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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.
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.
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).
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.
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: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), 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, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), 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), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
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).
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Query for this cancer: (TITLE:"Systemic mastocytosis" OR ABSTRACT:"Systemic mastocytosis" OR TITLE:"Advanced systemic mastocytosis AdvSM" OR ABSTRACT:"Advanced systemic mastocytosis AdvSM" OR TITLE:"Indolent systemic mastocytosis ISM" OR ABSTRACT:"Indolent systemic mastocytosis ISM" OR TITLE:"Smouldering systemic mastocytosis" OR ABSTRACT:"Smouldering systemic mastocytosis" OR TITLE:"Aggressive systemic mastocytosis" OR ABSTRACT:"Aggressive systemic mastocytosis" OR TITLE:"Mast cell leukaemia" OR ABSTRACT:"Mast cell leukaemia") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Systemic mastocytosis, not a curated reading list.
Nettleship and Tay describe the skin lesions; Unna links them to mast cells in 1887.
Ellis reports mast cell infiltration of internal organs at autopsy.
Nagata and colleagues (1995) confirm the activating mutation in most patients.
Valent criteria; imatinib found inactive against D816V.
Gotlib and colleagues (NEJM 2016); FDA approval April 2017.
EXPLORER and PATHFINDER; FDA approval June 2021.
PIONEER; FDA approval May 2023, the first therapy for the indolent form.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Take with food; antiemetic prophylaxis.
Possible QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Several lymphoma treatments knock out the part of the immune system that keeps a particular lung infection, Pneumocystis, at bay. A low-dose antibiotic three times a week prevents it, and a separate tablet prevents shingles.
See all on the product pages:AvapritinibAzacitidineCladribineMidostaurin·Printable cards in the navigator
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