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It represents less than 10% of all SM cases and the global prevalence is estimated in the order of between 1/250,000-400,000.

Aggressive systemic mastocytosis (ASM) may occur at any age, occurring predominantly in adults and very rarely in pediatric patients. Presentation is with organ dysfunction related to mast cell invasion (C-findings) and the intense release of mediators including syncope, recurrent flushing, diarrhea, pain, organomegaly. C-findings include bone marrow (BM) dysfunction, palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, skeletal involvement with large osteolytic lesions and/or pathological fractures, palpable splenomegaly with hypersplenism and malabsorption with ascites. Patients do not show signs of non-mast cell hematological disease. Cutaneous involvement is slightly less frequent than in indolent SM. The most serious complications include potentially fatal anaphylactic shock and transformation to mast cell leukemia (MCL). Disease progression can be either slow or rapid. In patients with rapid progression, serum tryptase levels increase rapidly, multi-organ damage occurs (or worsens) within a short time, and rapid progression to MCL is frequent. Due to the latter, ASM with >5% MC in BM smears is termed ASM in transformation.

The etiology is not well understood but there is evidence of an activating mutation of KIT, usually D816V, in the mast cells and sometimes in non-MC hematopoietic lineages. Additional and recurrent somatic mutations of other genes have been reported in ASM; the genes most frequently affected includeTET2, SRSF2, ASXL1, RUNX1, JAK2, N/KRAS, and CBL and, less frequently,EZH2, IDH2, ETV6, U2AF, or SF3B1. These defects contribute to aggressiveness of the disease, particularly in multi-mutated patients.

Diagnosis of SM is established using the WHO (World Health Organization) consensus criteria. The disease is then categorized according to the presence of B- and C-findings. The characteristics of ASM includes BM smear with <20% MC, and one or more C-findings. In rapidly progressive cases, the percentage of MC in the BM smears is of major prognostic significance and is usually elevated substantially (>5%).

Differential diagnoses include all causes of cytopenias (myelofibrosis, myelodysplasia and other hematological malignancies) and other abnormal types of mutation in JAK2, that are excluded by the detection of bone marrow infiltration by neoplastic mast cells with an activation mutation of KIT.

Treatment is constant with non-targeted or targeted cytoreductive therapy. Non-targeted therapies include interferon-(IFNalpha), which may be effective in a subset of patients, and cladribine (2CdA) which provides high, and sometimes long lasting, response rates. Allogeneic stem cell transplantation (allo-SCT) is rarely used and reserved for fit patients with a suitable donor. However, when applicable, allo-SCT provides frequently good response rates and complete remission. Targeted therapy is with KIT tyrosine kinase inhibitors (KIT TKIs) Midostaurin which inhibits the D816V mutant (approved in Europe and the USA), is regarded as the standard first-line therapy in ASM. Whilst it is efficacious, it does not induce complete hematologic remissions. Midostaurin may also be useful for patients who need debulking prior to allo-SCT or those who fail treatment with 2CdA or IFNalpha. Other TKIs included imatinib mesylate or masitinib and may be indicated for the few patients without the KITD816V mutation. Symptomatic treatment is mainly with antihistamines (anti-H1 and anti-H2). The use of iodinated contrast agents should be limited.

The prognosis is usually poor with a median survival of 2 to 4 years. Due to rapid progression to MCL, ASM patients with a MC count in the BM smears >5% have a worse outcome with reduced survival and progression-free survival compared to patients with <5%. Furthermore, the presence of mutations in other critical target genes, in particular SRSF2, ASXL1, RUNX1, is associated with progression and poor outcome.