Response to Dasatinib in Patients with Aggressive Systemic Mastocytosis with D816V Kit Mutation.
Authors: Rondoni Michela , Paolini Stefania , Colarossi Sabrina , Piccaluga Pier Paolo , Papayannidis Cristina , Palandri Francesca , Laterza Claudio , De Rosa Francesco , Pregno Patrizia , Gatto Simona , Ottaviani Emanuela , Saglio Giuseppe , Cilloni Daniela , Pane Fabrizio , Triggiani Massimo , Soverini Simona , Zaccaria Alfonso , Baccarani Michele , Martinelli Giovanni 
Published: April 2020

Abstract
Human systemic mastocytosis (SM) is a rare disease caused by an abnormal mast cells accumulation in various tissues. It usually occurs as a sporadic disease that is often persistent or progressive in adults. Clinical course is variable. The most aggressive forms have a rapid course and required treatments to reduce the neoplastic burden and to slacken the progression. Unfortunately no therapy have been demonstrated efficacy, mostly in the treatment of aggressive systemic mastocytosis (ASM). SM has been associated with constitutive activating c-kit somatic mutations, the most frequent of whom is the D816V mutation. Kinase inhibitors blocking constitutive c-kit activation, such as imatinib, have been used in SM, but they had no effect on D816V mutant kit. Here, we report on six patients with Systemic mastocytosis and with detectable D816V mutation treated with dasatinib 70 mg BID as in leukemia treatment. According to the WHO Classification of Systemic mastocytosis, we describe clinical characteristics of six cases of ASM with different organ damage treated with dasatinib for various period, and we made evaluation of response according to Valent criteria (Leuk Research, 2003). All patients excepting Patient 3 reached the dose of 140 mg daily. Patient 4 are on treatment after 10 months, without any signs or symptoms of disease progression. Patient 2 is still on treatment with low dose of dasatinib (20 mg daily) but he shows cytopenia and worsening clinical condition, he does not tolerate high dose of dasatinib for gastrointestinal toxicity and astenia. Patient 1 stopped therapy after 10 months of therapy and she relapsed with ascite and died after 1 month for progressive disease. Patient 3 and Patient 5 interrupted dasatinib for worsening clinical condition after 40 days and three months respectively. Patient 6 stopped dasatinib after five months for progression to acute leukemia. After dasatinib suspension, Patient 3 died for complication of leg fracture and Patient 5 died for progression of disease. We observed major response in three patients for the prompt resolution of sign of organ damage recorded during dasatinib treatment, and we also obteined a measurable decrease of the burden of neoplastic MCs by means of tryptase level monitoring in all but one patients. Toxicity of 140 mg daily in patients with advanced ASM is notable. All patients had to suspended therapy due to extra-haematological toxicity. The most commonly toxicity involved gastroenteric tract, with diarrohea and abdominal pain, hypotension and pleural effusion. Symptoms resolved or return to mild grade with dose reduction, but in frail patients therapy is not well tolerate. After interruption of therapy progression was recorded.