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

In 5-15% of systemic mastocytosis (SM) patients, SM coexists with another associated hematological neoplasm (AHN). Most SM-AHN patients harbor a KIT-mutation, mainly KIT p.D816V, together with other AHN-related genetic alterations; however, limited data exists about the frequency and the 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 SM-AHN patients classified into cases who: i) displayed distinct unrelated genetic alterations in BM mast cells (MC) and AHN cells (21/79, 27%); ii) 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; iii) patients presenting with AHN-associated alterations as a first event (25/79, 32%) present in both BM MC and AHN cells, and; iv) patients in whom both alterations involved 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), while those cases 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 out its association with the underlying oncogenic profile of neoplastic MC and AHN cells.