title: Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome.
abstract: We investigated the combination of midostaurin and azacitidine (AZA) in patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). Patients received AZA 75 mg m(-2) on days 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter. Fourteen patients were enrolled in the phase I and 40 in the phase II. Overall response rate was 26%. The median remission duration (RD) was 20 weeks and was significantly longer in patients with FLT3 mutations not previously exposed to other FLT3 inhibitors (P = 0.05) and in patients not previously transplanted (P = 0.01). Thirty-two (59%) patients have died, all of complications related to disease progression. G3-4 nonhematological toxicity was reported in 38 (70%) patients, most frequently infections (56%), ejection fraction reduction (11%), and diarrhea or nausea/vomiting (9% each). The combination of midostaurin and AZA is an effective and safe regimen in patients with AML and high-risk MDS. Patients with FLT3 mutations but not previously exposed to other FLT3 inhibitors and patients not previously transplanted derived the greatest benefit. Further studies with this combination are warranted.
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Strati
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Aziz
authors.initials: A
authors.lastname: Nazha
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Naval
authors.initials: N
authors.lastname: Daver
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Trivikram
authors.initials: T
authors.lastname: Rajkhowa
authors.forename: Menda
authors.initials: M
authors.lastname: Durand
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D019311:Staurosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin; D001374:Azacitidine