KIT mutation and AHN-associated oncogenic profiles in systemic mastocytosis with an associated hematological neoplasm

In 5% to 15% of patients with systemic mastocytosis (SM), SM coexists with an associated hematological neoplasm (AHN). Most patients with SM-AHN harbor a KIT mutation, mainly KIT p.D816V, together with other AHN-related genetic alterations; however, limited data exist about the frequency and clinical impact of the coexistence of both types of genetic alterations in the same vs distinct bone marrow (BM) cell compartments. Here, we analyzed 79 patients with SM-AHN classified into patients who (1) displayed distinct unrelated genetic alterations in BM mast cells (MC) and AHN cells (21/79 [27%]); (2) shared the KIT mutation as a first genetic event (24/79 [30%]) involving both BM MC and AHN cells, together with or without AHN-associated alterations restricted to the latter cells; (3) had AHN-associated alterations as a first event (25/79 [32%]) present in both BM MC and AHN cells; and (4) had both alterations involving virtually all SM and AHN cells (9/79 [11%]). Overall, patients with genetically unrelated SM and AHN more frequently showed clinical manifestations associated with SM (ie, anaphylaxis, osteoporosis, and skin lesions) together with prolonged progression-free survival (PFS), whereas those with shared genetic alterations displayed signs of more advanced disease (ie, cytopenias or organomegalies) and shorter PFS and overall survival. Our findings confirm the clinical, genetic, and prognostic heterogeneity of SM-AHN and point to its association with the underlying oncogenic profile of neoplastic MC and AHN cells.