Efficacy of posaconazole prophylaxis in acute myeloid leukemia and myelodysplastic syndrome patients treated with hypomethylating agents

Abstract

Background: Although many acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients have been treated with hypomethylating agents (HMAs) as a substitute for intensive chemotherapy in recent years, the incidence of invasive fungal infections (IFIs) and the efficacy of posaconazole as antifungal prophylaxis in these patients are not well known to date. Methods: We retrospectively analyzed 280 AML and MDS patients treated with HMAs to identify IFI incidence and posaconazole efficacy as antifungal prophylaxis in these patients. Results: The overall incidence of probable or proven IFIs was 7.9% (22/280 patients): 11.5% in the no-use group (17/148 patients) and 3.8% in the posaconazole group (5/132 patients). Most IFIs occurred during the early cycles of the HMAs (median: 3 cycles; range: 1–8 cycles), especially in patients who had neutropenia or did not respond to HMAs. Posaconazole significantly lowered IFI incidence compared with that in the no-use group in univariate and multivariate analyses. Moreover, patients who had reduced liver function at HMA initiation, were treated with decitabine therapy, and did not respond to HMA chemotherapy were independently associated with a higher IFI risk. In subgroup analysis, posaconazole appeared to be more beneficial for patients with good Eastern Cooperative Oncology Group performance score or liver function at HMA initiation. Conclusion: Thus, in AML and MDS patients receiving HMAs, IFI risk may be high during the early cycles, especially when the underlying disease is not controlled. Posaconazole could represent antifungal prophylaxis in these patients; further studies are needed for its appropriate indications.

Invasive fungal infection following venetoclax and posaconazole co‐administration

“…It is likely that posaconazole was facilitating IFI treatment, rather than prophylaxis. This tempo of onset is reported in other studies of AML/MDS patients 3,10,16 . Alternate prophylaxis strategies for venetoclax‐treated patients include prophylactic liposomal amphotericin (L‐AMB) to avoid the CYP‐mediated drug–drug interactions with posaconazole during the venetoclax ramp‐up period 17 .…”

“…10 Our predictors of IFI are also reflective of the literature, identifying chronic neutropenia and relapsed-refractory disease as predictors of IFI. 10 The finding that patients with more prior lines of therapy had lower IFI incidence is unusual, given relapsed/refractory disease is typically associated with IFI. This result may be explained by the inclusion of MDS patients in this study, who may have more subsequent lines of therapy.…”

“…This tempo of onset is reported in other studies of AML/MDS patients. 3,10,16 Alternate prophylaxis strategies for venetoclax-treated patients include prophylactic liposomal amphotericin (L-AMB) to avoid the CYP-mediated drug-drug interactions with posaconazole during the venetoclax ramp-up period. 17 L-AMB is less efficacious than mould-active azoles, and our results perhaps caution against its use in a potential high-risk time period.…”

“…This study demonstrates that when posaconazole was co-administered with venetoclax, the majority achieved adequate posaconazole exposure, posaconazole was safe, and IFI rates were lower than previously reported cohorts who did not receive prophylaxis. 3,10 Understanding the benefits of posaconazole in these groups will become increasingly important as further research is done into whether the obligatory dose reduction in venetoclax therapy with posaconazole co-administration has any impact on haematological outcomes. Venetoclax levels in the context of concurrent posaconazole administration would be equally important to explore, to better understand the impact of pharmacokinetic interactions and efficacy in the treatment of the myeloid malignancies.…”

“…However, 23% of our cohort did not receive therapeutic drug monitoring. Previous studies examining posaconazole tolerance and efficacy in Ven‐HMA treated have not commented on the adequacy of drug levels 3,10 …”