EFFICACY OF ANTIFUNGAL PROPHYLAXIS IN PREVENTING INVASIVE FUNGAL INFECTIONS IN ACUTE MYELOID LEUKEMIA PATIENTS TREATED WITH VENETOCLAX AND HYPOMETHYLATING AGENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Introduction: Acute Myeloid Leukemia (AML) is one of the most prevalent hematologic neoplasms in elderly patients. Standard treatment is based on intensive anthracycline induction chemotherapy, which is highly immunosuppressive, leading to a significant risk of death and complications due to opportunistic infections. To mitigate this, antifungal prophylaxis (AFP) is recommended to prevent invasive fungal infections (IFI). Nevertheless, an important part of AML patients is not eligible for the standard treatment due to fragility and other clinical comorbidities. For this subset of patients, the combination of the BCL-2 inhibitor venetoclax (VEN) and a hypomethylating agent (HMA) has emerged as an important therapeutic alternative. However, the evidence supporting the use of AFP in this specific patient population remains insufficient. Objective: We conducted a systematic review and meta-analysis evaluating the efficacy and safety of AFP in AML patients undergoing VEN + HMA treatment. Methods: We conducted a comprehensive search of the PubMed, EMBASE, and Cochrane databases to identify articles comparing the prevalence of IFI in AML patients undergoing treatment with VEN+HMA in groups with and without AFP. Relevant data were extracted and exported to the R software. We calculated risk ratios (RR) and their respective 95% confidence intervals (CI). The ’meta’ and ’metafor’ packages in R were utilized to perform a random-effects meta-analysis according to the method described by DerSimonian and Laird. Heterogeneity was assessed using the I²statistic, with I² > 50% indicating significant heterogeneity. A two-tailed p-value of 0.05 was considered statistically significant. Results: The initial search encompassed 871 studies, of which 5 were included to this review, with a total of 793 patients. The majority of them were male (60.5%), with a median age of 64 years (range 18-94). The incidence of IFI were lower in the AFP group (42 of 467, 8.9%) compared to the no use of AFP (30 of 316, 9.5%), with a RR of 0.58 (95% CI 0.37-0.9; p = 0.019; I² = 0%). However, in our sensibility analysis for only confirmed IFI, the risk to development of IFI did not differ between groups (RR 0.53; 95% CI 0.26-1.05; p = 0.068; I² = 20%). Discussion: To the best of our knowledge, this is the first systematic review and meta-analysis to evaluate the benefit of AFP in AML patients undergoing treatment with VEN+ HMA. Immunosuppression resulting from cancer treatment can be fatal for a significant subset of AML patients. While the incidence of IFI can reach as high as 36% with cytotoxic regimens, and mortality rates can reach 50%, the incidence of IFI in VEN+HMA treatment is substantially lower, around 5-10%, similar to our findings. However, the lower incidence of IFI in the VEN+HMA setting raises questions about the generalizability of our analysis. It is possible that a specific subset of these patients, particularly those with poor prognostic factors, may still derive benefit from AFP. Conclusion: IFI are a less common occurrence in AML patients undergoing VEN+ HMA treatment than anthracycline regimens, but still occur frequently. However, while the use of AFP holds the potential to benefit this subset of patients, the evidence for this review is not definitive, highlighting the need for prospective studies to clarify the role of AFP before implementation in clinical practice. Until then, the decision to use AFP in this group of patients should be individualized.