Antifungal Prophylaxis: Impact on Outcomes of Newly Diagnosed AML Patients Treated with a Hypomethylating Agent and Venetoclax
Authors: Chen Evan C. , Liu Yiwen , Winer Eric S. , Luskin Marlise R. , Wadleigh Martha , Lane Andrew A. , Vedula Rahul S. , Lindsley Coleman , Copson Kevin , Charles Anne , Neuberg Donna S. , Issa Nicolas C. , DeAngelo Daniel J. , Stone Richard M. , Garcia Jacqueline S. 
Published: November 2021

Abstract
Introduction: The Phase 3 VIALE-A study established the combination of venetoclax and a hypomethylating agent (VEN/HMA) as a new standard of care option for acute myeloid leukemia (AML) patients who are ineligible for intensive chemotherapy due to age (≥ 75 years) or comorbidities. The NCCN recommends antifungal prophylaxis (AFP) for relapsed/refractory AML patients receiving VEN/HMA, but its role in newly diagnosed AML patients treated with VEN/HMA remains controversial. Additionally, the impact of VEN dose-reduction due to concomitant azole use on AML outcomes and rates of fungal infection remains unclear. We evaluated the pattern of AFP use and its association with infectious and AML outcomes in patients receiving VEN/HMA at our institution.
Methods: Consecutive patients aged ≥18 who received frontline VEN/HMA for newly diagnosed AML at the Dana-Farber Cancer Institute between 2016-2021 were identified in the Hematologic Malignancy Data Repository for retrospective chart review. Antibacterial and antifungal prophylaxis use at any time during VEN/HMA therapy and reasons for hospitalizations were recorded. Invasive fungal infections (IFIs) were adjudicated as "possible," "probable," or "proven" according to consensus guidelines (Donnelly, Clin Infect Dis 2020). Rates of complete remission (CR) and CR with incomplete hematologic recovery (CRi) per European LeukemiaNet (ELN) criteria were determined. Descriptive statistics on patient characteristics were compared between groups via nonparametric testing including Wilcoxon rank-sum, chi-squared, and the Fisher's Exact tests. Overall survival (OS) was estimated using the method of Kaplan and Meier, and log-rank tests were used to compare survival between groups. Multivariable Cox proportional-hazards models were used to obtain hazard ratios between groups.
Results: 131 patients met inclusion criteria, of which 22 patients (16%) received AFP at any time. For the entire cohort, the median age at AML diagnosis was 72 (range 22-89), and the majority of patients were &lt;75 years old (66%), had ELN adverse risk (70%), and had secondary AML (sAML)/sAML-like disease (73%; "sAML-like" defined per Lindsley, Blood 2015). Frequently mutated genes include TP53 (37%), ASXL1 (22%), and RUNX1 (19%). These baseline characteristics did not differ between patients who did and did not receive AFP. However, compared to patients who never received AFP, patients receiving AFP at any time were more likely to have received HMA therapy for an antecedent hematologic malignancy (41% vs. 13%, p=0.004) and concomitant antibacterial prophylaxis at any time (82% vs. 54%, p=0.016). Among the 171 hospitalizations that occurred in 90/131 patients, bacterial infection was suspected or identified in 139 admissions, and possible/probable/proven IFIs were identified in 21. Receiving AFP prior to admission was not associated with fewer hospitalizations in which an IFI was suspected or identified (Table, p=0.36). 3/21 IFIs were deemed "probable" or "proven." All 21 IFIs prompted antifungal therapy. No patient experienced more than one hospitalization involving an IFI.
After a median of two cycles (range 1-15), best response (CR/CRi) for the entire cohort was 49%. Receiving AFP at any time was associated with lower CR/CRi than never receiving AFP (57% vs. 32%, p=0.014). The median OS for the entire cohort was 11.0 months (95% CI 8.8-14.6) and did not differ based on AFP use (11.9 months for patients without AFP, 8.1 months for those receiving AFP; p=0.23). In a multivariable model that included patient age, ELN risk, and AML ontogeny, AFP use was not significantly associated with OS (HR 1.40, p=0.22).
Conclusion: AFP use and incidence of invasive fungal infection were overall low at our institution. Receiving AFP was not associated with improved OS nor with decreased number of hospitalizations for a suspected or confirmed IFI. At an institution where the incidence of fungal infections is low, there is presently no clear role for antifungal prophylaxis in newly-diagnosed AML patients receiving HMA with venetoclax.
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Disclosures
Winer: Takeda: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Lane: AbbVie: Research Funding; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; N-of-One: Consultancy, Honoraria. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. DeAngelo: Blueprint Medicines Corporation: Consultancy; Takeda: Consultancy; GlycoMimetics: Research Funding; Autolus: Consultancy; Abbvie: Research Funding; Shire: Consultancy; Amgen: Consultancy; Agios: Consultancy; Forty-Seven: Consultancy; Pfizer: Consultancy; Incyte Corporation: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Stone: Syros: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; GlaxoSmithKline: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Janssen: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Boston Pharmaceuticals: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Garcia: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Pfizer: Research Funding; Genentech: Research Funding.