Borbényi, Zita

Bödör, Csaba

Csörgő Sándorné Bata, Zsuzsanna

Demeter, Judit

Korom, Irma

Marton, Imelda

Papp, Gergő

Pósfai, Éva

Varga, Erika

Marton Imelda

Pósfai Éva

Borbényi Zita

Bödör Csaba

Papp Gergő

Demeter Judit

Korom Irma

Varga Erika

Csörgő Sándorné Bata Zsuzsanna

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Abstract. – From a dermatological aspect, itposed a considerable challenge the skin-limitedform of mastocytosis, urticaria pigmentosa andindolent systemic mastocytosis (ISM) with cuta-neous lesions. Despite the favourable prognosis,lifelong dermatological control is needed, duringwhich the average symptomatic therapy doesnot always seem adequate.We report here the case of a female ISM pa-tient with recurrent cutaneous symptoms thatimpaired her quality of life, with a follow-up timeof 27 years. During this long follow-up period,the cutaneous lesions could be controlled by an-tihistamines, leukotriene antagonists, glucocor-ticoids, local immunosuppressants or local UVradiation for only relatively short periods. Ima-tinib mesylate was, therefore, introduced in anattempt to control the cutaneous lesions. Tyro-sine kinase inhibition is an unusual dermatologi-cal therapeutic option.This case illustrates that imatinib mesylate wasa good choice with which to achieve a reductionof the skin lesions in this KIT D816V mutation-neg-ative disease: it led to a temporary appreciable im-provement of the patient’s quality of life.Key Words:Myeloproliferative neoplasm, Indolent systemicmastocytosis, KIT D816V mutation, Imatinib mesylate,Tyrosine kinase inhibitor.IntroductionSystemic mastocytosis (SM) is a rare chronicmyeloproliferative neoplasm characterized by ab-normal mast cell proliferation with accumulationEuropean Review for Medical and Pharmacological SciencesTherapeutic challenge during thelong-term follow-up of a patient withindolent systemic mastocytosis withextensive cutaneous involvementI. MARTON, É. PÓSFAI, Z. BORBÉNYI, C. BÖDÖR1, G. PAPP1,J. DEMETER2, I. KOROM3, E. VARGA3, Z. BATA-CSÖRGŐ32nd Department of Medicine and Cardiology Centre, Medical Faculty, Albert Szent-Györgyi ClinicalCentre, University of Szeged, Szeged, Hungary11st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest,Hungary21st Department of Internal Medicine, Semmelweis University, Budapest, Hungary3Department of Dermatology and Allergology, Medical Faculty, Albert Szent-Györgyi Clinical Centre,University of Szeged, Szeged, HungaryCorresponding Author: Imelda Marton, MD; e-mail: imeldamarton@gmail.com 1607in one or more extracutaneous organs1,2. The2008 World Health Organization classificationdefines various subtypes of SM, including indo-lent SM (ISM), SM associated with a clonal non-mast cell lineage disease (SM-AHNMD), aggres-sive SM (ASM) and mast cell leukaemia1.For dermatologists, considerable challengesare posed by cutaneous mastocytosis withoutbone marrow involvement as a skin-limited dis-ease, and by ISM involving the bone marrowwith cutaneous symptoms. Though the masto-cytes in ISM involve several organs, includingthe bone marrow, it frequently presents clinicallywith cutaneous symptoms alone or in combina-tion with recurrent mediator-related systemicsymptoms (e.g. pruritus, flushing, diarrhoea andheadache)2. The life expectancy in ISM is morefavourable than in the other variants of SM: thegreat majority of the patients have an almost nor-mal life expectancy and a low disease progres-sion rate. Nevertheless, the quality of life of thesepatients can be severely affected by the mediator-related systemic and/or cutaneous symptoms3.The only therapeutic option for the specific cuta-neous symptoms is symptomatic therapy: com-monly antihistamines, leukotriene antagonists,glucocorticoids, local immunosuppressants or lo-cal UV radiation, and in selected special cases ty-rosine kinase inhibitors (TKIs)2,4,5. The usefulnessof TKIs in SM has been actively investigated in re-cent years, but the role of imatinib mesylate thera-py in controlling the cutaneous lesions in ISM hasnot been well established6-8.2015; 19: 1607-1609Figure 1. A, The diffuse brownish papular pruritic lesionsof this patient before the introduction of imatinib mesylatetreatment. B, A clear improvement of the skin lesions wasseen after imatinib mesylate treatment.I. Marton, É. Pósfai, Z. Borbényi, C. Bödör, G. Papp, J. Demeter, I. Korom, E. Varga, Z. Bata-CsörgőDiscussionIn recent years, TKIs, including imatinib, haverevolutionized the treatment of patients withchronic myeloid leukaemia and gastrointestinalstromal tumours9,10. Increasing evidence hasemerged to suggest that a small subset of SM pa-tients who are KIT D816V-unmutated or whohave a very rare imatinib-sensitive KIT mutationmay also benefit from imatinib mesylate therapy,which is presumed to reduce the mast cell media-tor levels and results in an improvement in themediator-related symptoms6-8,11,12. In cases of SMwith eosinophilia, molecular investigation(FIP1L1-PDGFRA rearrangement) is required, asonly patients with rearranged PDGFRA will re-spond to imatinib therapy. Interestingly, KITD816V-mutated SM patients with eosinophiliagive no response13. The published data concern-ing the effects of imatinib mesylate on the cuta-neous lesions in ISM are still a matter of debate.Only a small number of case reports in paediatricdiffuse cutaneous mastocytosis and in adult pa-tients with cutaneous mastocytosis associatedThis case report describes a female patientwith ISM who was followed up for 27 years, dur-ing which the recurrent specific cutaneous symp-toms frequently greatly impaired her quality oflife. Her case illustrates the potential value ofimatinib mesylate even in KIT D816V mutation-negative ISM, with achievement of a temporaryimprovement of the skin-related symptoms.Case PresentationThe patient presented with diffuse brownishpapular lesions on the face, the trunk and the up-per and lower extremities in 1986. Her lesionsregularly became red and elevated, with no obvi-ous cause. The Darier sign was positive.Histopathology of the skin biopsy confirmed thediagnosis of mastocytosis.The otherwise attractive young female patientwas highly disturbed by her skin symptoms,which included itching, and the appearance ofher skin greatly influenced her quality of life.She was treated first with antihistamines andPUVA. However, because of the worsening of theskin symptoms and the result of the bone marrowbiopsy, which confirmed ISM, interferon-alfa wasadministrated in weekly doses of 2x3 million IUfor 1 year. This resulted in relief of her symptomsfor a period of 2 years, during which she was giv-en only sodium-chromoglycate. Subsequently, inconsequence of the progression of her cutaneoussymptoms, repeated interferon-alfa therapy wasintroduced in weekly doses of 3x3 million IU foranother year, which again resulted in the tempo-rary relief of her symptoms. However, eosinophil-ia and cutaneous progression shortly appeared(Figure 1/a). As the recurring cutaneous symp-toms, greatly disturbed the patient’s quality of life,imatinib mesylate was introduced, even thoughneither FIP1L1-PDGFRA gene rearrangement nora KIT D816V mutation nor any imatinib-sensitiveKIT mutation was present. Shortly after the begin-ning of imatinib mesylate treatment her skinsymptoms improved, the lesions become macularand the itching disappeared. She took imatinibmesylate periodically between 2008 and 2010.When the newly introduced imatinib treatmentfirst given a daily dose of 400 mg was commencedfor 6 months, which was followed by a daily doseof 100 mg. She has currently been off imatinib formore than 2 years, and although she still hasbrownish macular lesions all over her body, the le-sions do not interfere with her quality of life; sheneeds antihistamine treatment only occasionally(Figure 1/b).1608with chronic myelomonocytic leukaemia havebeen found to demonstrate a marked improve-ment following the administration of imatinibmesylate7,14,15.In light of the previously reported rare imatinib-sensitive KIT mutations located in exons 9 and 11,we screened our patient for the most frequently re-ported KIT mutations in exons 9, 11 and 17, usingSanger sequencing13. Although sequence analysisdid not reveal any KIT mutations in exon 17,where the most common observed KIT D816Vmutation occurs and the other, though rare ima-tinib-resistant mutations are mostly located, wedecided to introduce imatinib mesylate in an effortto control the skin lesions. This case demonstratesthat imatinib mesylate therapy may be benefit,even in KIT D816V-unmutated cases of ISM, re-sulting at least temporarily in regression of the cu-taneous symptoms.ConclusionsOur case has revealed that imatinib mesylatecan be useful, even if with only a limited role, ina KIT D816V-unmutated ISM patient with exten-sive cutaneous involvement. When the cutaneouslesions in ISM can no longer be controlled by an-tihistamines, leukotriene antagonists, glucocorti-coids, local immunosuppressants or local UV ra-diation, imatinib mesylate may temporarily re-duce the skin lesions and improve the quality oflife of the patient.–––––––––––––––––-–––Conflict of InterestThe Authors declare that there are no conflicts of interest.References1) HORNY HP, SOTLAR K, VALENT P. Mastocytosis: stateof the art. Pathobiology 2007; 74: 121-132.2) VALENT P, AKIN C, ESCRIBANO L, FODINGER M, HART-MANN K, BROCKOW K, CASTELLS M, SPERR WR, KLUIN-NELEMANS HC, HAMDY N AT, LORTHOLARY O, ROBYN J,VAN DOORMAAL J, SOTLAR K, HAUSWIRTH AW, AROCK M,HERMINE O, HELLMANN A, TRIGGIANI M, NIEDOSZYTKOM, SCHWARTZ LB, ORFAO A, HORNY H-P, METCALFE D.Standards and standardization in mastocytosis:consensus statements on diagnostics, treatmentrecommendations and response criteria. Eur JClin Invest 2007; 37: 435-453.3) ESCRIBANO L, ALVAREZ-TWOSE I, SANCHEZ-MUNOZ L,GARCIA-MONTERO A, NUNEZ R, ALMEIDA J, JARA-ACEVE-DO M, TEODOSIO C, GARCIA-COSIO M, BELLAS C, ORFAOA. Prognosis in adult indolent systemic mastocy-tosis: a long-term study of the Spanish Networkon Mastocytosis in a series of 145 patients. J Al-lergy Clin Immunol 2009; 124: 514-521.4) PAUL C, SANS B, SUAREZ F, CASASSUS P, BARETE S,LANTERNIER F, GRANDPEIX-GUYODO C, DUBREUIL P,PALMERINI F, MANSFIELD CD, GINESTE P, MOUSSY A, HER-MINE O, LORTHOLARY O. Masitinib for the treatmentof systemic and cutaneous mastocytosis withhandicap: a phase 2a study. Am J Hematol 2010;85: 921-925.5) DROOGENDIJK HJ, KLUIN-NELEMANS HJ, VAN DOORMAALJJ, ORANJE AP, VAN DE LOOSDRECHT AA, VAN DAELE PL.Imatinib mesylate in the treatment of systemicmastocytosis: a phase II trial. Cancer 2006; 107:345-351.6) AKIN C, FUMO G, YAVUZ AS, LIPSKY PE, NECKERS L,METCALFE DD. A novel form of mastocytosis asso-ciated with a transmembrane c-kit mutation andresponse to imatinib. Blood 2004; 103: 3222-3225.7) HOFFMANN KM, MOSER A, LOHSE P, WINKLER A, BINDERB, SOVINZ P, LACKNER H, SCHWINGER W, BENESCH M,URBAN C. Successful treatment of progressive cu-taneous mastocytosis with imatinib in a 2-year-oldboy carrying a somatic KIT mutation. Blood 2008;112: 1655-1657.8) USTUN C, DEREMER DL, AKIN C. Tyrosine kinase in-hibitors in the treatment of systemic mastocytosis.Leuk Res 2011; 35: 1143-1152.9) Comert M, Baran Y, Saydam G. Changes in mole-cular biology of chronic myeloid leukemia in tyro-sine kinase inhibitor era. Am J Blood Res 2013; 3:191-200.10) LE CESNE A, BLAY JY, REICHARDT P, JOENSUU H. Opti-mizing tyrosine kinase inhibitor therapy in gas-trointestinal stromal tumors: exploring the benefitsof continuous kinase suppression. Oncologist2013; 18: 1192-1199.11) VEGA-RUIZ A, CORTES JE, SEVER M, MANSHOURI T,QUINTAS-CARDAMA A, LUTHRA R, KANTARJIAN HM, VER-STOVSEK S. Phase II study of imatinib mesylate astherapy for patients with systemic mastocytosis.Leuk Res 2009; 33: 1481-1484.12) MIHALIK N, HIDVEGI B, HARSING J, VARKONYI J, CSOMORJ, KOVALSZKY I, MARSCHALKO M, KARPATI S. Clinical ob-servations in cutan mastocytosis. Orv Hetil 2013;154: 1469-1475.13) VALENT P. Mastocytosis: a paradigmatic exampleof a rare disease with complex biology andpathology. Am J Cancer Res 2013; 3: 159-172.14) MORREN MA, HOPPE A, RENARD M, DEBIEC RYCHTER M,UYTTEBROECK A, DUBREUIL P, MARTIN L. Imatinib me-sylate in the treatment of diffuse cutaneous mas-tocytosis. J Pediatr 2013; 162: 205-207.15) VANNORSDALL EJ, COLLINS JA, CHEN QC, SARAI G, BAERMR. Symptomatic response to imatinib mesylatein cutaneous mastocytosis associated with chron-ic myelomonocytic leukemia. Curr Oncol 2013; 20:e349-353.1609Imatinib mesylate and skin-related systemic mastocytosis

Therapeutic challenge during the long-term follow-up of a patient with indolent systemic mastocytosis with extensive cutaneous involvement

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Therapeutic challenge during the long-term follow-up of a patient with indolent systemic mastocytosis with extensive cutaneous involvement

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