Evaluation of prognostic factors and outcomes in primary versus secondary myeloid sarcoma.

Myeloid sarcoma (MS) is a rare extramedullary manifestation of myeloid neoplasia that may present as an isolated disease without concurrent bone marrow involvement, primary disease or secondary to an antecedent myeloid neoplasm. The molecular landscape and prognostic determinants of these groups remain incompletely defined. This multi-institutional retrospective cohort study of 145 histologically confirmed MS cases from multiple academic centers incorporates clinical, cytogenetic, and next-generation sequencing data to characterize disease biology and outcomes. Patients with primary MS (56.6% of cases) more often received stem cell transplant and achieved remission, while those with secondary disease (43.4%) were more likely to receive local irradiation and less likely to achieve remission. Isolated MS (20.7% of cases) demonstrated preserved peripheral blood counts and significantly lower mutational burden. Myelodysplasia-related (MR) mutations (44.5% of cases) were associated with higher mutational burden and increased cytogenetic abnormalities but did not influence outcomes. Secondary MS exhibited more frequent TET2 mutations, consistent with evolution from antecedent myeloid neoplasia. NPM1 mutations (52.6% of cases) were associated with skin involvement, higher remission/relapse rates, and frequent FLT3 co-mutation. Additional mutations, including ASXL1 and NRAS, were associated with distinct clinical features but not survival differences. Overall, this comprehensive study highlights clinical and molecular heterogeneity in MS. Outcomes appear to be influenced by an interplay of disease context, clonal architecture, and therapeutic strategy rather than individual mutations alone, underscoring the need for integrated molecular profiling and prospective studies to guide management. This study highlights that MS with MR mutations may follow different cellular pathways to evolution.