Ibrutinib delays the progression to symptomatic disease in patients with early-stage chronic lymphocytic leukemia (CLL), according to results from the German CLL Study Group's phase III CLL12 trial. The study, however, found no overall survival benefit with the use of ibrutinib compared to placebo. The findings, published in the Journal of Clinical Oncology, suggest that while ibrutinib can postpone disease progression, the standard watch-and-wait approach remains relevant in the era of targeted therapies.
The double-blind, multicenter trial enrolled 363 patients with asymptomatic, treatment-naive Binet stage A CLL who were at increased risk of disease progression. Participants were randomized to receive either ibrutinib at 420 mg/day (n = 182) or placebo (n = 181). An additional 152 low-risk patients were allocated to a watch-and-wait group.
The primary endpoint of the study was the time to symptomatic disease. Ibrutinib significantly delayed progression to symptomatic disease, with a hazard ratio of 0.276 (95% confidence interval [CI] = 0.188–0.407, P < .001). However, no statistically significant difference in overall survival was observed between the ibrutinib and placebo groups (P = .562). After a median follow-up of 69.3 months, 26 deaths were reported. The overall survival rate at 5 years was 93.3% with ibrutinib, 93.6% with placebo, and 97.9% in the low-risk watch-and-wait group. The estimated 10-year overall survival rates were 89.8%, 86.5%, and 95.3%, respectively.
Safety Profile
Grade ≥ 3 adverse events were reported in 71.8% of patients in the ibrutinib group and 66.1% in the placebo group. The most common adverse events in both groups were atrial fibrillation (8.8% vs 2.4%) and pneumonia (4.7% vs 6.5%). Serious adverse events occurred in 60% of patients in each group. The incidence of any-grade cardiovascular toxicity was higher in the ibrutinib group.
Expert Commentary
The study's investigators concluded that while ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo, no survival benefit was demonstrated within the observation period. They emphasized that, despite the availability of targeted therapies, the watch-and-wait strategy remains the standard of care for early-stage CLL, irrespective of risk factors.
Petra Langerbeins, MD, of the Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, German CLL Study Group, Faculty of Medicine, and University Hospital Cologne, served as the corresponding author for the Journal of Clinical Oncology article. The trial was supported by Janssen.
