Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly, with the majority of patients older than 65 years at diagnosis. Historically, younger, more fit patients were eligible for aggressive chemoimmunotherapy treatments, but older age and comorbid conditions can limit options due to tolerability concerns. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by the FDA for the treatment of patients with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Results from the phase 3 RESONATE and RESONATE-2 trials established ibr as a standard option in relapsed/refractory (R/R) and treatment-naïve (TN) CLL/SLL.1,2 Woyach and colleagues now report on the safety and efficacy data from these studies by age.
RESONATE randomized 391 patients with R/R CLL/SLL to receive ibr 420 mg once daily until progressive disease (PD) or unacceptable toxicity (n = 195), or intravenous ofatumumab 300 mg at week 1, 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks (n = 196). RESONATE-2 randomized TN patients aged ≥65 years to receive ibr 420 mg once daily until PD (n = 136), or to receive chlorambucil (clb) 0.5 mg/kg to a maximum of 0.8 mg/kg on days 1 and 15 of a 28-day cycle for up to 12 cycles (n = 133). Patient data from both studies were grouped by age and analyzed for effect of age on outcome.
The ibr group included 136 TN patients: 65 to <75 years of age (termed mid, n = 90) and ≥75 years of age (termed old, n = 46), and 195 R/R patients: <65 years of age (termed young, n = 77), 65 to <75 years of age (mid, n = 75), and ≥75 years of age (old, n = 43). For ibr, median follow-up was 28.6 months for TN and 36.1 months for R/R patients. For TN ibr patients, the 24-month progression-free survival (PFS) rates were 88% (mid) and 89% (old), whereas clb patients aged ≥75 years did worse than those aged 65 to <75 years (23% vs 40%). For R/R patients, the 24-month PFS was 75% (young), 77% (mid), and 62% (old). For ibr, median overall survival was not reached for any age subgroup (R/R or TN). The CR+CRi rates for TN ibr patients were 19% (mid) and 17% (old) and for R/R patients were 6% (young), 9% (mid), and 9% (old). The most frequent any-grade adverse events (AEs) were diarrhea, fatigue, cough, upper respiratory tract infection, nausea, pyrexia, and anemia for all patients and age subgroups. The prevalence of common grade ≥3 AEs was typically highest in the first 12 months of ibr therapy, and decreased thereafter for all age groups. Patients ≥75 years of age had a higher rate of grade ≥3 neutropenia and urinary tract infection in both TN and R/R populations. R/R ibr patients <65 years experienced a lower frequency of grade ≥3 pneumonia and atrial fibrillation (AF) than the older subgroups. Any grade AF occurred in 11% (mid) and 9% (old) of TN ibr patients, and 1% (young), 20% (mid), and 14% (old) of R/R ibr patients.
The authors concluded that the PFS rate for TN ibr patients was similar regardless of age subgroup, whereas it was shorter for clb-treated patients ≥75 years compared with those 65 to <75 years. In the R/R population, ibr patients ≥75 years had a numerically (but not statistically significant) lower PFS compared with those <75 years. There was no perceivable difference in CR rate by age within the TN and R/R ibr populations. The rates of grade ≥3 AEs tended to be higher in patients aged ≥75 years for both ibr and comparator arms, but age did not impact discontinuation rates due to AEs for TN patients treated with ibr. This analysis supports single-agent ibrutinib as a treatment option regardless of patient age, but reinforces the need for close toxicity monitoring, especially in older patients and particularly during the initial stage of treatment.
Woyach JA, et al. ASH 2016. Abstract 2041.
- O’Brien S, et al. Lancet Oncol. 2014;15:48-58.
- Byrd JC, et al. N Engl J Med. 2013;369:32-42.