Universität zu Köln

Gotlib, Jason, Kluin-Nelemans, Hanneke C., George, Tracy I., Akin, Cem ORCID: 0000-0001-6301-4520, Sotlar, Karl, Hermine, Olivier ORCID: 0000-0003-2574-3874, Awan, Farrukh T., Hexner, Elizabeth ORCID: 0000-0002-1125-4060, Mauro, Michael J., Sternberg, David W., Villeneuve, Matthieu, Labed, Alice Huntsman, Stanek, Eric J., Hartmann, Karin ORCID: 0000-0002-4595-8226, Horny, Hans-Peter, Valent, Peter ORCID: 0000-0003-0456-5095 and Reiter, Andreas (2016). Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N. Engl. J. Med., 374 (26). S. 2530 - 2542. WALTHAM: MASSACHUSETTS MEDICAL SOC. ISSN 1533-4406

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Abstract

BACKGROUND Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response. RESULTS The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias. CONCLUSIONS In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gotlib, Jason UNSPECIFIED UNSPECIFIED UNSPECIFIED Kluin-Nelemans, Hanneke C. UNSPECIFIED UNSPECIFIED UNSPECIFIED George, Tracy I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Akin, Cem UNSPECIFIED orcid.org/0000-0001-6301-4520 UNSPECIFIED Sotlar, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermine, Olivier UNSPECIFIED orcid.org/0000-0003-2574-3874 UNSPECIFIED Awan, Farrukh T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hexner, Elizabeth UNSPECIFIED orcid.org/0000-0002-1125-4060 UNSPECIFIED Mauro, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sternberg, David W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Villeneuve, Matthieu UNSPECIFIED UNSPECIFIED UNSPECIFIED Labed, Alice Huntsman UNSPECIFIED UNSPECIFIED UNSPECIFIED Stanek, Eric J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Karin UNSPECIFIED orcid.org/0000-0002-4595-8226 UNSPECIFIED Horny, Hans-Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Valent, Peter UNSPECIFIED orcid.org/0000-0003-0456-5095 UNSPECIFIED Reiter, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271943
DOI:	10.1056/NEJMoa1513098
Journal or Publication Title:	N. Engl. J. Med.
Volume:	374
Number:	26
Page Range:	S. 2530 - 2542
Date:	2016
Publisher:	MASSACHUSETTS MEDICAL SOC
Place of Publication:	WALTHAM
ISSN:	1533-4406
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTERNATIONAL WORKING GROUP; MAST-CELL DISORDERS; RESPONSE CRITERIA; KINASE INHIBITOR; INTERFERON-ALPHA; THERAPY; PKC412; ADULTS; CLASSIFICATION; ACTIVATION Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27194