Incidence of Breakthrough Fungal Infections in Acute Myeloid Leukemia Patients Receiving Low Intensity Therapy in the Upfront and Relapsed/Refractory Setting

Introduction: New treatment strategies with low intensity therapy have emerged for acute myeloid leukemia (AML) patients who are not candidates for intensive therapy. To date, there is limited data on the frequency of invasive fungal infections (IFIs) in patients treated with low intensity regimens, and there is no consensus on the most appropriate prophylactic antifungal agent to use in either the newly diagnosed or relapsed/refractory setting. At our institution, fluconazole is the prophylactic antifungal agent of choice for neutropenic patients receiving low intensity therapy, however the appropriateness of fluconazole is being questioned due to the depth and duration of neutropenia observed in these patients. Rates of breakthrough IFIs need to be better characterized to optimize antifungal prophylaxis in this patient population.

Methods: This is a retrospective review of AML patients treated with low intensity therapy from January 2017 through May 2020 for both newly diagnosed and relapsed/refractory disease. Patients were included if they received fluconazole as prophylaxis during periods of neutropenia and received at least two cycles of low intensity treatment. Low intensity regimens included hypomethylating agent (HMA) monotherapy or a combination of venetoclax with either a HMA or low dose cytarabine (LDAC). Any patient with a contraindication to fluconazole or those who received prophylaxis with an alternative antifungal agent (i.e. posaconazole, voriconazole, isavuconazole, and micafungin), history of previous IFI, or history of a stem cell transplant were excluded. The primary objective was to determine the incidence of breakthrough IFIs. The secondary objective was to further characterize IFI occurrences as possible, probable or proven using criteria defined by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC). An occurrence of IFI was defined as receipt of any systemic antifungal agent, aside from fluconazole, for four or more days for suspected IFI. Patients were evaluated for antifungal escalation from the time of low intensity treatment initiation through 30 days after treatment discontinuation.

Results: Eighty encounters were included for analysis. The median age of the cohort was 73 years (interquartile range [IQR] 67 - 80) and 70% of patients were newly diagnosed (n = 56). HMA/venetoclax was the most commonly utilized regimen (66%, n = 53) followed by HMA monotherapy (29%, n = 23) and LDAC/venetoclax (5%, n = 4). The median number of treatment cycles was 5 (IQR 3 - 9). Nineteen IFI occurrences (24%) were documented, with ten in the newly diagnosed population (18%, n = 10/56) and nine in relapsed/refractory patients (38%, n = 9/24). There were no proven, four probable and fourteen possible IFIs. Of the four probable infections, three were in relapsed/refractory patients. Median times to IFI onset from low intensity treatment initiation were 82 and 80 days for the newly diagnosed and relapsed/refractory populations, respectively. Of the patients with an IFI, 15/19 (79%) were neutropenic at IFI onset.

Conclusions: IFIs are a serious complication of AML as these infections are associated with significant morbidity and mortality. With 24% of patients requiring antifungal escalation, our study demonstrates that breakthrough IFIs remain a concern for patients receiving low intensity therapy and fluconazole prophylaxis. Incidence of IFI was higher in the relapsed/refractory setting, which is an expected finding as these patients are typically subjected to multiple lines of therapy, leading to poor hematopoietic reserves and more prolonged periods of profound neutropenia. Additional analysis is needed for determination of risk factors, beyond relapsed/refractory disease, to potentially identify subsets of patients at highest risk of developing IFIs as these patients may benefit from closer monitoring and longer durations of prophylaxis. Given these findings, it is reasonable to consider prophylaxis with an extended spectrum antifungal agent against molds for patients receiving low intensity therapy.

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