Real-World Experience with Venetoclax Therapeutic Drug Monitoring in Acute Myeloid Leukemia: Role of Posaconazole, Correlation with Safety and Efficacy

Venetoclax (VEN) is approved for acute myeloid leukemia (AML) in association with azacitidine, in a 28-day schedule at a fixed dosage, which requires reduction if azoles are co-administered. The present study aims to evaluate VEN therapeutic drug monitoring (TDM) in a real-word setting, where the VEN schedule is frequently reduced, investigating: (i) the posaconazole impact, and (ii) whether VEN exposure correlates with safety and efficacy.

We analyzed data from 43 AML patients treated with different VEN-containing regimens, for whom a near-trough VEN plasma concentration (Cmin) was determined at different timepoints (days 5-8-11-15-22-29) across different cycles (163 cycles, 290 determinations). The posaconazole impact was explored in the whole study population, while safety and efficacy were investigated only in patients treated with azacitidine-VEN, respectively in the safety (35 patients) and in the efficacy subset (29 patients at their first cycle). VEN exposure was expressed through multiple parameters, taking into account both VEN concentrations and the days of VEN administration.

Posaconazole was used in 40.5% of cycles and, despite dose adjustment, was associated with: (i) greater interpatient variability, (ii) higher VEN concentrations, (iii) delayed elimination, (iv) accumulation along the cycle, and (v) the need for VEN-dosage change. In the safety subset, VEN exposure correlated with neutropenia and its duration, Granulocyte Colony-Stimulating Factor requirement, platelet transfusions, cycle duration, and infections. Finally, no correlation was found between VEN exposure and response in the efficacy subset.

VEN TDM appears valuable in clinical practice to reduce toxicity, especially in patients receiving posaconazole, where VEN exposure remains highly unpredictable.