Venetoclax TDM Shows Posaconazole Raises AML Exposure

Key Takeaways

• In routine AML care, posaconazole was coadministered in 40.5% of venetoclax cycles and remained associated with higher, less predictable exposure despite dose reduction.
• Venetoclax concentrations rose from day 5 to day 8 in posaconazole-treated cycles, while cycles without antifungal coadministration did not show the same accumulation pattern.
• Among azacitidine-venetoclax recipients, higher venetoclax exposure tracked with hematologic and infectious toxicity measures, including neutropenia, granulocyte colony-stimulating factor use, platelet transfusions, longer cycles, and infections.
• First-cycle efficacy analyses did not show a statistically significant association between venetoclax exposure and response.

Patients with acute myeloid leukemia (AML) receiving venetoclax in routine care often also receive azole antifungal prophylaxis and shorter-than-labeled treatment courses, making actual drug exposure difficult to predict from dose alone. That uncertainty becomes more important when concomitant medications change from cycle to cycle and cytopenias or infections shorten therapy. Therapeutic drug monitoring (TDM) can therefore provide a practical way to follow near-trough venetoclax exposure under real-world conditions.

At Mauriziano Hospital in Torino, Italy, the Sani et al real-world venetoclax therapeutic drug monitoring study in acute myeloid leukemia followed 43 adults with AML across 163 venetoclax-containing cycles and 290 near-trough determinations in an observational, single-center retrospective and prospective analysis. Samples were drawn during routine morning blood work about 3 to 4 hours before the next dose, and the article focused on days 5, 8, 11, 15, 22, and 29 ±1. Pharmacokinetic analyses included all regimens, safety analyses were limited to 35 azacitidine-venetoclax recipients, and efficacy analyses focused on first-cycle azacitidine-venetoclax patients with active disease and marrow assessment.

Posaconazole was used in 40.5% of cycles and was associated with higher venetoclax concentrations despite dose reduction (p < 0.0001). Concentrations also rose from day 5 to day 8 in the posaconazole group but not in cycles without antifungal coadministration (p = 0.03). TDM-driven dose modification occurred in 22 of 65 evaluable posaconazole cycles (33.8%) and in 11 of 23 cycles (47.8%) when posaconazole was introduced for the first time. Within azacitidine-venetoclax treatment, higher exposure tracked with neutropenia, longer neutropenia duration, granulocyte colony-stimulating factor (G-CSF) use, platelet transfusions, longer cycles, and infections, while bleeding events, red blood cell transfusions, and response in the 29-patient efficacy subset did not show a statistically significant exposure association.

Dose changes were physician-directed in an observational study without a standardized intervention or randomization, so the findings support feasibility and association rather than proving that TDM-guided adjustment improves outcomes. The efficacy subset was small, and near-trough samples were collected 3 to 4 hours before the next dose, which may have slightly overestimated true trough concentrations. Few posaconazole levels were available to test whether posaconazole accumulation explained venetoclax accumulation, and cycles with more than 14 days of venetoclax were limited.

Venetoclax TDM appeared feasible in routine AML care and seemed most informative when exposure was hardest to predict, particularly with posaconazole. Higher exposure aligned more clearly with toxicity signals than with a measurable response advantage in the first-cycle efficacy analysis. Because venetoclax dose-reduction labels with posaconazole differ between Europe and the United States, these Italian data may be more useful as a signal about exposure variability than as a direct dosing template for North American practice.

Clinician Questions

How were venetoclax concentrations measured in this real-world AML analysis?

Investigators used near-trough venetoclax plasma measurements collected during routine morning blood draws about 3 to 4 hours before the next dose. The article analyzed samples from days 5, 8, 11, 15, 22, and 29 ±1, and exposure was summarized as the highest and average near-trough concentrations, days of venetoclax administration, and an exposure index that combined concentration with treatment duration.

Which AML patients were included in the safety and efficacy analyses of venetoclax exposure?

Safety analyses were restricted to patients receiving azacitidine plus venetoclax, while efficacy analyses were further limited to first-cycle azacitidine-venetoclax patients with active disease and a bone marrow assessment. Those efficacy findings therefore should not be generalized to all venetoclax-treated AML patients in the cohort or to later treatment cycles.

What toxicities tracked with higher venetoclax exposure during azacitidine-venetoclax treatment in AML?

Higher venetoclax exposure correlated with neutropenia and longer neutropenia duration, greater G-CSF use, more platelet transfusions, longer cycle duration, and infectious adverse events. These associations were reported in azacitidine-venetoclax recipients, while bleeding events and red blood cell transfusion requirements did not correlate with exposure.