SYSTEMIC MASTOCYTOSIS: CURRENT PROGRESS AND CHALLENGES

Mastocytosis refers to a group of rare disorders caused by the expansion and accumulation of clonal mast cells in various organs and tissues.1 Two main entities can be distinguished: cutaneous forms, typically occurring in childhood, and systemic forms with multi-organ involvement, which are more common in adults. The clinical course of systemic mastocytosis (SM) is heterogeneous, ranging from indolent or non-advanced variants (nonAdvSM), which may be accompanied by cutaneous involvement and have a life expectancy comparable to that of the general population, to advanced variants (AdvSM), associated with a poorer prognosis and reduced survival.2,3 Clinically, non-advanced forms are mainly characterised by mediator-related symptoms (e.g., anaphylaxis, gastrointestinal disturbances, osteoporosis or osteopenia), which may significantly impair quality of life, while advanced forms are usually associated with signs and symptoms of organ infiltration.4 Accurate diagnosis and classification require a multidisciplinary approach and bone marrow evaluation, including morphological, histological, immunophenotypic, and molecular analyses for KIT mutations.4 For many years, basal serum tryptase (BST) has represented the most relevant biomarker for selecting patients requiring further diagnostic work-up in suspected SM. However, its role as a diagnostic criterion has recently been reappraised. Elevated BST levels can also result from non-clonal conditions such as hereditary α-tryptasemia (HαT), an autosomal dominant genetic trait caused by increased copy numbers of the TPSAB1 gene encoding α-tryptase.5 A more accurate and less invasive diagnostic strategy now relies on the integration of predictive algorithms and the highly sensitive detection of KIT D816V in peripheral blood by droplet digital PCR (ddPCR). From a therapeutic standpoint, the advent of KIT tyrosine kinase inhibitors has dramatically changed the scenario for advanced SM, significantly improving survival, and has also shown clinical benefit in non-advanced forms.6-9 Nevertheless, several challenges are still unresolved. Given the complexity of systemic mastocytosis, referral to specialised centres of expertise remains essential to ensure accurate diagnostic work-up, optimal therapeutic decision-making, and access to innovative treatment strategies. References Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007 Jun;37(6):435-53. doi: 10.1111/j.1365-2362.2007.01807.x 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 Jul;36(7):1703-1719. doi: 10.1038/s41375-022-01613-1. Epub 2022 Jun 22. 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 Dec;6(12):e638-e649. doi: 10.1016/S2352-3026(19)30166-8. Epub 2019 Oct 31. Pardanani A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am J Hematol. 2023 Jul;98(7):1097-1116. doi: 10.1002/ajh.26962. Epub 2023 May 22. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec;48(12):1564-1569. doi: 10.1038/ng.3696. Epub 2016 Oct 17. 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 Dec;27(12):2192-2199. doi: 10.1038/s41591-021-01539-8. Epub 2021 Dec 6.. 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 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098. Gotlib J, Castells M, Elberink HO, Siebenhaar F, Hartmann K, Broesby-Olsen S, et al. Avapritinib versus Placebo in Indolent Systemic Mastocytosis. NEJM Evid. 2023 Jun;2(6):EVIDoa2200339. doi: 10.1056/EVIDoa2200339. Epub 2023 May 23. Valent P, Hartmann K, Schwaab J, Alvarez-Twose I, Brockow K, Bonadonna P, et al. Personalized Management Strategies in Mast Cell Disorders: ECNM-AIM User’s Guide for Daily Clinical Practice. J Allergy Clin Immunol Pract. 2022 Aug;10(8):1999-2012.e6. doi: 10.1016/j.jaip.2022.03.007. Epub 2022 Mar 25.