BOVen Regimen Appears Effective in High-Risk MCL

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Data from a phase 2 study (NCT03824483) support the use and further investigation of the frontline BOVen regimen consisting of zanubrutinib (Brukinsa), obinutuzumab (Gazvya), and venetoclax (Venclexta) in patients with mantle cell lymphoma (MCL) with a TP53 mutation.

With a median follow-up of 28.2 months (range, 7.2-44.6), the best overall response rate (ORR) among the 25 evaluated patients was 96% (n = 24) with a complete response rate (CRR) of 88% (n = 22). Following 2 cycles of zanubtrutinb and obinutuzumab, the ORR was 88% (n = 22), and the CRR was 68% (n = 17).

Two-year progression-free survival (PFS) was 72% (95% CI, 56%-92%), meeting the study’s primary end point. The 2-year overall survival (OS) rate was 76% (95% CI, 61%-95%). The 2-year PFS rate was 72% (95% CI, 56 to 92), and the 2-year OS rate was 76% (95% CI, 61 to 95). Further, the median PFS and OS have not yet been reached.

Minimal residual disease frequency at 1 x 10-6 and 1 x 10-5 sensitivity at cycle 13 was 95% (n = 18/19) and 84% (n = 16/19), respectively.

“Although ongoing randomized phase 3 clinical trials, MANGROVE (NCT04002297) and ENRICH (CRUK/14/026), will more definitively compare [Bruton tyrosine kinase inhibitor (BTKi)] and rituximab [Rituxan] to chemoimmunotherapy in transplant-ineligible MCL, based on our data, the BOVen combination is one of the most highly active and well-tolerated novel agent combinations in MCL. Future studies may consider addition of consolidative CD20-CD3 bispecific antibody therapy in patients with incomplete clinical or molecular response,” authors wrote in the study published in Blood.

Patient Characteristics and the BOVen Regimen

Patients were eligible for enrollment in the phase 2, investigator-initiated, open-label, multicenter trial if they had histologically confirmed, previously untreated MCL. TP53 mutational status was confirmed in patients by next-generation sequencing or polymerase chain reaction assay.

A total of 25 patients were enrolled between September 2020 and April 2022. Most mutations were within the p53 protein DNA-binding domain. Patients were a median of 68 years old (range, 29-82), and 76% of patients were male.

BOVen was administered in 28-day cycles with zanubrutinib at 160 mg orally and obinutuzumab at 1000 mg intravenously on cycle 1, day 1, and venetoclax was administered starting on cycle 3, day 1 using a 5-week ramp-up from 200 mg to 400 mg.

Safety of the BOVen Regimen

The most common treatment-related adverse events (TRAEs) were diarrhea (64%), COVID-19 infection (56%), neutropenia (32%), and infusion-related reactions (24%). Grade 3 or higher thrombocytopenia was observed in 1 patient and was managed with dose reduction, and 1 incidence of grade 4 tumor lysis syndrome was reported during the initial split-dose administration of obinutuzumab.

REFERENCE:

Kumar A, Soumerai J, Abramson J, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood. Published online October 22, 2024. doi:10.1182/blood.2024025563