Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma

J Clin Oncol. 2025 Jul 10;43(20):2276-2284. doi: 10.1200/JCO-25-00690. Epub 2025 May 1.

Abstract

Purpose: 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 (PFS), but without improvement in overall survival (OS), likely because of 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 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m2 once daily; days 1 and 2) and rituximab (375 mg/m2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points.

Results: In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 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. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.

Conclusion: The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Trial registration: ClinicalTrials.gov NCT02972840.

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Clinical Trial, Phase III

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Bendamustine Hydrochloride / administration & dosage
  • Bendamustine Hydrochloride / adverse effects
  • Benzamides / administration & dosage
  • Benzamides / adverse effects
  • Double-Blind Method
  • Female
  • Humans
  • Lymphoma, Mantle-Cell* / drug therapy
  • Lymphoma, Mantle-Cell* / mortality
  • Lymphoma, Mantle-Cell* / pathology
  • Male
  • Progression-Free Survival
  • Pyrazines / administration & dosage
  • Pyrazines / adverse effects
  • Rituximab / administration & dosage
  • Rituximab / adverse effects

Substances

  • Bendamustine Hydrochloride
  • acalabrutinib
  • Rituximab
  • Pyrazines
  • Benzamides

Associated data

  • ClinicalTrials.gov/NCT02972840