Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia

Purpose An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. Methods The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML. Results Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (P = 0.01). Median duration of grade 3 neutropenia was 28 days (range 8-46 days). Area under the concentration-time curve (AUC(0-24)) was significantly higher among patients with protracted grade 3 neutropenia (>= 28 days) than those with a shorter duration (< 28 days) (P = 0.03); multivariate analysis revealed that a higher AUC(0-24) was a significant predictor of a longer duration of neutropenia (odds ratio 54.3, P = 0.007). Conclusion Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.