title: A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Seidman Cancer Center, University Hospitals, Case Medical Center, Cleveland, OH. Electronic address: brenda.cooper@uhhospitals.org.
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Cooper
authors.affiliation: Department of Medicine, Seidman Cancer Center, University Hospitals, Case Medical Center, Cleveland, OH.
authors.forename: Tamila L
authors.initials: TL
authors.lastname: Kindwall-Keller
authors.affiliation: Hematopoietic Malignancy and Blood and Marrow Transplantation Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Craig
authors.affiliation: Department of Medicine, Seidman Cancer Center, University Hospitals, Case Medical Center, Cleveland, OH.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Creger
authors.affiliation: Hematopoietic Malignancy and Blood and Marrow Transplantation Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hamadani
authors.affiliation: Hematopoietic Malignancy and Blood and Marrow Transplantation Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV.
authors.forename: William W
authors.initials: WW
authors.lastname: Tse
authors.affiliation: Department of Medicine, Seidman Cancer Center, University Hospitals, Case Medical Center, Cleveland, OH.
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin; D001374:Azacitidine
keywords: Azacitidine; Elderly AML; FLT3 inhibitor; Midostaurin