Predicting the toxicity-efficacy ratio of venetoclax in real-world patients

This study investigates the pharmacokinetic variability and exposure-response relationships of Venetoclax (VEN) in adult patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. The study was conducted in a real-world clinical setting and included 48 patients who were treated with VEN in combination with azacytidine. We found significant inter-individual variability of 68% and intra-individual variability of 39% in plasma VEN concentrations. In addition, higher VEN concentrations were associated with better hematological responses. Median overall survival for the entire cohort was 17.8 months, with 1- and 2-year survival rates of 51% and 36.4%, respectively. A comparison of the 14-day VEN and 28-day VEN protocols showed that patients benefited from longer treatment durations, which resulted in more courses being administered. Plasma concentrations in the 14-day VEN protocol were higher than in the 28-day VEN protocol (2330 + 1675 ng/mL vs. 1503 + 966 ng/mL, respectively) without an increase in toxicities. The optimal protocol would be 400 mg/14d if we consider survival as a function of the 1818ng/mL cutoff. These results highlight the importance of considering therapeutic drug monitoring (TDM) as a strategy to optimize treatment outcomes by balancing efficacy and safety.