Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia

BackgroundWhether 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.MethodsIn 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.ResultsA 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.ConclusionsAcalabrutinib–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.)