Background: Mediator-related symptoms in patients with systemic mastocytosis (SM) range from mild episodic to severe life-threatening events. Methods: We examined a series of 137 consecutive patients with mastocytosis (63 females and 74 males) referred to our center between 1988 and 2010. Almost all patients received prophylactic histamine receptor (HR1 and HR2) antagonists. Results: Forty-two patients suffered from one or more mediator-related symptoms (hypotension, headache, flush, abdominal cramping, diarrhea) requiring therapy (SMSY). Severe life-threatening events (grade IV) occurred in 17 patients (12%). In 4 of these 17 patients, a deteriorating clinical course was recorded. One patient died of an apallic syndrome 1.5 years after an hymenoptera sting and cerebral hypoxia. One patient was disabled for months after an insect sting and cerebral hypoxia. Two patients with smoldering SM (SSM) suffered from severe recurrent hypotension requiring hospitalization and repeated resuscitation. Symptoms in these SSM patients did not respond to any of the antimediator-type drugs applied. However, after therapy with cladribine (2CdA), a major durable response was obtained in both cases. In patients with aggressive SM and mast cell leukemia (n = 6), life-threatening mediator-related events (grade IV) were not recorded. Conclusions: SM may be accompanied by life-threatening mediator-related symptoms. Most of these patients have indolent SM or SSM. In patients with SSMSY with uncontrolled symptoms (grade IV), therapy with 2CdA should be considered.

Metcalfe DD: Classification and diagnosis of mastocytosis: current status. J Invest Dermatol 1991;96:2S–4S.
Valent P: Biology, classification and treatment of human mastocytosis. Wien Klin Wochenschr 1996;108:385–397.
Valent P, Akin C, Sperr WR, Horny HP, Arock M, Lechner K, Bennett JM, Metcalfe DD: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:695–717.
Akin C, Metcalfe DD: Systemic mastocytosis. Annu Rev Med 2004;55:419–432.
Horny HP, Valent P: Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res2001;25:543–551.
Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD: 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 1995;92:10560–10564.
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs P, Tang LH, Modlin I: Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm.Nat Genet 1996;12:312–314.
Féger F, Ribadeau Dumas A, Leriche L, Valent P, Arock M: Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts. Int Arch Allergy Immunol 2002;127:110–114.
Bodemer C, Hermine O, Palmérini F, Yang Y, Grandpeix-Guyodo C, Leventhal PS, Hadj-Rabia S, Nasca L, Georgin-Lavialle S, Cohen-Akenine A, Launay JM, Barete S, Feger F, Arock M, Catteau B, Sans B, Stalder JF, Skowron F, Thomas L, Lorette G, Plantin P, Bordigoni P, Lortholary O, de Prost Y, Moussy A, Sobol H, Dubreuil P: Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol 2010;130:804–815.
Escribano L, Orfao A, Diaz-Agustin B, Villarrubia J, Cervero C, Lopez A, Marcos, MA, Bellas C, Fernandez-Canadas S, Cuevas M, Sanchez A, Velasco JL, Navarro JL, Miguel JF: Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood 1998;91:2731–2736.
Valent P, Schernthaner GH, Sperr WR, Fritsch G, Agis H, Willheim M, Bühring HJ, Orfao A, Escribano L: Variable expression of activation-linked surface antigens on human mast cells in health and disease. Immunol Rev 2001;179:74–81.
Schwartz LB, Sakai K, Bradford TR, Ren S, Zweiman B, Worobec AS, Metcalfe DD: The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest 1995;96:2702–2710.
Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T: Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med 1987;316:1622–1626.
Sperr WR, Jordan JH, Fiegl M, Escribano L, Bellas C, Dirnhofer S, Simonitsch-Klupp I, Horny HP, Valent P: 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;128:136–141.
Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, Marone G, Nunez R, Akin C, Sotlar K, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Austen KF, Lennert K, Metcalfe DD, Vardiman JW, Bennett JM: Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res 2001;25:603–625.
Valent P, Horny HP, Li CY, Longley JB, Metcalfe DD, Parwaresch RM, Bennett JM: Mastocytosis; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization (WHO) Classification of Tumours. Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2001, pp 291–302.
Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal J, Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD: Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007;37:435–453.
Horny HP, Metcalfe DD, Bennett JM, Bain BJ, Akin C, Escribano L, Valent P, Bain B: Mastocytosis; in Swerdlow SH, Campo E, Harris NL, Jaffee ES, Pileri SA, Stein H, Thiele J, Varderman JW (eds): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC Press, 2008, pp 54–63.
Müller UR, Horat W, Wüthrich B, Conroy M, Reisman RE: Anaphylaxis after hymenoptera stings in three patients with urticaria pigmentosa. J Allergy Clin Immunol 1983;72:685–689.
Kors JW, van Doormaal JJ, de Monchy JG: Anaphylactoid shock following hymenoptera sting as a presenting symptom of systemic mastocytosis. J Intern Med 1993;233:255–258.
Oude Elberink JN, de Monchy JG, Kors JW, van Doormaal JJ, Dubois AE: Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis. J Allergy Clin Immunol 1997;99:153–154.
Escribano L, Akin C, Castells M, Orfao A, Metcalfe DD: Mastocytosis: current concepts in diagnosis and treatment. Ann Hematol 2002;81:677–690.
Florian S, Krauth MT, Simonitsch-Klupp I, Sperr WR, Fritsche-Polanz R, Sonneck K, Födinger M, Agis H, Böhm A, Wimazal F, Horny HP, Valent P: Indolent systemic mastocytosis with elevated serum tryptase, absence of skin lesions, and recurrent severe anaphylactoid episodes. Int Arch Allergy Immunol 2005;136:273–280.
González de Olano D, Alvarez-Twose I, Esteban-López MI, Sánchez-Muñoz L, de Durana MD, Vega A, García-Montero A, González-Mancebo E, Belver T, Herrero-Gil MD, Fernández-Rivas M, Orfao A, de la Hoz B, Castells MC, Escribano L: Safety and effectiveness of immunotherapy in patients with indolent systemic mastocytosis presenting with Hymenoptera venom anaphylaxis. J Allergy Clin Immunol 2008;121:519–526.
Niedoszytko M, de Monchy J, van Doormaal JJ, Jassem E, Oude Elberink JN: Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy. Allergy 2009;64:1237–1245.
Böhm A, Sonneck K, Gleixner KV, Schuch K, Pickl WF, Blatt K, Peter B, Herrmann H, Schernthaner GH, Pehamberger H, Rabitsch W, Sperr WR, Valent P: In vitro and in vivo growth-inhibitory effects of cladribine on neoplastic mast cells exhibiting the imatinib-resistant KIT mutation D816V. Exp Hematol 2010;38:744–755.
Valent P, Sperr WR, Schwartz LB, Horny HP: Diagnosis and classification of mast cell proliferative disorders: delineation from immunologic diseases and non-mast cell hematopoietic neoplasms. J Allergy Clin Immunol 2004;114:3–11.
Metcalfe DD, Schwartz LB: Assessing anaphylactic risk? Consider mast cell clonality. J Allergy Clin Immunol 2009;123:687–688.
Akin C: Anaphylaxis and mast cell disease: what is the risk? Curr Allergy Asthma Rep 2010;10:34–38.
Fricker M, Helbling A, Schwartz L, Müller U: Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients. J Allergy Clin Immunol 1997;100:11–15.
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;63:226–232.
Alvarez-Twose I, González de Olano D, Sánchez-Muñoz L, Matito A, Esteban-López MI, Vega A, Mateo MB, Alonso Díaz de Durana MD, de la Hoz B, Del Pozo Gil MD, Caballero T, Rosado A, Sánchez Matas I, Teodósio C, Jara-Acevedo M, Mollejo M, García-Montero A, Orfao A, Escribano L: Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol 2010;125:1269–1278.e2.
Arock M, Valent P: Pathogenesis, classification, and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol 2010;3:497–516.
Tefferi A, Li CY, Butterfield JH, Hoagland HC: Treatment of systemic mast-cell disease with cladribine. N Engl J Med 2001;344:307–309.
Escribano L, Pérez de Oteyza J, Núñez R, Orfao A: Cladribine induces immunophenotypical changes in bone marrow mast cells from mastocytosis. Report of a case of mastocytosis associated with a lymphoplasmacytic lymphoma. Leuk Res 2002;26:1043–1046.
Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, van’t Wout JW, Verhoef G, Gerrits WB, van Dobbenburgh OA, Pasmans SG, Fijnheer R: Cladribine therapy for systemic mastocytosis. Blood 2003;102:4270–4276.
Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A: Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res 2004;28:127–131.
Aichberger KJ, Sperr WR, Gleixner KV, Kretschmer A, Valent P: Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosis. Eur J Clin Invest 2008;38:869–873.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.