Indolent and smouldering systemic mastocytosis

Systemic mastocytosis is a clonal myeloid neoplasm of mast cells driven in more than nine in ten patients by the KIT D816V mutation. The indolent form, which accounts for most cases, is defined by the WHO and ICC criteria of multifocal mast cell aggregates in the marrow with abnormal CD25 or CD2 or CD30 expression, raised serum tryptase and the KIT mutation, without the organ damage ('C findings') that defines advanced disease; smouldering disease has a higher mast cell burden ('B findings') but still no organ damage, and bone marrow mastocytosis lacks skin lesions. Patients suffer from mediator release: flushing, urticaria pigmentosa, pruritus, abdominal cramps, diarrhoea, brain fog, fatigue and, in a substantial minority, anaphylaxis, classically after insect stings; osteoporosis and fractures are common. Hereditary alpha-tryptasaemia, a common germline duplication of the tryptase gene, raises baseline tryptase and worsens symptoms in some patients and must be accounted for when interpreting tryptase levels. Progression to advanced disease is uncommon, and mutations in SRSF2, ASXL1 or RUNX1 identify the minority at risk.

Management for decades was symptomatic: H1 and H2 antihistamines, cromoglicate, leukotriene antagonists, proton-pump inhibitors, omalizumab for recurrent anaphylaxis, adrenaline autoinjectors for every patient, venom immunotherapy after sting anaphylaxis, and bisphosphonates for osteoporosis, with cladribine or interferon alfa for the few with intolerable symptoms. The KIT D816V-selective inhibitor avapritinib changed that: the PIONEER trial (NEJM Evidence 2023) randomised 212 patients with moderate to severe symptoms to avapritinib 25 mg daily or placebo on top of best supportive care and showed a greater fall in total symptom score, in serum tryptase, in KIT D816V allele burden and in marrow mast cells, and avapritinib was approved for indolent systemic mastocytosis in the United States in May 2023 and in Europe later that year; it does not carry the intracranial bleeding risk seen at higher doses in advanced disease but is avoided when platelets are low. Newer KIT D816V inhibitors, elenestinib (HARBOR) and bezuclastinib (Summit), are in randomised trials aiming for greater selectivity, and the disease is otherwise followed with tryptase, KIT allele burden and bone density.