Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia.
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.
Kang
Huining
H
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.
Chen
I-Ming
IM
Wilson
Carla S
CS
Bedrick
Edward J
EJ
Harvey
Richard C
RC
Atlas
Susan R
SR
Devidas
Meenakshi
M
Mullighan
Charles G
CG
Wang
Xuefei
X
Murphy
Maurice
M
Ar
Kerem
K
Wharton
Walker
W
Borowitz
Michael J
MJ
Bowman
W Paul
WP
Bhojwani
Deepa
D
Carroll
William L
WL
Camitta
Bruce M
BM
Reaman
Gregory H
GH
Smith
Malcolm A
MA
Downing
James R
JR
Hunger
Stephen P
SP
Willman
Cheryl L
CL
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
C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D053612:Janus Kinases