Patients with mantle cell lymphoma (MCL) would benefit from additional safe and effective treatment options. Investigators from Dana-Farber Cancer Institute led by Austin Kim, MD, are conducting a phase I/II study evaluating the safety and activity of time-limited, chemotherapy-free treatment with the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib, the Bcl-2 inhibitor venetoclax, and the CD20 monoclonal antibody obinutuzumab (hereafter, AVO) for individuals with relapsed and refractory (R/R) and treatment-naïve (TN) MCL (Dana-Farber 21-040; NCT04855695). Participants receive acalabrutinib 100 mg twice daily beginning in cycle 1; obinutuzumab induction in cycles 2-7 and bimonthly maintenance in cycles 9-31; and venetoclax ramp-up beginning in cycle 3 to a target dose of 400 mg daily. The primary endpoint for TN patients is the complete remission (CR) rate after 7 cycles of induction. Acalabrutinib and venetoclax (AV) continue indefinitely but can be discontinued in TN patients who maintain minimal residual disease (MRD)-negative CR for three months based on clonoSEQ testing.
Dr. Kim presented initial results at the 2025 American Society of Hematology (ASH) Annual Meeting. Among 24 individuals with high-risk TN MCL, of whom 71% harbored TP53 mutations, AVO achieved an overall response rate (ORR) of 88%, a CR rate of 83%, and a 2-year progression-free survival (PFS) of 79% at a median follow-up of 24 months (Figure 1). Among 12 patients with low-risk TN MCL, the ORR, CR rate, and one-year PFS were 100% at a median follow-up of 13 months. This compares favorably to historical results with frontline chemoimmunotherapy, where 2-year PFS rates of 20-55% in TP53-aberrant MCL have been reported. They also corroborate findings from the BOVen trial of triplet targeted therapy incorporating the BTKi zanubrutinib (NCT03824483) with a 2-year PFS of 72% in 25 individuals with TP53-mutated MCL.
In high-risk TN patients, 79% of those whose MCL was tracked by clonoSEQ (sensitivity 10-6) achieved MRD-negative CR after seven cycles of induction and discontinued AV. This includes 75% of those with TP53-aberrant disease. Only one patient has relapsed after discontinuing AV. Adverse events (AEs) were generally manageable and consistent with the known effects of individual drugs in this combination regimen. Within all study cohorts, common grade ≥3 AEs included cytopenias, with grade 3-4 neutropenia in 30%. This was managed with growth factor support but led to discontinuation of acalabrutinib or venetoclax in 5%. Infections were observed in 32% of participants, most commonly grade 1-2 upper respiratory infections, though grade ≥3 COVID-19 infection was observed in 5% including one participant with a grade 5 event. While longer follow-up is needed, these findings motivated a 16-patient expansion of the high-risk TN cohort, which is accruing briskly.
