Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

• Published in: Leukemia 2020-03, Vol.34 (3), p.787-798
• Main Authors: Burger, Jan A., Barr, Paul M., Robak, Tadeusz, Owen, Carolyn, Ghia, Paolo, Tedeschi, Alessandra, Bairey, Osnat, Hillmen, Peter, Coutre, Steven E., Devereux, Stephen, Grosicki, Sebastian, McCarthy, Helen, Simpson, David, Offner, Fritz, Moreno, Carol, Dai, Sandra, Lal, Indu, Dean, James P., Kipps, Thomas J.
• Format: Article
• Language: English
• Subjects: 692/699/67/1059/602; 692/699/67/1990/283/1895; Adenine - analogs & derivatives; Aged; Aged, 80 and over; Anemia; Cancer; Cancer Research; Chlorambucil; Chlorambucil - administration & dosage; Chronic lymphocytic leukemia; Comparative analysis; Critical Care Medicine; Development and progression; Disease-Free Survival; Drug Administration Schedule; Drug therapy; Female; Follow-Up Studies; Gene deletion; Hematology; Humans; Hypertension; Hyponatremia; Inhibitor drugs; Intensive; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphatic leukemia; Lymphoma; Male; Medicine; Medicine & Public Health; Mutation; Neutropenia; Oncology; Oncology, Experimental; p53 Protein; Patient Safety; Piperidines; Prognosis; Progression-Free Survival; Pyrazoles - administration & dosage; Pyrimidines - administration & dosage; Risk; Survival; Targeted cancer therapy; Treatment Outcome
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-019-0602-x

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years ( n  = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1–66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098–0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk ( TP53 mutation, 11q deletion, and/or unmutated IGHV ) (PFS: HR [95% CI]: 0.083 [0.047–0.145]; OS: HR [95% CI]: 0.366 [0.181–0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.