Systemic Mastocytosis: Diagnosis and Management in 2024

Authors

  • Stephanie Lee, MD, MSc, FRCPC Division of Hematology/Oncology, St. Michael's Hospital, Toronto, ON

DOI:

https://doi.org/10.58931/cht.2024.3149

Abstract

Mastocytosis is a group of clonal disorders characterized by an accumulation of neoplastic mast cells (MCs) in one or more organ systems. The clinical presentation of mastocytosis is heterogenous as are the clinical outcomes. For example, some variants are associated with near normal life expectancy, while others are amongst the most aggressive known malignancies. Mastocytosis can occur in both pediatric and adult populations and can be classified into three major groups: systemic mastocytosis (SM), cutaneous mastocytosis (CM), and localized mast cell sarcoma. This review will focus on SM in adults with the aim of providing a general overview of the (1) pathophysiology, (2) diagnostic approach, and (3) current treatment landscape in Canada.

Author Biography

Stephanie Lee, MD, MSc, FRCPC, Division of Hematology/Oncology, St. Michael's Hospital, Toronto, ON

Dr. Lee received an MD from the University of British Columbia and completed internal medicine and hematology residency at the University of Toronto. She completed a fellowship in the Acute Leukemia and Myeloproliferative Neoplasms Program at the Princess Margaret Cancer Centre in Toronto followed by a MSc degree in Epidemiology and Clinical Research at Stanford University. She is currently a hematologist at St. Michael’s Hospital in Toronto and an Assistant Professor at the University of Toronto. She helped establish St. Michael’s Hospital as the only Canadian centre of excellence in mast cell disorders with the American Initiative in Mast Cell Diseases and is currently the primary investigator of the program at St. Michael’s Hospital.

References

van Doormaal JJ, Arends S, Brunekreeft KL, van der Wal VB, Sietsma J, van Voorst Vader PC, et al. Prevalence of indolent systemic mastocytosis in a Dutch region. J Allergy Clin Immunol. 2013;131(5):1429-1431.e1421. doi:10.1016/j.jaci.2012.10.015

Cohen SS, Skovbo S, Vestergaard H, Kristensen T, Møller M, Bindslev-Jensen C, et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014;166(4):521-528. doi:10.1111/bjh.12916

Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727-5736. doi:10.1182/blood-2009-02-205237

Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991;146(5):1410-1415.

Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol. 2005;23:749-786. doi:10.1146/annurev.immunol.21.120601.141025

Galli SJ, Tsai M. Mast cells: versatile regulators of inflammation, tissue remodeling, host defense and homeostasis. J Dermatol Sci. 2008;49(1):7-19. doi:10.1016/j.jdermsci.2007.09.009

Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev. 1997;77(4):1033-1079. doi:10.1152/physrev.1997.77.4.1033

Miettinen M, Lasota J. KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 2005;13(3):205-220. doi:10.1097/01.pai.0000173054.83414.22

Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92(4):1736-1744. doi:10.1172/jci116761

Kitayama H, Kanakura Y, Furitsu T, Tsujimura T, Oritani K, Ikeda 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. 1995;85(3):790-798.

Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112(4):946-956. doi:10.1182/blood-2007-11-078097

González de Olano D, de la Hoz Caballer B, Núñez López R, Sánchez Muñoz L, Cuevas Agustín M, Diéguez MC, 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. 2007;37(10):1547-1555. doi:10.1111/j.1365-2222.2007.02804.x

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. 2008;63(2):226-232. doi:10.1111/j.1398-9995.2007.01569.x

Alvarez-Twose I, Zanotti R, González-de-Olano D, Bonadonna P, Vega A, Matito A, et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol. 2014;133(2):520-528. doi:10.1016/j.jaci.2013.06.020

Niedoszytko M, Bonadonna P, Oude Elberink JN, Golden DB. Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am. 2014;34(2):365-381. doi:10.1016/j.iac.2014.02.004

Jimenez-Rodriguez TW, Garcia-Neuer M, Alenazy LA, Castells M. Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers. J Asthma Allergy. 2018;11:121-142. doi:10.2147/jaa.S159411

Valent P. Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clin Exp Allergy. 2014;44(7):914-920. doi:10.1111/cea.12318

van Anrooij B, van der Veer E, de Monchy JG, van der Heide S, Kluin-Nelemans JC, van Voorst Vader PC, et al. Higher mast cell load decreases the risk of Hymenoptera venom-induced anaphylaxis in patients with mastocytosis. J Allergy Clin Immunol. 2013;132(1):125-130. doi:10.1016/j.jaci.2012.12.1578

Gulen T, Hägglund H, Dahlén B, Nilsson G. Mastocytosis: The puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease. Journal of Internal Medicine. 2015;279. doi:10.1111/joim.12410

van der Veer E, van der Goot W, de Monchy JG, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy. 2012;67(3):431-438. doi:10.1111/j.1398-9995.2011.02780.x

Degboé Y, Eischen M, Nigon D, Apoil PA, Mailhol C, Tournier E, et al. Prevalence and risk factors for fragility fracture in systemic mastocytosis. Bone. 2017;105:219-225. doi:10.1016/j.bone.2017.09.005

Riffel P, Schwaab J, Lutz C, Naumann N, Metzgeroth G, Fabarius A, et al. An increased bone mineral density is an adverse prognostic factor in patients with systemic mastocytosis. J Cancer Res Clin Oncol. 2020;146(4):945-951. doi:10.1007/s00432-019-03119-3

Acosta-Mérida Á, Ojeda-Bruno S. Multiple vertebral fractures as the first manifestation of systemic mastocytosis. Osteoporos Int. 2019;30(5):1121-1124. doi:10.1007/s00198-019-04897-9

Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, 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. 2016;137(1):35-45. doi:10.1016/j.jaci.2015.08.034

Berezowska S, Flaig MJ, Ruëff F, Walz C, Haferlach T, Krokowski M, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. 2014;27(1):19-29. doi:10.1038/modpathol.2013.117

Veitch S, Radia DH. Mastocytosis demystified. Hematology Am Soc Hematol Educ Program. 2023;2023(1):396-406. doi:10.1182/hematology.2023000505

Pardanani A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am J Hematol. 2023;98(7):1097-1116. doi:10.1002/ajh.26962

National Comprehensive Cancer Network. Systemic Mastocytosis. [accessed 2024 February 15, 2024]. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1490.

Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1

Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-1228. doi:10.1182/blood.2022015850

Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition. IARC, Lyon, 2017

González de Olano D, Alvarez-Twose I, Esteban-López MI, Sánchez-Muñoz L, de Durana MD, Vega A, et al. Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol. 2008;121(2):519-526. doi:10.1016/j.jaci.2007.11.010

Bonadonna P, Gonzalez-de-Olano D, Zanotti R, Riccio A, De Ferrari L, Lombardo C, et al. Venom immunotherapy in patients with clonal mast cell disorders: efficacy, safety, and practical considerations. J Allergy Clin Immunol Pract. 2013;1(5):474-478. doi:10.1016/j.jaip.2013.06.014

DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018;32(2):470-478. doi:10.1038/leu.2017.234

Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016;374(26):2530-2541. doi:10.1056/NEJMoa1513098

DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, et al. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021;27(12):2183-2191. doi:10.1038/s41591-021-01538-9

Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, et al. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021;27(12):2192-2199. doi:10.1038/s41591-021-01539-8

Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009;84(12):790-794. doi:10.1002/ajh.21561

Tefferi A, Kittur J, Farrukh F, Begna KH, Patnaik MM, Al-Kali A, et al. Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases. Br J Haematol. 2022;196(4):975-983. doi:10.1111/bjh.17932

Barete S, Lortholary O, Damaj G, Hirsch I, Chandesris MO, Elie C, et al. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood. 2015;126(8):1009-1016; quiz 1050. doi:10.1182/blood-2014-12-614743

Shomali W, Gotlib J. Response criteria in advanced systemic mastocytosis: evolution in the era of KIT inhibitors. Int J Mol Sci. 2021;22(6). doi:10.3390/ijms22062983

Ustun C, Gotlib J, Popat U, Artz A, Litzow M, Reiter A, et al. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transplant. 2016;22(8):1348-1356. doi:10.1016/j.bbmt.2016.04.018

Escribano L, Alvarez-Twose I, Sánchez-Muñoz L, Garcia-Montero A, Núñez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol. 2009;124(3):514-521. doi:10.1016/j.jaci.2009.05.003

Trizuljak J, Sperr WR, Nekvindová L, Elberink HO, Gleixner KV, Gorska A, et al. Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification. Allergy. 2020;75(8):1927-1938. doi:10.1111/all.14248

Pardanani A, Lim KH, Lasho TL, Finke CM, McClure RF, Li CY, et al. WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood. 2010;115(1):150-151. doi:10.1182/blood-2009-10-249979

Sperr WR, Kundi M, Alvarez-Twose I, van Anrooij B, Oude Elberink JNG, Gorska A, et al. International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 2019;6(12):e638-e649. doi:10.1016/S2352-3026(19)30166-8

Published

2024-04-25

How to Cite

1.
Lee S. Systemic Mastocytosis: Diagnosis and Management in 2024. Can Hematol Today [Internet]. 2024 Apr. 25 [cited 2024 Oct. 12];3(1):34–42. Available from: https://canadianhematologytoday.com/article/view/3-1-Lee

Issue

Section

Articles