Systemic mastocytosis
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.
Overview
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.
Treatment 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.
Open 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.
State of the art today
- 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.
Where it starts and where it drains
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)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)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sitesIndolent systemic mastocytosis (with or without skin involvement) · Cutaneous mastocytosis (children; usually resolves)
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD)
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).
- Liquid biopsy (ctDNA)Standard of care
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
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).
Avapritinib 200 mg daily (platelets above 50 x 10^9/L) as preferred agent; midostaurin as alternative or where platelets are low.
Switch between avapritinib and midostaurin; cladribine; clinical trials (bezuclastinib, elenestinib); allogeneic transplant for mast cell leukaemia or high-risk SM-AHN.
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).
Subtypes & biomarkers
top- 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)
- 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)
Target prevalence in this cancer
- 1869Urticaria pigmentosa described
Nettleship and Tay describe the skin lesions; Unna links them to mast cells in 1887.
- 1949Systemic involvement recognised
Ellis reports mast cell infiltration of internal organs at autopsy.
- 1993KIT D816V identified in mastocytosis
Nagata and colleagues (1995) confirm the activating mutation in most patients.
- 2001WHO classification of mastocytosis
Valent criteria; imatinib found inactive against D816V.
- 2016Midostaurin in advanced SM
Gotlib and colleagues (NEJM 2016); FDA approval April 2017.
- 2021Avapritinib approved for advanced SM
EXPLORER and PATHFINDER; FDA approval June 2021.
- 2023Avapritinib approved for indolent SM
PIONEER; FDA approval May 2023, the first therapy for the indolent form.
Open problems, and what is being done about each
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.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- via Small-molecule kinase inhibitors
- via Small-molecule kinase inhibitors
- Centre Léon BérardLyon, FRvia Small-molecule kinase inhibitors
- via Allogeneic stem cell transplantation
- via Small-molecule kinase inhibitors
- GIMEMARome, ITvia Small-molecule kinase inhibitors
- Guangdong Provincial People's HospitalGuangzhou, CNvia Small-molecule kinase inhibitors
- Hospital Clínic de Barcelona / IDIBAPSBarcelona, ESvia Small-molecule kinase inhibitors
- Hunan Cancer HospitalChangsha, CNvia Small-molecule kinase inhibitors
- Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolis, IN, USNCI comprehensivevia Allogeneic stem cell transplantation
- via Small-molecule kinase inhibitors
- International Association for the Study of Lung CancerDenver, CO, USvia Small-molecule kinase inhibitors
- Istituto di Candiolo IRCCS – FPOCandiolo, ITvia Small-molecule kinase inhibitors
- Juravinski Cancer Centre / Escarpment Cancer Research InstituteHamilton, ON, CAvia Allogeneic stem cell transplantation
- Korean Cancer Study GroupSeoul, KRvia Small-molecule kinase inhibitors
- via Allogeneic stem cell transplantation
- National Taiwan University HospitalTaipei, TWvia Small-molecule kinase inhibitors
- via Small-molecule kinase inhibitors
- via Small-molecule kinase inhibitors
- Shanghai Chest HospitalShanghai, CNvia Small-molecule kinase inhibitors
- Shanghai Pulmonary HospitalShanghai, CNvia Small-molecule kinase inhibitors
- The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research InstituteColumbus, OH, USNCI comprehensivevia Small-molecule kinase inhibitors
- via Small-molecule kinase inhibitors
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimore, MD, USNCI comprehensivevia Allogeneic stem cell transplantation
- via Azacitidine
- West Japan Oncology GroupOsaka, JPvia Small-molecule kinase inhibitors
Questions to ask
topQuestions to ask your oncologist about Systemic mastocytosis
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Serum tryptase, KIT D816V by high-sensitivity ddPCR in blood, Marrow mast cell aggregates with CD25, CD2, CD30 expression, C-findingsdefining advanced disease, SRSF2, ASXL1, RUNX1mutations; MARS and IPSM prognostic scores), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Indolent systemic mastocytosis, Bone marrow mastocytosis, Smouldering systemic mastocytosis.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Indolent SM, symptomatic
- For my situation (indolent sm, symptomatic), which of the standard options do you recommend and why?Why: Guideline options include: 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).
- Am I a candidate for Avapritinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Advanced SM, first line
- For my situation (advanced sm, first line), which of the standard options do you recommend and why?Why: Guideline options include: Avapritinib 200 mg daily (platelets above 50 x 10^9/L) as preferred agent; midostaurin as alternative or where platelets are low.
- Am I a candidate for Avapritinib, Midostaurin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Advanced SM, subsequent lines
- For my situation (advanced sm, subsequent lines), which of the standard options do you recommend and why?Why: Guideline options include: Switch between avapritinib and midostaurin; cladribine; clinical trials (bezuclastinib, elenestinib); allogeneic transplant for mast cell leukaemia or high-risk SM-AHN.
- Am I a candidate for Cladribine, Midostaurin, Avapritinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
SM-AHN
- For my situation (sm-ahn), which of the standard options do you recommend and why?Why: Guideline options include: 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).
- Am I a candidate for Azacitidine, Avapritinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Avapritinib, Allogeneic stem cell transplantation?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Avapritinib carries intracranial bleeding risk at low platelet counts and cognitive effects; bezuclastinib and elenestinib are designed to avoid them”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “The associated neoplasm in SM-AHN, not the mast cells, usually determines survival; combination strategies with hypomethylating agents and transplant are being studied”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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