Abstract 2082: PKC412 (Midostaurin) is safe and highly effective in Systemic Mastocytosis patients: the Bologna experience.
Authors: Papayannidis Cristina , Abbenante Mariachiara , Parisi Sarah , Paolini Stefania , Iacobucci Ilaria , Ottaviani Emanuela , Ferrari Anna , Guadagnuolo Viviana , Sartor Chiara , Soverini Simona , De Benedittis Caterina , Baldazzi Carmen , Baccarani Michele , Cavo Michele , Martinelli Giovanni 
Published: August 2014

Abstract
Introduction. Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs, mostly bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent (ISM), an aggressive (ASM) and a leukemic subvariant (MCL). The c-kit mutation D816V is detectable in most adult patients with SM. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied.
Methods. From 2008, 18 patients (male/female=7/11) affected by SM, have been referred to our Institution. The median age was 49 years. All the patients underwent a bone marrow biopsy, with flow citometry and molecular biology analysis, in order to identify the presence of D816V mutation of c-Kit gene. Serum tryptase level was tested, resulting elevated in all cases. Systemic symptoms were characterized by nausea, diarrhoea, asthenia, weight loss, pruritus and serotine fever, identifying an aggressive form of the disease in 7/18 patients, due to skeletal involvement, ascitis, liver function impairment, and bone marrow disfunction. Therefore, since a first line therapy (mainly represented by IFN) and supportive care with histamine receptor antagonists werne't followed by a significant benefit, a personalized use of PKC412 was asked and obtained for 5 out of 7 ASM patients.
Results. From March 2011 5 out of 7 patients with ASM have received a prolonged period of treatment with PKC412, which was administered orally, at the dosage of 100 mg twice daily, without rest periods. The drug was well tolerated. No serious adverse events were observed. All the patients obtained a quick and prolonged improvement of clinical symptoms, in terms of weight gain, bowel function and skeletal pain. At the bone marrow evaluation, the persistence of the D816V c-kit mutation was observed, despite a significant decrease of mast cell marrow involvement. In one case we observed, after a first good response, a disease progression, characterized by the sudden reoccurrence of the same symptoms detected at diagnosis, confirmed by a relevant expansion of a pathologic mast cell population in the bone marrow. After a rest period, the drug was readministered, and a second remission was obtained.
Conclusions. PKC412 is safe and effective in patients with SM, being able to significantly improve not only the gastrointestinal and systemic symptoms, but also the haematological profile. The persistence of the D816V c-kit mutation, despite a morphologic remission, suggests that many other oncogenic factors may be responsible for the pathogenesis of the disease.
Acknowledgments. Work supported by European LeukemiaNet, AIRC, AIL, PRIN, University of Bologna and BolognAIL.
Citation Format: Cristina Papayannidis, Mariachiara Abbenante, Sarah Parisi, Stefania Paolini, Ilaria Iacobucci, Emanuela Ottaviani, Anna Ferrari, Viviana Guadagnuolo, Chiara Sartor, Simona Soverini, Caterina De Benedittis, Carmen Baldazzi, Michele Baccarani, Michele Cavo, Giovanni Martinelli. PKC412 (Midostaurin) is safe and highly effective in Systemic Mastocytosis patients: the Bologna experience. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2082. doi:10.1158/1538-7445.AM2013-2082