A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients. Clin Lymphoma Myeloma Leuk 2015 Jul;15(7):428-432.e2
Date
03/18/2015Pubmed ID
25776192Pubmed Central ID
PMC4484305DOI
10.1016/j.clml.2015.02.017Scopus ID
2-s2.0-84937521005 (requires institutional sign-in at Scopus site) 68 CitationsAbstract
BACKGROUND: Midostaurin is a novel, orally available Fms-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor that induces cell cycle arrest and apoptosis of leukemic cells expressing mutant and wild type FLT3 receptors, and has shown potential synergism with cytotoxic chemotherapy.
PATIENTS AND METHODS: We conducted a phase I study of azacitidine (intravenous 75 mg/m(2) daily for 7 days) with escalating doses of oral midostaurin (25 mg twice per day [b.i.d.], 50 mg b.i.d., and 75 mg b.i.d.) on days 8 to 21 of a 28-day cycle in untreated acute myeloid leukemia (AML) in older patients and/or relapsed AML. Patients were eligible regardless of FLT3 mutation status. Trough blood samples for pharmacokinetics were obtained on days 8, 15, and 21 before midostaurin dosing.
RESULTS: Seventeen patients with a median age of 73 (range, 57-83) years were enrolled; 5 patients had previous conventional treatment and none of the patients had FLT3 mutations. Dose-limiting toxicities were not observed. Hospitalizations, primarily for infections, occurred in one-third of treatment cycles. Fourteen patients were evaluable for response: 3 attained complete remission and 2 had hematologic improvement. Median (range) survival from enrollment was 6 (1 to ≥ 19) months. Three patients died within 60 days of enrollment (2 progressive disease, 1 non-dose-limiting toxicity, treatment-related). Pharmacokinetic data at 75 mg orally b.i.d. showed increased trough levels of midostaurin during cycle 2 compared with cycle 1 and persistent and increasing levels of its active metabolite, CGP52421.
CONCLUSION: The combination of sequential azacitidine and midostaurin is safe and tolerable with response rates comparable with azacitidine alone and should be studied further in FLT3 mutation-positive AML.
Author List
Cooper BW, Kindwall-Keller TL, Craig MD, Creger RJ, Hamadani M, Tse WW, Lazarus HMAuthor
Mehdi H. Hamadani MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAged, 80 and over
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Azacitidine
Female
Humans
Leukemia, Myeloid, Acute
Male
Middle Aged
Mutation
Neoplasm Recurrence, Local
Staurosporine
Treatment Outcome
fms-Like Tyrosine Kinase 3
