title: FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.
abstract: The clinical impact of FLT3-internal tandem duplications (ITDs), an adverse prognostic marker in adults aged < 60 years with primary cytogenetically normal acute myeloid leukemia (CN-AML), requires further investigation in older patients. In CN-AML patients aged ≥ 60 years treated on Cancer and Leukemia Group B frontline trials, we found that FLT3-ITD remained associated with shorter disease-free survival (P < .001; hazard ratio = 2.10) and overall survival (P < .001; hazard ratio = 1.97) in multivariable analyses. This impact on shorter disease-free survival and overall survival was in patients aged 60-69 (P < .001, each) rather than in those aged ≥ 70 years. An FLT3-ITD-associated gene-expression signature revealed overexpression of FLT3, homeobox genes (MEIS1, PBX3, HOXB3), and immunotherapeutic tar-gets (WT1, CD33) and underexpression of leukemia-associated (MLLT3, TAL1) and erythropoiesis-associated (GATA3, EPOR, ANK1, HEMGN) genes. An FLT3-ITD-associated microRNA-expression signature included overexpressed miR-155 and underexpressed miR-144 and miR-451. FLT3-ITD identifies older CN-AML patients with molecular high risk and is associated with gene- and microRNA-expression signatures that provide biologic insights for novel therapeutic approaches.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Dean
authors.initials: D
authors.lastname: Margeson
authors.forename: Kelsi B
authors.initials: KB
authors.lastname: Holland
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003582:Cytogenetics; D005260:Female; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3