Author(s): Jennifer R. Brown, M.D.1; John F. Seymour, M.D.2,3; Wojciech Jurczak, M.D.4; Andrew Aw, M.D.5; Malgorzata Wach, M.D.6; Arpad Illes, M.D.7; Alessandra Tedeschi, M.D.8; Carolyn Owen, M.D.9; Alan Skarbnik, M.D.10; Daniel Lysak, M.D.11; Ki-Seong Eom, M.D.12; Martin Šimkovič, M.D.13; Miguel Arturo Pavlovsky, M.D.14; Arnon Philip Kater, M.D.15; Barbara Eichhorst, M.D.16; Kara Miller, M.S.17; Veerendra Munugalavadla, Ph.D.17; Ting Yu, M.D.17; Marianne de Borja, M.S.18; Paolo Ghia, M.D.19,20; for the AMPLIFY investigators.
BACKGROUND
Whether fixed-duration acalabrutinib–venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown.
METHODS
In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib–venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib–venetoclax–obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator’s choice of fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib–venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review.
RESULTS
A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib–venetoclax, 286 acalabrutinib–venetoclax–obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine–cyclophosphamide–rituximab and 147 bendamustine–rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib–venetoclax, 83.1% with acalabrutinib–venetoclax–obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib–venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P=0.004; for the comparison of acalabrutinib–venetoclax–obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib–venetoclax, 87.7% with acalabrutinib–venetoclax–obinutuzumab, and 85.9% with chemoimmunotherapy. Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively; death from coronavirus disease 2019 was reported in 10, 25, and 21 patients in the three groups.
CONCLUSIONS
Acalabrutinib–venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.)
Author Affiliations
1Dana–Farber Cancer Institute, Boston; 2Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; 3Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; 4Maria Sklodowska-Curie National Institute of Oncology, Kraków, Poland; 5University of Ottawa, Ottawa; 6Medical University of Lublin, Lublin, Poland; 7Faculty of Medicine, Division of Hematology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary; 8ASST Grande Ospedale Metropolitano Niguarda, Niguarda Cancer Center, Milan; 9University of Calgary, Calgary, AB, Canada; 10Novant Health Cancer Institute, Charlotte, NC; 11Fakultní Nemocnice Plzen, Pilsen, Czech Republic; 12Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea; 134th Department of Internal Medicine–Hematology, Faculty of Medicine in Hradec Králové, University Hospital and Charles University, Hradec Kralove, Czech Republic; 14FUNDALEU, Clinical Research Center, Buenos Aires; 15Amsterdam University Medical Centers, University of Amsterdam, Amsterdam; 16University Hospital Cologne, Cologne, Germany; 17AstraZeneca, South San Francisco, CA; 18AstraZeneca, Mississauga, ON, Canada; 19Università Vita-Salute San Raffaele, Milan; 20IRCCS Ospedale San Raffaele, Milan.
