Systemic Mastocytosis

Overview

• Definition: a myeloid neoplasm caused by accumulation of abnormal mast cells in bone marrow, liver, spleen, and skin.
• Driver: KIT D816V, detected in ~90% of patients, encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis.
• Symptoms: from release of vasoactive mediators (mast-cell activation) and from organ damage due to neoplastic mast-cell infiltration.
  • Mediator-related: allergic reactions triggered by ethanol, medications, and allergens; flushing, pruritus, anaphylaxis.
  • Organ-damage findings: cytopenias, liver-function abnormalities, hypoalbuminemia, weight loss, ascites, and osteolytic bone lesions.
• Tryptase: elevated serum tryptase correlates with disease burden; persistent level >20 ng/mL is a minor diagnostic criterion.
• Immunophenotype: mast cells are CD117+ (c-kit), with aberrant CD25+ and/or CD2+, and tryptase+; CD30 may be aberrantly expressed.

WHO diagnostic criteria

• B findings (high mast-cell burden, no organ dysfunction): BM ≥30% mast cells and/or serum total tryptase ≥200 ng/mL and/or KIT D816V VAF ≥10%; myelodysplasia or myeloproliferation in a non-mast-cell lineage not meeting AHN criteria, with normal or only slightly abnormal counts (C-finding cytopenia requires ANC <1.0, Hb <10, and/or platelets <100 x10^9/L); hepatomegaly, splenomegaly, and/or lymphadenopathy without impaired organ function.
• C findings (end-organ damage, define advanced disease): cytopenias, hepatomegaly with impaired liver function or ascites, splenomegaly with hypersplenism, skeletal lesions (large osteolysis), and malabsorption with weight loss.

Subtypes and prognosis

• Bone marrow mastocytosis (new WHO 2022).
• Indolent systemic mastocytosis: 0 to 1 B findings and NO C findings; near-normal life expectancy, though some evolve to aggressive disease.
• Smoldering systemic mastocytosis: high burden (≥2 B findings) without C findings.
• Advanced SM, comprising ASM (requires at least one C finding), SM-AHN, and MCL (SM-AHN and MCL do not require mast-cell C findings):
  • Aggressive SM (ASM): median overall survival ~3.5 years.
  • SM with an associated hematologic neoplasm (SM-AHN): median OS ~2 years.
  • Mast cell leukemia (MCL): defined by a bone marrow aspirate with ≥20% mast cells; median OS <6 months.

Treatment

• All patients: epinephrine autoinjector for anaphylaxis; avoid triggers.
• Supportive / mediator control: H1 and H2 blockers, antileukotriene agents, cromolyn sodium, topical steroids (for indolent SM).
• Advanced SM (cytoreduction needed for end-organ damage):
  • Midostaurin (multikinase KIT inhibitor active against D816V; FDA approved 2017 for advanced SM) and avapritinib (selective KIT D816V inhibitor).
  • Other acceptable options: interferon-alfa or cladribine.
  • Imatinib: KIT D816V does NOT respond well to imatinib; imatinib is approved only for patients WITHOUT KIT D816V or with unknown KIT mutation status.
  • Allo-HSCT for aggressive SM / mast cell leukemia.
• Avapritinib in indolent SM (FDA May 2023; advanced SM approval June 2021): PIONEER trial (Gotlib, NEJM Evidence 2023) improved Total Symptom Score and reduced tryptase; 25 mg PO daily.
• Bezuclastinib (KIT D816V-selective inhibitor): SUMMIT phase 2 in non-advanced SM (Hartmann, ASH 2024, promising tryptase and symptom-score reduction); APEX phase 2 in advanced SM. Investigational: NDAs under FDA review (PDUFA Dec 30, 2026 non-advanced SM; June 29, 2027 advanced SM).
• Elenestinib (BLU-263), KIT D816V-selective, in indolent SM: HARBOR phase 2/3 (primary population ISM; includes an exploratory smoldering-SM cohort). Investigational.

Hereditary alpha-tryptasemia (HαT)

• Cause: inherited extra copies of the alpha-tryptase gene TPSAB1, raising baseline blood tryptase (a key confounder when interpreting tryptase in suspected SM).
• Features: allergic-like symptoms (itching, flushing, hives, anaphylaxis), GI symptoms (diarrhea, bloating, abdominal pain, GERD, dysphagia), connective-tissue features (joint hypermobility, scoliosis), and cardiovascular symptoms (tachycardia, syncope).
• Treatment: symptom-directed anti-allergy medications.