KIT D816V mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes
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Abstract Background Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations. Methods Here, we correlated the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood‐purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow‐up and its association with disease outcome. Results Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V‐mutated cells in blood (P = .0004) and a high rate of discordant BM+/blood− samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well‐differentiated variants of indolent SM (7%). Purification of different compartments of blood‐derived myeloid cells was done in 28 patients who were BM mast cell (MC)+/blood− for KITD816V, revealing KITD816V‐mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V‐mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression‐free survival (PFS). Conclusions These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood‐purified myeloid cell populations.
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Patients with a very low disease burden, who usually fail to meet a full diagnosis of systemic mastocytosis and are classified as clonal mast cell activation syndrome (MMAS/cMCAS), display the greatest discrepancies in KIT analysis between bone marrow and peripheral blood.
“Several studies have shown that patients with a very low disease burden, who usually fail to meet a full diagnosis of SM and are classified as clonal mast cell activation syndrome (MMAS/cMCAS), display the greatest discrepancies in KIT analysis between BM and PB (49).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [49]
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Experimental — accuracy not yet measuredNavarro et al. found a correlation between the percentage of KIT D816V-mutated cells in both PB and BM and BST levels.
“Similarly, Navarro et al. found a correlation between the percentage of KIT D816V-mutated cells in both PB and BM and BST levels (49).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [49]
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- Garcia-Montero AC, Jara-Acevedo M, Alvarez-Twose I, et al. KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression. Blood. 2016;127(6):761-768. doi:10.1182/blood-2015-07 · DOI
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- Authors
- Navarro‐Navarro, P., Álvarez‐Twose, I., Pérez‐Pons, A., Henriques, A., Mayado, A., García‐Montero, A. C., Sánchez‐Muñoz, L., González‐López, O., Matito, A., Caldas, C., Jara‐Acevedo, M., & Orfao, A.
- Affiliations
- Universidad de Salamanca (ES)
- Red Española de Mastocitosis (REMA) Toledo and Salamanca Spain
- Hospital Virgen del Valle (ES)
- Cancer Research Center (IBMCC, USAL‐CSIC) Cytometry Service (NUCLEUS) Department of Medicine Biomedical Research Institute of Salamanca (IBSAL) University of Salamanca Salamanca Spain
- ORCID
- Venue
- Allergy
- Publisher
- Wiley
- Published
- 2022-11-28
- Volume
- 78
- Issue
- 5
- Pages
- 1347-1359
- ISSN
- 0105-4538 (ISSN-L)
- 1398-9995
- OpenAlex
- W4309245134
- Cited by
- 35
- References
- 47
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 10 · 2023: 6
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Allergy (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc)
- Funders
- European Regional Development Fund
- Agencia Estatal de Investigación
- European Social Fund
- FP7 Research infrastructures
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Health Sciences › Medicine › Rheumatology › Eosinophilic Disorders and Syndromes
- Keywords
- KIT D816V mutation, systemic mastocytosis, mast cell activation syndrome, diagnostic screening, bone marrow mastocytosis, cutaneous mastocytosis, indolent systemic mastocytosis, eosinophils, basophils, progression-free survival, prognostic factors
- MeSH terms
- Mast Cell Activation Syndrome, Adult, Humans, Mast Cells, Mastocytosis, Mutation, Proto-Oncogene Proteins c-kit, Mastocytosis, Systemic
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