TAILORing ibrutinib dose and plasma levels in the real-life patient with chronic lymphocytic leukemia

Ibrutinib is the cornerstone of treatment of chronic lymphocytic leukemia (CLL); however, cardiovascular adverse events (AE) may limit its long-term use. We performed a prospective, multicenter, real-life study that investigated the relationships between ibrutinib steady-state trough plasma concentrations (C_min), the risk of development of AE, and the effects of dose reduction. Forty-eight patients with CLL treated with 420 mg/day ibrutinib were enrolled. Thirteen patients developed AE and exhibited significantly higher C_min (geometric mean of 18.3 ng/mL) than patients without AE (geometric mean of 2.6 ng/mL, P < .0001). Logistic regression analyses showed that age and ibrutinib plasma levels were independent predictors of AE. Following temporary ibrutinib discontinuation, leading to resolution or mitigation of AE, ibrutinib was resumed at 280 mg/day, which lowered C_min to a geometric mean of 3.4 ng/mL, similar to the C_min measured in patients without AE. Adverse events did not recur in patients managed by DR. These real-life data show that dose reduction helps to normalize ibrutinib plasma exposure in CLL patients at risk of AE. SIGNIFICANCE STATEMENT: In patients with chronic lymphocytic leukemia (CLL) treated with the Bruton tyrosine kinase inhibitor ibrutinib, development of cardiovascular adverse events (AE) seems to associate with increased ibrutinib plasma levels compared with patients without AE. Dose reduction from 420 to 280 mg/day effectively reduces ibrutinib plasma levels and helps to resolve or mitigate AE. These findings call for reconsidering the ibrutinib dose in CLL patients and provide clinical pharmacology evidence that individualized dose reduction may improve the therapeutic index of ibrutinib.