Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Therapeutic management and outcome of patients with advanced systemic mastocytosis treated with midostaurin: A comprehensive real-life study in the French national healthcare database.

Advanced Systemic Mastocytosis (Adv-SM) is rare and has a poor prognosis. Midostaurin (Rydapt® ) is one of the few treatments for Adv-SM in Europe. The study aims were to describe the characteristics of patients treated with midostaurin, their treatment modalities, outcomes, and serious events requiring hospitalization. This retrospective observational study was conducted using the French National Healthcare Database (SNDS) and included adult Adv-SM patients treated with midostaurin between 01-01-2012 and 09-30-2018. Kaplan-Meier method was used to assess survival and treatment duration. Eighty-one patients were included: 37 with Aggressive Systemic Mastocytosis (SM) (46%), 31 with SM with an Associated Hematological Neoplasm (38%), and 4 with Mast Cell Leukemia (5%). The SM subtype was undetermined in 9 patients (11%). The median age was 67 years; 64% of patients were male. Over the mean follow-up of 11.4 months, median midostaurin treatment duration was 8.4 months and 28 patients (35%) were still under treatment at the end of the study. One-year and 5-year overall survival rates estimated since the time of diagnosis were 83% and 56%, respectively. Twelve serious events (among those frequently reported during clinical trials and compassionate use) requiring hospitalization were identified; a causal association with Adv-SM treatment could neither be excluded nor established. In this first real-life study on patients treated with midostaurin for Adv-SM, the patients' characteristics, their management, treatment discontinuation, and survival were in line with previous results (compassionate use and clinical trials).