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Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma

Authors: Michael Wang, MD, David Salek, MD, David Belada, MD, Yuqin Song, MD, Wojciech Jurczak, MD, PhD, Brad S. Kahl, MD, Jonas Paludo, MD, Michael P. Chu, MD, Iryna Kryachok, MD, Laura Fogliatto, MD, Chan Y. Cheah, DMSc, Marta Morawska, MD, PhD, Juan-Manuel Sancho, MD, Yufu Li, MD, Caterina Patti, MD, Cecily Forsyth, MD, Jingyang Zhang, PhD, Robin Lesley, PhD, Safaa Ramadan, MD, PhD, Simon Rule, MD, PhD, and Martin Dreyling, MD, PhD 

Journal of Clinical Oncology

2 May 2025

Key Objective: Should acalabrutinib be added to bendamustine plus rituximab as frontline therapy in older patients with mantle cell lymphoma (MCL)?

Knowledge Generated: The addition of acalabrutinib to bendamustine plus rituximab significantly improved progression-free survival compared with placebo and bendamustine plus rituximab in patients with previously untreated MCL, including those with high-risk features. Toxicity in both study arms was manageable.

Relevance (J.W. Friedberg): These results directly led to approval by the US FDA for the combination of acalabrutinib, bendamustine, and rituximab for adults with previously untreated mantle cell lymphoma ineligible for autologous stem cell transplantation. Future studies should determine optimal duration and sequencing of BTK inhibition for patients with mantle cell lymphoma and should define subsets of patients who no longer require chemotherapy treatment for this disease.

*Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD.

ABSTRACT BACKGROUND: The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival, but without improvement to overall survival likely due to toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS: Patients aged ≥65 years with previously untreated mantle cell lymphoma received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus 6 cycles of bendamustine (90 mg/m2 ; days 1 and 2) and rituximab (375 mg/m2 ; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. Primary endpoint was progression-free survival per independent review committee; overall response rate and overall survival were secondary endpoints. RESULTS: In total, 598 patients were randomized, with 299 in each arm. At a median followup of 44.9 months, median progression-free survival was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio, 0.73; 95% confidence interval, 0.57 to 0.94; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. Overall survival was not significantly different (hazard ratio, 0.86; 95% confidence interval, 0.65 to 1.13; P = .27). Grade 3 or greater adverse events were reported ACCEPTED UNEDITED in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.

CONCLUSIONS: Combination of acalabrutinib with bendamustine-rituximab significantly improved progression-free survival. Clinical benefit of acalabrutinib with bendamustinerituximab was achieved with manageable toxicity.

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