Symposium | Disease biology and molecular architecture in advanced systemic mastocytosis

At the European Hematology Association (EHA) 2026 Congress, June 11–14, 2026, Stockholm, SE, the MPN Hub held a symposium, titled Advanced systemic mastocytosis: Redefining the disease, rethinking patient outcomes. During the symposium, Deepti H Radia, Guy's and St Thomas' NHS Foundation Trust, London, UK, delivered a presentation on disease biology and molecular architecture in advanced systemic mastocytosis (AdvSM). 

In this presentation, Radia discusses the classification and biology of AdvSM, covering mast cell disease biology, the clinical and biological spectrum of AdvSM, KIT as a central molecular driver of AdvSM, additional somatic mutations, clonal architecture and disease evolution, and the mechanisms of disease progression and organ damage. 

Key points 

• Systemic mastocytosis (SM) is a heterogeneous clonal disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other tissues (Figure 1).¹ 

• Mast cell activation leads to mediator release, while clonal expansion drives tissue infiltration and organ damage in advanced disease (Figure 2).

• AdvSM comprises distinct subtypes with differing clinical and biological characteristics (Figure 3).³ 

• KIT is the central molecular driver of AdvSM, with activating KIT mutations driving mast cell proliferation, survival, and disease biology.⁶ 
  • KIT is a type III receptor tyrosine kinase for stem cell factor and is the principal regulator of mast cell growth and survival.⁶ 
  • Activating KIT mutations are present in >80% of SM cases and >70% of AdvSM cases.⁶ 
  • KIT D816V is the most common mutation; however, >20 additional KIT mutations have been described.⁶ 
  • Constitutive KIT activation promotes mast cell proliferation, survival, and accumulation in tissues.⁵ 
  • KIT D816V can be detected in multiple hematopoietic lineages, reflecting multi-lineage involvement in advanced disease.⁶ 
• Additional mutations contribute to disease heterogeneity and are associated with more aggressive clinical behavior and adverse outcomes in AdvSM (Figure 4).^2,5,6 
  • Additional mutations have been found in ~90% of patients and frequently involve genes regulating epigenetic modification and RNA splicing.^2,5,6 
  • Certain mutations, particularly within the SRSF2/ASXL1/RUNX1 (S/A/R) panel, are associated with inferior overall survival.²  
  • Somatic mutations are increasingly incorporated into prognostic risk stratification models in AdvSM, including the MARS-R.⁵  

• The clinical heterogeneity and progression of AdvSM are driven by a stem cell-derived clonal population that acquires mutations over time.⁵ 
  • KIT D816V mutation can be detected in hematopoietic progenitor cells and myeloid lineages, supporting a stem/progenitor cell origin.⁵  
  • Additional somatic mutations may arise prior to KIT D816V during hematopoiesis.⁵ 
  • Accumulation of additional mutations (e.g., S/A/R) is associated with more aggressive disease and poorer clinical outcomes.⁵ 
• Disease progression in AdvSM results from clonal expansion and tissue infiltration, leading to organ damage (Figure 5).^3,5 

This educational resource is independently supported by Blueprint medicines. All content is developed by the faculty in collaboration with SES. Funders are allowed no influence.