Management of Adverse Events in the HELIOS Trial in Patients with Previously Treated CLL/SLL
Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton’s tyrosine kinase that is approved for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) in patients who have received at least 1 prior therapy and in patients with the high-risk deletion 17p cytogenetic feature.1 The HELIOS trial is a randomized, double-blind, placebo-controlled, phase 3 trial, which demonstrated that the addition of ibrutinib to the bendamustine/rituximab (BR) regimen resulted in an 80% reduction in disease progression or death in patients with previously treated CLL/small lymphocytic leukemia (SLL), who had ?1 prior lines of systemic therapy.1 At ASH 2015, Chanan-Khan and colleagues reported on the overall safety and management of adverse events with ibrutinib in comparison to placebo treatment in the HELIOS trial.2
In terms of anemia, rates of all-grade (22.3% vs 28.9%) and grade 3/4 incidence (3.5% vs 8.0%) were lower with ibrutinib/BR therapy compared with placebo/BR. Patients also required fewer transfusions with ibrutinib/BR therapy compared with placebo/BR (23% vs 29%); the use of growth factor support was similar in the 2 treatment arms (54% vs 52%, respectively). Grade 3/4 neutropenia occurred at similar rates between the 2 arms (53.7% vs 50.5%); treatment discontinuations due to neutropenia occurred less frequently in the ibrutinib/BR arm compared with placebo/BR (1.0% vs 2.8%). Although rates of all-grade thrombocytopenia were slightly higher in the ibrutinib/BR arm (30.7% vs 24.0%), rates of grade 3/4 events were similar between arms (15.0% both arms). The safety analysis showed that the rates of infection (both all-grade and grade 3/4) were similar in the ibrutinib/BR and placebo/BR arms.
Consistent with its known toxicity profile, higher rates of bleeding (31.0% and 14.6%) and atrial fibrillation (AF; 7.3% vs 2.8%) were reported in the ibrutinib/BR arm. Grade 3/4 major bleeding occurred in 2.1% of patients treated with ibrutinib/BR (vs 1.7% in control). Grade 3/4 AF events were higher (2.8% vs 0.7%) with ibrutinib/BR, and resulted in treatment discontinuations in 4 patients; these were managed by dose interruptions and restarting at the same dose (420 mg). Median time to AF onset was 3.0 months with ibrutinib/BR and 2.4 months with placebo/BR. Notably, the majority of patients with a history of AF or abnormal heart rhythm did not experience recurrent episodes with ibrutinib/BR therapy (7/25 vs 2/22). Overall, these results showed that the addition of ibrutinib to BR did not result in exacerbation of known BR treatment-related toxicities or in any unexpected toxicities, establishing its positive risk–benefit profile.
- Imbruvica (ibrutinib) [Prescribing information]. 2015.
- Chanan-Khan A, et al. ASCO 2015. LBA7005.
- Chanan-Khan A, et al. ASH 2015. Abstract 2936.