Precision Medicine

Systemic Mastocytosis

Systemic mastocytosis (SM) is a rare, clonal mast cell neoplasm driven by the KIT D816V mutation1,2

Patients experience significant symptom burden with poor quality of life that can result in a reduced ability to work, higher rates of health care visits, use of multiple medications, and severe pain3

Signs and Symptoms

Activated mast cells release granules containing proinflammatory mediators and can result in:

  • Maculopapular lesions with Darier’s sign
  • Recurrent or unexplained anaphylaxis often coupled with hypotension and syncope
  • Anaphylaxis due to insect sting
  • Recurring and unexplained gastrointestinal upset (i.e., recurring and unexplained nausea, vomiting, and/or diarrhea)
  • Persistently elevated baseline serum tryptase levels
  • Serum tryptase levels that increase by 20% above the baseline level plus an additional 2 ng/mL if measured within 4 hours after the onset of the acute event3
  • Unexplained osteoporosis (particularly in males)
  • Unexplained hepatopathy with ascites
  • Presence of adult onset cutaneous mastocytosis
  • Chronic use of prescription medications for the treatment of unexplained allergies (e.g., corticosteroids, mast cell stabilizers)

Diagnostics and Testing

Proceed to a diagnostic workup if SM is suspected with symptoms consistent with mast cell disorder and no known cause:

  • A diagnostic workup consisting of a history and physical including metabolic panel, CBC with differential, and blood smear examination
  • Test for serum tryptase levels
  • Molecular testing for KIT D816V; NCCN Guidelines recommends a highly sensitive assay such as ASO-qPCR or digital droplet PCR on peripheral blood for initial screening; A thorough analysis of KIT mutational status should include bone marrow evaluation
  • Bone marrow aspirate and biopsy with flow cytometry (CD34, CD117, CD25, CD30, CD2), IHC (CD117, CD25, CD30, tryptase), cytogenetics
  • FISH as needed for associated hematologic neoplasm (AHN)-related abnormalities
  • Test for additional genomic mutations via NGS, especially in advanced SM
  • Evaluation of B- and C- findings and organ involvement


How to Identify
Illustration of small monomorphic lesions appear on the thighs or trunk of the body
Illustration of wheal-and-flare reaction is elicited by stroking lesion with a tongue spatula

WHO Diagnostic Criteria

Diagnosis of SM requires the major criterion alone (ICC)10 or with 1 minor criteria (WHO)12 OR ≥3 minor criteria (ICC and WHO)10, 12, 13:

Major Criterion

  • Multifocal dense infiltrates of MCs (≥15 mast cells in aggregates) detected in sections of bone marrow and/or sections of other extracutaneous organ(s) such as the GI tract

Minor Criterion

  • More than 25% of MCs in bone marrow (biopsy section or aspirate smears) or other extracutaneous organ(s) show abnormal morphology (i.e., atypical MC type 1 or are spindle-shaped MCs) in multifocal lesions in histologic examination
  • KIT mutation at codon 816 in extracutaneous organ(s) (in most cases bone marrow) or peripheral blood
  • KIT+ MCs in bone marrow show abnormal expression of CD25 (and/or less specifically CD2)
  • Serum total tryptase > 20 ng/mL (except in patients with associated hematologic neoplasm (AHN)-type disease.)
Identification of SM Subtype

If SM is confirmed, proceed to identification of SM subtype11, 12:

Indolent SM

Meets the general criteria for systemic mastocytosis; <2 B-findings*; No C-findings¥; Low mast cell burden; No evidence of an associated hematologic neoplasm; Skin lesions are frequently present.

Smoldering SM

Meets the general criteria for systemic mastocytosis; ≥2 B-findings; No C-findings; No evidence of an associated hematologic neoplasm; Does not meet the criteria for mast cell leukemia.

Aggressive SM

Meets the general criteria for systemic mastocytosis; ≥1 C-finding; Does not meet the criteria for mast cell leukemia; Skin lesions are usually absent.

SM with an associated hematologic neoplasm

Meets the general criteria for systemic mastocytosis; Meets the criteria for an associated neoplasm.

Mast Cell Leukemia

Bone marrow aspirate smears show ≥20% mast cells; In classic cases, mast cells account.

*B-Findings: Indicate a high burden of MCs and expansion of the neoplastic process into multiple hematopoietic lineages, without evidence of organ damage

¥C-Findings: Are indicative of organ damage produced by MC infiltration (should be confirmed by biopsy if possible)

NCCN Guidelines13: Systemic Mastocytosis Treatment Recommendations

Indolent & Smoldering SM

  • Referral to specialized centers
  • Patient education
  • Avoiding triggers
  • Use of epinephrine to manage anaphylaxis
  • Anti-mediator drug therapy
  • Clinical trial
  • Avapritinib for ISM

Agressive SM

  • ISM and SSM treatment options
  • Clinical trial
  • Avapritinib (if platelets ≥50 x 109/L) or midostaurin
  • Cladribine or peginterferon alfa-2a ± prednisone

SM with an associated hematologic neoplasm

  • ISM and SSM treatment options
  • Avapritinib (if platelets ≥50 x 109/L) or midostaurin
  • Other recommended regimens: cladribine or peginterferon alfa- 2a ± prednisone
  • Immedate treatment requirement or on progression: AHN-directed therapy including consideration of allogenic HCT with concurrent management of SM

Mast Cell Leukeima

  • ISM and SSM treatment options
  • Avapritinib or midostaurin
  • Other recommended regimens: cladribine
  • AHN-directed therapy (including multiagent chemotherapy)
  • Consider evaluation for allogeneic HCT


Find a Provider
Commercial Laboratories Offering High-Sensitivity KIT D816V Assays
ARUP Laboratories
Test Code / Name
1-800 522-2787
Mayo Clinic Laboratories
Test Code / Name
Virant Diagnostics
Test Code / Name
High Sensitivity cKIT D816V Mutation Hotspot
Test Code / Name
Blueprint-sponsored Biomarker Testing Program
Test Code / Name

Connect with
Dr. Pankit Vachhani

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