title: Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse.
abstract: In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, MD, USA. levisma@jhmi.edu
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Eunice S
authors.initials: ES
authors.lastname: Wang
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Alexander
authors.initials: A
authors.lastname: Perl
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
authors.forename: Harry
authors.initials: H
authors.lastname: Erba
authors.forename: Robert K
authors.initials: RK
authors.lastname: Stuart
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Larry D
authors.initials: LD
authors.lastname: Cripe
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Giovanna
authors.initials: G
authors.lastname: Meloni
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Langston
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: Karen
authors.initials: K
authors.lastname: Yee
authors.forename: Anjali
authors.initials: A
authors.lastname: Advani
authors.forename: Dan
authors.initials: D
authors.lastname: Douer
authors.forename: W
authors.initials: W
authors.lastname: Wiktor-Jedrzejczak
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.forename: Stephen
authors.initials: S
authors.lastname: Petersdorf
authors.forename: Miguel
authors.initials: M
authors.lastname: Sanz
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Lothar
authors.initials: L
authors.lastname: Tremmel
authors.forename: Debra M
authors.initials: DM
authors.lastname: Bensen-Kennedy
authors.forename: Donald
authors.initials: D
authors.lastname: Small
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D005260:Female; D005663:Furans; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D016019:Survival Analysis; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D002227:Carbazoles; D005663:Furans; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; C119379:lestaurtinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3