{"entity":{"id":"systemic-mastocytosis","kind":"cancer","name":"Systemic mastocytosis","aka":["SM","Advanced systemic mastocytosis (AdvSM)","Indolent systemic mastocytosis (ISM)","Smouldering systemic mastocytosis","Aggressive systemic mastocytosis","Mast cell leukaemia","SM with an associated haematological neoplasm (SM-AHN)"],"tldr":"Systemic mastocytosis is a clonal disease of mast cells, the immune cells that release histamine; almost every case is driven by a single mutation in the KIT gene. Precise KIT-blocking pills now shrink the mast cell burden, ease symptoms and, in the aggressive forms, prolong life. Most patients have the indolent form, where the goal is controlling symptoms and preventing anaphylaxis.","summary":"Systemic mastocytosis (SM) is a myeloid neoplasm defined by multifocal mast cell infiltrates in marrow or other organs, with KIT D816V present in about nine of ten patients. WHO 2022 divides it into indolent SM (ISM; the majority, with skin lesions, mediator symptoms and anaphylaxis risk but near-normal life expectancy), smouldering SM, and advanced SM (AdvSM), comprising aggressive SM, mast cell leukaemia and SM with an associated haematological neoplasm (SM-AHN), where the associated CMML, MDS or AML often decides outcome. Diagnosis uses serum tryptase (with correction for hereditary alpha-tryptasaemia), high-sensitivity KIT D816V PCR in peripheral blood, and marrow biopsy with CD25/CD30 mast cell immunophenotyping; additional mutations (SRSF2, ASXL1, RUNX1, the S/A/R panel) mark high-risk disease.\n\nTreatment is stratified. In ISM, antihistamines, cromolyn, omalizumab, epinephrine autoinjectors and trigger avoidance manage mediator symptoms; osteoporosis is treated. The 2023 approval of avapritinib for ISM (PIONEER: 25 mg daily improved total symptom scores and reduced tryptase, KIT D816V allele burden and skin lesions) made it the first disease-modifying therapy for the indolent form. In AdvSM, midostaurin (2017; multikinase KIT inhibitor, responses in about 60 percent in the pivotal trial) was the first approved drug, and avapritinib (2021; PATHFINDER and EXPLORER, selective KIT D816V inhibition with high response rates including complete remissions) is now the preferred first-line agent for patients with platelets above 50 x 10^9/L. Cladribine remains an option, interferon is historic, and allogeneic transplant is used for mast cell leukaemia or SM-AHN with high-risk associated neoplasms. Next-generation KIT D816V inhibitors, bezuclastinib (Summit and Apex trials) and elenestinib (Harbor), aim for equal efficacy with less intracranial bleeding and cognitive toxicity.\n\nOpen problems are the associated haematological neoplasm in SM-AHN, avapritinib's bleeding risk at low platelet counts, and the years-long diagnostic delay in indolent disease.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Mastocytosis","links":[{"label":"NCI PDQ: mastocytosis (within myeloproliferative neoplasms)","url":"https://www.cancer.gov/types/myeloproliferative"},{"label":"PATHFINDER: avapritinib in advanced SM (Nature Medicine 2021)","url":"https://doi.org/10.1038/s41591-021-01539-8"},{"label":"PIONEER: avapritinib in indolent SM (NEJM Evidence 2023)","url":"https://doi.org/10.1056/EVIDoa2200339"},{"label":"Midostaurin in advanced SM (NEJM 2016)","url":"https://doi.org/10.1056/NEJMoa1513098"},{"label":"NCCN: Systemic Mastocytosis","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1463"}],"tags":["nci-coverage","rare","haematologic"],"related":["cmml","mds","aml","gist"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","liquid-biopsy","histopathology-ihc","flow-cytometry-mrd"],"targets":["kit","flt3"],"drugs":["avapritinib","midostaurin","cladribine","interferon-alfa","azacitidine","imatinib"],"companies":[],"institutions":[],"pathways":["rtk-activation","clonal-haematopoiesis"],"terms":["driver-mutation","cytopenias","molecular-response"],"trials":["nct04910685"],"people":[],"bottlenecks":["b-rare-cancers","b-toxicity-qol"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Roughly one to two new cases per 100,000 per year, most of them indolent; advanced forms are rare, and many indolent cases go undiagnosed for years because symptoms mimic allergy (WHO; ECNM registry).","subtypes":["Indolent systemic mastocytosis (with or without skin involvement)","Bone marrow mastocytosis","Smouldering systemic mastocytosis","Aggressive systemic mastocytosis","Systemic mastocytosis with an associated haematological neoplasm (SM-AHN)","Mast cell leukaemia","Cutaneous mastocytosis (children; usually resolves)"],"biomarkers":["Serum tryptase (adjusted for hereditary alpha-tryptasaemia)","KIT D816V by high-sensitivity ddPCR in blood (allele burden tracks response)","Marrow mast cell aggregates with CD25, CD2, CD30 expression","C-findings (cytopenias, liver dysfunction, hypoalbuminaemia, malabsorption, lytic bone lesions) defining advanced disease","SRSF2, ASXL1, RUNX1 (S/A/R) mutations; MARS and IPSM prognostic scores","Platelet count (avapritinib eligibility in AdvSM)"],"standardOfCare":[{"setting":"Indolent SM, symptomatic","approach":"H1 and H2 antihistamines, cromolyn, leukotriene antagonists, omalizumab for anaphylaxis, epinephrine autoinjector, bone protection; avapritinib 25 mg daily for moderate to severe symptoms uncontrolled by these (PIONEER).","refs":["avapritinib"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Systemic Mastocytosis; PIONEER (NEJM Evidence 2023)","url":"https://doi.org/10.1056/EVIDoa2200339"}},{"setting":"Advanced SM, first line","approach":"Avapritinib 200 mg daily (platelets above 50 x 10^9/L) as preferred agent; midostaurin as alternative or where platelets are low.","refs":["avapritinib","midostaurin","kit","kinase-inhibitors"],"guideline":{"nccn":"Category 2A (preferred: avapritinib)","version":"NCCN Guidelines: Systemic Mastocytosis; PATHFINDER (Nature Medicine 2021)","url":"https://doi.org/10.1038/s41591-021-01539-8"}},{"setting":"Advanced SM, subsequent lines","approach":"Switch between avapritinib and midostaurin; cladribine; clinical trials (bezuclastinib, elenestinib); allogeneic transplant for mast cell leukaemia or high-risk SM-AHN.","refs":["cladribine","allogeneic-hsct","midostaurin","avapritinib"]},{"setting":"SM-AHN","approach":"Treat the dominant component: KIT inhibitor for mast cell burden plus the standard therapy for the associated CMML, MDS or AML (hypomethylating agents, intensive chemotherapy, transplant).","refs":["azacitidine","allogeneic-hsct","avapritinib"]}],"stateOfArt":["Selective KIT D816V inhibition with avapritinib gives deep molecular and morphological responses in advanced disease and is the first drug to improve symptoms in indolent disease.","Midostaurin (2017) was the first approved therapy and remains important where platelets are low or avapritinib is not tolerated.","Blood-based KIT D816V allele burden now tracks response, reducing repeat marrow biopsies.","Second-generation KIT inhibitors aim to remove the intracranial bleeding and cognitive side effects seen with avapritinib."],"history":[{"year":1869,"title":"Urticaria pigmentosa described","note":"Nettleship and Tay describe the skin lesions; Unna links them to mast cells in 1887.","refs":[]},{"year":1949,"title":"Systemic involvement recognised","note":"Ellis reports mast cell infiltration of internal organs at autopsy.","refs":[]},{"year":1993,"title":"KIT D816V identified in mastocytosis","note":"Nagata and colleagues (1995) confirm the activating mutation in most patients.","refs":["kit"]},{"year":2001,"title":"WHO classification of mastocytosis","note":"Valent criteria; imatinib found inactive against D816V.","refs":[]},{"year":2016,"title":"Midostaurin in advanced SM","note":"Gotlib and colleagues (NEJM 2016); FDA approval April 2017.","refs":["midostaurin"]},{"year":2021,"title":"Avapritinib approved for advanced SM","note":"EXPLORER and PATHFINDER; FDA approval June 2021.","refs":["avapritinib"]},{"year":2023,"title":"Avapritinib approved for indolent SM","note":"PIONEER; FDA approval May 2023, the first therapy for the indolent form.","refs":["avapritinib"]}],"pipeline":["avapritinib","allogeneic-hsct","elenestinib"],"openProblems":["Avapritinib carries intracranial bleeding risk at low platelet counts and cognitive effects; bezuclastinib and elenestinib are designed to avoid them.","The associated neoplasm in SM-AHN, not the mast cells, usually determines survival; combination strategies with hypomethylating agents and transplant are being studied.","Diagnostic delay of years in indolent disease; blood KIT D816V testing and tryptase genotyping are shortening it.","Long-term safety of chronic KIT inhibition in indolent patients with a normal life expectancy."]},"route":"/cancers/systemic-mastocytosis/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"advanced-systemic-mastocytosis","kind":"cancer","name":"Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia)","route":"/cancers/advanced-systemic-mastocytosis/"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"gist","kind":"cancer","name":"Gastrointestinal stromal tumour (GIST)","route":"/cancers/gist/"},{"id":"indolent-systemic-mastocytosis","kind":"cancer","name":"Indolent and smouldering systemic mastocytosis","route":"/cancers/indolent-systemic-mastocytosis/"},{"id":"mds","kind":"cancer","name":"Myelodysplastic syndromes / neoplasms (MDS)","route":"/cancers/mds/"}],"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"flow-cytometry-mrd","kind":"technology","name":"Multiparameter flow cytometry MRD","route":"/technologies/flow-cytometry-mrd/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"flt3","kind":"target","name":"FLT3","route":"/targets/flt3/"},{"id":"kit","kind":"target","name":"KIT","route":"/targets/kit/"},{"id":"prkcb","kind":"target","name":"PRKCB","route":"/targets/prkcb/"},{"id":"prkcd","kind":"target","name":"PRKCD","route":"/targets/prkcd/"},{"id":"prkce","kind":"target","name":"PRKCE","route":"/targets/prkce/"},{"id":"prkcg","kind":"target","name":"PRKCG","route":"/targets/prkcg/"},{"id":"prkch","kind":"target","name":"PRKCH","route":"/targets/prkch/"},{"id":"prkci","kind":"target","name":"PRKCI","route":"/targets/prkci/"},{"id":"prkcq","kind":"target","name":"PRKCQ","route":"/targets/prkcq/"},{"id":"prkcz","kind":"target","name":"PRKCZ","route":"/targets/prkcz/"},{"id":"prkd1","kind":"target","name":"PRKD1","route":"/targets/prkd1/"},{"id":"prkd3","kind":"target","name":"PRKD3","route":"/targets/prkd3/"}],"drug":[{"id":"avapritinib","kind":"drug","name":"Avapritinib","route":"/drugs/avapritinib/"},{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"cladribine","kind":"drug","name":"Cladribine","route":"/drugs/cladribine/"},{"id":"elenestinib","kind":"drug","name":"Elenestinib","route":"/drugs/elenestinib/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"interferon-alfa","kind":"drug","name":"Interferon alfa-2a/2b","route":"/drugs/interferon-alfa/"},{"id":"midostaurin","kind":"drug","name":"Midostaurin","route":"/drugs/midostaurin/"}],"pathway":[{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","route":"/pathways/clonal-haematopoiesis/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"cytopenias","kind":"term","name":"Cytopenias and myelosuppression","route":"/terms/cytopenias/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"molecular-response","kind":"term","name":"Molecular response (MMR, MR4, treatment-free remission)","route":"/terms/molecular-response/"}],"trial":[{"id":"nct04996875","kind":"trial","name":"(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis","route":"/trials/nct04996875/"},{"id":"nct04910685","kind":"trial","name":"(HARBOR) Study to Evaluate Efficacy and Safety of BLU-263 Versus Placebo in Patients With Indolent Systemic Mastocytosis","route":"/trials/nct04910685/"},{"id":"nct03731260","kind":"trial","name":"(PIONEER) Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, Versus Placebo ","route":"/trials/nct03731260/"},{"id":"nct05186753","kind":"trial","name":"(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis","route":"/trials/nct05186753/"},{"id":"explorer","kind":"trial","name":"EXPLORER","route":"/trials/explorer/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"biomarker":[{"id":"kit-d816v","kind":"biomarker","name":"KIT D816V","route":"/biomarkers/kit-d816v/"}]}}