title: FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications.
abstract: The prognostic relevance of FLT3 D835/I836 mutations (FLT3-TKD) in cytogenetically normal acute myeloid leukemia (CN-AML) remains to be established. After excluding patients with FLT3 internal tandem duplications, we compared treatment outcome of 16 de novo CN-AML patients with FLT3-TKD with that of 123 patients with wild-type FLT3 (FLT3-WT), less than 60 years of age and similarly treated on Cancer and Leukemia Group B protocols. All FLT3-TKD(+) patients and 85% of FLT3-WT patients achieved a complete remission (P = .13). Disease-free survival (DFS) of FLT3-TKD(+) patients was worse than DFS of FLT3-WT patients (P = .01; estimated 3-year DFS rates, 31% vs 60%, respectively). In a multivariable analysis, FLT3-TKD was associated with worse DFS (P = .02) independent of NPM1 status and percentage of bone marrow blasts. To gain further biologic insights, a gene-expression signature differentiating FLT3-TKD(+) from FLT3-WT patients was identified. The signature (333 probe sets) included overexpression of VNN1, C3AR1, PTPN6, and multiple other genes involved in monocarboxylate transport activity, and underexpression of genes involved in signal transduction regulation. These associations with outcome, other prognostic markers, and the elucidated expression signature enhance our understanding of FLT3-TKD-associated biology and may lead to development of novel therapies that improve clinical outcome of CN-AML patients with FLT3-TKD.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43240, USA. susan.whitman@osumc.edu
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Frederick
authors.initials: F
authors.lastname: Racke
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
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: D000328:Adult; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism; D003582:Cytogenetics; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007532:Isoleucine / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000716967:NPM1 protein, human; D007532:Isoleucine; D000090243:Nucleophosmin; D001224:Aspartic Acid; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3