Primary prevention of acute leukemias in high-risk patients: The therapeutic promise of GLP-1 receptor agonists.

Abstract

10507 Background: Despite advances in understanding leukemogenesis, no validated primary prevention strategies exist. Obesity is a dose-dependent risk factor for leukemia. Emerging data implicate epigenetic regulators, specifically the histone methyltransferase GLP (EHMT1), as a driver of leukemic survival; its inhibition induces cell death in CLL and promotes differentiation in AML. We present the first real-world analysis evaluating GLP-1 receptor agonists (GLP-1RA) for the primary prevention of leukemia in high-risk populations. Methods: Using the TriNetX global research network (150 million patients across 108 healthcare organizations), we identified adults at elevated leukemia risk based on ≥1 factor (prior chemo/radiation, MDS, MPN, family history, genetic syndromes, tobacco use, or BMI ≥30). Patients with ≥2 months of GLP-1RA use were propensity-matched 1:1 to non-users by demographics, comorbidities, and prior chemotherapy. The primary endpoint was the incidence of ALL, AML, CLL, or CML; secondary endpoints were adverse events related to GLP-1RA. Individuals with pre-existing leukemia were excluded. Cox proportional hazards models and sensitivity analyses were used to assess associations. Sensitivity and subgroup analysis confirmed robustness. Results: Of 426,670 high-risk individuals, 213,335 were matched to each cohort; standardized mean differences were <0.1 for all covariates. Across >1.2 million person-years of follow-up, GLP-1RA use was associated with a 63% risk reduction in incident AML (47/213,300 vs 75/213,261; HR 0.37, 95% CI 0.26–0.53; p < 0.001) and a 50% reduction in ALL (42/213,304 vs 53/213,277; HR 0.50, 95% CI 0.33–0.75; p = 0.001). The protective effect for AML remained significant when restricted to patients with prior chemotherapy exposure and was independent of baseline BMI. No significant reductions were observed for CML or CLL. While GI adverse events were higher in the GLP-1RA cohort, the protective signal was consistent across age and ethnic subgroups. Conclusions: This is the first large-scale study to demonstrate a significant reduction in incident AML and ALL using GLP-1 receptor agonists in high-risk patients. By linking clinical metabolic intervention to the EHMT1 epigenetic pathway, these findings provide a novel, scalable pharmacologic strategy for the primary prevention of acute leukemias, potentially transforming the management of high-risk and obese populations.