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/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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (274)
David Salek
4Department of Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital, Brno, Czech Republic
Brad S. Kahl
30Division of Oncology, Washington University School of Medicine, St. Louis, MO
Michael P. Chu
Alberta Health Services, Edmonton, Canada
Chan Y. Cheah
12Department of Haematology, Sir Charles Gairdner Hospital, Perth, Australia
Jingyang Zhang
Key Laboratory for Green Chemical Technology of Ministry of Education, Collaborative Innovation Center of Chemical Science and Engineering, School of Chemical Engineering and Technology
Robin Lesley
22AstraZeneca, South San Francisco, United States
Safaa Ramadan
AstraZeneca, Cambridge, United Kingdom
Simon Rule
18AstraZeneca, Cambridge, United Kingdom
Nicolás Cazap
5CEMIC, Buenos Aires, Argentina
Maria Cecilia Foncuberta
Gonzalo Garate
Jarchum Gustavo
Miguel A Pavlovsky
Dardo Riveros
Ross Baker
1Perth Blood Institute, Perth, Australia
Jason Butler
1University of Florida, Medicine, Gainesville, United States
Paul Cannell
11Fiona Stanley Hospital, Murdoch, Australia
Chan Cheah
20Sir Charles Gairdner Hospital, Nedlands, Australia
Tara Cochrane
3Gold Coast University Hospital, Southport, Australia
Cecily Forsyth
4Gosford Hospital, Gosford, Australia
Pratyush Giri
26Royal-Adelaide-Hospital, Adelaide, Australia
Amanda Johnston
3Polaris Pharmaceuticals, Inc., San Diego, United States
Denise Lee
Hui-Peng Lee
Sally Mapp
Fernando Roncolato
Aung Thant
Patricia Walker
9Peninsula Health and Peninsula Private Hospital, Melbourne, Australia
Nicole Wong Doo
5Concord Hospital, Concord Clinical School, University of Sydney, Haematology, Sydney, Australia
Hilde Demuynck
Fritz Offner
Vanessa Van Hende
Vibeke Vergote
Ka Lung Wu
Carlos Chiattone
4Department of Medicine, Santa Casa Medicine School, Sao Paulo, Brazil
Sérgio de Azevedo
João Samuel de Holanda Farias
3Hematology Department, Hospital Erasto Gaertner, Curitiba, Brazil
Laura Fogliatto
19Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
Ana Fonseca
Nelson Hamerschlak
Nicolas Lazaretti
Vanderson Rocha
Jose Salvador Rodrigues de Oliveira
Marco Salvino
Rodrigo Santucci
38Instituto Hemomed de Oncologia e Hematologia, Sao Paulo, Brazil
Mariza Schaan
Phillip Scheinberg
1Hospital A Beneficência Portuguesa, Sao Paulo, Brazil
Adriana Scheliga
9Instituto Oncoclinicas, Rio de Janeiro, Brazil
Garles Miller Vieira
Neil Berinstein
14Sunnybrook Health Sciences Centre, Toronto, Canada
Melina Boutin
5Canada Centre Intégré de Cancérologie de la Montérégie, Université de Sherbrooke, Quebec, Canada
Michael Chu
1University of Alberta, Hematology, Edmonton, Canada
Mary-Margaret Keating
Dalhousie University, Nova Scotia, Nova Scotia, Canada
Ariah Schattner
Diego Villa Restrepo
Xinan Cen
3Department of Hematology, Peking University First Hospital Beijing, China, beijing, China
Xin Du
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China
Ru Feng
Sujun Gao
2The First Bethune Hospital of Jilin University, Changchun, China
Haiwen Huang
Jie Ji
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry
Jie Jin
School of Emergency Management, School of the Environment and Safety Engineering
Xiaoyan Ke
Dengju Li
8Department of Hematology, Tongji hospital, Tongji Medical College，Huazhong University of Science and Technology, Wuhan, China
Fei Li
Jianyong Li
Department of Pathogenic Biology, Army Medical University
Junmin Li
Yan Li
Yufu Li
Zhenyu Li
Li'e Lin
29Hainan Provincial People's Hospital, Haikou, China
Tingbo Liu
Fangfang Lv
15Fudan University, Shanghai, China
Yuerong Shuang
Yuqin Song
Lan Sun
State Key Laboratory of Physical Chemistry of Solid Surfaces and Department of Chemistry, College of Chemistry and Chemical Engineering
Xiuhua Sun
Zhao Wang
State Key Laboratory of Bioinspired Interfacial Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Materials, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, College of Chemistry, Chemical Engineering and Materials Science
Huijing Wu
3Department of Lymphoma Medicine, Hubei Cancer Hosipital, Tongji Medical College, Huazhong University of Science and Technology, wuhan, China
Yaming Xi
Ruixiang Xia
21The First Affiliated Hospital of Anhui Medical University, Hefei, China
Hongwei Xue
1The Affiliated Hospital of Qingdao University, Qingdao, China
Haiyan Yang
Shuhua Yi
4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Cheng Zhang
Huilai Zhang
Mingzhi Zhang
Qingyuan Zhang
Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China
Xielan Zhao
13Xiangya Hospital Central South University, Changsha, China
Hui Zhou
Department of Chemistry and Materials
David Belada
4th Department of Internal Medicine - Haematology, University Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic
Roman Hajek
Pavel Jindra
9Charles University Hospital, Pilsen, Czech Republic
Jiri Mayer
6Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University Brno, Brno, Czech Republic
Jan Novak
Julie Abraham
31Service Hématologie Clinique et Thérapie Cellulaire, Centre Hospitalier Universitaire de Limoges–Hôpital Dupuytren, Limoges, France
Fontanet Bijou
24Service d'Hématologie, Institut Bergonie, Bordeaux, France
Kamal Bouabdallah
Florence Cymbalista
Sophie de Guilbert
Vincent Delwail
Philippe Genet
Kamel Laribi
13CH du mans, Le Mans, France
Philippe Rodon
Thomas Decker
16Oncological Practice, Ravensburg, Germany
Peter Dreger
Martin Dreyling
LMU Hospital, Munich, Germany
Georg Hess
4Department of Hematology/Oncology, Johannes Gutenberg-Universität Mainz, Mainz, Germany
Georg Lenz
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Dirk Tummes
Konstantinos Anargyrou
Meletios-Athanassios Dimopoulos
Eleni Kapsali
Eirini Katodritou
Theagenio Cancer Hospital, Thessaloniki, Greece
Despoina Kyriakou
Panayiotis Panayiotidis
National and Kapodistrian University of Athens, Athens, Greece
Vasiliki Pappa
5National and Kapodistrian University of Athens School of Medicine, Attikon University Hospital, Second Department of Internal Medicine and Research Unit, Hematology Unit, Athens, Greece
Niki Stavroyianni
Argiris Symeonidis
Hoi Ching Cheng
Yok-Lam Kwong
11University of Hong Kong, Hong Kong, Hong Kong
Harold Lee
Ting Ying Ng
Tuen Mun Hospital, Hong Kong, Hong Kong
Raymond Wong
7The Chinese University of Hong Kong, Shatin, Hong Kong
Zita Borbenyi
Arpad Illes
Zsolt Lazar
3Petz Aladár County Teaching Hospital, Győr, Hungary
Ágnes Nagy
Zsolt Nagy
32Semmelweis University, Department of Internal Medicine and Hematology, Division of Hematology, Budapest, Hungary
Tamas Schneider
Irit Avivi
From Tel Aviv Sourasky Medical Center (Y.C.C., I.A.), and the Faculty of Medical and Health Sciences, Tel Aviv University (Y.C.C., H.M., I.A.), Tel Aviv, Chaim Sheba Medical Center, Ramat Gan (H.M.), and Hadassah Hebrew University Medical Center, Jerusalem (M.G.) — all in Israel; McGill University and McGill University Health Centre, Montreal (M.S.), and Alberta Health Services, Edmonton (M.P.C.) — all in Canada; Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), Seoul St. Mary’s Hospital, Catholic University of Korea (C.-K.M.), and Seoul National University College of Medicine (S.-S.Y.) — all in Seoul, South Korea; Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, Universidad de Cantabria, Santander (E.M.O.), Cancer Center Clínica Universidad de Navarra, Center for Applied Medical Research, Pamplona (P.R.-O.), Institut Català d’Oncologia, Josep Carreras Leukemia Research Institute, and the Hospital Germans Trias i Pujol, Barcelona (A.O.)...
Ronit Gurion
2Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel
Netanel Horowitz
2Rambam Medical Center, Haifa, Israel
Aaron Ronson
11Shaare Zedek Medical Center, Hematology, Jerusalem, Israel
Luca Arcaini
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Carola Boccomini
Azienda Ospedaliero–Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
Paolo Ghia
School of Medicine, Università Vita Salute San Raffaele, Milan
Stefano Luminari
Azienda Unita Sanitaria Locale IRCCS of Reggio Emilia, Reggio Emilia, Italy
Caterina Patti
21“Villa Sofia – Cervello” Hospital, Palermo, Italy
Caterina Plenteda
19Azienda Ospedaliera-Universitaria di Parma, Parma, Italy
Armando Santoro
IRCCS Humanitas Research Hospital, Milan
Vittorio Ruggero Zilioli
12Division of Hematology, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy
Pier Luigi Zinzani
12IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli,” Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
Ilseung Choi
33National Hospital Organization Kyushu Cancer Center, Department of Hematology, Fukuoka, Japan
Daisuke Ennishi
4Okayama University Hospital, Center for Comprehensive Genomic Medicine, Okayama, Japan
Kentaro Fukushima
University of Osaka Graduate School of Medicine, Suita, Japan
Satoshi Ichikawa
Takayuki Ishikawa
Koji Izutsu
National Cancer Center Hospital, Tokyo, Japan
Koji Kato
Dai Maruyama
Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Tokyo
Hirokazu Nagai
19National Hospital Organization Nagoya Medical Center, Aichi, Japan
Shuichi Ota
Toko Saito
Rika Sakai
Ritsuro Suzuki
1Shimane University, Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Izumo, Japan
Hiro Tatetsu
15Kumamoto University Hospital, Department of Hematology, Rheumatology, and Infectious diseases, Kumamoto, Japan
Nobuhiko Uoshima
8Japanese Red Cross Kyoto Daini Hospital, Hematology, Kyoto-shi, Japan
Takahiro Yano
Isao Yoshida
Ki-Seong Eom
5Catholic Hematology Hospital, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
Jin Seok Kim
10Yonsei University College of Medicine, Severance Hospital, Seoul, Korea
Sang-A Kim
Seok Jin Kim
Jung-Hee Lee
Yeung Chul Mun
Sung Yong Oh
14Department of Oncology, Dong-A University Hospital, Busan, South Korea, Busan, Korea
Sung Soo Yoon
Elsa Veronica Avila Arreguin
Adriana Dominguez Andrade
David Gomez Almaguer
Maria Silvia Rivas Vera
Luis Solis Anaya
Leanne Berkahn
Samar Issa
Lucy Pemberton
3Southern Blood and Cancer Service, Dunedin Hospital, Dunedin, New Zealand
David Simpson
6BeiGene, Aukland, New Zealand
Brady Beltran
6Hospital Edgardo Rebagliati, Lima, Peru
Shirely Quintana
Jose Carlos Revilla
Ernesto Vargas
Sebastian Grosicki
Department of Cancer Prevention, Medical University of Silesia, Katowice, Poland
Janusz Halka
Wieslaw Jedrzejczak
Wojciech Jurczak
Wanda Knopinska-Posluszny
Jacek Krzanowski
7Specialist Hospital in Brzozow, Podkarpackie Oncology Center, Brzozow, Poland
Ewa Lech-Maranda
13Institute of Hematology and Transfusion Medicine, Warsaw, Poland
Marta Morawska
Tadeusz Robak
36Department of Hematology, Medical University of Lodz, Lodz, Poland
Piotr Rzepecki
Tomasz Wróbel
Gabriela Borsaru
Tudor Eliade Ciuleanu
Catalin Danaila
Mihaela Lazaroiu
17Policlinica de Diagnostic Rapid Brasov, Department of Hematology, Brasov, Romania
Julia Alexeeva
Valeriy Chistyakov
Georgy Manikhas
Natalia Mikhailova
Andrey Proydakov
Elena Mikhailovna Volodicheva
Sergey Voloshin
Mariana Bastos
Javier Briones
1Hematology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Raúl Córdoba
Jose Gomez Codina
Hospital Universitari i Politècnic La Fe, Valencia, Spain
Eva Maria Gonzalez
Ana Marin
1Vall d'Hebron University Hospital, Barcelona, Spain
Carlos Panizo
Guillermo Rodriguez
Antonio Salar
39Hospital Universitario de la Arrixaca, Hematology, Murcia, Spain
Juan-Manuel Sancho
36Hospital Universitario Germans Trias i Pujol-ICO-Badalona, Hematology, Barcelona, Spain
Jose A Velo
Victor Jimenez Yuste
Chien-Yuan Chen
Chang-Fang Chiu
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
Liang-Tsai Hsiao
Ching-Yuan Kuo
3Chang Gung Memorial Hospital at Kaohsiung, Hematology-Oncology, Kaohsiung, Taiwan
Tung-Liang Lin
1Chang Gung Memorial Hospital at Linkou, Hematology-Oncology, Taoyuan, Taiwan
Iryna Kryachok
Department of Oncohematology, National Cancer Institute, Kyiv, Ukraine
Tamila Lysa
Zvenyslava Maslyak
Larysa Nogaieva
9CNE CCOHTPC of Cherkasy Regional Council, Cherkasy, Ukraine
Sergey Polenkov
Ganna Usenko
Richie Agajanian
Bertrand Anz
3Tennessee Oncology, Chattanooga, United States
Arvind Chaudhry
Summit Cancer Centers, Spokane Valley, WA
Alden Chiu
Jennifer Cultrera
8Florida Cancer Specialists & Research Institute, Leesburg, United States
James D'Olimpio
13Clinical Research Alliance, Westbury, United States
Kieron Dunleavy
2Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, United States
Suzanne Fanning
8Prisma Health Cancer Institute, Greenville, United States
Ian Flinn
10OneOncology and Tennessee Oncology, Nashville, TN
Nashat Gabrail
6Gabrail Cancer Center, Canton, United States
David Gallinson
Cooperman Barnabas Medical Center, Livingston, NJ
Alec Goldenberg
Andre Goy
14Division of Oncology, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ
Solomon Graf
3VA Puget Sound, Seattle, United States
Natalie Grover
11Division of Hematology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
Brian Hess
7Department of Medicine, Division of Hematology and Oncology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
Marc Hoffman
Iris Isufi
Brad Kahl
8Washington University, Division of Oncology, St. Louis, United States
Suman Kambhampati
9Kansas City VA Medical Center, Kansas City, United States
Dean Kirkel
Guillermo Lazo Diaz
Moshe Levy
4Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, United States
Delong Liu
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
Monica Mead
Division of Hematology/Oncology, University of California, Los Angeles (UCLA), Los Angeles, CA
Jonas Paludo
1Mayo Clinic, Rochester, United States
Anjan Patel
Shachar Peles
7Florida Cancer Specialists and Research Institute, Atlantis, United States
Daniel Persky
13BeOne Medicines Ltd, San Carlos, United States
Craig Portell
1University of Virginia, Charlottesville, United States
Allison Rosenthal
1Mayo Clinic, Hematology/Oncology, Rochester, United States
Dahlia Sano
1Division of Hematology/Oncology, University of Michigan, Ann Arbor, United States
Sonali Smith
11University of Chicago, Medicine, Chicago, United States
Stephen Smith
Stephen Spurgeon
1Oregon Health & Sciences University, Knight Cancer Institute, Portland, United States
Don Stevens
3Norton Cancer Institute, Louisville, United States
Jason Tache
Michaela Tsai
Lauren Veltri
1West Virginia University School of Medicine, Internal Medicine, Morgantown, United States
Michael Wang
Habte Yimer
9Texas Oncology-Tyler, US Oncology Research, Tyler, United States
Quoc Khanh Bach
Huyen Nga Do
Hung Vu Luu
Trong Khoa Mai
Nhu Hiep Pham
Thanh Tung Tran