BACKGROUND: The WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis. METHODS: We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Española de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017. FINDINGS: The prognostic value of the WHO classification was confirmed in our study (p<0·0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10·75, 95% CI 5·68-20·32) and a concentration of alkaline phosphatase 100 U/L or higher (2·91, 1·60-5·30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0·0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2·14, 95% CI 1·42-3·22), a concentration of tryptase 125 ng/mL or higher (1·81, 1·20-2·75), a leukocyte count of 16 × 109 per L or higher (1·88, 1·27-2·79), haemoglobin of 11 g/dL or lower (1·71, 1·13-2·57), a platelet count of 100 × 109 per L or lower (1·63, 1·13-2·34), and skin involvement (0·46, 0·30-0·69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0·0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort. INTERPRETATION: The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials. FUNDING: Austrian Science Fund, Deutsche Forschungsgemeinschaft, Koeln Fortune Program, Charles and Ann Johnson Foundation, Instituto de Salud Carlos III, Fondos FEDER, Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek, Clinical Research-Fund of the University Hospitals Leuven, and Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek.

3 Medizinische Klinik Universitätsmedizin Mannheim Universität Heidelberg Mannheim Germany

Allergy Unit Verona University Hospital Verona Italy

Centro de Investigación del Cáncer IBMCC CIBERONC and IBSAL Departamento de Medicina and Servicio General de Citometría University of Salamanca Salamanca Spain

Department of Allergology Medical University of Gdańsk Gdańsk Poland

Department of Allergology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Dermatology and Allergy School of Medicine Technical University of Munich Munich Germany

Department of Dermatology and Venereology University Hospital Graz Graz Austria

Department of Dermatology and Venerology Kepler University Hospital Johannes Kepler University Linz Austria

Department of Dermatology Medical University of Gdańsk Gdańsk Poland

Department of Dermatology University of Cologne Cologne Germany

Department of Dermatology University of Cologne Cologne Germany; Division of Allergy Department of Dermatology and Department of Biomedicine University of Basel Basel Switzerland

Department of Hematological Biologie Pitié Salpêtrière Hospital Paris Sorbonne University Paris UMR8113 Ecole France

Department of Hematology Oncology and Stem Cell Transplantation Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Hematology Oncology and Stem Cell Transplantation Medical Center Faculty of Medicine University of Freiburg Freiburg Germany; Department of Hematology and Oncology Medical Center University of Schleswig Holstein Campus Lübeck Lübeck Germany

Department of Hematology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Hematology University Medical Center Groningen University of Groningen Groningen Netherlands; Department of Allergology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Internal Medicine 1 Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna Austria

Department of Internal Medicine 1 Division of Hematology and Hemostaseology and Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna Austria; Internal Medicine Small Animals University Clinic for Small Animals Department University Clinic for Companion Animals and Horses University of Veterinary Medicine Vienna Austria

Department of Molecular Medicine and Department of Hematology Oncology University of Pavia and Fondazione IRCCS Policlinico San Matteo Pavia Italy

Department of Oncology Haematology Haemostaseology and Stem Cell Transplantation University Hospital RWTH Aachen Aachen Germany

Division of Allergy and Clinical Immunology University of Salerno Salerno Italy

Division of Hematology Department of Medical Sciences Uppsala University Uppsala Sweden

Division of Hematology Department of Medicine Stanford University School of Medicine Stanford CA USA

Division of Hematology Istanbul Medical School University of Istanbul Istanbul Turkey

Faculty of Medicine and Health Sciences Department of Immunology Allergology Rheumatology University of Antwerp and Antwerp University Hospital Antwerp Belgium

Imagine Institute Université Paris Descartes Sorbonne Paris Cité Centre national de référence des mastocytoses Paris France

Institute of Environmental Health Medical University of Vienna Vienna Austria

Instituto de Estudios de Mastocitosis de Castilla La Mancha Hospital Virgen del Valle Toledo Spain

KU Leuven Department of Microbiology Immunology and Transplantation Allergy and Clinical Immunology Research Group and MASTeL University Hospitals Leuven Leuven Belgium

Pediatric Dermatology Unit Department of Medicine University of Padua Padua Italy

Section of Hematology Department of Medicine Verona University Hospital Verona Italy

University Clinic for Hematology and Internal Oncology Kepler University Hospital Johannes Kepler University Linz Austria

University Hospital and CEITEC Masaryk University Brno Czech Republic

University Hospital of Leipzig Leipzig Germany

Lancet Haematol. 2019 Dec;6(12):e604-e605. doi: 10.1016/S2352-3026(19)30212-1. PubMed

Zobrazit více v PubMed

Cohen SS, Skovbo S, Vestergaard H, et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014;166:521–28. PubMed

Valent P, Akin C, Metcalfe DD. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017;129:1420–27. PubMed PMC

Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603–25. PubMed

Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113:5727–36. PubMed

Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435–53. PubMed

Valent P, Oude Elberink JNG, Gorska A, et al. The data registry of the European Competence Network on Mastocytosis (ECNM): set up, projects, and perspectives. J Allergy Clin Immunol Pract. 2019;7:81–87. PubMed PMC

Sperr WR, Escribano L, Jordan JH, et al. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res. 2001;25:529–36. PubMed

Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004;55:419–32. PubMed

Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112:946–56. PubMed PMC

Escribano L, Díaz-Agustín B, Bellas C, et al. Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res. 2001;25:563–70. PubMed

Sperr WR, Jordan JH, Fiegl M, 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. 2002;128:136–41. PubMed

Escribano L, Alvarez-Twose I, Sánchez-Muñoz L, 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;124:514–21. PubMed

Jawhar M, Schwaab J, Hausmann D, et al. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis. Leukemia. 2016;30:2342–50. PubMed

Teodosio C, Mayado A, Sanchez-Muñoz L, et al. The immunophenotype of mast cells and its utility in the diagnostic work-up of systemic mastocytosis. J Leukoc Biol. 2015;97:49–59. PubMed

Pardanani A, Reichard KK, Zblewski D, et al. CD123 immunostaining patterns in systemic mastocytosis: differential expression in disease subgroups and potential prognostic value. Leukemia. 2016;30:914–18. PubMed

Hoermann G, Gleixner KV, Dinu GE, et al. The KIT D816V allele burden predicts survival in patients with mastocytosis and correlates with the WHO type of the disease. Allergy. 2014;69:810–13. PubMed PMC

Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013;122:2460–66. PubMed

Jawhar M, Schwaab J, Schnittger S, et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V+ advanced systemic mastocytosis. Leukemia. 2016;30:136–43. PubMed

Greiner G, Witzeneder N, Berger A, et al. CCL2 is a KIT D816V-dependent modulator of the bone marrow microenvironment in systemic mastocytosis. Blood. 2017;129:371–82. PubMed PMC

Pardanani A, Lasho TL, Reichard KK, Hanson CA, Tefferi A. World Health Organization class-independent risk categorization in mastocytosis. Blood Cancer J. 2019;9:29. PubMed PMC

Pardanani A, Shah S, Mannelli F, et al. Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models. Blood Adv. 2018;2:2964–72. PubMed PMC

Jawhar M, Schwaab J, Naumann N, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood. 2017;130:137–45. PubMed

Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16. PubMed PMC

Muñoz-González JI, Jara-Acevedo M, Alvarez-Twose I, et al. Impact of somatic and germline mutations on the outcome of systemic mastocytosis. Blood Adv. 2018;2:2814–28. PubMed PMC

Siebenhaar F, von Tschirnhaus E, Hartmann K, et al. Development and validation of the mastocytosis quality of life questionnaire: MC-QoL. Allergy. 2016;71:869–77. PubMed

Hermine O, Lortholary O, Leventhal PS, et al. Case-control cohort study of patients’ perceptions of disability in mastocytosis. PLoS One. 2008;3:e2266. PubMed PMC

Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530–41. PubMed

Kluin-Nelemans HC, Jansen JH, Breukelman H, et al. Response to interferon alfa-2b in a patient with systemic mastocytosis. N Engl J Med. 1992;326:619–23. PubMed

Barete S, Lortholary O, Damaj G, et al. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood. 2015;126:1009–16. PubMed

Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014;32:3264–74. PubMed PMC

Serum chemistry profiling and prognostication in systemic mastocytosis: a registry-based study of the ECNM and GREM

Mast cell leukemia: clinical and molecular features and survival outcomes of patients in the ECNM Registry

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis