Systemic Mastocytosis
Systemic mastocytosis (SM) is a rare clonal disorder characterized by the abnormal proliferation and accumulation of neoplastic mast cells in one or more extracutaneous organs, most commonly the bone marrow, liver, spleen, and gastrointestinal tract. The pathogenesis of SM is most frequently driven by activating mutations in the KIT gene, particularly the KIT D816V mutation, which leads to constitutive activation of the KIT receptor tyrosine kinase, promoting mast cell survival and proliferation. The aberrant accumulation of mast cells results in the release of mediators such as histamine, tryptase, and cytokines, causing a spectrum of clinical manifestations ranging from mild cutaneous symptoms to severe organ dysfunction. Health impacts may include episodic flushing, pruritus, gastrointestinal disturbances, anaphylactic reactions, osteoporosis, cytopenias, and organomegaly. Advanced forms can lead to organ failure and significantly reduced survival.
Indolent systemic mastocytosis is the most common variant, characterized by the presence of multifocal mast cell infiltrates in extracutaneous organs, but with minimal or no organ dysfunction. Patients typically exhibit symptoms related to mast cell mediator release, such as urticaria pigmentosa, flushing, and gastrointestinal complaints, but life expectancy is generally normal and progression to more aggressive forms is rare.
Smoldering systemic mastocytosis is an intermediate form with a higher burden of mast cell infiltration compared to ISM, but without the full criteria for aggressive disease. Patients may have organomegaly and mild cytopenias, and are at increased risk of progression to aggressive systemic mastocytosis or mast cell leukemia.
Aggressive systemic mastocytosis is defined by significant organ dysfunction (so-called 'C-findings') due to mast cell infiltration, such as cytopenias, liver dysfunction, malabsorption, or pathologic fractures. Cutaneous involvement may be absent, and the prognosis is poor without effective cytoreductive therapy.
This variant involves the coexistence of systemic mastocytosis and a separate clonal hematologic non-mast cell lineage disease, most commonly myeloid neoplasms such as chronic myelomonocytic leukemia or myelodysplastic syndromes. Both disease processes require targeted management.
Mast cell leukemia is the rarest and most aggressive form of systemic mastocytosis, characterized by a high percentage of neoplastic mast cells in the bone marrow and peripheral blood, rapid clinical deterioration, and extremely poor prognosis.
Systemic mastocytosis is a rare disorder, with an estimated prevalence of approximately 1 in 10,000 to 1 in 20,000 individuals in Western populations. The disease affects both genders, though some studies suggest a slight male predominance in advanced forms. Most cases present in adulthood, with a median age at diagnosis in the fifth decade of life. Pediatric cases are uncommon and typically manifest as cutaneous forms. The indolent variant accounts for the majority of cases, while aggressive forms and mast cell leukemia are much less frequent. Epidemiological data are limited due to the rarity and underdiagnosis of the disease.
The diagnosis of systemic mastocytosis is based on the World Health Organization (WHO) criteria, which require the presence of one major and one minor criterion or at least three minor criteria. The major criterion is multifocal, dense infiltrates of mast cells (≥15 mast cells per aggregate) detected in bone marrow or other extracutaneous organs. Minor criteria include: (1) more than 25% of mast cells in infiltrates are spindle-shaped or display atypical morphology; (2) detection of a KIT point mutation at codon 816 in bone marrow, blood, or other extracutaneous organs; (3) mast cells in bone marrow or other extracutaneous organs express CD2 and/or CD25 in addition to normal mast cell markers; and (4) serum total tryptase level persistently exceeds 20 ng/mL (unless there is an associated clonal myeloid disorder). Diagnostic procedures include a thorough clinical assessment, laboratory evaluation of serum tryptase, bone marrow aspirate and biopsy with immunohistochemistry and molecular testing for KIT mutations, flow cytometry for aberrant surface marker expression, and imaging studies to assess organ involvement. Additional workup may be necessary to evaluate for associated hematologic neoplasms or organ dysfunction.
Avapritinib is approved for the treatment of systemic mastocytosis and acts as a potent and selective inhibitor of mutant KIT, including the KIT D816V mutation commonly implicated in this disease. Midostaurin is utilized in the management of advanced systemic mastocytosis and exerts its therapeutic effects through inhibition of multiple kinases, notably KIT, thereby targeting the neoplastic mast cell population. Imatinib mesylate is indicated for certain cases of systemic mastocytosis, particularly in patients lacking the KIT D816V mutation, and functions as a tyrosine kinase inhibitor with activity against wild-type KIT. Cromoglycate sodium, also known as cromolyn sodium, is employed as a mast cell stabilizer to alleviate mediator-related symptoms in systemic mastocytosis by inhibiting the release of mast cell mediators such as histamine, thus providing symptomatic relief for affected individuals.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | avapritinib (Rec INN; USAN) | 1703793-34-3 | C26 H27 F N10 | 498.558 |
 | midostaurin (Prop INN; USAN) | 120685-11-2 | C35 H30 N4 O4 | 570.637 |
 | imatinib mesylate (Rec INNM; USAN) | 152459-95-5 (free base); 220127-57-1 | C29 H31 N7 O . C H4 O3 S | 589.708 |
 | cromoglycate sodium; cromolyn sodium (USAN); disodium cromoglycate; sodium cromoglycate (Prop INNM; BANM) | 15826-37-6 | C23 H14 O11 . 2 Na | 512.33 |
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