Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia

Brown, JR; Seymour, JF; Jurczak, W; Aw, A; Wach, M; Illes, A; Tedeschi, A; Owen, C; Skarbnik, A; Lysak, D; Eom, KS; Šimkovič, M; Pavlovsky, MA; Kater, AP; Eichhorst, B; Miller, K; Munugalavadla, V; Yu, T; de Borja, M; Ghia, P; AMPLIFY investigators

Author(s): Brown, JR; Seymour, JF; Jurczak, W; Aw, A; Wach, M; Illes, A; Tedeschi, A; Owen, C; Skarbnik, A; Lysak, D; Eom, KS; Šimkovič, M; Pavlovsky, MA; Kater, AP; Eichhorst, B; Miller, K; Munugalavadla, V; Yu, T; de Borja, M; Ghia, P; AMPLIFY investigators;
Details: Publication Year 2025-02-20,Volume 392,Issue #8,Page 748-762
Journal Title: New England Journal of Medicine
Publication Type: Research article
Abstract: 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.).
Keywords: Humans; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality; Male; Female; Middle Aged; Aged; *Pyrazines/adverse effects/administration & dosage; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects; *Progression-Free Survival; *Benzamides/adverse effects/administration & dosage; *Sulfonamides/administration & dosage/adverse effects; *Rituximab/administration & dosage/adverse effects; *Bridged Bicyclo Compounds, Heterocyclic/administration & dosage/adverse; effects/therapeutic use; *Cyclophosphamide/administration & dosage/adverse effects; Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects; Aged, 80 and over; Vidarabine/analogs & derivatives/administration & dosage/adverse effects; Adult
Department(s): Haematology
Publisher's Version: https://doi.org/10.1056/NEJMoa2409804
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-03-14 07:06:22

Last Modified: 2025-03-14 07:08:56