The CLL12 trial: Ibrutinib versus placebo in treatment-naïve, early stage chronic lymphocytic leukemia.

Observation is the current standard of care for patients with early stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (N=182) or placebo (N=181) at a dose of 420 mg daily. At a median follow up of 31 months the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs. 47.8 months; hazard ratio=0.25; 95% confidence interval=0.14-0.43, P<0.0001). Compared to placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events. The most common serious adverse events were atrial fibrillation, pneumonia and rash in the ibrutinib group, and basal cell carcinoma, pneumonia and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Taken together, ibrutinib confirms efficacy in CLL patients at early stage with increased risk of progression. However, the results do not justify to change the current standard of 'watch and wait'. The trial is registered at clinicaltrials.gov as NCT02863718.