Background: Acute Myeloid Leukemia (AML) imposes a significant clinical burden, with an estimated 22,010 new diagnoses and 11,090 deaths projected in the United States in 2025, according to the American Cancer Society. The disease's intrinsic pathophysiology, compounded by the immunosuppressive effects of standard treatments, including chemotherapy, hypomethylating agents - renders patients highly susceptible to severe infections. These infections contribute substantially to early morbidity and mortality. Despite advances in AML therapeutics, real-world data on infection risk stratification and long-term outcomes remain limited. This retrospective analysis aims to identify pre-treatment risk factors associated with infections within the first year of AML therapy and to evaluate three-year survival outcomes across treatment modalities, thereby informing clinical decision-making and supportive care strategies.

Methods: This retrospective, multicenter Real-World Evidence (RWE) analysis was conducted using the TriNetX Global Network, incorporating data from 204 healthcare organizations as of July 28, 2025. The study population included 9,510 adult patients (≥18 years) diagnosed with Acute Myeloid Leukemia (AML) who received chemotherapy agents (cytarabine, idarubicin hydrochloride, daunorubicin) or methylating agents (azacitidine, decitabine) between January 1, 2015, and May 30, 2025. Patients with a history of other primary hematologic malignancies or prior stem cell transplantation were excluded. Two cohorts were defined: Cohort 1 (n=4,160) comprised AML patients who developed serious infections post-treatment, while Cohort 2 (n=5,350) included those who did not. Measures of association were used to compare outcome proportions between cohorts, estimating risk, risk difference, risk ratio, and odds ratio. Three-year mortality outcomes were also assessed.

To reduce confounding, propensity score matching was applied across all listed baseline characteristics, resulting in matched cohort sizes of 3,900 patients each, thereby enhancing the validity of comparative analyses.

Results: Among the AML patients studied, those who developed serious infections exhibited significantly higher rates of baseline hematologic abnormalities. Pre-treatment risk factors included neutropenia (43.8% vs. 30.5%, P < 0.001), thrombocytopenia (32.7% vs. 26.4%, P < 0.001), and agranulocytosis (7.7% vs. 4.9%, P = 0.001). Laboratory findings further revealed more severe neutropenia (absolute neutrophil count < 0.5 × 10³/μL: 45% vs. 37.2%, P < 0.001), thrombocytopenia (platelet count < 100 × 10³/μL: 72.4% vs. 64.3%, P < 0.001), and elevated ferritin levels in patients who developed infections post-treatment.

Over a three-year follow-up period, AML patients with infections had a significantly higher risk of death (53.8% vs. 42.6%), with a risk difference of 0.113 (95% CI: 0.091–0.135), a risk ratio of 1.265 (95% CI: 1.207–1.325), and an odds ratio of 1.574 (95% CI: 1.440–1.722).

Conclusion: This large, real-world analysis underscores the significant clinical impact of serious infections in AML patients undergoing chemotherapy or hypomethylating agent therapy. Patients who developed infections exhibited markedly higher rates of pre-treatment hematologic abnormalities, including neutropenia, thrombocytopenia, and agranulocytosis, as well as more severe laboratory derangements such as profound neutropenia and elevated ferritin levels. These findings suggest a vulnerable immunologic profile even before treatment initiation.

Crucially, the presence of serious infections was associated with a 26.5% increased relative risk of death over a three-year period, highlighting infections as a major determinant of long-term survival in AML. These results emphasize the need for early identification of high-risk patients and the integration of infection risk stratification into AML treatment planning. Proactive infection prevention and supportive care strategies may be pivotal in improving outcomes in this high-risk population.

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2025
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