Chronic myeloproliferative neoplasms

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial

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Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a 50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

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We thank the patients and their families for their dedication to the study. We express gratitude to the Charles and Ann Johnson Foundation (to JG) and the European Competency Network in Mastocytosis (ECNM) for their support of mastocytosis research.

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Correspondence to J Gotlib.

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Competing interests

Dr DeAngelo/Dana Farber Cancer Institute has received funding to conduct the current trial; he has also received funding to conduct the trial of BLU-285 (Blueprint Medicines) in advanced SM. Dr George served on the Study Steering Committee for the Novartis-sponsored global trial and she has served on an advisory board and received honoraria from Novartis. She has also received honoraria from Blueprint Medicine and research funding from Allakos, Inc. The University of New Mexico has received funding for Dr George’s participation in the Novartis-sponsored global trial of midostaurin in advanced SM, the Seattle Genetics-sponsored trial of brentuximab vedotin in advanced SM and the Blueprint Medicine-sponsored trial of BLU-285 in advanced SM. Dr Graubert/Washington University received funding to conduct the current trial. Dr Gotlib served as Chairman of the Study Steering Committee for the Novartis-sponsored global trial of midostaurin in advanced SM, received funding to conduct this trial and the global trial and he has served on an advisory board and received honoraria from Novartis. Stanford has also received funding for Dr Gotlib’s participation in the following trials in advanced SM: BLU-285 (Blueprint Medicines), brentuximab vedotin (Seattle Genetics) and ibrutinib (Pharmacyclics).

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DeAngelo, D., George, T., Linder, A. et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia 32, 470–478 (2018) doi:10.1038/leu.2017.234

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