Long-Awaited Advance in Drug Development! Midostaurin Shows Efficacy in Advanced Systemic Mastocytosis (Implications for Our Disease Community)

Feb 02, 2017

Advanced forms of systemic mastocytosis (SM) are a set of hematologic neoplasms that includes aggressive systemic mastocytosis (ASM), SM with an associated hematologic neoplasm (SM-AHN), formerly called SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD),1 and mast cell leukemia (MCL), and have significantly poorer prognoses compared to indolent SM. Mutations in the tyrosine kinase, KIT, a growth factor receptor protein found on the surface of mast cells, are considered drivers of the disease process in SM. The D816V KIT mutation, in particular, has been shown to be present in over 80% of patients with SM.2 Few drugs for the treatment of advanced SM are available, and those currently used in the clinic have shown limited rates and persistence of response. The only chemotherapy approved for treating ASM, imatinib, is not effective in SM patients who have the KIT D816V mutation, leaving most SM patients without an effective, approved treatment. Investigators have been exploring additional therapies and methods to help such patients (see HERE for a recent update).

The results from an international, multicenter clinical trial to treat advanced SM using midostaurin (PKC412), a kinase inhibitor drug developed by Novartis Pharmaceuticals, were published in a 2016 article by Jason Gotlib, MD, MS, and colleagues in the New England Journal of Medicine.3 Midostaurin was shown to have activity in advanced SM, including in patients with the KIT D816V mutation. The trial involved administration of twice daily, 100 mg oral doses of midostaurin in 4-week continuous cycles and evaluated 89 patients in the primary efficacy population (16 with ASM, 57 with SM-AHN and 16 with MCL).

In 60% of these 89 study participants, either partial or complete resolution of organ damage was documented. Reductions in bone marrow mast cell burden, serum levels of the mediator, tryptase, and spleen size were also seen. Efficacy of midostaurin was independent of KIT mutation status, such that the drug displayed an effect on patients with and without the KIT D816V mutation. Responses were seen in all forms of advanced SM and in those who had previously been given other therapies.

Patients reported improvement in nearly all of the 32 symptoms evaluated and in their quality of life. The authors suggest that these improvements may be due to the ability of midostaurin to not only inhibit mast cell growth, but also mediator release,4 as a number of mast cell mediators have been shown to cause clinically significant symptoms.

Responses lasted for a median time of just over 2 years in the primary efficacy population, indicating durability of the response. Although the median duration of response was much lower for those with SM-AHN (12.7 months), this measure had not even been reached for those with ASM or MCL at the time of data cut-off.

Overall median survival was 28.7 months for the 89 patients in the primary efficacy population, with 14.1 months of progression-free survival. In patients who responded to midostaurin, overall median survival was 44.4 months, significantly longer than the 15.4 months seen for those who did not respond to the drug.

MCL, the most advanced form of SM, generally has an average survival time of less than 6 months.5 The median survival time for all the MCL patients in the trial was 9.4 months, showing clinical activity. However, half of the MCL patients in the midostaurin trial responded to the drug, and for those patients, the median overall survival had not yet been reached, compared to 7.6 months for those with MCL who did not respond to the drug (see the article’s supplemental data for details). The authors are careful to note that the heterogeneity of MCL has made historical survival comparisons of this population difficult.

The most common side effects of midostaurin were related to low-grade gastrointestinal problems, including nausea, vomiting and diarrhea. However, these effects appeared to be reduced in some cases by the use of anti-nausea treatments and taking midostaurin with meals. Grade 3 or 4 myelosuppression was seen, more often in patients who had cytopenias at the start of the study.
The authors note that additional studies are worth conducting for midostaurin in combination with other drugs for advanced SM or in patients with indolent SM who have symptoms that are not resolved by current therapies. There may also be a potential role for midostaurin as a bridge to hematopoietic stem cell transplantation in suitable candidates with an available donor.
In November 2016, Novartis Pharmaceuticals announced that the new drug application for midostaurin use in advanced SM variants had been given Priority Review status by the US Food and Drug Administration (FDA). Novartis also noted that the European Medicines Agency (EMA) had already accepted the marketing authorization application for use of midostaurin in advanced SM.

Please see the FULL TEXT of the New England Journal of Medicine midostaurin article, which is freely available online, for more details on these clinical trial results. Patients should consult their physicians, or mast cell disorder specialists, when necessary, regarding considerations of any treatment or therapy changes.

The Mastocytosis Society, Inc. greatly appreciates the dedicated physicians, researchers, drug company representatives and government agencies who have been involved in mastocytosis research and drug development over the years and, in particular, the patients, along with their support systems, who have participated or will participate in the future, in the many trials and exploratory studies in the search to cure mastocytosis and other mast cell disorders.

Article by:

Susan Jennings, PhD

Research Committee Chair

The Mastocytosis Society, Inc.

January 2017 

The Mastocytosis Society, Inc. thanks Jason Gotlib, MD, MS, for his review of the accuracy of this article.


  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405. http://www.ncbi.nlm.nih.gov/pubmed/27069254
  2. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015 Jun;29(6):1223-32. http://www.ncbi.nlm.nih.gov/pubmed/25650093
  3. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. http://www.ncbi.nlm.nih.gov/pubmed/27355533
  4. Krauth MT, Mirkina I, Herrmann H, Baumgartner C, Kneidinger M, Valent P. Midostaurin (PKC412) inhibits immunoglobulin E-dependent activation and mediator release in human blood basophils and mast cells. Clin Exp Allergy. 2009 Nov;39(11):1711-20. http://www.ncbi.nlm.nih.gov/pubmed/19860818
  5. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013 Feb 21;121(8):1285-95. http://www.ncbi.nlm.nih.gov/pubmed/23243287