Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2

Abstract

Results of RESONATE-2 (PCYC-1115/1116) supported approval of ibrutinib for first-line treatment of chronic lymphocytic leukemia. Extended analysis of RESONATE-2 was conducted to determine long-term efficacy and safety of ibrutinib in older patients with chronic lymphocytic leukemia. A total of 269 patients aged ≥65 years with previously untreated chronic lymphocytic leukemia without del(17p) were randomized 1:1 to ibrutinib (n=136) or chlorambucil (n=133) on days 1 and 15 of a 28-day cycle for 12 cycles. Median ibrutinib treatment duration was 28.5 months. Ibrutinib significantly prolonged progression-free survival versus chlorambucil (median, not reached vs 15 months; hazard ratio, 0.12; 95% confidence interval, 0.07-0.20; P<0.0001). The 24-month progression-free survival was 89% with ibrutinib (97% and 89% in patients with del[11q] and unmutated immunoglobulin heavy chain variable region gene, respectively). Progression-free survival rates at 24 months were also similar regardless of age (<75 years [88%], ≥75 years [89%]). Overall response rate was 92% (125/136). Rate of complete response increased substantially from 7% at 12 months to 18% with extended follow up. Greater quality of life improvements occurred with ibrutinib versus chlorambucil in Functional Assessment of Chronic Illness Therapy-Fatigue (P=0.0013). The most frequent grade ≥3 adverse events were neutropenia (12%), anemia (7%), and hypertension (5%). Rate of discontinuations due to adverse events was 12%. Results demonstrated that first-line ibrutinib for elderly patients with chronic lymphocytic leukemia provides sustained response and progression-free survival benefits over chemotherapy, with depth of response improving over time without new toxicity concerns. This trial was registered at clinicaltrials.gov identifier 01722487 and 01724346.

Trial registration: ClinicalTrials.gov NCT01722487 NCT01724346.

Figure 1.

PFS for the intent-to-treat population. Survival analyses from randomization until event or censored at last follow up using the Kaplan-Meier method. Vertical ticks indicate censored patients. PFS: progression-free survival.

Figure 2.

PFS subgroup analysis.

Figure 3.

Response rates over time in ibrutinib-treated patients. CR: complete response; CRi: complete response with incomplete blood-count recovery; nPR: nodular partial response (defined according to the International Workshop on Chronic Lymphocytic Leukemia criteria for response as a complete response with lymphoid nodules in the bone marrow); PR: partial response; PR-L: partial response with lymphocytosis.

Figure 4.

Safety and tolerability of ibrutinib over time. Rate of grade ≥3 AEs, discontinuations due to AEs, and dose reductions over different periods of time. AE, adverse events.