Evaluation of Infection in Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Systematic Review

BACKGROUND: Acute myeloid leukemia (AML) is characterized by bone marrow failure, cytopenias, and complications related to bleeding and infection. In many adults with AML, hypomethylating agents (e.g., azacitidine, decitabine) comprise the backbone of outpatient chemotherapy. Due to underlying disease and/or treatments, patients with AML frequently have severe and prolonged neutropenia, which increases risk of infectious complications. The frequency and severity of infectious complications have not been well defined for patients receiving treatment with hypomethylating agents, either alone or in combination with venetoclax.

OBJECTIVE: To inform optimal supportive care therapy to minimize infection risk, we evaluated the incidence and severity of neutropenia, febrile neutropenia, and infections among patients with AML treated with hypomethylating therapy. We also aimed to study the incremental risk with combination hypomethylating therapy, and the reported use of antimicrobial prophylaxis (CRD42022339158).

POPULATION: Adult patients (age ≥ 18 years) with AML (≥80% of the study population) treated with hypomethylating agents.

OUTCOMES: Our primary outcome was febrile neutropenia, as per the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes included infection of any grade, grade 3 or 4 infections, death due to infection, microbial and clinical infection subtype, frequency of grade 3 or 4 neutropenia, duration of neutropenia, and use of antimicrobial prophylaxis.

METHODS: We searched Medline, Embase, CENTRAL and CINAHL from inception to April 2021. We included randomized controlled trials if they evaluated hypomethylating therapy in patients with AML and reported at least one outcome of interest. We used Freeman-Tukey transformation to calculate the weighted summary proportion using a random effects model.

RESULTS: From 13,225 citations, we included 18 unique trials (published between 2010 and 2021), enrolling 2,788 patients. Azacitidine was evaluated in 8/18 trials (n = 984 patients) while 6/18 trials (n = 877 patients) evaluated decitabine, and 4/18 trials (n = 927 patients) evaluated combination therapy with hypomethylating agents and venetoclax. The median patient age was 74 years (interquartile range 72 to 76 years); males represented 53% of the population. 31% of patients had grade 3 or 4 neutropenia (95% confidence interval (CI) 21% to 41%; n = 9 trials; 1,407 patients). Febrile neutropenia affected 31% patients receiving single agent hypomethylating therapy (95% CI 26% to 37%; n = 11 trials; 1,382 patients), with increased risk among patients treated with the combination of hypomethylating therapy and venetoclax (46%; 95% CI 35% to 57%; n = 2 trials; 398 patients). 45% of AML patients reported infection (95% CI 33% to 57%; n = 11 trials; 1,232 patients). The most frequent infections were respiratory infections (31%), bacteremias (24%), skin and soft tissue infections (18%), and urinary tract infections (11%). Infection-related death occurred in 8% of patients with AML (95% CI 6% to 11%; n = 9 studies; 898 patients). Microbial subtype of infection and duration of neutropenia were not reported. Antimicrobial prophylaxis was reported in only one trial.

CONCLUSION: Neutropenia and infection occur commonly in patients with AML treated with hypomethylating agents, with increased risk with venetoclax combination therapy. Reported risks were heterogenous among trials, and limited data was available to evaluate the relationship between neutropenia and infection. Antimicrobial prophylaxis was rarely reported. Clinical trials are needed to inform optimal supportive care interventions to decrease infection risk in this high-risk patient population.

Sanford:Pfizer: Research Funding; Abbvie: Other: Advisory Board ; Astellas: Other: Advisory Board. Mozessohn:Abbvie: Current holder of stock options in a privately-held company; Bristol Myers Squibb: Current holder of stock options in a privately-held company; Johnson & Johnson: Current holder of stock options in a privately-held company; Merck and Co: Current holder of stock options in a privately-held company; Novo Nordisk: Current holder of stock options in a privately-held company. Buckstein:Takeda: Research Funding; Taiho: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hay:AbbVie: Research Funding; Roche: Research Funding; Karyopharm: Research Funding; Seagen: Research Funding; Merck: Research Funding.