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.

4th Department of Internal Medicine Haematology Charles University Hospital and Faculty of Medicine Hradec Králové Czech Republic

AstraZeneca Cambridge United Kingdom

AstraZeneca South San Francisco CA

Central Coast Haematology North Gosford Australia

Clinical Hematology Department ICO IJC Hospital Germans Trias i Pujol Badalona Spain

Department of Clinical Hematology Hospital de Clinicas de Porto Alegre Porto Alegre Brazil

Department of Clinical Oncology MSC National Research Institute of Oncology Krakow Poland

Department of Haematology Sir Charles Gairdner Hospital Nedlands Australia

Department of Hematology Henan Cancer Hospital Zheng Zhou China

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Lymphoma Myeloma MD Anderson Cancer Center University of Texas Houston TX

Department of Medical Oncology Cross Cancer Institute University of Alberta Edmonton Canada

Department of Oncohematology National Cancer Institute Kyiv Ukraine

Division of Hematology Department of Medicine Mayo Clinic Rochester MN

Experimental Hematooncology Department Medical University of Lublin Lublin Poland

Hematology Department St John's Cancer Center Lublin Poland

Key Laboratory of Carcinogenesis and Translational Research Department of Lymphoma Peking University Cancer Hospital and Institute Beijing China

Medical School University of Western Australia Perth Australia

Medizinische Klinik 3 Klinikum der Universitaet Munchen Muenchen Germany

Oncohematology Unit A O O R Villa Sofia Cervello Palermo Italy

Pratia MCM Maków Krakow Poland

Washington University in St Louis St Louis MO

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