title: Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia.
abstract: To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate- (62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retainedindependent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603.
authors.affiliation: University of New Mexico Cancer Center and Departments of Pathology, Internal Medicine, Mathematics and Statistics, and Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA.
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Carla S
authors.initials: CS
authors.lastname: Wilson
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bedrick
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Susan R
authors.initials: SR
authors.lastname: Atlas
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Xuefei
authors.initials: X
authors.lastname: Wang
authors.forename: Maurice
authors.initials: M
authors.lastname: Murphy
authors.forename: Kerem
authors.initials: K
authors.lastname: Ar
authors.forename: Walker
authors.initials: W
authors.lastname: Wharton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D005820:Genetic Testing / Q000379:methods* / Q000592:standards; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007223:Infant; D053612:Janus Kinases / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D018365:Neoplasm, Residual / Q000235:genetics* / Q000401:mortality*; D020411:Oligonucleotide Array Sequence Analysis; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012008:Recurrence; D015203:Reproducibility of Results; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D053612:Janus Kinases