In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

3 Medizinische Klinik Universitätsmedizin Mannheim Universität Heidelberg Mannheim Germany

Allergy Unit Verona University Hospital Verona Italy

Department of Allergology Medical University of Gdansk Gdańsk Poland

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

Department of Dermatology and Venereology Allergy Centrr Kepler University Hospital Linz Austria

Department of Dermatology and Venereology Medical University of Graz Graz Austria

Department of Dermatology and Venerology Uniklinik Köln Köln Germany

Department of Dermatology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Germany; German Cancer Consortium Partner Site Freiburg Freiburg Germany

Department of Dermatology University Hospitals Leuven Leuven Belgium

Department of Dermatology Venereology and Allergology Medical University of Gdansk Gdańsk Poland

Department of Haematology University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Hematology and Oncology Medical Center University of Schleswig Holstein Campus Lübeck Lübeck Germany

Department of Hematology Gustave Roussy Cancer Center Villejuif France

Department of Hematology Oncology and Stem Cell Transplantation Medical Center Faculty of Medicine University of Freiburg Freiburg Germany; German Cancer Consortium Partner Site Freiburg Freiburg Germany

Department of Hematology Semmelweis University Budapest Hungary

Department of Internal Medicine 1 Division of Hematology and Hemostaseology Medical University of Vienna 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 Hematology Hemostaseology and Stem Cell Transplantation University Hospital RWTH Aachen Aachen Germany

Dept Immunol Genetics and Pathology Uppsala University Hospital Uppsala University Uppsala Sweden

Division of Allergy and Clinical Immunology University of Salerno Salerno Italy

Division of Allergy Department of Dermatology University of Basel Basel Switzerland ; Department of Biomedicine University of Basel Basel Switzerland

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

Division of Hematology Istanbul Medical School University of Istanbul Istanbul Turkey

Division of Hematology Oncology Department of Medicine University of California San Francisco San Francisco USA

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

French Reference Center for Mastocytosis Hôpital Necker Assistance Publique Hôpitauxde Paris Imagine Institute University Paris Descartes Paris France

Institute of Environmental Health Medical University of Vienna Vienna Austria

Internal Medicine section Allergology University Medical Center Groningen University of Groningen Groningen The Netherlands

Laboratory of Hematology Pitié Salpêtrière Hospital Paris France

Ludwig Boltzmann Institute for Hematology and Oncology

Medical Clinic and Policlinic 1 Hematology and Cellular Therapy Leipzig University Hospital Germany

Pediatric Dermatology Unit Department of Medicine University of Padova Padova Italy

Section of Hematology Department of Medicine Verona University Hospital Verona Italy

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

University Hospital and CEITEC Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373:163–172. PubMed

Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O. et al. Mast cells as a unique hematopoietic lineage and cell system; from Paul Ehrlich's vision to precision medicine concepts. Theranostics. 2020;10:10743–68. PubMed PMC

Valent P, Horny H-P, Li C-Y, Longley BJ, Metcalfe JA, Parwaresch MR, Mastocytosis (Mast cell disease) In: Jaffe ES, Harris NL, Stein H, Vardiman J, Eds. WHO Classification of Tumours: Tumours of Haematopoietic and Lymphoid Tissues. 3rd ed. Lyon: IARC Press. 2001. p: 292-302.

Horny H-P, Akin C, Arber DA, Peterson LC, Tefferi A, Metcalfe DD, Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al. Eds. WHO classification of tumours of haematopoietic and lymphoid tissues. revised 4th ed. Lyon: IARC Press. 2017. p: 62-69.

Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O. et al. Advances in the classification and treatment of mastocytosis: current status and outlook toward the future. Cancer Res. 2017;77:1261–1270. PubMed PMC

Reiter A, George TI, Gotlib J. New developments in diagnosis, prognostication, and treatment of advanced systemic mastocytosis. Blood. 2020;135:1365–1376. PubMed

Gonzalez de OD, de la Hoz CB, Nunez LR, Sanchez ML, Cuevas AM, Dieguez 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;37:1547–1555. PubMed

Scherber RM, Borate U. How we diagnose and treat systemic mastocytosis in adults. Br J Haematol. 2018;180:11–23. PubMed

Sperr WR, Kundi M, Alvarez-Twose I, van AB, Oude Elberink JNG, Gorska A. et al. International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. Lancet Haematol. 2019;6:e638–e649. PubMed PMC

Jawhar M, Schwaab J, Schnittger S, Meggendorfer M, Pfirrmann M, Sotlar K. 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;30:136–143. PubMed

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;113:5727–5736. PubMed

Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Curr Opin Hematol. 2010;17:125–132. PubMed

Jawhar M, Schwaab J, Meggendorfer M, Naumann N, Horny HP, Sotlar K. et al. The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematol. 2017;102:1035–1043. PubMed PMC

Naumann N, Jawhar M, Schwaab J, Kluger S, Lubke J, Metzgeroth G. et al. Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis. Genes Chromosomes Cancer. 2018;57:252–259. PubMed

Jawhar M, Schwaab J, Hausmann D, Clemens J, Naumann N, Henzler T. 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;30:2342–2350. PubMed

Valent P, Oude Elberink JNG, Gorska A, Lange M, Zanotti R, van Anrooij B. et al. The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives. J Allergy Clin Immunol Pract. 2019;7:81–89. PubMed PMC

Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L. et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015;29:1223–1232. PubMed PMC

Gülen T, Ljung C, Nilsson G, Akin C. Risk Factor Analysis of Anaphylactic Reactions in Patients With Systemic Mastocytosis. J Allergy Clin Immunol Pract. 2017;5:1248–1255. PubMed

Jawhar M, Schwaab J, Alvarez-Twose I, Shoumariyeh K, Naumann N, Lubke J. et al. MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. J Clin Oncol. 2019;37:2846–2856. PubMed PMC

Pardanani A, Lim KH, Lasho TL, Finke C, McClure RF, Li CY. et al. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood. 2009;114:3769–3772. PubMed

Munoz-Gonzalez JI, Alvarez-Twose I, Jara-Acevedo M, Henriques A, Vinas E, Prieto C. et al. Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis. Blood. 2019;134:456–468. PubMed

Parwaresch MR, Horny HP, Lennert K. Tissue mast cells in health and disease. Path Res Pract. 1985;179:439–461. PubMed

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;137:35–45. PubMed

Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB. et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603–625. PubMed

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;67:431–438. PubMed

Cohen SS, Skovbo S, Vestergaard H, Kristensen T, Moller M, Bindslev-Jensen C. et al. Epidemiology of systemic mastocytosis in Denmark. Br J Haematol. 2014;166:521–528. PubMed

Meni C, Bruneau J, Georgin-Lavialle S, Le Sache de PL, Damaj G, Hadj-Rabia S. et al. Paediatric mastocytosis: a systematic review of 1747 cases. Br J Dermatol. 2015;172:642–651. PubMed

Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF. et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23:1969–1978. PubMed

Shah S, Pardanani A, Elala YC, Lasho TL, Patnaik MM, Reichard KK. et al. Cytogenetic abnormalities in systemic mastocytosis: WHO subcategory-specific incidence and prognostic impact among 348 informative cases. Am J Hematol. 2018;93:1461–1466. PubMed

Pardanani A, Shah S, Mannelli F, Elala YC, Guglielmelli P, Lasho TL. et al. Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models. Blood Adv. 2018;2:2964–2972. PubMed PMC

Pardanani A, Lasho T, Elala Y, Wassie E, Finke C, Reichard KK. et al. Next-generation sequencing in systemic mastocytosis: Derivation of a mutation-augmented clinical prognostic model for survival. Am J Hematol. 2016;91:888–893. PubMed

Steensma DP. Clinical Implications of Clonal Hematopoiesis. Mayo Clin Proc. 2018;93:1122–1130. PubMed

Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–2498. PubMed PMC

Bowman RL, Busque L, Levine RL. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell. 2018;22:157–170. PubMed PMC

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;374:2530–2541. PubMed