Ibrutinib Is Associated With Increased Cardiovascular Events and Major Bleeding in Older CLL Patients.

ABSTRACT

Background: Early ibrutinib trials showed an association between ibrutinib use and risk of bleeding and atrial fibrillation (AF) in younger chronic lymphocytic leukemia (CLL) patients. Little is known about these adverse events in older CLL patients and whether increased AF rates are associated with increased stroke risk. Objectives: To compare the incidence of stroke, AF, myocardial infarction, and bleeding in CLL patients treated with ibrutinib with those who were treated without ibrutinib in a linked SEER-Medicare database. Methods: The incidence rate of each adverse event for treated and untreated patients was calculated. Among those treated, inverse probability weighted Cox proportional hazards regression models were used to calculate HRs and 95% CIs for the association between ibrutinib treatment and each adverse event. Results: Among 4,958 CLL patients, 50% were treated without ibrutinib and 6% received ibrutinib. The median age at first treatment was 77 (IQR 73-83) years. Compared with those treated without ibrutinib, those treated with ibrutinib had a 1.91-fold increased risk of stroke (95% CI 1.06-3.45), 3.65-fold increased risk of AF (95% CI 2.42-5.49), a 4.92-fold increased risk of bleeding (95% CI 3.46-7.01) and a 7.49-fold increased risk of major bleeding (95% CI 4.32-12.99). Conclusions: In patients a decade older than those in the initial clinical trials, treatment with ibrutinib was associated with an increased risk of stroke, AF, and bleeding. The risk of major bleeding is higher than previously reported and underscores the importance of surveillance registries to identify new safety signals.