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Clinical potential of midostaurin in advanced systemic mastocytosis

Authors Chandesris MO, Damaj G, Lortholary O, Hermine O

Received 4 October 2016

Accepted for publication 17 January 2017

Published 3 May 2017 Volume 2017:7 Pages 25—35

DOI https://doi.org/10.2147/BLCTT.S87186

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 3

Editor who approved publication: Professor David Dingli


Marie Olivia Chandesris,1–3 Gandhi Damaj,1,4 Olivier Lortholary,1,3,5 Olivier Hermine1–3,6

On behalf of the CEREMAST study group

1French Reference Center for Mastocytosis (CEREMAST), 2Department of Hematology, Necker Children’s Hospital, APHP, 3Sorbonne Paris Cité, Paris Descartes University, Imagine Institute, Paris, 4Department of Hematology, University Hospital, University of Basse Normandy, School of Medicine, Caen, 5Infectious Diseases Department, Necker Children’s Hospital, APHP, 6INSERM U1163 and CNRS ERL 8654, Imagine Institute, Paris, France

Abstract: Advanced (Ad) systemic mastocytoses (SM) include aggressive SM (ASM) and mast cell leukemia (MCL) with or without an associated clonal hematological non-mast cell lineage disease (AHNMD). They are rare (<15%) but are associated with a poor prognosis due to rapid organ dysfunction. To date, responses to high-dose chemotherapy, cladribine, and imatinib were revealed to be suboptimal with a median survival time of 24 months. Midostaurin is a potent multikinase inhibitor including the most frequent KIT D816V mutation (>80%). We herein present a review of the most recent data of the use of midostaurin in AdSM. First, a multicenter Phase II study (CPKC412D2213) revealed an unprecedented overall response rate (ORR) of 69% regardless of KIT mutational status, with 38% of major response (MR) among 26 AdSM patients treated with midostaurin alone 200 mg daily. Second, a sponsor-initiated, multicenter, single-arm open Phase II study (CPKC412D2201) confirmed a high and durable ORR of 60% including 45% of MR among 89 AdSM patients. Finally, a French compassionate use program managed by the French Reference Centre for Mastocytosis allowed the treatment of almost a hundred AdSM patients to date in France since the CPKC412D2201 study closure. The outcome of the first 28 treated patients under cover of this on-going procedure revealed an ORR of 71% including 57% of MR. Most importantly, survival analysis revealed in comparison to a historical control cohort of AdSM patients who did not receive midostaurin a twofold lower risk of death (p=0.02) in midostaurin-treated patients. Side effects revealed were acceptable and manageable (mostly digestive). Midostaurin appears to be an effective and safe treatment of AdSM. However, its effect on the course of the AHNMD is less clear. For the future, combined therapy (hypomethylating agents, cladribine, mammalian target of rapamycin inhibitors, chemotherapy, and allogeneic bone marrow transplantation) may further improve long-term survival, particularly that of MCL and AdSM patients with AHNMD.

Keywords: aggressive systemic mastocytosis, mast cell leukemia, tyrosine kinase inhibitor, midostaurin

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