ASH 2025 | A Phase I/II study of acalabrutinib, venetoclax, & obinutuzumab in R/R and treatment-naive MCL

In mantle cell lymphoma, the most common first-line treatments remain chemoimmunotherapy and a combination of targeted BTK inhibitors with chemoimmunotherapy. However, doublet and triplet chemotherapy-free combinations of a BTK inhibitor, BCL-2 inhibitor, and an anti-CD20 are challenging the current standard of care. So this MAVO study includes acalabrutinib, venetoclax, and obinutuzumab. And our hypothesis was that it would be safe and effective in both relapsed/refractory and treatment-naive mantle cell lymphoma. And finally, we aim to study using minimal residual disease to help study time-limited therapy for discontinuing therapy with acalabrutinib and venetoclax. 

I’m excited to present the results on Sunday. So this was a phase I/II study looking at relapse refractory and treatment-naive mantle cell lymphoma. So it was a three-part study. First started in the very high-risk relapse refractory mantle cell lymphoma. And if safety was confirmed, it would expand to the high-risk treatment-naive mantle cell lymphoma cohort, which included a transplant ineligible and TP53 aberrant. And then if efficacy was met, there was a third cohort which was low-risk treatment-naive mantle cell lymphoma. 

So the study started in the relapsed/refractory setting and safety was met. So there was an 11 patient expansion cohort. So there were 20 patients that were enrolled in the relapsed/refractory setting, and what we found was a complete remission rate was 75%. So then the study opened to 24 treatment-naive mantle cell lymphoma patients who were high risk. And what we found was that 17 of those patients had a high-risk TP53 mutation, which is associated with more difficult or aggressive disease. And what we found overall was the primary endpoint was met with a complete remission rate of 83%, and then within the 17 patients with a TP53 mutation, the two-year progression-free survival was 82%, and overall survival was 94%. Also part of this study for the treatment-naive cohort was that patients who were in undetectable minimal residual disease after the seven cycles of induction, acalabrutinib, venetoclax, and obinutuzumab were able to discontinue therapy if they remained in uMRD complete remission for three consecutive months. So we did find within this cohort that 15 of 19 patients were able to achieve uMRD complete remission and discontinue therapy. So that was 79% of patients. So far, only one patient has recurred after discontinuing therapy. 

And then finally going to cohort C, which is the low-risk treatment-naive mantle cell lymphoma cohort. As a primary endpoint for cohort B was met, we found 100% complete remission rate. And at a median follow-up of a year, 100% remained alive and without progression. And we also found that eight of nine patients were able to discontinue therapy after achieving minimal residual disease complete remission. 

So in summary, the AVO combination had high rates of complete remission in all three cohorts. It also had very high rates of undetectable MRD complete remission, allowing for many patients to discontinue acalabrutinib and venetoclax after only 10 cycles of therapy. I think what we did find for a future study is that it does appear that patients who had highly proliferative or blastoid variant TP53-mutated mantle cell lymphoma, further investigation needs to be done in that specific population. But with these results, there is a 16 patient expansion cohort opening for the TP53-mutated treatment-naive cohort. And finally, I think this triplet chemotherapy-free regimen of AVO or acalabrutinib, venetoclax, and obinutuzumab warrants further investigation and randomized studies.

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