Addition of Venetoclax to Lenalidomide and Rituximab Therapy for Patients With Previously Untreated MCL

Kami J. Maddocks, MD, James Cancer Hospital, Ohio State University, Columbus, Ohio, discusses the results of a multicenter, open-label, nonrandomized, single-arm study which explored the addition of venetoclax to lenalidomide and rituximab treatment for patients with previously untreated mantle cell lymphoma (MCL). 

The study, though it included a limited number of patients, demonstrated the combination of lenalidomide, rituximab, and venetoclax to be a safe and effective regimen. 

Transcript: 

I'm Kami Maddocks from the James Cancer Hospital at Ohio State University where I treat lymphomas. Today, I'm going to be discussing some data on the treatment of frontline mantle cell lymphoma, including adding venetoclax to lenalidomide and rituximab in patients with untreated mantle cell lymphoma. We know that the R2, or rituximab and lenalidomide combination, has been evaluated in patients with previously untreated mantle cell lymphoma, showing a high overall response rate and promising progression-free survival, including with longer-term follow-up.

This study looked at adding the BCL-2 inhibitor, venetoclax, to the R2 regimen in the frontline treatment of untreated mantle cell lymphoma. This study included 28 patients who were treated with this triplet combination. The study was to initially find the recommended dosing for this, and there were no [dose-limiting toxicities] (DLTs) noted in the study. Further, patients were planned to be treated with a combination of rituximab, lenalidomide, and venetoclax for 1-year induction followed by maintenance therapy. The maintenance was given with venetoclax, rituximab given every other cycle, and lenalidomide.

The trial showed very high overall response rates and complete response rates, including an overall response rate of 96% and a complete response rate of 86%. They did [minimal residual disease] (MRD) testing, or minimal residual disease testing, in this trial, and 86% of the patients who achieved response, achieved MRD-detectable state via next-generation sequencing to test MRD.

[The] most common toxicities were cytopenias, diarrhea, anemia, and fatigue, with the most common high-grade toxicities being cytopenias. There was a high rate of cytopenia seen in this trial, both neutropenia and thrombocytopenia, and that led to a change in the protocol. Whereas the initial plan was to give the induction phase for 12 months for patients who achieved an MRD-negative [complete response] (CR), the induction phase stopped at 6 months. At that time, they went into the maintenance phase with the dose of lenalidomide dropping by half, for most patients going from 20 milligrams, which was the dosing and the induction, down to 10 milligrams. As far as maintenance, venetoclax was given for 1 year, lenalidomide was given for 2 years, and then rituximab maintenance was given for up to 36 months or 3 years.

The one thing that this study did suggest [was] that the triplet combination was potentially more effective than the doublet combination for the treatment of patients with untreated mantle cell lymphoma. Although, again, there were very small numbers of patients treated in this trial. The one notable thing is that, of the 5 patients with TP53 mutation, 4 of those patients either did not respond to the treatment or progressed on treatment with only 1 patient remaining on treatment at reporting on the trial, who had a median duration of response of 16.6 months. In terms of the follow-up in that patient, I would say it's rather short. 

While it appeared to be an effective regimen in this cohort of patients, it did suggest that [for] patients with those high-risk disease features, as defined by TP53 mutation, this triplet combination is unlikely to overcome the poor prognostic factor of the TP53 mutation.

Source:

Phillips TJ, 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