CONTEXT : Ibrutinib is the only once-daily inhibitor of Bruton's tyrosine kinase with significant overall survival benefit versus established therapies in patients with previously untreated CLL/SLL. Data on long-term treatment, outcomes, and safety are essential to inform clinical decision making.

OBJECTIVE : To describe characteristics of patients on long-term ibrutinib treatment (≥5 years) in the RESONATE-2 study.

DESIGN : Phase 3, open-label, multicenter, international, randomized study (PCYC-1115/PCYC-1116; NCT01722487/NCT01724346).

SETTING : Academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, Europe, and USA.

PATIENTS OR OTHER PARTICIPANTS : Patients aged ≥65 years with previously untreated CLL/SLL and without del(17p).

INTERVENTIONS : Patients were randomly assigned 1:1 to once-daily single-agent ibrutinib 420 mg until disease progression or unacceptable toxicity (n=136) or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles (n=133).

MAIN OUTCOME MEASURES : Outcomes for this analysis were baseline demographics and clinical characteristics, best overall response rates, prevalence of adverse events (AEs), and AEs leading to dose modifications among patients on long-term ibrutinib treatment.

RESULTS : Baseline characteristics within the intent-to-treat population (n=136) were generally similar between patients who remained on ibrutinib treatment ≥5 years (n=79), versus those off treatment by 5 years (n=57): median age, 71 versus 74 years; male, 62% versus 68%; Rai stage III/IV, 47% versus 40%; TP53 mutated, 9% versus 7%; and unmutated IGHV, 46% versus 39%. Several baseline characteristics favored long-term ibrutinib treatment (female sex, age ≤73 years, no cytopenia, no bulky disease [<5 cm]); none reached statistical significance. In patients on long-term treatment, complete response rates improved over time, reaching 42% (33/79 patients) by 5 years. Prevalence of the most common any-grade AEs decreased over time. Dose reductions (16/79 [20%]) and dose holds (45/79 patients [57%]) were used for AE management. AE resolution occurred in nearly all patients who had a dose reduction (14/16 [88%]) or dose hold (43/45 [96%]).

CONCLUSIONS : Across patient subgroups, more than half (58%) of ibrutinib-randomized patients benefitted from long-term ibrutinib treatment for ≥5 years. Responses deepened over time through 5 years. Dose modification was effective in resolving AEs for the majority of patients, thereby allowing patients to remain on treatment.