Systemic Mastocytosis (SM)

Midostaurin (CGP41251, PKC412) is a prototype kinase inhibitor. It was first created as a protein kinase C inhibitor and then repurposed as an angiogenesis inhibitor because of its ability to inhibit vascular endothelial growth factor receptor.1 Rydapt® (midostaurin) is a multitargeted inhibitor of several kinases, including FMS-like tyrosine kinase 3 mutation-positive (FLT3+) and KIT, that has been approved for the treatment of acute myeloid leukaemia (AML) and 3 types of advanced systemic mastocytosis (SM).2

Rydapt was developed by Novartis. The US Food and Drug Administration (FDA) granted priority review status to Rydapt for FLT3+ AML and for 3 types of SM, including aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). The drug was also designated as a breakthrough therapy and received an orphan drug designation. The FDA granted marketing approval for Rydapt to Novartis in April 2017.2

Mechanism of Action

Midostaurin is a small molecule that blocks many tyrosine kinase receptors. Midostaurin or its major human active metabolites, CGP62221 and CGP52421, inhibit the activity of FLT3 wild type, FLT3 mutant kinases (internal tandem duplication [ITD] and tyrosine kinase domain [TKD]), KIT (wild type and D816V mutant), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and members of the serine/threonine kinase protein kinase C (PKC) family in vitro in biochemical or cellular assays. Midostaurin has shown the ability to inhibit FLT3 receptor signaling and cell proliferation. It induced apoptosis in leukemic cells that expressed ITD and TKD mutant FLT3 receptors or overexpressed wild-type FLT3 and PDGFR. Midostaurin also inhibited KIT signaling, cell proliferation, and histamine secretion and induced apoptosis in mast cells. The drug is available in capsules containing a dose of 25 mg.2

Dosage and Administration in Systemic Mastocytosis

​​Rydapt is available as a capsule for oral administration. In ASM, SM-AHN, and MCL, the recommended dosage is 100 mg orally twice daily with food. Treatment should be continued until disease progression or unacceptable toxicity. Continued monitoring of toxicity is recommended every other week for the next eight weeks and monthly thereafter while on treatment.3 

Get full prescribing information about Rydapt (midostaurin) on MPR

Clinical Trial Results

Rydapt received FDA approval for the treatment of advanced SM, including ASM, SM-AHN, and MCL, on the basis of 2 single-arm, open-label, multicenter clinical trials. The efficacy of Rydapt was proved in clinical studies by confirmed complete remission (CR) plus incomplete remission (ICR) after 6 cycles of treatment according to the modified Valent criteria. A total response rate of 21% was also found in the investigations. In a post hoc analysis, the efficacy of Rydapt was evaluated in 2013 with the consensus criteria established by the International Working Group-Myeloproliferative Neoplasms Research and Treatment and the European Competence Network on Mastocytosis (IWG-MRT-ECNM).2 

Warnings, Precautions, and Adverse Reactions

When given to a pregnant woman, Rydapt may harm the fetus. Evidence of pulmonary toxicity and fatality has been found. Therefore, patients undergoing treatment should be monitored for any signs and symptoms of pneumonitis and interstitial lung disease.The drug should be discontinued in case any such symptoms develop.4

In 2 single-arm, open-label, multicenter studies, the safety of Rydapt (100 mg twice daily) as a single treatment in patients with ASM, SM-AHN, or MCL was assessed in 142 individuals. The median duration of Rydapt exposure was 11.4 months. The most common adverse drug reactions noted were nausea (82%), vomiting (68%), diarrhea (51%), peripheral edema (35%), and fatigue (31%). The most common grade 3/4 adverse drug reactions were fatigue (8.5%), sepsis (7.7%), pneumonia (7%), febrile neutropenia (7%), and diarrhea (6.3%). The most common nonhematologic laboratory abnormalities were hyperglycemia (93.7%); increased total bilirubin (40.1%); and increased lipase (39.4%), aspartate aminotransferase (AST) (33.8%), and alanine aminotransferase (ALT) (33.1%). The most common hematologic laboratory abnormalities were decreased absolute lymphocyte count (73.2%) and absolute neutrophil count (ANC) (58.5%). In general, the most common grade 3/4 laboratory abnormalities were decreased absolute lymphocyte count (45.8%), decreased absolute neutrophil count (26.8%), hyperglycemia (19%), and increased lipase level (17.6%).5 

Drug Interactions

Exposure to midostaurin and its active metabolites may be increased by strong CYP3A4 inhibitors. Alternative treatments that are not potent inhibitors of  CYP3A4 or monitoring for an elevated risk for adverse effects are suggested. CYP3A inhibitors like Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juice, idelalisib, indinavir and ritonavir should be avoided.4

Concomitant use of midostaurin with strong CYP3A4 inducers should be avoided because they reduce exposure to midostaurin and its active metabolites. CYP3A4 inducers like carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John’s wort should be avoided.4


  1. Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2018;2(4):444-453. doi:10.1182/bloodadvances.2017011080
  2. Rydapt (midostaurin) for the treatment of acute myeloid leukaemia and systemic mastocytosis. Clinical Trials Arena. Published May 2, 2017. Accessed April 13, 2022.  
  3. Rydapt (midostaurin). CenterWatch. Accessed April 13, 2022.
  4. RYDAPT® (midostaurin). Novartis. Revised April 2017. Accessed April 13, 2022.
  5. Rydapt 25 mg soft capsules. European Medicines Agency. Accessed April 13, 2022.

Reviewed by Debjyoti Talukdar, MD, on 4/27/2022.