Review Addresses Antifungal Prophylaxis in AML and Provides Guidance for Novel Agents

Patients with acute myeloid leukemia (AML) who have undergone intensive chemotherapy are at a very high risk for invasive fungal disease, and a changing treatment landscape warrants further research on drug-drug interactions and outcomes.

In the past 3 decades, antifungal prophylaxis has improved overall survival rates for patients with acute myeloid leukemia (AML), an aggressive hematological malignancy with a relatively poor prognosis. A recent review assessed current treatment guidelines and future areas of research to optimize therapeutic strategies for AML.

AML patients who have undergone intensive chemotherapy are at a very high risk for invasive fungal disease, which has a high mortality rate. Patients with longer neutropenia duration and those with relapsed or refractory AML are at an even greater risk of invasive fungal disease and death. Therefore, there are various guidelines in place for antifungal treatment in the prophylaxis setting for AML patients.

The review and guidance were completed by a cohort of experts on infectious diseases, hematology, oncology, clinical pharmacology, and methodology from the European Hematology Association Scientific Working Group on Infections in Hematology and Scientific Working Group on Acute Myeloid Leukemia as well as the Cochrane Hematology Group.

The group identified 18 novel targeted agents for AML treatment, including those approved, those in development, or those with potential for off-label use in AML. They reviewed literature for incidence of invasive fungal disease, length of hospitalization, number of days spent in the intensive-care unit, mortality due to invasive fungal disease, quality of life, and potential drug-drug interactions (DDIs) in AML patients.

In most cases, the panel recommends prophylactic antifungal treatment for patients with AML, especially when a novel agent is combined with intensive induction chemotherapy. When patients are treated with ivosidenib, lestaurtinib, quizartinib, and venetoclax, they recommend adjusting antileukemic agent dosing while triazoles are administered—the first guidance aiding clinical decision-making in patients given targeted drugs for AML. More research is needed to pinpoint the role of dosing adjustment during antifungal administration.

A triazole antifungal—the CYP3A4 inhibitor posaconazole being the recommended agent—is also important for AML patients during induction therapy, the authors noted. Of course, each patient’s individual situation must be considered, including medical history and the local epidemiology of invasive fungal disease.

The moderate CYP3A4 inhibitor isavuconazole might also have a larger role in the DDI setting going forward, with studies showing it has lower toxicity and lower rates of adverse events than other triazoles. Additional antifungals such as rezafungin are currently in phase 3 trials and have lower chances of DDI.

In addition to novel agents, active surveillance and preemptive treatment for invasive fungal disease are often implemented but carry the risk of not detecting invasive antifungal disease if a patient does experience it.

The authors also note that additional novel agents for AML treatment, including eprenetapopt and olutasidenib, will be investigated in trials or potentially become available soon. Combining new targeted agents with chemotherapy will affect rates of invasive fungal disease.

The guidelines do not reach conclusions about a clear antifungal of choice in the prophylaxis setting or about dosing specifications based on currently available research. Scarcity of data is one issue with formulating guidelines in this patient population, as trials and pharmaceutical companies are not required to address the incidence of infections or invasive fungal disease in detail.

“We encourage clinical trial designers and regulatory authorities to assess risks of DDI of antineoplastic drugs in pivotal phase-3 studies by including therapeutic drug monitoring studies,” study authors wrote. “When pharmacokinetic data hint towards increased toxicity, pharmacokinetics should be standard during treatment with novel antifungals. Otherwise, the treating physicians will be forced to trade one life-saving drug for another, instead of combining both benefits for their patients.”

Reference

Stemler J, de Jonge N, Skoetz N, et al. Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association. Lancet Haematol. 2022;9(5):e361-e373. doi:10.1016/S2352-3026(22)00073-4