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Mastocytosis

Nature Reviews Disease Primers volume 11, Article number: 30 (2025) Cite this article

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Abstract

Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems. The disease is divided into cutaneous mastocytosis, systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms. The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favourable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor. During the past 15 years, major advances have been made in the diagnosis, prognosis and management of patients with mast cell neoplasms. Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis. The preclinical and clinical development of KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients.

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Fig. 1: Structure of KIT and of the corresponding KIT receptor.
Fig. 2: Differences in signalling pathways evoked by the wild-type KIT and the mutant KIT-D816V receptor.
Fig. 3: Organ involvement patterns and relevant mast cell mediators in non-advanced and advanced mastocytosis.
Fig. 4: Skin lesions in different mastocytosis variants.
Fig. 5: Basic diagnostic algorithm in patients with typical skin lesions.
Fig. 6: Bone marrow pathology in systemic mastocytosis.
Fig. 7: Morphological subsets of atypical mast cells detectable in patients with systemic mastocytosis.

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References

  1. Theoharides, T. C., Valent, P. & Akin, C. Mast cells, mastocytosis, and related disorders. N. Engl. J. Med. 373, 163–172 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Ustun, C. et al. Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice. Haematologica 101, 1133–1143 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Valent, P., Akin, C. & Metcalfe, D. D. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood 129, 1420–1427 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Valent, P. et al. New insights into the pathogenesis of mastocytosis: emerging concepts in diagnosis and therapy. Annu. Rev. Pathol. 18, 361–386 (2023).

    Article  CAS  PubMed  Google Scholar 

  5. Valent, P. et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk. Res. 25, 603–625 (2001). Basic diagnostic consensus criteria and classification of mastocytosis: these criteria were reviewed, discussed and approved in the Year 2000 Working Conference on Mastocytosis.

    Article  CAS  PubMed  Google Scholar 

  6. Metcalfe, D. D. Mast cells and mastocytosis. Blood 112, 946–956 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hartmann, K. et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. J. Allergy Clin. Immunol. 137, 35–45 (2016).

    Article  PubMed  Google Scholar 

  8. Valent, P. et al. Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res. 77, 1261–1270 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Radia, D. H. & Moonim, M. T. Update on diagnostic approaches and therapeutic strategies in systemic mastocytosis. Best Pract. Res. Clin. Haematol. 35, 101380 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Lim, K. H. et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 113, 5727–5736 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Pardanani, A. et al. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood 114, 3769–3772 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Sperr, W. R. et al. International Prognostic Scoring System for Mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 6, e638–e649 (2019). Comprehensive international prognostic scoring system for SM, including non-advanced and advanced forms of the disease.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Reiter, A., George, T. I. & Gotlib, J. New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis. Blood 135, 1365–1376 (2020).

    Article  PubMed  Google Scholar 

  14. Valent, P., Akin, C., Sperr, W. R., Horny, H. P. & Metcalfe, D. D. Smouldering mastocytosis: a novel subtype of systemic mastocytosis with slow progression. Int. Arch. Allergy Immunol. 127, 137–139 (2002).

    Article  PubMed  Google Scholar 

  15. Tefferi, A., Shah, S., Reichard, K. K., Hanson, C. A. & Pardanani, A. Smoldering mastocytosis: survival comparisons with indolent and aggressive mastocytosis. Am. J. Hematol. 94, E1–E2 (2019).

    Article  PubMed  Google Scholar 

  16. Zanotti, R. et al. Refined diagnostic criteria for bone marrow mastocytosis: a proposal of the European competence network on mastocytosis. Leukemia 36, 516–524 (2022). This article provides revised definitions and refined diagnostic consensus criteria for bone marrow mastocytosis: based on this study, bone marrow mastocytosis becomes an independent separate variant of SM in the updated WHO classification 2022.

    Article  CAS  PubMed  Google Scholar 

  17. Valent, P. et al. Updated diagnostic criteria and classification of mast cell disorders: a consensus proposal. Hemasphere 5, e646 (2021). Updated diagnostic consensus criteria and classification of mastocytosis: this paper provided the basis for the revised WHO classification of mastocytosis 2022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Akin, C. et al. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood 103, 3222–3225 (2004). This article is the first description of WDSM and reports that imatinib can induce major clinical responses in patients with KIT-D816V-negative mastocytosis: in this particular responder, neoplastic mast cells displayed the KIT germline mutation Phe522Cys.

    Article  CAS  PubMed  Google Scholar 

  19. Alvarez-Twose, I. et al. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J. Allergy Clin. Immunol. 137, 168–178.e161 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Khoury, J. D. et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia 36, 1703–1719 (2022). Revised WHO classification of myeloid neoplasms including mastocytosis 2022.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Loghavi, S. et al. Fifth Edition of the World Health Classification of tumors of the hematopoietic and lymphoid tissue: myeloid neoplasms. Mod. Pathol. 37, 100397 (2024). Revised WHO classification of myeloid neoplasms (WHO blue book) including mastocytosis.

    Article  CAS  PubMed  Google Scholar 

  22. Arber, D. A. et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood 140, 1200–1228 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, S. A. et al. The international consensus classification of eosinophilic disorders and systemic mastocytosis. Am. J. Hematol. 98, 1286–1306 (2023). An international consensus classification provides an alternative classification of mastocytosis with slightly modified diagnostic criteria deviating marginally from the WHO classification.

    Article  CAS  PubMed  Google Scholar 

  24. Nagata, H. et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc. Natl Acad. Sci. USA 92, 10560–10564 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Longley, B. J. et al. Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat. Genet. 12, 312–314 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Fritsche-Polanz, R. et al. Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis. Br. J. Haematol. 113, 357–364 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Arock, M. et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia 29, 1223–1232 (2015). Basic consensus recommendations for the use and application of molecular markers and assays, including KIT mutational studies, in patients with mastocytosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Muñoz-González, J. I. et al. Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis. Blood 134, 456–468 (2019).

    Article  PubMed  Google Scholar 

  29. Hoermann, G. et al. Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US cooperative group. J. Allergy Clin. Immunol. Pract. 10, 1953–1963 (2022).

    Article  CAS  PubMed  Google Scholar 

  30. Bergstrom, A., Hagglund, H., Berglund, A., Nilsson, G. & Lambe, M. Epidemiology of mastocytosis: a population-based study (Sweden). Acta Oncol. 63, 44–50 (2024).

    Article  PubMed  Google Scholar 

  31. Schuler, C. F. T. et al. Prevalence of mastocytosis and Hymenoptera venom allergy in the United States. J. Allergy Clin. Immunol. 148, 1316–1323 (2021).

    Article  PubMed  Google Scholar 

  32. Zanotti, R. et al. A multidisciplinary diagnostic approach reveals a higher prevalence of indolent systemic mastocytosis: 15-years’ experience of the GISM network. Cancers 13, 6380 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jorgensen, M. P. et al. Prevalence and incidence of mastocytosis in adults: a Danish nationwide register study. Eur. J. Epidemiol. 40, 43–53 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kaakati, R. N., Khokhar, D. & Akin, C. Demographics, types of patient-reported allergic diseases, and anaphylaxis in mastocytosis: a single-center US experience. J. Allergy Clinic. Immunologist. Pract. 13, 398–406 (2025).

    Article  CAS  Google Scholar 

  35. Aldama, L. N. D. et al. Prevalence and impact of the KIT M541L variant in patients with mastocytosis. Oncotarget 15, 521–531 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jennings, S. V. et al. Mast cell diseases in practice and research: issues and perspectives raised by patients and their recommendations to the scientific community and beyond. J. Allergy Clin. Immunol. Pract. 10, 2039–2051 (2022).

    Article  PubMed  Google Scholar 

  37. Trizuljak, J. et al. Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification. Allergy 75, 1927–1938 (2020).

    Article  PubMed  Google Scholar 

  38. Kluin-Nelemans, H. C. et al. Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis. Theranostics 11, 292–303 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Galatà, G. et al. Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis. Am. J. Hum. Genet. 108, 284–294 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Popadic, S. et al. Mastocytosis in children: a single-center long-term follow-up study. Int. J. Dermatol. 62, 616–620 (2023).

    Article  CAS  PubMed  Google Scholar 

  41. Castells, M. & Austen, K. F. Mastocytosis: mediator-related signs and symptoms. Int. Arch. Allergy Immunol. 127, 147–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Valent, P. et al. Global classification of mast cell activation disorders: an ICD-10-CM-adjusted proposal of the ECNM-AIM consortium. J. Allergy Clin. Immunol. Pract. 10, 1941–1950 (2022).

    Article  CAS  PubMed  Google Scholar 

  43. Broesby-Olsen, S. et al. Risk of solid cancer, cardiovascular disease, anaphylaxis, osteoporosis and fractures in patients with systemic mastocytosis: a nationwide population-based study. Am. J. Hematol. 91, 1069–1075 (2016).

    Article  PubMed  Google Scholar 

  44. Kaszuba, A. et al. Mastocytosis and skin cancer: the current state of knowledge. Int. J. Mol. Sci. 24, 9840 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Meni, C. et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br. J. Dermatol. 172, 642–651 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Czarny, J., Renke, J., Żawrocki, A., Nowicki, R. J. & Lange, M. Natural evolution in pediatric cutaneous mastocytosis: 10-year follow-up. Int. J. Dermatol. 60, 1253–1257 (2021).

    Article  PubMed  Google Scholar 

  47. Auquit-Auckbur, I. et al. Malignant transformation of mastocytoma developed on skin mastocytosis into cutaneous mast cell sarcoma. Am. J. Surg. Pathol. 36, 779–782 (2012).

    Article  PubMed  Google Scholar 

  48. Chantorn, R. & Shwayder, T. Death from mast cell leukemia: a young patient with longstanding cutaneous mastocytosis evolving into fatal mast cell leukemia. Pediatr. Dermatol. 29, 605–609 (2012).

    Article  PubMed  Google Scholar 

  49. Bautista-Quach, M. A. et al. Mast cell sarcoma in an infant: a case report and review of the literature. J. Pediatr. Hematol. Oncol. 35, 315–320 (2013).

    Article  PubMed  Google Scholar 

  50. Wimazal, F., Geissler, P., Shnawa, P., Sperr, W. R. & Valent, P. Severe life-threatening or disabling anaphylaxis in patients with systemic mastocytosis: a single-center experience. Int. Arch. Allergy Immunol. 157, 399–405 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Niedoszytko, M. et al. Prevalence of hypersensitivity reactions in various forms of mastocytosis: a pilot study of 2485 adult patients with mastocytosis collected in the ECNM registry. Allergy 79, 2470–2481 (2024).

    Article  CAS  PubMed  Google Scholar 

  52. Alvarez-Twose, I. et al. Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J. Allergy Clin. Immunol. 125, 1269–1278.e1262 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Bonadonna, P. et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J. Allergy Clin. Immunol. 123, 680–686 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Niedoszytko, M., Bonadonna, P., Oude Elberink, J. N. & Golden, D. B. Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol. Allergy Clin. North Am. 34, 365–381 (2014).

    Article  PubMed  Google Scholar 

  55. Castells, M. C., Hornick, J. L. & Akin, C. Anaphylaxis after hymenoptera sting: is it venom allergy, a clonal disorder, or both? J. Allergy Clin. Immunol. Pract. 3, 350–355 (2015).

    Article  PubMed  Google Scholar 

  56. Rossini, M. et al. Bone involvement and osteoporosis in mastocytosis. Immunol. Allergy Clin. North Am. 34, 383–396 (2014).

    Article  PubMed  Google Scholar 

  57. Degboe, Y. et al. Prevalence and risk factors for fragility fracture in systemic mastocytosis. Bone 105, 219–225 (2017).

    Article  PubMed  Google Scholar 

  58. Greene, L. W., Asadipooya, K., Corradi, P. F. & Akin, C. Endocrine manifestations of systemic mastocytosis in bone. Rev. Endocr. Metab. Disord. 17, 419–431 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Fritsche-Polanz, R. et al. High frequency of concomitant mastocytosis in patients with acute myeloid leukemia exhibiting the transforming KIT mutation D816V. Mol. Oncol. 4, 335–346 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ustun, C. et al. Core-binding factor acute myeloid leukemia with t(8;21): risk factors and a novel scoring system (I-CBFit). Cancer Med. 7, 4447–4455 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Craig, J. W. et al. Detection of the KIT(D816V) mutation in myelodysplastic and/or myeloproliferative neoplasms and acute myeloid leukemia with myelodysplasia-related changes predicts concurrent systemic mastocytosis. Mod. Pathol. 33, 1135–1145 (2020).

    Article  CAS  PubMed  Google Scholar 

  62. Jahn, N. et al. Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication. Blood Adv. 4, 6342–6352 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Jawhar, M. et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis. Leukemia 30, 136–143 (2016). This article describes the prognostic impact of multiple somatic mutations in critical target genes in patients with SM.

    Article  CAS  PubMed  Google Scholar 

  64. Pardanani, A. D. et al. ASXL1 and CBL mutations are independently predictive of inferior survival in advanced systemic mastocytosis. Br. J. Haematol. 175, 534–536 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Jawhar, M. et al. MARS: Mutation-Adjusted Risk Score for advanced systemic mastocytosis. J. Clin. Oncol. 37, 2846–2856 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pardanani, A. et al. Mayo Alliance Prognostic System for mastocytosis: clinical and hybrid clinical-molecular models. Blood Adv. 2, 2964–2972 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Muñoz-González, J. I. et al. Proposed Global Prognostic Score for Systemic Mastocytosis: a retrospective prognostic modelling study. Lancet Haematol. 8, e194–e204 (2021).

    Article  PubMed  Google Scholar 

  68. Pardanani, A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am. J. Hematol. 98, 1097–1116 (2023).

    Article  CAS  PubMed  Google Scholar 

  69. Gulen, T., Ljung, C., Nilsson, G. & Akin, C. Risk factor analysis of anaphylactic reactions in patients with systemic mastocytosis. J. Allergy Clin. Immunol. Pract. 5, 1248–1255 (2017).

    Article  PubMed  Google Scholar 

  70. Brockow, K., Jofer, C., Behrendt, H. & Ring, J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 63, 226–232 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Gonzalez de Olano, D. et al. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish Network on Mastocytosis (REMA). Clin. Exp. Allergy 37, 1547–1555 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Vos, B., van Anrooij, B., van Doormaal, J. J., Dubois, A. E. J. & Oude Elberink, J. N. G. Fatal anaphylaxis to yellow jacket stings in mastocytosis: options for identification and treatment of at-risk patients. J. Allergy Clin. Immunol. Pract. 5, 1264–1271 (2017).

    Article  PubMed  Google Scholar 

  73. Bonadonna, P. et al. Anaphylactic reactions after discontinuation of hymenoptera venom immunotherapy: a clonal mast cell disorder should be suspected. J. Allergy Clin. Immunol. Pract. 6, 1368–1372 (2018).

    Article  PubMed  Google Scholar 

  74. Fodinger, M. et al. Origin of human mast cells: development from transplanted hematopoietic stem cells after allogeneic bone marrow transplantation. Blood 84, 2954–2959 (1994). Report demonstrating that allogeneic stem cell transplantation in a patient with advanced SM is a potentially curative treatment approach and that neoplastic mast cells are replaced by normal donor-derived mast cells several months after transplantation.

    Article  CAS  PubMed  Google Scholar 

  75. Valent, P. Cytokines involved in growth and differentiation of human basophils and mast cells. Exp. Dermatol. 4, 255–259 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Valent, P. et al. Mast cells as a unique hematopoietic lineage and cell system: from Paul Ehrlich’s visions to precision medicine concepts. Theranostics 10, 10743–10768 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Boyce, J. A. Advances in mast cell biology. J. Allergy Clin. Immunol. 149, 1919–1925 (2022).

    Article  CAS  PubMed  Google Scholar 

  78. Dahlin, J. S. et al. The ingenious mast cell: contemporary insights into mast cell behavior and function. Allergy 77, 83–99 (2022).

    Article  PubMed  Google Scholar 

  79. Valent, P. The riddle of the mast cell: kit(CD117)-ligand as the missing link? Immunol. Today 15, 111–114 (1994).

    Article  CAS  PubMed  Google Scholar 

  80. Galli, S. J., Tsai, M. & Wershil, B. K. The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. Am. J. Pathol. 142, 965–974 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Costa, J. J. et al. Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J. Exp. Med. 183, 2681–2686 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Chatterjea, D. et al. Adoptive transfer of mast cells does not enhance the impaired survival of Kit(W)/Kit(W-v) mice in a model of low dose intraperitoneal infection with bioluminescent Salmonella typhimurium. Immunol. Lett. 99, 122–129 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Maurer, M. et al. The c-kit ligand, stem cell factor, can enhance innate immunity through effects on mast cells. J. Exp. Med. 188, 2343–2348 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Akahoshi, M. et al. Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice. J. Clin. Invest. 121, 4180–4191 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Starkl, P. et al. IgE antibodies increase honeybee venom responsiveness and detoxification efficiency of mast cells. Allergy 77, 499–512 (2022).

    Article  CAS  PubMed  Google Scholar 

  86. Abraham, S. N. & Malaviya, R. Mast cells in infection and immunity. Infect. Immun. 65, 3501–3508 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Malaviya, R., Ikeda, T., Ross, E. & Abraham, S. N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 381, 77–80 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Cerny-Reiterer, S. et al. Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia. Oncotarget 6, 3071–3084 (2015).

    Article  PubMed  Google Scholar 

  89. Lev, S., Yarden, Y. & Givol, D. Dimerization and activation of the kit receptor by monovalent and bivalent binding of the stem cell factor. J. Biol. Chem. 267, 15970–15977 (1992).

    Article  CAS  PubMed  Google Scholar 

  90. Ashman, L. K. The biology of stem cell factor and its receptor c-kit. Int. J. Biochem. Cell Biol. 31, 1037–1051 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Qiu, F. H. et al. Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family-oncogenic activation of v-kit involves deletion of extracellular domain and C terminus. EMBO J. 7, 1003–1011 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nocka, K., Buck, J., Levi, E. & Besmer, P. Candidate ligand for the c-kit transmembrane kinase receptor: KL, a fibroblast derived growth factor stimulates mast cells and erythroid progenitors. EMBO J. 9, 3287–3294 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Roskoski, R. Jr. Structure and regulation of Kit protein-tyrosine kinase-the stem cell factor receptor. Biochem. Biophys. Res. Commun. 338, 1307–1315 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Kuriu, A. et al. Proliferation of human myeloid leukemia cell line associated with the tyrosine-phosphorylation and activation of the proto-oncogene c-kit product. Blood 78, 2834–2840 (1991).

    Article  CAS  PubMed  Google Scholar 

  95. Blechman, J. M., Lev, S., Givol, D. & Yarden, Y. Structure-function analyses of the kit receptor for the steel factor. Stem Cell 11, 12–21 (1993).

    Article  CAS  Google Scholar 

  96. Blechman, J. M. & Yarden, Y. Structural aspects of receptor dimerization. c-kit as an example. Ann. N. Y. Acad. Sci. 766, 344–362 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Lev, S., Yarden, Y. & Givol, D. A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. J. Biol. Chem. 267, 10866–10873 (1992).

    Article  CAS  PubMed  Google Scholar 

  98. Lemmon, M. A., Pinchasi, D., Zhou, M., Lax, I. & Schlessinger, J. Kit receptor dimerization is driven by bivalent binding of stem cell factor. J. Biol. Chem. 272, 6311–6317 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Roskoski, R. Jr. Signaling by Kit protein-tyrosine kinase—the stem cell factor receptor. Biochem. Biophys. Res. Commun. 337, 1–13 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Harir, N. et al. Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade. Blood 112, 2463–2473 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tsai, M., Valent, P. & Galli, S. J. KIT as a master regulator of the mast cell lineage. J. Allergy Clin. Immunol. 149, 1845–1854 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Baumgartner, C. et al. Expression of activated STAT5 in neoplastic mast cells in systemic mastocytosis: subcellular distribution and role of the transforming oncoprotein KIT D816V. Am. J. Pathol. 175, 2416–2429 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bibi, S. et al. Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy. Haematologica 99, 417–429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Agarwal, S., Kazi, J. U., Mohlin, S., Pahlman, S. & Ronnstrand, L. The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V. Oncogene 34, 4581–4590 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Park, H., Kim, D., Koh, Y. & Yoon, S. S. The upregulation of Pim kinases is essential in coordinating the survival, proliferation, and migration of KIT D816V-mutated neoplastic mast cells. Leuk. Res. 83, 106166 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Eisenwort, G. et al. Identification of a leukemia-initiating stem cell in human mast cell leukemia. Leukemia 33, 2673–2684 (2019). This study describes that MCL and other forms of advanced SM originate from a small pool of CD34+/CD38−/CD117+ disease-initiating (leukaemia-initiating) neoplastic stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Akin, C. & Metcalfe, D. D. The biology of Kit in disease and the application of pharmacogenetics. J. Allergy Clin. Immunol. 114, 13–19 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Arock, M. et al. Clinical impact and proposed application of molecular markers, genetic variants, and cytogenetic analysis in mast cell neoplasms: status 2022. J. Allergy Clin. Immunol. 149, 1855–1865 (2022).

    Article  CAS  PubMed  Google Scholar 

  109. Chantran, Y., Valent, P. & Arock, M. KIT mutations and other genetic defects in mastocytosis: implications for disease pathology and targeted therapies. Immunol. Allergy Clin. North Am. 43, 651–664 (2023).

    Article  PubMed  Google Scholar 

  110. Bodemer, C. et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J. Invest. Dermatol. 130, 804–815 (2010). This article describes the broad spectrum of diverse KIT mutations that can be detected in patients with childhood-onset mastocytosis.

    Article  CAS  PubMed  Google Scholar 

  111. Meni, C. et al. Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of KIT. A prospective study. Br. J. Dermatol. 179, 925–932 (2018).

    Article  CAS  PubMed  Google Scholar 

  112. Bibi, S. et al. Molecular defects in mastocytosis: KIT and beyond KIT. Immunol. Allergy Clin. North Am. 34, 239–262 (2014).

    Article  PubMed  Google Scholar 

  113. Kitayama, H. et al. Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. Blood 85, 790–798 (1995).

    Article  CAS  PubMed  Google Scholar 

  114. Kitamura, Y., Tsujimura, T., Jippo, T., Kasugai, T. & Kanakura, Y. Regulation of development, survival and neoplastic growth of mast cells through the c-kit receptor. Int. Arch. Allergy Immunol. 107, 54–56 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Mayerhofer, M. et al. Unique effects of KIT D816V in BaF3 cells: induction of cluster formation, histamine synthesis, and early mast cell differentiation antigens. J. Immunol. 180, 5466–5476 (2008). This study shows that KIT-D816V alone is a strong differentiation-inducing oncoprotein (mast cell differentiation), but only a relatively weak oncogene regarding its capacity to trigger proliferation.

    Article  CAS  PubMed  Google Scholar 

  116. Rajan, V. et al. KIT D816V is dimerization-independent and activates downstream pathways frequently perturbed in mastocytosis. Br. J. Haematol. 202, 960–970 (2023).

    Article  CAS  PubMed  Google Scholar 

  117. Hartmann, K. et al. Expression of Bcl-2 and Bcl-xL in cutaneous and bone marrow lesions of mastocytosis. Am. J. Pathol. 163, 819–826 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Aichberger, K. J. et al. Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs. Blood 114, 5342–5351 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Aichberger, K. J. et al. Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412. Blood 109, 3031–3041 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Longley, B. J., Reguera, M. J. & Ma, Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk. Res. 25, 571–576 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Conde-Fernandes, I. et al. Systemic mastocytosis with KIT V560G mutation presenting as recurrent episodes of vascular collapse: response to disodium cromoglycate and disease outcome. Allergy Asthma Clin. Immunol. 13, 21 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Joris, M. et al. Mast cell leukaemia: c-KIT mutations are not always positive. Case Rep. Hematol. 2012, 517546 (2012).

    PubMed  PubMed Central  Google Scholar 

  123. Kennedy, V. E. et al. Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM registry. Blood Adv. 7, 1713–1724 (2023).

    Article  CAS  PubMed  Google Scholar 

  124. Matsumoto, N. P. et al. Mast cell sarcoma: clinicopathologic and molecular analysis of 10 new cases and review of literature. Mod. Pathol. 35, 865–874 (2022).

    Article  CAS  PubMed  Google Scholar 

  125. Ryan, R. J. et al. Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications. Mod. Pathol. 26, 533–543 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Lyons, J. J. et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat. Genet. 48, 1564–1569 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lyons, J. J., Greiner, G., Hoermann, G. & Metcalfe, D. D. Incorporating tryptase genotyping into the workup and diagnosis of mast cell diseases and reactions. J. Allergy Clin. Immunol. Pract. 10, 1964–1973 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Khoury, P. & Lyons, J. J. Mast cell activation in the context of elevated basal serum tryptase: genetics and presentations. Curr. Allergy Asthma Rep. 19, 55 (2019).

    Article  PubMed  Google Scholar 

  129. Greiner, G. et al. Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis. Blood 137, 238–247 (2021). This article describes a relationship between hereditary α-tryptasaemia and severe mediator-related symptoms in patients with mastocytosis.

    Article  CAS  PubMed  Google Scholar 

  130. Chollet, M. B. & Akin, C. Hereditary alpha tryptasemia is not associated with specific clinical phenotypes. J. Allergy Clin. Immunol. 149, 728–735.e722 (2022).

    Article  CAS  PubMed  Google Scholar 

  131. Sordi, B. et al. Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis. J. Allergy Clin. Immunol. 151, 485–493.e411 (2023).

    Article  CAS  PubMed  Google Scholar 

  132. Polivka, L. et al. Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes. J. Allergy Clin. Immunol. 153, 349–353.e344 (2024).

    Article  CAS  PubMed  Google Scholar 

  133. Gonzalez-de-Olano, D. et al. Clinical impact of the TPSAB1 genotype in mast cell diseases: a REMA study in a cohort of 959 individuals. Allergy 79, 711–723 (2024).

    Article  CAS  PubMed  Google Scholar 

  134. Serafin, W. E. & Austen, K. F. Mediators of immediate hypersensitivity reactions. N. Engl. J. Med. 317, 30–34 (1987).

    Article  CAS  PubMed  Google Scholar 

  135. Schwartz, L. B. Mediators of human mast cells and human mast cell subsets. Ann. Allergy 58, 226–235 (1987).

    CAS  PubMed  Google Scholar 

  136. Gordon, J. R. & Galli, S. J. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 346, 274–276 (1990).

    Article  CAS  PubMed  Google Scholar 

  137. Boyce, J. A. Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation. Immunol. Rev. 217, 168–185 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Kalesnikoff, J. & Galli, S. J. New developments in mast cell biology. Nat. Immunol. 9, 1215–1223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Elieh Ali Komi, D., Wohrl, S. & Bielory, L. Mast cell biology at molecular level: a comprehensive review. Clin. Rev. Allergy Immunol. 58, 342–365 (2020).

    Article  PubMed  Google Scholar 

  140. Marcella, S. et al. Vascular endothelial growth factors and angiopoietins as new players in mastocytosis. Clin. Exp. Med. 21, 415–427 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Caughey, G. H. Update on mast cell proteases as drug targets. Immunol. Allergy Clin. North Am. 43, 777–787 (2023).

    Article  PubMed  Google Scholar 

  142. Greiner, G. et al. Tumor necrosis factor alpha promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis. Blood 143, 1006–1017 (2024).

    Article  CAS  PubMed  Google Scholar 

  143. Chia, S. L., Kapoor, S., Carvalho, C., Bajenoff, M. & Gentek, R. Mast cell ontogeny: from fetal development to life-long health and disease. Immunol. Rev. 315, 31–53 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Tomita, Y., Maeda, K. & Tagami, H. Mechanisms for hyperpigmentation in postinflammatory pigmentation, urticaria pigmentosa and sunburn. Dermatologica 179, 49–53 (1989).

    Article  PubMed  Google Scholar 

  145. Longley, B. J. Jr. et al. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N. Engl. J. Med. 328, 1302–1307 (1993).

    Article  PubMed  Google Scholar 

  146. Brockow, K. et al. Levels of mast-cell growth factors in plasma and in suction skin blister fluid in adults with mastocytosis: correlation with dermal mast-cell numbers and mast-cell tryptase. J. Allergy Clin. Immunol. 109, 82–88 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Aberer, E. et al. Clinical impact of skin lesions in mastocytosis: a multicenter study of the european competence network on mastocytosis. J. Invest. Dermatol. 141, 1719–1727 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Escribano, L. et al. Indolent systemic mastocytosis without skin involvement vs. isolated bone marrow mastocytosis. Haematologica 96, e26 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Akin, C., Scott, L. M. & Metcalfe, D. D. Slowly progressive systemic mastocytosis with high mast-cell burden and no evidence of a non-mast-cell hematologic disorder: an example of a smoldering case? Leuk. Res. 25, 635–638 (2001).

    Article  CAS  PubMed  Google Scholar 

  150. Akin, C. et al. Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp. Hematol. 28, 140–147 (2000). Demonstration of multilineage involvement with KITD816V mutation in SM proving the haematopietic stem cell nature of the disease.

    Article  CAS  PubMed  Google Scholar 

  151. Grootens, J. et al. Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis. EBioMedicine 43, 150–158 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Jara-Acevedo, M. et al. Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications. Mod. Pathol. 28, 1138–1149 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Yavuz, A. S., Lipsky, P. E., Yavuz, S., Metcalfe, D. D. & Akin, C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood 100, 661–665 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Hoermann, G. et al. The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease. Allergy 69, 810–813 (2014).

    Article  CAS  PubMed  Google Scholar 

  155. Teodosio, C. et al. An immature immunophenotype of bone marrow mast cells predicts for multilineage D816V KIT mutation in systemic mastocytosis. Leukemia 26, 951–958 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Schwaab, J. et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 122, 2460–2466 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Damaj, G. et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS ONE 9, e85362 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Shah, S. et al. Cytogenetic abnormalities in systemic mastocytosis: WHO subcategory-specific incidence and prognostic impact among 348 informative cases. Am. J. Hematol. 93, 1461–1466 (2018).

    Article  CAS  PubMed  Google Scholar 

  159. Naumann, N. et al. Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis. Genes Chromosomes Cancer 57, 252–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Soucie, E. et al. In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 120, 4846–4849 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Ellis, J. M. Urticaria pigmentosa; a report of a case with autopsy. Arch. Pathol. 48, 426–435 (1949).

    CAS  Google Scholar 

  162. Wolff, K., Komar, M. & Petzelbauer, P. Clinical and histopathological aspects of cutaneous mastocytosis. Leuk. Res. 25, 519–528 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Lennert, K. & Parwaresch, M. R. Mast cells and mast cell neoplasia: a review. Histopathology 3, 349–365 (1979).

    Article  CAS  PubMed  Google Scholar 

  164. Akin, C. How to evaluate the patient with a suspected mast cell disorder and how/when to manage symptoms. Hematol. Am. Soc. Hematol. Educ. Program. 2022, 55–63 (2022).

    Article  Google Scholar 

  165. Carter, M. C. et al. A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis. J. Allergy Clin. Immunol. 141, 180–188.e183 (2018).

    Article  CAS  PubMed  Google Scholar 

  166. Fuchs, D. et al. Scoring the risk of having systemic mastocytosis in adult patients with mastocytosis in the skin. J. Allergy Clin. Immunol. Pract. 9, 1705–1712.e1704 (2021).

    Article  CAS  PubMed  Google Scholar 

  167. Gulen, T., Hagglund, H., Sander, B., Dahlen, B. & Nilsson, G. The presence of mast cell clonality in patients with unexplained anaphylaxis. Clin. Exp. Allergy 44, 1179–1187 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Chovanec, J. et al. Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms. Blood Adv. 7, 1796–1810 (2023).

    Article  CAS  PubMed  Google Scholar 

  169. Rossini, M. et al. Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis. Osteoporos. Int. 27, 2411–2421 (2016).

    Article  CAS  PubMed  Google Scholar 

  170. Makovoz, A. et al. Assessment of osteoporosis and fracture risk in mastocytosis within a North American Cohort. J. Allergy Clinic. Immunologist. Pract. 9, 4459–4467 (2021).

    Article  CAS  Google Scholar 

  171. Tanasi, I. et al. Underlying systemic mastocytosis in patients with unexplained osteoporosis: score proposal. Bone 186, 117141 (2024).

    Article  PubMed  Google Scholar 

  172. Valent, P. et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur. J. Clin. Invest. 37, 435–453 (2007).

    Article  CAS  PubMed  Google Scholar 

  173. Valent, P., Sotlar, K., Horny, H. P., Arock, M. & Akin, C. World Health Organization classification and diagnosis of mastocytosis: update 2023 and future perspectives. Immunol. Allergy Clin. North Am. 43, 627–649 (2023).

    Article  PubMed  Google Scholar 

  174. Valent, P. et al. Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann. Oncol. 25, 1691–1700 (2014). This article describes updated consensus criteria and a revised consensus classification of MCL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Sperr, W. R. et al. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk. Res. 25, 529–536 (2001). This article provides the basic morphological criteria to identify and delineate various types of abnormal (neoplastic) mast cells in bone marrow smears in patients with mastocytosis.

    Article  CAS  PubMed  Google Scholar 

  176. Escribano, L. et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood 91, 2731–2736 (1998).

    Article  CAS  PubMed  Google Scholar 

  177. Valent, P. et al. Variable expression of activation-linked surface antigens on human mast cells in health and disease. Immunol. Rev. 179, 74–81 (2001).

    Article  CAS  PubMed  Google Scholar 

  178. Escribano, L. et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytom. B Clin. Cytom. 58, 1–8 (2004).

    Article  Google Scholar 

  179. Krauth, M. T. et al. Effects of the CD33-targeted drug gemtuzumab ozogamicin (Mylotarg) on growth and mediator secretion in human mast cells and blood basophils. Exp. Hematol. 35, 108–116 (2007).

    Article  CAS  PubMed  Google Scholar 

  180. Mueller, N. et al. CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis. Blood 132, 1936–1950 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Morgado, J. M. et al. CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis. Histopathology 63, 780–787 (2013).

    Article  PubMed  Google Scholar 

  182. Huang, L. et al. Well-differentiated systemic mastocytosis showed excellent clinical response to imatinib in the absence of known molecular genetic abnormalities: a case report. Medicine 95, e4934 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Blatt, K. et al. Identification of the Ki-1 antigen (CD30) as a novel therapeutic target in systemic mastocytosis. Blood 126, 2832–2841 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Greiner, G. et al. Digital PCR: a sensitive and precise method for KIT D816V quantification in mastocytosis. Clin. Chem. 64, 547–555 (2018).

    Article  CAS  PubMed  Google Scholar 

  185. Kristensen, T., Vestergaard, H. & Moller, M. B. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J. Mol. Diagn. 13, 180–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Akin, C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J. Mol. Diagn. 8, 412–419 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Zhang, L. Y. et al. A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk. Res. 30, 373–378 (2006).

    Article  CAS  PubMed  Google Scholar 

  188. de Melo Campos, P. et al. Familial systemic mastocytosis with germline KIT K509I mutation is sensitive to treatment with imatinib, dasatinib and PKC412. Leuk. Res. 38, 1245–1251 (2014).

    Article  PubMed  Google Scholar 

  189. Chan, E. C. et al. Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype. J. Allergy Clin. Immunol. 134, 178–187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Schwartz, L. B., Metcalfe, D. D., Miller, J. S., Earl, H. & Sullivan, T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N. Engl. J. Med. 316, 1622–1626 (1987). This study shows that the basal serum tryptase level is a solid biomarker for the total body burden of normal and neoplastic mast cells and that the event-induced increase in tryptase over the individual´s baseline is indicative of anaphylaxis caused by systemic mast cell activation.

    Article  CAS  PubMed  Google Scholar 

  191. Schwartz, L. B. & Irani, A. M. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol. Oncol. Clin. North Am. 14, 641–657 (2000).

    Article  CAS  PubMed  Google Scholar 

  192. Sperr, W. R. et al. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int. Arch. Allergy Immunol. 128, 136–141 (2002).

    Article  CAS  PubMed  Google Scholar 

  193. Akin, C., Valent, P. & Metcalfe, D. D. Mast cell activation syndrome: proposed diagnostic criteria. J. Allergy Clin. Immunol. 126, 1099–1104.e1094 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Valent, P. et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int. Arch. Allergy Immunol. 157, 215–225 (2012).

    Article  PubMed  Google Scholar 

  195. Valent, P. et al. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J. Allergy Clin. Immunol. Pract. 7, 1125–1133.e1121 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Lyons, J. J. Inherited and acquired determinants of serum tryptase levels in humans. Ann. Allergy Asthma Immunol. 127, 420–426 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Lyons, J. J. et al. Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1. J. Allergy Clin. Immunol. 147, 622–632 (2021).

    Article  CAS  PubMed  Google Scholar 

  198. Valent, P. et al. The normal range of baseline tryptase should be 1 to 15 ng/mL and covers healthy individuals with HαT. J. Allergy Clin. Immunol. Pract. 11, 3010–3020 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Hagen, W. et al. A case of bone marrow mastocytosis associated with multiple myeloma. Ann. Hematol. 76, 167–174 (1998).

    Article  CAS  PubMed  Google Scholar 

  200. Sotlar, K. et al. “Occult” mastocytosis with activating c-kit point mutation evolving into systemic mastocytosis associated with plasma cell myeloma and secondary amyloidosis. J. Clin. Pathol. 59, 875–878 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Prabahran, A. A. & Juneja, S. K. Systemic mastocytosis with concurrent multiple myeloma. Blood 131, 1494 (2018).

    Article  CAS  PubMed  Google Scholar 

  202. Gadde, R. & Oduro, K. A. Jr. Systemic mastocytosis with an associated plasma cell myeloma. Int. J. Lab. Hematol. 45, 409–410 (2023).

    Article  PubMed  Google Scholar 

  203. Valent, P. et al. Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage. Ann. Hematol. 94, 223–231 (2015).

    Article  PubMed  Google Scholar 

  204. Jain, P. et al. Mast cell leukemia (MCL): clinico-pathologic and molecular features and survival outcome. Leuk. Res. 59, 105–109 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Galura, G. M., Cherukuri, S. V., Hakim, N., Gaur, S. & Orazi, A. Acute aleukemic mast cell leukemia: report of a case and review of the literature. Leuk. Res. Rep. 14, 100230 (2020).

    PubMed  PubMed Central  Google Scholar 

  206. Zanelli, M. et al. Mast cell leukemia: an update with a practical review. Cancers 15, 1664–1680 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Akin, C. Mast cell activation syndromes. J. Allergy Clin. Immunol. 140, 349–355 (2017).

    Article  CAS  PubMed  Google Scholar 

  208. Wiechers, T. et al. Large maculopapular cutaneous lesions are associated with favorable outcome in childhood-onset mastocytosis. J. Allergy Clin. Immunol. 136, 1581–1590.e1583 (2015). This article describes the prognostic impact of two types of skin lesion in childhood patients with MPCM: in patients with small-sized symmetrical lesions the disease usually persists into adulthood, whereas large polymorphic skin lesions are mostly seen in children as these lesions disappear during or shortly after puberty.

    Article  PubMed  Google Scholar 

  209. Galen, B. T. & Rose, M. G. Darier’s sign in mastocytosis. Blood 123, 1127 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Carter, M. C. & Metcalfe, D. D. Paediatric mastocytosis. Arch. Dis. Child. 86, 315–319 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Carter, M. C. et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J. Allergy Clin. Immunol. 136, 1673–1679.e1673 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Alvarez-Twose, I. et al. Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Allergy 67, 813–821 (2012).

    Article  CAS  PubMed  Google Scholar 

  213. Carter, M. C. et al. Detection of KIT D816V in peripheral blood of children with manifestations of cutaneous mastocytosis suggests systemic disease. Br. J. Haematol. 183, 775–782 (2018).

    Article  CAS  PubMed  Google Scholar 

  214. Voelker, D., Bednarski, J. J., Nieman, E., Carter, M. C. & Polk, B. Hematopoietic KIT D816Y mutation presenting as in utero aggressive systemic mastocytosis with response to midostaurin. J. Allergy Clin. Immunol. Pract. 11, 1323–1325.e1321 (2023).

    Article  CAS  PubMed  Google Scholar 

  215. Carter, M. C., Metcalfe, D. D., Clark, A. S., Wayne, A. S. & Maric, I. Abnormal bone marrow histopathology in paediatric mastocytosis. Br. J. Haematol. 168, 865–873 (2015).

    Article  PubMed  Google Scholar 

  216. Ke, H., Kazi, J. U., Zhao, H. & Sun, J. Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis. Cell Biosci. 6, 55 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Tanasi, I. et al. Familial occurrence of systemic and cutaneous mastocytosis in an adult multicentre series. Br. J. Haematol. 193, 845–848 (2021).

    Article  PubMed  Google Scholar 

  218. Wasag, B. et al. Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis. Exp. Hematol. 39, 859–865.e852 (2011).

    Article  CAS  PubMed  Google Scholar 

  219. Wohrl, S. et al. A c-kit mutation in exon 18 in familial mastocytosis. J. Invest. Dermatol. 133, 839–841 (2013).

    Article  PubMed  Google Scholar 

  220. Hartmann, K. et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology 129, 1042–1046 (2005).

    Article  CAS  PubMed  Google Scholar 

  221. Brockow, K. et al. Mediator-related symptoms and anaphylaxis in children with mastocytosis. Int. J. Mol. Sci. 22, 2684 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Valent, P. et al. Personalized management strategies in mast cell disorders: ECNM-AIM user’s guide for daily clinical practice. J. Allergy Clin. Immunol. Pract. 10, 1999–2012.e1996 (2022).

    Article  CAS  PubMed  Google Scholar 

  223. Shibata, Y., Hirota, S., Saito, I. & Asahina, A. Diffuse cutaneous mastocytosis: identification of KIT mutation and long-term follow-up with serum tryptase level. J. Dermatol. 48, 672–675 (2021).

    Article  CAS  PubMed  Google Scholar 

  224. Carter, M. C. et al. Adverse reactions to drugs and biologics in patients with clonal mast cell disorders: a work group report of the mast cells disorder committee, american academy of allergy, asthma & immunology. J. Allergy Clin. Immunol. 143, 880–893 (2019).

    Article  PubMed  Google Scholar 

  225. Akin, C. et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood 110, 2331–2333 (2007). Report of demonstration of mastocytosis as the underlying pathology in patients presenting with ‘idiopathic’ anaphylaxis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Castells, M. & Butterfield, J. Mast cell activation syndrome and mastocytosis: initial treatment options and long-term management. J. Allergy Clin. Immunol. Pract. 7, 1097–1106 (2019).

    Article  PubMed  Google Scholar 

  227. Gulen, T. & Akin, C. Pharmacotherapy of mast cell disorders. Curr. Opin. Allergy Clin. Immunol. 17, 295–303 (2017).

    Article  PubMed  Google Scholar 

  228. Tolar, J., Tope, W. D. & Neglia, J. P. Leukotriene-receptor inhibition for the treatment of systemic mastocytosis. N. Engl. J. Med. 350, 735–736 (2004).

    Article  CAS  PubMed  Google Scholar 

  229. Butterfield, J. H. Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 88, 122–124 (2009).

    Article  CAS  PubMed  Google Scholar 

  230. Horan, R. F., Sheffer, A. L. & Austen, K. F. Cromolyn sodium in the management of systemic mastocytosis. J. Allergy Clin. Immunol. 85, 852–855 (1990).

    Article  CAS  PubMed  Google Scholar 

  231. Dykewicz, M. S., Wong, S. S., Patterson, R. & Harris, K. E. Evaluation of ketotifen in corticosteroid-dependent idiopathic anaphylaxis. Ann. Allergy 65, 406–410 (1990).

    CAS  PubMed  Google Scholar 

  232. Akin, C. Omalizumab for mast cell disorders. J. Allergy Clin. Immunol. 155, 81–83 (2025).

    Article  CAS  PubMed  Google Scholar 

  233. Jendoubi, F. et al. Omalizumab in the treatment of adult patients with mastocytosis: a systematic review. Clin. Exp. Allergy 50, 654–661 (2020).

    Article  CAS  PubMed  Google Scholar 

  234. Joshi, S. R., Anstey, K. M. & Khan, D. A. Chronic spontaneous urticaria: an update on the evaluation and management. Immunol. Allergy Clin. North Am. 44, 503–515 (2024).

    Article  PubMed  Google Scholar 

  235. Brazzelli, V. et al. Narrow-band UVB phototherapy and psoralen-ultraviolet A photochemotherapy in the treatment of cutaneous mastocytosis: a study in 20 patients. Photodermatol. Photoimmunol. Photomed. 32, 238–246 (2016).

    Article  CAS  PubMed  Google Scholar 

  236. Czarnetzki, B. M., Rosenbach, T., Kolde, G. & Frosch, P. J. Phototherapy of urticaria pigmentosa: clinical response and changes of cutaneous reactivity, histamine and chemotactic leukotrienes. Arch. Dermatol. Res. 277, 105–113 (1985).

    Article  CAS  PubMed  Google Scholar 

  237. Czarnetzki, B. M. & Behrendt, H. Urticaria pigmentosa: clinical picture and response to oral disodium cromoglycate. Br. J. Dermatol. 105, 563–567 (1981).

    Article  CAS  PubMed  Google Scholar 

  238. Czarnetzki, B. M. A double-blind cross-over study of the effect of ketotifen in urticaria pigmentosa. Dermatologica 166, 44–47 (1983).

    Article  CAS  PubMed  Google Scholar 

  239. Kettelhut, B. V., Berkebile, C., Bradley, D. & Metcalfe, D. D. A double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine in the treatment of pediatric mastocytosis. J. Allergy Clin. Immunol. 83, 866–870 (1989).

    Article  CAS  PubMed  Google Scholar 

  240. Lemal, R. et al. Omalizumab therapy for mast cell-mediator symptoms in patients with ISM, CM, MMAS, and MCAS. J. Allergy Clin. Immunol. Pract. 7, 2387–2395.e2383 (2019).

    Article  CAS  PubMed  Google Scholar 

  241. Broesby-Olsen, S. et al. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations. Allergy 73, 230–238 (2018).

    Article  CAS  PubMed  Google Scholar 

  242. Distler, M. et al. Efficacy of omalizumab in mastocytosis: allusive indication obtained from a prospective, double-blind, multicenter study (XOLMA Study). Dermatology 236, 529–539 (2020).

    Article  CAS  PubMed  Google Scholar 

  243. McComish, J. S. et al. Randomized controlled trial of omalizumab in treatment-resistant systemic and cutaneous mastocytosis (ROAM). J. Allergy Clin. Immunol. Pract. 11, 2248–2250.e2243 (2023).

    Article  CAS  PubMed  Google Scholar 

  244. Akin, C., Arock, M. & Valent, P. Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: are we there yet. J. Allergy Clin. Immunol. 149, 1912–1918 (2022).

    Article  CAS  PubMed  Google Scholar 

  245. Alvarez-Twose, I. et al. Complete response after imatinib mesylate therapy in a patient with well-differentiated systemic mastocytosis. J. Clin. Oncol. 30, e126–e129 (2012).

    Article  CAS  PubMed  Google Scholar 

  246. Gotlib, J. et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat. Med. 27, 2192–2199 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. DeAngelo, D. J. et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat. Med. 27, 2183–2191 (2021). This study describes that avapritinib is a disease-modifying drug that can induce major clinical responses and haematological remission in a subset of patients with SM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Reiter, A. et al. Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis. Blood Adv. 6, 5750–5762 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Pardanani, A., Reichard, K. & Tefferi, A. Advanced systemic mastocytosis-Revised classification, new drugs and how we treat. Br. J. Haematol. 204, 402–414 (2024).

    Article  CAS  PubMed  Google Scholar 

  250. Costa, A. et al. Systemic mastocytosis: 2023 update on diagnosis and management in adults. Expert Opin. Emerg. Drugs 28, 153–165 (2023).

    Article  PubMed  Google Scholar 

  251. Ma, Y. et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 99, 1741–1744 (2002).

    Article  CAS  PubMed  Google Scholar 

  252. Akin, C. et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp. Hematol. 31, 686–692 (2003).

    Article  CAS  PubMed  Google Scholar 

  253. Gotlib, J. et al. Avapritinib versus placebo in indolent systemic mastocytosis. NEJM Evid. 2, EVIDoa2200339 (2023). This clinical trial shows that avapritinib is an effective drug that can decrease the symptom burden and increase the QoL in patients with indolent SM.

    Article  PubMed  Google Scholar 

  254. Gotlib, J. et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N. Engl. J. Med. 374, 2530–2541 (2016). This study documents the clinical efficacy and disease-modifying effect of midostaurin in patients with advanced SM.

    Article  CAS  PubMed  Google Scholar 

  255. Akin, C. Tyrosine kinase inhibitors in non-advanced systemic mastocytosis. Immunol. Allergy Clin. North Am. 43, 743–750 (2023).

    Article  PubMed  Google Scholar 

  256. Growney, J. D. et al. Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood 106, 721–724 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Degenfeld-Schonburg, L. et al. Antineoplastic efficacy profiles of avapritinib and nintedanib in KIT D816V+ systemic mastocytosis: a preclinical study. Am. J. Cancer Res. 13, 355–378 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Frost, M. J., Ferrao, P. T., Hughes, T. P. & Ashman, L. K. Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol. Cancer Ther. 1, 1115–1124 (2002).

    CAS  PubMed  Google Scholar 

  259. Peter, B. et al. Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth. Leukemia 30, 464–472 (2016).

    Article  CAS  PubMed  Google Scholar 

  260. Krauth, M. T. et al. Midostaurin (PKC412) inhibits immunoglobulin E-dependent activation and mediator release in human blood basophils and mast cells. Clin. Exp. Allergy 39, 1711–1720 (2009).

    Article  CAS  PubMed  Google Scholar 

  261. Valent, P. et al. Midostaurin: a magic bullet that blocks mast cell expansion and activation. Ann. Oncol. 28, 2367–2376 (2017).

    Article  CAS  PubMed  Google Scholar 

  262. Ebeling, P. R., Daly, R. M., Kerr, D. A. & Kimlin, M. G. An evidence-informed strategy to prevent osteoporosis in Australia. Med. J. Aust. 198, 90–91 (2013).

    Article  PubMed  Google Scholar 

  263. Kluin-Nelemans, H. C. et al. Response to interferon alfa-2b in a patient with systemic mastocytosis. N. Engl. J. Med. 326, 619–623 (1992).

    Article  CAS  PubMed  Google Scholar 

  264. Tefferi, A., Li, C. Y., Butterfield, J. H. & Hoagland, H. C. Treatment of systemic mast-cell disease with cladribine. N. Engl. J. Med. 344, 307–309 (2001).

    Article  CAS  PubMed  Google Scholar 

  265. Casassus, P. et al. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br. J. Haematol. 119, 1090–1097 (2002).

    Article  CAS  PubMed  Google Scholar 

  266. Tefferi, A. et al. Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases. Br. J. Haematol. 196, 975–983 (2022).

    Article  CAS  PubMed  Google Scholar 

  267. Valent, P., Sperr, W. R. & Akin, C. How I treat patients with advanced systemic mastocytosis. Blood 116, 5812–5817 (2010).

    Article  CAS  PubMed  Google Scholar 

  268. Kluin-Nelemans, H. C. et al. Cladribine therapy for systemic mastocytosis. Blood 102, 4270–4276 (2003).

    Article  CAS  PubMed  Google Scholar 

  269. Gotlib, J. et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 106, 2865–2870 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Valent, P. et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk. Res. 27, 635–641 (2003).

    Article  CAS  PubMed  Google Scholar 

  271. Gotlib, J. et al. International working group-myeloproliferative neoplasms research and treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood 121, 2393–2401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Castells, M. & Akin, C. Finding the right KIT inhibitor for advanced systemic mastocytosis. Nat. Med. 27, 2081–2082 (2021).

    Article  CAS  PubMed  Google Scholar 

  273. Gotlib, J., Reiter, A. & DeAngelo, D. J. Avapritinib for advanced systemic mastocytosis. Blood 140, 1667–1673 (2022).

    Article  CAS  PubMed  Google Scholar 

  274. Tashi, T. & Deininger, M. W. Management of advanced systemic mastocytosis and associated myeloid neoplasms. Immunol. Allergy Clin. North Am. 43, 723–741 (2023).

    Article  PubMed  Google Scholar 

  275. Ustun, C. et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J. Clin. Oncol. 32, 3264–3274 (2014). This multicentre study provides definitive evidence that allogeneic HSCT is a potentially curative treatment approach in patients with advanced mastocytosis.

    Article  PubMed  PubMed Central  Google Scholar 

  276. Ustun, C. et al. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol. Blood Marrow Transpl. 22, 1348–1356 (2016).

    Article  Google Scholar 

  277. McLornan, D. P. et al. Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee. Leukemia 38, 699–711 (2024).

    PubMed  Google Scholar 

  278. Lubke, J. et al. Allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis: a retrospective analysis of the DRST and GREM registries. Leukemia 38, 810–821 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  279. Jennings, S. et al. The mastocytosis society survey on mast cell disorders: patient experiences and perceptions. J. Allergy Clin. Immunol. Pract. 2, 70–76 (2014).

    Article  PubMed  Google Scholar 

  280. Russell, N. et al. The mastocytosis society survey on mast cell disorders: part 2-patient clinical experiences and beyond. J. Allergy Clin. Immunol. Pract. 7, 1157–1165.e1156 (2019).

    Article  PubMed  Google Scholar 

  281. Pulfer, S. et al. Health-related quality of life and influencing factors in adults with nonadvanced mastocytosis-a cross-sectional study and qualitative approach. J. Allergy Clin. Immunol. Pract. 9, 3166–3175.e3162 (2021).

    Article  CAS  PubMed  Google Scholar 

  282. Pyatilova, P. & Siebenhaar, F. Measuring symptom severity and quality of life in mastocytosis. Immunol. Allergy Clin. North Am. 43, 751–762 (2023).

    Article  PubMed  Google Scholar 

  283. Vermeiren, M. R., Kranenburg, L. W., van Daele, P. L. A., Gerth van Wijk, R. & Hermans, M. A. W. Psychological functioning and quality of life in patients with mastocytosis: a cross-sectional study. Ann. Allergy Asthma Immunol. 124, 373–378.e372 (2020).

    Article  PubMed  Google Scholar 

  284. Sagues-Sese, E., Garcia-Casares, N. & Alvarez-Twose, I. Cognitive, neuropsychiatric and neurological alterations in mastocytosis: a systematic review. Clin. Transl. Allergy 13, e12319 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Siebenhaar, F. et al. Development and validation of the mastocytosis quality of life questionnaire: MC-QoL. Allergy 71, 869–877 (2016).

    Article  CAS  PubMed  Google Scholar 

  286. Taylor, F. et al. Psychometric evaluation of the advanced systemic mastocytosis symptom assessment form (AdvSM-SAF). Leuk. Res. 108, 106606 (2021).

    Article  PubMed  Google Scholar 

  287. Hartmann, K. et al. Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis. J. Allergy Clin. Immunol. 146, 356–366.e354 (2020).

    Article  CAS  PubMed  Google Scholar 

  288. Gonzalez de Olano, D., Cain, W. V., Bernstein, J. A. & Akin, C. Disease spectrum of anaphylaxis disorders. J. Allergy Clin. Immunol. Pract. 11, 1989–1996 (2023).

    Article  CAS  PubMed  Google Scholar 

  289. Akin, C., Siebenhaar, F., Wechsler, J. B., Youngblood, B. A. & Maurer, M. Detecting changes in mast cell numbers versus activation in human disease: a roadblock for current biomarkers? J. Allergy Clin. Immunol. Pract. 12, 1727–1737 (2024).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

P.V. was supported in part by the Austrian Science Fund (FWF) project PAT6394523.

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Authors and Affiliations

  1. Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Cem Akin

  2. CEREMAST, Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), Paris, France

    Michel Arock

  3. Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA

    Melody C. Carter

  4. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Tracy I. George

  5. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

    Peter Valent

  6. Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria

    Peter Valent

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Contributions

Introduction (C.A. and P.V.); Epidemiology (C.A. and M.C.C.); Mechanisms/pathophysiology (M.A., C.A. and P.V.); Diagnosis, screening and prevention (M.C.C., T.I.G., C.A. and P.V.); Management (M.C.C., C.A. and P.V.); Quality of life (C.A. and P.V.); Outlook (C.A. and P.V.); overview of the Primer (C.A. and P.V.). All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Cem Akin or Peter Valent.

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Competing interests

P.V. declares consultancy (honoraria) for Novartis, Blueprint, Cogent, Incyte, AOP Orphan, Stemline and Daiichi Sankyo. M.A. receives research grants from Blueprint; honoraria from AB Science, Blueprint and Novartis. T.I.G. declares consultancy for Incyte, Blueprint, Celgene/BMS and Cogent Biosciences. C.A. declares consultancy (honoraria) for Blueprint, Novartis, Cogent and Telios; research grant from Blueprint, Cogent and Telios; Investigator in clinical trial for Blueprint, Cogent and Telios. M.C.C. declares no competing interests.

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Nature Reviews Disease Primers thanks M. Bonifacio, S. Broesby-Olsen, D. Radia, P. Van Daele and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Akin, C., Arock, M., Carter, M.C. et al. Mastocytosis. Nat Rev Dis Primers 11, 30 (2025). https://doi.org/10.1038/s41572-025-00611-8

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