# Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia)

Source: https://onco.cc/cancers/advanced-systemic-mastocytosis/  
OnCo record `advanced-systemic-mastocytosis` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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 poor 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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: AdvSM; Aggressive systemic mastocytosis; ASM; SM-AHN; Mast cell leukaemia; MCL
- Tags: subtype-page; haematologic
- Group: haematologic
- Burden: A minority of systemic mastocytosis, mostly in older adults; survival was measured in months for mast cell leukaemia and a few years for aggressive disease before KIT inhibitors, and the associated haematological neoplasm often determines the outcome.
- Subtypes: Aggressive systemic mastocytosis (C findings: cytopenias, liver, gut or bone damage); Systemic mastocytosis with an associated haematological neoplasm (SM-AHN; usually CMML, MDS or MPN); Systemic mastocytosis with acute myeloid leukaemia (SM-AML); Mast cell leukaemia (20 percent or more marrow mast cells; acute or chronic); Advanced systemic mastocytosis with SRSF2, ASXL1 or RUNX1 mutations (high-risk); Advanced systemic mastocytosis with thrombocytopenia (avapritinib restricted)
- Biomarkers: C findings (cytopenias, liver dysfunction, hypoalbuminaemia, malabsorption, lytic bone lesions); Serum tryptase and KIT D816V allele burden (response and molecular remission); Mast cell percentage in marrow aspirate (20 percent defines mast cell leukaemia); SRSF2, ASXL1 and RUNX1 mutations; MARS and IPSM prognostic scores; Platelet count (avapritinib eligibility above 50 x 10^9/L); Molecular and morphological characterisation of the associated neoplasm

## Standard of care

- 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. ([Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [KIT](https://onco.cc/targets/kit/), [Cytopenias and myelosuppression](https://onco.cc/terms/cytopenias/))
- 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). ([Avapritinib](https://onco.cc/drugs/avapritinib/), [Midostaurin](https://onco.cc/drugs/midostaurin/), [KIT](https://onco.cc/targets/kit/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/))
- Associated haematological neoplasm: Treat the neoplasm on its own merits (azacitidine for CMML or MDS, intensive chemotherapy for AML) alongside or after KIT inhibition. ([Azacitidine](https://onco.cc/drugs/azacitidine/), [Midostaurin](https://onco.cc/drugs/midostaurin/))
- Relapsed or intolerant: Switch between avapritinib and midostaurin; cladribine; interferon alfa; bezuclastinib in the Apex trial. ([Cladribine](https://onco.cc/drugs/cladribine/), [Interferon alfa-2a/2b](https://onco.cc/drugs/interferon-alfa/), [Bezuclastinib](https://onco.cc/drugs/bezuclastinib/), [(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis](https://onco.cc/trials/nct04996875/))
- Fit patients, especially mast cell leukaemia or high-risk SM-AHN: Allogeneic haematopoietic cell transplantation after response to a KIT inhibitor. ([Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))

## State of the art

- KIT-selective inhibition with avapritinib produces deep molecular responses in most patients.
- Midostaurin and avapritinib gave the disease its first approved drugs within four years.
- Prognostic scores incorporating myeloid mutations guide the decision to transplant.

## Open problems

- The associated myeloid neoplasm, not the mast cells, now causes most deaths in SM-AHN.
- Whether KIT inhibitors improve survival has not been shown in a randomised trial.
- Thrombocytopenic patients cannot receive avapritinib safely.
- Transplant outcomes rest on small retrospective series.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Mastocytosis
- Midostaurin in advanced SM (NEJM 2016): https://doi.org/10.1056/NEJMoa1513098
- NCCN Systemic Mastocytosis: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478
- Wikipedia: https://en.wikipedia.org/wiki/Mastocytosis

## Connected records

- cancers: [Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms](https://onco.cc/cancers/cmml/), [Indolent and smouldering systemic mastocytosis](https://onco.cc/cancers/indolent-systemic-mastocytosis/), [Secondary and therapy-related acute myeloid leukaemia](https://onco.cc/cancers/aml-secondary/), [Systemic mastocytosis](https://onco.cc/cancers/systemic-mastocytosis/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [FLT3](https://onco.cc/targets/flt3/), [KIT](https://onco.cc/targets/kit/)
- drugs: [Avapritinib](https://onco.cc/drugs/avapritinib/), [Azacitidine](https://onco.cc/drugs/azacitidine/), [Bezuclastinib](https://onco.cc/drugs/bezuclastinib/), [Cladribine](https://onco.cc/drugs/cladribine/), [Interferon alfa-2a/2b](https://onco.cc/drugs/interferon-alfa/), [Midostaurin](https://onco.cc/drugs/midostaurin/)
- terms: [Cytopenias and myelosuppression](https://onco.cc/terms/cytopenias/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Molecular response (MMR, MR4, treatment-free remission)](https://onco.cc/terms/molecular-response/)
- trials: [(Apex) Bezuclastinib in Patients With Advanced Systemic Mastocytosis](https://onco.cc/trials/nct04996875/)
- key papers: [Efficacy and safety of midostaurin in advanced systemic mastocytosis](https://onco.cc/key-papers/paper-gotlib-midostaurin-advanced-systemic-mastocytosis-nejm-2016/), [EXPLORER: safety and efficacy of avapritinib in advanced systemic mastocytosis (phase 1)](https://onco.cc/key-papers/paper-explorer-avapritinib-advanced-systemic-mastocytosis-nat-med-2021/), [PATHFINDER: efficacy and safety of avapritinib in advanced systemic mastocytosis (phase 2 interim analysis)](https://onco.cc/key-papers/paper-pathfinder-avapritinib-advanced-systemic-mastocytosis-nat-med-2021/), [WHO classification of haematolymphoid tumours, fifth edition: myeloid and histiocytic neoplasms](https://onco.cc/key-papers/paper-who-2022-myeloid-khoury-leukemia-2022/)

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