Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature

// Iván Alvarez-Twose 1, 5 , Almudena Matito 1, 5 , José Mário Morgado 1, 5 , Laura Sánchez-Muñoz 1, 5 , María Jara-Acevedo 2, 5 , Andrés García-Montero 2, 5 , Andrea Mayado 2, 5 , Carolina Caldas 2, 5 , Cristina Teodósio 3 , Javier Ignacio Muñoz-González 2, 5 , Manuela Mollejo 4, 5 , Luis Escribano 2, 5 and Alberto Orfao 2, 5 1 Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Toledo, Spain 2 Centro de Investigación del Cáncer/IBMCC (USAL/CSIC) and IBSAL, Departamento de Medicina and Servicio General de Citometría, University of Salamanca, Salamanca, Spain 3 Department of Immunology, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands 4 Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain 5 Spanish Network on Mastocytosis (REMA), Toledo and Salamanca, Spain Correspondence to: Iván Alvarez-Twose, email: ivana@sescam.jccm.es Keywords: mast cell, mastocytosis, well-differentiated systemic mastocytosis, imatinib, KIT Received: March 01, 2016 Accepted: May 29, 2016 Published: July 19, 2016 ABSTRACT Resistance to imatinib has been recurrently reported in systemic mastocytosis (SM) carrying exon 17 KIT mutations. We evaluated the efficacy and safety of imatinib therapy in 10 adult SM patients lacking exon 17 KIT mutations, 9 of which fulfilled criteria for well-differentiated SM (WDSM). The World Health Organization 2008 disease categories among WDSM patients were mast cell (MC) leukemia ( n = 3), indolent SM ( n = 3) and cutaneous mastocytosis ( n = 3); the remainder case had SM associated with a clonal haematological non-MC disease. Patients were given imatinib for 12 months –400 or 300 mg daily depending on the presence vs. absence of > 30% bone marrow (BM) MCs and/or signs of advanced disease–. Absence of exon 17 KIT mutations was confirmed in highly-purified BM MCs by peptide nucleic acid-mediated PCR, while mutations involving other exons were investigated by direct sequencing of purified BM MC DNA. Complete response (CR) was defined as resolution of BM MC infiltration, skin lesions, organomegalies and MC-mediator release-associated symptoms, plus normalization of serum tryptase. Criteria for partial response (PR) included ≥ 50% reduction in BM MC infiltration and improvement of skin lesions and/or organomegalies. Treatment was well-tolerated with an overall response rate of 50%, including early and sustained CR in four patients, three of whom had extracellular mutations of KIT , and PR in one case. This later patient and all non-responders ( n = 5) showed wild-type KIT . These results together with previous data from the literature support the relevance of the KIT mutational status in selecting SM patients who are candidates for imatinib therapy.