OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Midostaurin	120685-11-2	C35-H30-N4-O

ANNOTATED BIBLIOGRAPHY

References updated: 10 April 2019

Abbreviations: FLT3, FMS-like tyrosine kinase-3; AML, acute myelogenous leukemia.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of kinase inhibitors).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013 before the availability of midostaurin).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Danan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• https://www​.accessdata​.fda.gov/scripts/cder/daf/

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy; mentions that ALT elevations arose in similar proportions of patients receiving midostaurin as placebo during induction therapy of AML [69% vs 68%] but elevations above 5 times ULN were more frequent with midostaurin [20% vs 16%] although ALT elevations with hyperbilirubinemia were less frequent [3% vs 5%]).
• Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med 2016; 374: 2530-41. [PubMed: 27355533]

  (Among 116 patients with advanced systemic mastocytosis treated with midostaurin in an open-label study, the objective response rate was 56% and adverse events were frequent including nausea [79%], diarrhea [54%] and cytopenias; no mention of ALT elevations or hepatotoxicity and no discontinuations for liver injury).
• Midostaurin (Rydapt) for AML and advanced systemic mastocytosis. Med Lett Drugs Ther 2017; 59 (1527): e140. [PubMed: 28787746]

  (Concise review of the trials showing efficacy and safety of midostaurin in systemic mastocytosis shortly after its approval for this indication in the US mentions adverse events of febrile neutropenia, nausea, vomiting and mucositis, but not ALT elevations or hepatotoxicity).
• Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, Claxton D, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol 2017; 18: 1061-75. [PMC free article: PMC5572576] [PubMed: 28645776]

  (Among 252 adults with refractory or relapsed AML treated with different doses of gilteritinib, responses occurred in 40% and complete remission in 8%; adverse events were frequent including febrile neutropenia, sepsis, and pneumonia, while ALT elevations arose in 18% of recipients which were above 5 times ULN in 5%, but there were no instances of clinically apparent liver injury).
• Fathi AT, Chen YB. The role of FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia. Eur J Haematol 2017; 98: 330-6. [PubMed: 28000291]

  (Review of the role of mutated FLT3 in AML and efficacy of drugs with potent, specific activity against FLT3 in AML, including sorafenib, quizartinib, crenolanib and gilteritinib, as well as the nonspecific tyrosine kinase inhibitors with some activity against FLT3 such as midostaurin, sunitinib and sorafenib).
• Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377: 454-64. [PMC free article: PMC5754190] [PubMed: 28644114]

  (Among 717 patients with AML and FLT3 mutations treated with standard chemotherapy with or without midostaurin, median overall survival was longer in midostaurin treated patients [75 vs 32 months], while adverse event rates were similar in the two groups including febrile neutropenia [82% vs 82%], ALT elevations [13% vs 9%] and hyperbilirubinemia [7% vs 8%]).
• Kasamon YL, Ko CW, Subramaniam S, Ma L, Yang Y, Nie L, Shord S, et al. FDA approval summary: midostaurin for the treatment of advanced systemic mastocytosis. Oncologist 2018; 23: 1511-9. [PMC free article: PMC6292539] [PubMed: 30115735]

  (Review of the open-label clinical trial that was the basis for approval of midostaurin for advanced systemic mastocytosis during which 56% of patients had dose interruptions and 21% discontinuation for adverse events; no mention of ALT elevations or hepatotoxicity).
• Click ZR, Seddon AN, Bae YR, Fisher JD, Ogunniyi A. New Food and Drug Administration-approved and emerging novel treatment 0ptions for acute myeloid leukemia. Pharmacotherapy 2018; 38: 1143-54. [PubMed: 30220082]

  (Review of recently developed targeted antineoplastic agents active in treating AML including midostaurin, the first FLT3-targeted therapy for AML; no mention of ALT elevations or hepatotoxicity).
• Kim M, Williams S. Midostaurin in combination with standard chemotherapy for treatment of newly diagnosed FMS-like tyrosine kinase 3 (FLT3) mutation-positive acute myeloid leukemia. Ann Pharmacother 2018; 52: 364-9. [PubMed: 29231051]

  (Review of the efficacy and safety of midostaurin combined with standard induction chemotherapy for AML; mentions frequency of adverse events and severe adverse events of febrile neutropenia, pulmonary fibrosis, drug-drug interactions and embryo-fetal toxicity, but not hepatotoxicity or ALT elevations).
• DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, Westervelt P, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia 2018; 32: 470-8. [PubMed: 28744009]

  (Among 26 patients with advanced systemic mastocytosis treated with midostaurin for up to 10 years, no new or unexpected toxicity arose; no mention of ALT elevations or hepatotoxicity).