Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma

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.

FIG 1.

CONSORT diagram showing patient disposition. BR, bendamustine-rituximab.

FIG 2.

PFS and OS with and without COVID-19 deaths and PFS by acalabrutinib exposure. (A) PFS in the full analysis population. (B) PFS when COVID-19 deaths were censored. (C) OS in the full analysis population, including crossover. (D) OS when COVID-19 deaths were censored. Symbols in all panels indicate censored data. BR, bendamustine-rituximab; HR, hazard ratio; NE, not estimable; OS, overall survival; PD, progressive disease; PFS, progression-free survival.

FIG 3.

Subgroup analysis of PFS (full analysis population). Forest plot of subgroup analysis for PFS assessed by the independent review committee. ^aPer interactive voice/web response system record. BR, bendamustine-rituximab; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; MCL, mantle cell lymphoma; MIPI, Mantle Cell Lymphoma International Prognostic Index; PFS, progression-free survival.