Comparative outcomes of posaconazole vs. voriconazole/isavuconazole for antifungal prophylaxis in neutropenic adults with Acute Myeloid Leukemia: A propensity-matched retrospective cohort study

Abstract Background: Patients with acute myeloid leukemia (AML) undergoing chemotherapy are at high risk for invasive fungal infections (IFIs) due to prolonged neutropenia. Antifungal prophylaxis is standard in this setting, yet real-world comparative outcomes of commonly used agents remain underexplored. This study compared clinical outcomes between posaconazole and voriconazole/isavuconazole prophylaxis in neutropenic AML patients. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network database comprising 67 healthcare organizations. Adult AML patients (≥18 years) with neutropenia (ANC <0.5 x10³/μL) who received chemotherapy and antifungal prophylaxis with either posaconazole or voriconazole/isavuconazole were included. Patients who received both antifungal classes were excluded. After 1:1 propensity score matching, 4,068 patients remained in each cohort. Outcomes were assessed over a 30-day period starting from antifungal initiation. Primary outcomes included 30-day mortality and hospitalization; secondary outcomes included shock, respiratory failure, acute respiratory distress syndrome (ARDS) and disseminated candidiasis. Results: Posaconazole was associated with significantly lower 30-day mortality compared to voriconazole/isavuconazole (10.0% vs. 12.0%; HR 0.819, 95% CI 0.718–0.935; p=0.003). However, patients receiving posaconazole experienced higher hospitalization rates (57.8% vs. 54.4%; HR 1.147, 95% CI 1.069–1.230; p<0.001). Shock occurred less frequently in the posaconazole group (14.3% vs. 15.8%; HR 0.887, 95% CI 0.793–0.993; p=0.037). No significant differences were observed in rates of respiratory failure (12.6% vs. 12.9%; HR 0.969; p=0.613) or ARDS (8.4% vs. 7.8%; HR 1.076; p=0.343). There were no significant differences between the two groups in the incidence of candida esophagitis, candida eye infections, or urogenital candidiasis, with all comparisons yielding p-values greater than 0.16. Conclusion: In this large, matched cohort of neutropenic AML patients, posaconazole prophylaxis was associated with improved survival and reduced incidence of shock compared to voriconazole/isavuconazole, albeit at the cost of slightly increased hospitalization. These findings support the preferential use of posaconazole in select high-risk AML populations, while highlighting the need for individualized risk–benefit assessment in antifungal prophylaxis strategies.