvement (80%), and did not have gastrointestinal involvement (68%). The median TP53 variant allele frequency was 49.8% (range, 4.9%-96.2%).

Further Efficacy Data and Safety Findings

Additional efficacy findings revealed that the ORR and CR rates at day 1 of cycle 3 were 88% and 68%, respectively. Notably, 4 patients who had a partial metabolic response and 1 patient who had stable disease at cycle 3 day 1 converted to a metabolic CR after initiation of venetoclax. In uMRD-evaluable patients, the uMRD5 rates in the peripheral blood at cycle 3, cycle 13, and end of treatment were 77% (n = 17/22), 95% (n = 18/19), and 100% (n = 17/17), respectively. These respective rates in the intention-to-treat analysis were 68%, 72%, and 68%. The uMRD6 rates in the peripheral blood were 32% (n = 7/22), 84% (n = 16/19), and 71% (n = 12/15), respectively. In the intention-to-treat population, the uMRD6 rates in the peripheral blood were 28%, 64%, and 48%, respectively.

In terms of safety, the most common any-grade treatment-related adverse effects (TRAEs) included diarrhea (64%), COVID-19 infection (56%), neutropenia (32%), and infusion-related reactions (24%). Grade 3 TRAEs included decreased neutrophil count (16%) and infusion-related reaction (8%), as well as COVID-19 infection, decreased platelet count, increased aspartate aminotransferase levels, maculo-papular rash, hypertension, and lung infection, which each occurred in 1 patient (4%). There were no grade 4 TRAEs and decreased neutrophil count was the only grade 5 TRAE (8%). Any-grade serious AEs encompassed COVID-19 infection (24%) and lung infection (8%), among others. Overall, patients died during treatment due to COVID-19 (n = 2), lung infection (n = 1), aspiration (n = 1), and an unknown cause (n = 1).

“Although the ongoing randomized phase 3 clinical trials MANGROVE [NCT04002297] and ENRICH (CRUK/14/026) will more definitively compare [a] BTK inhibitor and rituximab [Rituxan] with chemoimmunotherapy in transplant-ineligible MCL, based on our data, the BOVen combination is 1 of the most highly active and well-tolerated novel agent combinations in MCL to our knowledge,” the study authors wrote in conclusion. “Future studies may consider the addition of consolidative CD20-CD3 bispecific antibody therapy in patients with incomplete clinical or molecular response. In conclusion, these data provide compelling evidence to support the use of BOVen for the frontline treatment of TP53-mutant MCL.”

Reference

1. Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood. 2025;145(5):497-507. doi:10.1182/blood.2024025563