In a recent study published in Blood Advances, Sekeres et al examined whether exposure to Agent Orange, a dioxin-contaminated herbicide used during the Vietnam War, is associated with the development and clinical characteristics of myelodysplastic syndromes (MDS). Given the established links between Agent Orange and several malignancies—but the absence of definitive data in MDS—the authors sought to clarify whether environmental exposure contributes to disease risk, genomic features, and outcomes in patients with cytopenias undergoing evaluation for MDS.
Study Details
This analysis leveraged data from the National Heart, Lung, and Blood Institute National MDS Natural History Study, a large prospective cohort conducted across 161 U.S. sites between 2016 and 2024. The study enrolled 2,115 patients with suspected MDS or related conditions, all of whom underwent centralized clinical, genomic, and cytogenetic assessment, along with detailed exposure histories (including Agent Orange).
Approximately half of patients were ultimately diagnosed with MDS or related myeloid neoplasms, allowing comparisons between exposed and unexposed individuals. Statistical analyses included bivariate testing and multivariable logistic regression to identify correlates of Agent Orange exposure, as well as Cox proportional hazard models to assess associations with disease progression and survival. Molecular profiling encompassed a 96-gene panel, and cytogenetic abnormalities were assessed by metaphase karyotyping.
Key Results
Among the cohort, 6.1% of patients reported Agent Orange exposure, predominantly older male patients with a history of military service. Exposure was associated with a higher likelihood of MDS or clonal cytopenias (54% vs 37%, P = .022) and with adverse biologic features, including increased mutational burden and higher rates of poor- or very poor–risk cytogenetics (odds ratio = 2.39, P = .03). Specific genomic alterations were enriched in exposed patients, including mutations in TET2, SRSF2, U2AF1, ZRSR2, and KRAS, as well as cytogenetic abnormalities such as del(20q); RNA splicing pathway mutations remained significant after multiple testing correction. Agent Orange exposure was associated with younger age at MDS diagnosis and a higher prevalence among Black patients, even after adjustment for confounders.
Overall survival did not differ significantly between exposed and unexposed groups; however, Agent Orange exposure was linked to an increased risk of disease progression within the first 2 years following diagnosis (hazard ratio = 1.8, P = .004). These findings suggest that Agent Orange exposure may contribute to genomic instability and disease aggressiveness, potentially through dioxin-related epigenetic and DNA damage mechanisms.
The authors concluded: “For the first time, we were able to demonstrate the impact of Agent Orange exposure on this large cohort of patients with unexplained cytopenias, 57% of whom were ultimately diagnosed with MDS and related conditions.”
Mikkael A. Sekeres, MD, MS, of Sylvester Cancer Center, University of Miami, is the corresponding author for the Blood Advances article.
DISCLOSURE: The study was supported by the National Heart, Lung, and Blood Institute and the National Cancer Institute. For full disclosures of the study authors, visit ashpublications.org.
