title: Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia.
abstract: The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA-positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 x 10(9)/L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P = .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P = .04, but no significant difference in relapse risk (28% vs 23%; P = .5) or overall survival (59% vs 67%; P = .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n = 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD+ cells, but this inhibition was reduced in the presence of ATRA. Furthermore, in the presence of CEP-701, ATRA-induced differentiation was reduced in FLT3/ITD+ cells. These data carry implications for the use of FLT3 inhibitors as frontline therapy for APL.
authors.affiliation: Department of Haematology, University College London Hospitals, United Kingdom.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Pizzey
authors.forename: Panagiotis D
authors.initials: PD
authors.lastname: Kottaridis
authors.forename: David
authors.initials: D
authors.lastname: Swirsky
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Gilkes
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nugent
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Mills
authors.forename: Keith
authors.initials: K
authors.lastname: Wheatley
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005663:Furans; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007223:Infant; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016019:Survival Analysis; D014212:Tretinoin / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D007211:Indoles; D014212:Tretinoin; C119379:lestaurtinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3