Prevalence and clinical relevance of Janus kinase 2 (JAK2) mutation in myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.

e18586 Background: MDS/MPN is a group of myeloid malignancies characterized by overlapping dysplastic and proliferative features. JAK2 mutations are rare in isolated MDS (2-5%), while previous studies on MDS/MPN overlap syndromes report 19-25%. We evaluated the prevalence and impact of JAK2 mutations on outcomes in MDS/MPN overlap syndromes. Methods: We identified adults aged ≥18 years with MDS/MPN, unclassifiable from the National Cancer Database (NCDB) between 2010 and 2022 using ICD-O3 code 9975. We obtained sociodemographic and clinical characteristics, including age, sex, race/ethnicity, insurance, Charlson Deyo comorbidity index, socioeconomic status, treatment received, and JAK2 mutation status. Median overall survival(OS) was estimated using Kaplan-Meier methods, and differences between groups were compared with log-rank tests. Multivariable Cox analysis was used to assess factors independently associated with OS. A p-value <0.05 was considered statistically significant. Results: We identified 5,759 patients with MDS/MPN-U, median age 77 years, and 56% men. Most individuals were non-Hispanic White (82%), insured by Medicare (74%), and resided in metropolitan areas (78%). Based on the area of residence, 13.4% lived in a locality of lowest-income quartile and 16% in lowest-education quartile. Overall, 34% had a JAK2 mutation, which was more frequent among women (37% vs 32%) and ranged from 28% in non-Hispanic Black (NHB) individuals to 39% in other minorities (p <0.01). Allogeneic stem cell transplantation was rare in 2%, with 19% of transplanted individuals having JAK2 mutation. Overall, only 2% of patients received palliative care during their lifetime. Prevalence of JAK2 mutation did not vary with other demographics or comorbidity burden. JAK inhibitors/chemotherapy was reported in 45% of all comers (55% JAK2 mutated vs 23% JAK2 unmutated). Among all comers, survival varied by race (p = 0.02), with a median OS ranging from 17.5 months (m) in NHB to 22.3m in Hispanic individuals. On unadjusted survival analysis, JAK2-positivity (28.4 m vs 15.2 m) and receipt of chemo/JAK inhibitor therapy were associated with longer survival (20.8 vs 16.2 m)(all p< 0.001). In a multivariable cox analysis adjusted for age, sex, race, insurance status, comorbidity and chemo receipt, female sex (hazard ratio (HR) 0.87) and JAK2 positivity were associated with improved OS (HR 0.64) while older age, higher comorbidity burden, and NHB individuals (HR 1.2) were found to have worse survival (all p< 0.001). Conclusions: This is the largest cohort of MDS/MPN-U to be reported. It showed significant racial differences, while both race and JAK2 mutation were independently associated with survival in this cohort. Lack of granularity is a major limitation to this study, and larger multi-center studies are needed to further understand this rare entity.