Clinical outcomes of venetoclax with and without azole antifungals in acute myeloid leukemia: A large real-world cohort study.

Abstract

e18540 Background: Venetoclax is widely used in the treatment of acute myeloid leukemia (AML) and is frequently co-administered with azole antifungals for prophylaxis or treatment of fungal infections. Azoles are strong CYP3A inhibitors and increase venetoclax exposure, potentially exacerbating toxicity and affecting outcomes. However, real-world data evaluating the clinical impact of this combination on survival, infectious complications, and hematologic toxicity remain limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adult patients with AML treated with venetoclax. Patients were stratified into two cohorts: venetoclax monotherapy and venetoclax plus azole antifungals (itraconazole, voriconazole, or posaconazole). Propensity score matching (1:1) was performed to balance baseline demographics and comorbidities. Outcomes included all-cause mortality, sepsis with or without septic shock, invasive fungal infections (IFI), severe neutropenia (≤0.5 ×10³/µL), and severe thrombocytopenia (≤50 ×10³/µL). Outcomes were assessed at 1 month, with analyses at 3 and 6 months using risk analyses and Kaplan–Meier survival models. Results: After matching, 12,984 patients were included in each cohort. At 1 month, mortality was lower in the venetoclax-only cohort compared with venetoclax plus azoles (7.5% vs 8.9%; risk difference −1.4%, 95% CI −2.1% to −0.7%; p < 0.001; hazard ratio 0.83, 95% CI 0.77–0.91). This survival advantage persisted at both 3 and 6 months, with hazard ratios favoring venetoclax monotherapy. There was no difference in sepsis ± septic shock at 1 month (4.8% vs 5.1%; p = 0.24), and this association remained non-significant at 3 and 6 months. The incidence of IFI was lower in the venetoclax-only cohort at 1 month (2.4% vs 3.3%; risk difference −0.9%; p < 0.001; 0.73), with this difference remaining statistically significant at 3 and 6 months. In contrast, hematologic toxicity was more frequent with azole co-administration: severe neutropenia occurred in 60.5% vs 57.0% (p < 0.001) and severe thrombocytopenia in 72.0% vs 69.0% (p < 0.001) for venetoclax plus azoles versus venetoclax alone. Conclusions: In this large real-world cohort of patients with acute myeloid leukemia treated with venetoclax, concomitant azole antifungal use was associated with higher mortality and increased hematologic toxicity compared with venetoclax monotherapy, without a reduction in sepsis risk. Invasive fungal infections were less frequent in patients treated without azole antifungals; however, interpretation of this finding is limited by the observational nature of the study. These results highlight the clinical impact of venetoclax–azole drug–drug interactions and support the need for prospective studies to define optimal antifungal strategies in venetoclax-based regimens.