Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL.

With up to 10 years of follow-up, we report results from the final analysis of RESONATE-2 (NCT01722487/NCT01724346), a phase 3 study of first-line ibrutinib versus chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/day; n = 136) or chlorambucil (0.5-0.8 mg/kg ≤12 cycles; n = 133) until disease progression/unacceptable toxicity. With a median follow-up of 9.6 in the ibrutinib arm, median PFS was 8.9 years (95% CI, 7.0-NE) versus 1.3 years (95% CI, 0.9-1.6) for the chlorambucil arm. Among patients with unmutated IGHV, del(11q), mutated TP53, or complex karyotype median PFS was 8.4 years (95% CI, 6.8-NE) with ibrutinib and 0.7 years (95% CI, 0.4-1.2) with chlorambucil. Median overall survival (OS) with ibrutinib was not reached. Most common adverse events (AEs) of any grade included diarrhea (52%), fatigue (41%), cough (39%), nausea (32%), arthralgia (31%), peripheral edema (31%), and hypertension (30%). During the entire study period, 34/136 patients (25%) had an ibrutinib dose reduction due to AEs; these AEs improved in 30/34 patients (88%). At study completion, 27% of patients remained on first-line ibrutinib treatment. With the longest follow-up to date from a phase 3 study of any targeted CLL/SLL therapy, this landmark RESONATE-2 study defines median PFS and demonstrates continued OS benefit of first-line ibrutinib treatment for patients with CLL/SLL, including those with high-risk genomic features. Sustained efficacy and tolerability of ibrutinib reemphasize the favorable benefit-risk profile.