The Clinical and Molecular Characteristics of Systemic Mastocytosis with Associated Non-Mast Cell Myeloid Neoplasm

Background: Systemic mastocytosis (SM) with associated non-mast cell myeloid neoplasm is a rare condition, defined by the presence of both SM and a clonal non-mast cell neoplasm. Due to its rarity, the demographic and molecular characteristics are poorly understood. This study investigated seven patients diagnosed with this condition at our institution. Methods: Our institutional database was searched for "systemic mastocytosis" from 1 January 2020, to 31 December 2025. Each case was annotated to identify the primary cohort of this study, systemic mastocytosis with associated non-mast cell myeloid neoplasm (SM-AHN). Demographic characteristics, outcome, hematologic features at diagnosis, cytogenetics, and molecular characteristics were annotated. Eight cases of isolated SM diagnosed during the same period were also analyzed for comparison. All patients in the database were followed until their death or until 31 December 2025. All data were exported to SPSS v. 28 (IBM, Armonk, NY, USA^®). Results: A total of seven patients were diagnosed with SM-AHN. Compared to isolated SM, SM-AHN patients showed older age at presentation, poorer hematologic values (increased anemia and thrombocytopenia), higher mutational burden, and poorer outcomes. KIT mutations were most common, predominantly D816V, with other variants like D816Y and L576F also observed. Additional frequent mutations included DNMT3A, TET2, ASXL1, SF3B1, EZH2, JAK2, NRAS, and SRSF2. Conclusions: Our findings, though limited by a small sample size, suggest that SM with associated myeloid neoplasm presents with distinct clinical and molecular features compared to isolated SM. This combined disorder is associated with older age, worse hematologic parameters, a higher mutational burden, and poorer prognosis. The frequent co-occurrence of mutations in other genes, in addition to KIT mutations, highlights the complex molecular landscape.