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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Advanced systemic mastocytosis is the dangerous form of this rare blood cancer, in which KIT-mutant mast cells damage the marrow, liver, gut or bones, grow alongside a second blood cancer such as chronic myelomonocytic leukaemia, or flood the blood as mast cell leukaemia. The KIT-blocking tablets midostaurin and avapritinib have replaced older chemotherapy, and fit patients may have a transplant.
Advanced systemic mastocytosis comprises three WHO entities united by KIT D816V-driven mast cell proliferation with organ damage or an accompanying neoplasm. Aggressive systemic mastocytosis is defined by C findings: cytopenias from marrow infiltration, liver dysfunction with ascites, hypoalbuminaemia and weight loss from gut involvement, or large lytic bone lesions. Systemic mastocytosis with an associated haematological neoplasm (SM-AHN), the commonest advanced form, pairs mastocytosis with a myeloid neoplasm, usually chronic myelomonocytic leukaemia, a myelodysplastic or myeloproliferative neoplasm or acute myeloid leukaemia, which arises from the same KIT-mutant or an earlier clone and often carries SRSF2, ASXL1 or RUNX1 mutations that predict shorter survival on the MARS and IPSM scores. Mast cell leukaemia, with 20 percent or more mast cells in the marrow aspirate, is the rarest and most lethal form. Serum tryptase is usually very high and KIT D816V allele burden in blood reflects the whole disease.
Before 2017 treatment was cladribine, interferon alfa or hydroxycarbamide, with responses in a minority. Midostaurin, a multikinase inhibitor active against KIT D816V, produced responses in 60 percent of 116 patients with advanced disease in a phase 2 trial (New England Journal of Medicine 2016) and was approved in 2017; avapritinib, a selective KIT D816V inhibitor, produced responses in three quarters of patients in the EXPLORER and PATHFINDER trials with deep falls in tryptase and allele burden and was approved in June 2021 for advanced disease, restricted to patients with platelets of 50 x 10^9/L or more because of intracranial haemorrhage at higher doses in thrombocytopenic patients. Avapritinib is now the preferred first-line agent in the NCCN guideline, midostaurin the alternative, and bezuclastinib is in the Apex trial as a further selective inhibitor. The associated neoplasm is treated on its own merits, for example with azacitidine for chronic myelomonocytic leukaemia or intensive chemotherapy for acute myeloid leukaemia, and allogeneic transplantation is the only curative option, considered for mast cell leukaemia, aggressive disease responding to a KIT inhibitor and SM-AHN with a high-risk neoplasm. Supportive care for mediator symptoms, bone disease and anaphylaxis continues throughout.
| Setting | Approach | Guideline |
|---|---|---|
| Diagnosis and risk assessment | Bone marrow biopsy and aspirate, KIT D816V allele burden, myeloid mutation panel, tryptase, imaging for organomegaly and bone lesions, MARS or IPSM score. | not mapped |
| First line | Avapritinib 200 mg daily when platelets are 50 x 10^9/L or more (EXPLORER, PATHFINDER, approved 2021); midostaurin as the alternative (approved 2017). | not mapped |
| Associated haematological neoplasm | Treat the neoplasm on its own merits (azacitidine for CMML or MDS, intensive chemotherapy for AML) alongside or after KIT inhibition. | not mapped |
| Relapsed or intolerant | Switch between avapritinib and midostaurin; cladribine; interferon alfa; bezuclastinib in the Apex trial. | not mapped |
| Fit patients, especially mast cell leukaemia or high-risk SM-AHN | Allogeneic haematopoietic cell transplantation after response to a KIT inhibitor. | not mapped |