Venetoclax Plus Lenalidomide, Rituximab ‘Safe’ in Frontline MCL Treatment

A study examining the efficacy of adding venetoclax to lenalidomide and rituximab (R2) in patients with untreated mantle cell lymphoma (MCL) showed that the regimen was tolerable.

The open-label, nonrandomized, multicenter study observed an overall response rate (ORR) of 96%. The investigators, led by Tycel Phillips, MD, published their results in Blood Advances.

Citing a phase II study which found the combination of lenalidomide plus rituximab resulted in durable remissions in patients with untreated MCL, the investigators sought expand upon the treatment with the addition of venetoclax. The study was conducted at three institutions: the University of Michigan, Ann Arbor; City of Hope in Duarte, California; and the Ohio State University in Columbus.

One of the study’s primary objectives was to determine the maximum tolerated dose (MTD) among five different dose levels of venetoclax combined with R2. The investigators also sought to assess progression-free survival (PFS) as well as the occurrence of any dose-limiting toxicities (DLTs). Secondary objectives included evaluating ORR, the status of measurable residual disease (MRD) testing at the end of the induction phase, and the incidence of adverse events (AEs).

Twenty-eight patients met the inclusion criteria for the study. All patients were aged >18 years, diagnosed with MCL, demonstrated immunohistochemistry expression of SOX11, and had not undergone any systemic treatment previously.

Patients began induction therapy with oral lenalidomide, taking 20 mg daily from days one through 21 in a 28-day cycle, followed by a seven-day pause (days 22-28). Rituximab was administered weekly, beginning on cycle one, day one, and continuing until cycle two, day two, at a dose of 375 mg/m². Patients also took 81 mg of aspirin daily, unless already using other anticoagulants. The study’s DLT assessment began with venetoclax initiation, planned at five dose levels. Venetoclax was initiated at 50 mg on day eight of cycle one. Weekly escalation followed, either reaching a maximum 400 mg or stopping for DLT.

During the study, 86% of patients achieved an undetectable MRD test result using next-generation sequencing. Among the patients, 57% reached an undetectable result within three months, which then rose to 75% by the sixth month. All 28 patients experienced AEs. The most commonly observed AEs were neutropenia, thrombocytopenia, diarrhea, anemia, and fatigue.

The investigators further analyzed patients based on their p53 mutation status. Upon categorizing patients according to their p53 mutation status, Patients without a p53 mutation experienced notably extended PFS compared to those carrying the mutation. Among the patients without a p53 mutation, the ORR was 100%, with 91% achieving a complete response. Conversely, patients with a p53 mutation exhibited an ORR of 80%, with a complete response rate of 60%.

“Overall, the regimen was tolerable, with no responding patients stopping therapy during induction,” the investigators wrote.

The investigators conceded the longer follow-up is needed but the results are promising.

“Although longer follow-up is needed, the results obtained thus far in those without p53 mutations suggest that durable responses can be achieved without the addition of cytotoxic agents in patients with MCL, irrespective of age or fitness,” they concluded.

References

1. Phillips T, Bond D, Takiar R, et al. Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Blood Adv. 2023;7(16):4518–4527. doi:10.1182/bloodadvances.2023009992
2. Ruan J, Martin P, Shah B, et al. Lenalidomide plus Rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237