Systemic mastocytosis in adults — current classification, pathogenesis, comprehensive diagnostics, and therapeutic strategies

Systemic mastocytosis (SM) is a clonal hematologic neoplasm marked by the accumulation of morphologically and immunophenotypically aberrant mast cells in extracutaneous organs, particularly the bone marrow, liver, spleen, and gastrointestinal tract. Although cutaneous lesions are common, their presence alone is insufficient for diagnosing SM. The incidence of SM is estimated at 5–10 cases per 1 million people annually, most commonly affecting adults over the age of 30. Diagnosis is based on World Health Organization (WHO) criteria, which include the presence of mast cell clusters in bone marrow, elevated serum tryptase levels, expression of characteristic antigens (CD25, CD2), and the presence of the KIT D816V mutation. According to WHO, advanced forms of systemic mastocytosis include: (1) aggressive systemic mastocytosis (ASM), (2) systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and (3) mast cell leukemia (MCL). MCL has the poorest prognosis among these, with a median survival of approximately two months. Prognostic factors in SM include clinical, laboratory and molecular parameters. In particular, the presence of mutations in the SRSF2 , RUNX1 and ASXL1 genes is associated with poor outcomes. Regardless of SM subtype, therapeutic management should involve avoiding mast cell degranulation triggers and treating mediator-related symptoms when necessary. For cases involving organ damage due to mast cell infiltration, the primary treatment is midostaurin, a tyrosine kinase inhibitor which is effective in around 60% of patients with the KIT D816V mutation (Valent Criteria), or 28% (IWG criteria). As of 1 st January 2025, avapritinib, a selective KIT D816V inhibitor with efficacy of 60% assessed by mIWG criteria, is available as a second-line of treatment. Other therapeutic options include cladribine, imatinib and pegylated interferon alpha. The only potentially curative treatment for SM is allogeneic haematopoietic stem cell transplantation (allo-HSCT). This paper outlines the current approach to diagnosing and treating this rare disease.