RESONATE-2: Ibrutinib benefits in older CLL/SLL patients sustained at 5 years

The single-agent ibrutinib demonstrates significant and durable survival benefits compared with chlorambucil in the first-line treatment of older patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), including those with high-risk prognostic features, according to 5-year data from the RESONATE-2 study.

“This is the longest follow-up report of patients receiving first-line treatment with a BTK inhibitor in a phase III study to date,” researchers said.

The analysis included 269 patients aged ≥65 years randomized to once-daily ibrutinib 420 mg continuously (n=136) or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles (n=133). Over a median follow-up of 60 months, 56 patients (41 percent) on ibrutinib discontinued treatment, while 96 of those on chlorambucil experienced disease progression and 75 of them crossed over to the other treatment arm.

The survival advantage previously seen with ibrutinib remained significant. Five-year estimates for progression-free survival (PFS) were 70 percent vs 12 percent with chlorambucil (hazard ratio [HR], 0.146, 95 percent CI, 0.098–0.218). The corresponding estimates for overall survival (OS) were 83 percent vs 68 percent (HR, 0.450, 95 percent CI, 0.266–0.761). [Leukemia 2020;34:787-798]

Results were consistent in the subgroups of patients with high prognostic risk, namely TP53 mutation, 11q deletion and/or unmutated IGHV (PFS: HR, 0.083, 95 percent CI, 0.047–0.145; OS: HR, 0.366, 95 percent CI, 0.181–0.736).

Additionally, depth of response improved over time with first-line ibrutinib. Investigator-assessed overall response rate was 92 percent. Complete response (CR) or CR with incomplete marrow recovery rates improved from 11 percent at the primary analysis (median follow-up, 18.4 months) to 30 percent after a median follow-up of 5 years. [N Engl J Med 2015;373:2425-2437]

“As the majority of patients with CLL (including those in this study) are elderly and may be less tolerant of toxicities, treatments with a tolerable safety profile in long-term use are essential. Late high-grade toxicities have been observed with other CLL therapies. In this study, no unexpected AEs were identified after extended follow-up of ibrutinib-treated patients,” the researchers pointed out. [Leuk Lymphoma 2015;56:2779-2786]

Common grade ≥3 adverse events (AEs) included neutropoenia (13 percent), pneumonia (12 percent), hypertension (8 percent), anaemia (7 percent) and hyponatremia (6 percent). Notably, ibrutinib discontinuations due to AEs decreased over time: 7 percent of patients in years 0–1, 6 percent in years 1–2, 5 percent in years 2–3, 6 percent in years 3–4, and 1 percent in years 4–5.

The researchers emphasized the importance of closely monitoring CLL/SLL patients during treatment to maximize optimal management of AEs with dose modifications (dose holds and reductions). “[This should] mitigate the impact of AEs and enable patients to continue to benefit from ongoing first-line ibrutinib.

“[N]ovel agents continue to be developed for CLL, [and] long-term data are crucial to inform practice… Here, we demonstrated that with a median of 5 years of follow-up, over half of patients with CLL/SLL were able to receive long-term continuous first-line treatment with single-agent ibrutinib and had sustained efficacy benefits,” they added.