Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma
Michael Wang, David Šálek, David Belada, Yuqin Song, Wojciech Jurczak, Brad S. Kahl, Jonas Paludo, Michael P. Chu, Iryna Kryachok, Laura Maria Fogliatto, Chan Y. Cheah, Marta Morawska, Juan‐Manuel Sancho, Yufu Li, Caterina Patti, Cecily Forsyth, Jingyang Zhang, Robin Lesley, Safaa Ramadan, Simon Rule, Martin Dreyling, for the ECHO investigators, Nicolas Cazap, Maria Cecilia Foncuberta, Gonzalo Garate, Jarchum Gustavo, Miguel A Pavlovsky, Dardo Riveros, Ross Baker, Jason Butler, Paul Cannell, Chan Cheah, Tara Cochrane, Cecily Forsyth, Pratyush Giri, Amanda Johnston, Denise Lee, Hui-Peng Lee, Sally Mapp, Fernando Roncolato, Aung Thant, Patricia Walker, Nicole Wong Doo, Hilde Demuynck, Fritz Offner, Vanessa Van Hende, Vibeke Vergote, Ka Lung Wu, Carlos Chiattone, Sergio de Azevedo, Joao Samuel de Holanda Farias, Laura Fogliatto, Ana Fonseca, Nelson Hamerschlak, Nicolas Lazaretti, Vanderson Rocha, Jose Salvador Rodrigues de Oliveira, Marco Salvino, Rodrigo Santucci, Mariza Schaan, Phillip Scheinberg, Adriana Scheliga, Garles Miller Vieira, Neil Berinstein, Melina Boutin, Michael Chu, Mary-Margaret Keating, Ariah Schattner, Diego Villa Restrepo, Xinan Cen, Xin Du, Ru Feng, Sujun Gao, Haiwen Huang, Jie Ji, Jie Jin, Xiaoyan Ke, Dengju Li, Fei Li, Jianyong Li, Junmin Li, Yan Li, Yufu Li, Zhenyu Li, Li'e Lin, Tingbo Liu, Fangfang LV, Yuerong Shuang, Yuqin Song, Lan Sun, Xiuhua Sun, Zhao Wang, Huijing Wu, Yaming Xi, Ruixiang Xia, Hongwei Xue, Haiyan Yang, Shuhua Yi, Cheng Zhang, Huilai Zhang
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/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 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.