title: Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation.
abstract: Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. fravandi@mdanderson.org
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Mona Lisa
authors.initials: ML
authors.lastname: Alattar
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grunwald
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Trivikram
authors.initials: T
authors.lastname: Rajkhowa
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Richie
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.forename: Naval
authors.initials: N
authors.lastname: Daver
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Aziz
authors.initials: A
authors.lastname: Nazha
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Jan
authors.initials: J
authors.lastname: Burger
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.forename: Sara
authors.initials: S
authors.lastname: Dellasala
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D012074:Remission Induction; D000077157:Sorafenib; D015996:Survival Rate; D020080:Tandem Repeat Sequences / Q000235:genetics*; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D001374:Azacitidine