Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia.
OBJECTIVE
To identify children with T-cell acute lymphoblastic leukemia (T-ALL) at high risk of induction chemotherapy failure by using DNA copy number analysis of leukemic cells collected at diagnosis.


METHODS
Array comparative genomic hybridization (CGH) was performed on genomic DNA extracted from diagnostic lymphoblasts from 47 children with T-ALL treated on Children's Oncology Group Study P9404 or Dana-Farber Cancer Institute Protocol 00-01. These samples represented nine patients who did not achieve an initial complete remission, 13 who relapsed, and 25 who became long-term, event-free survivors. The findings were confirmed in an independent cohort of patients by quantitative DNA polymerase chain reaction (DNA-PCR), an assay that is well suited for clinical application.


RESULTS
Analysis of the CGH findings in patients in whom induction chemotherapy failed compared with those in whom induction chemotherapy was successful identified the absence of biallelic TCRgamma locus deletion (ABD), a characteristic of early thymocyte precursors before V(D)J recombination, as the most robust predictor of induction failure (P < .001). This feature was also associated with markedly inferior event-free (P = .002) and overall survival (P < .001) rates: 25% versus 58% and 25% versus 72%, respectively. Using a rapid and inexpensive quantitative DNA-PCR assay, we validated ABD as a predictor of a poor response to induction chemotherapy in an independent series of patients.


CONCLUSIONS
Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRgamma locus. Patients lacking biallelic deletion, which confers a high probability of induction failure with contemporary therapy, should be assigned to alternative therapy in the context of a prospective clinical trial.
Gutierrez
Alejandro
A
Department of Pediatric Oncology, Dana-Farber Cancer Institute,Boston, MA 02115, USA.
Dahlberg
Suzanne E
SE
Neuberg
Donna S
DS
Zhang
Jianhua
J
Grebliunaite
Ruta
R
Sanda
Takaomi
T
Protopopov
Alexei
A
Tosello
Valeria
V
Kutok
Jeffery
J
Larson
Richard S
RS
Borowitz
Michael J
MJ
Loh
Mignon L
ML
Ferrando
Adolfo A
AA
Winter
Stuart S
SS
Mullighan
Charles G
CG
Silverman
Lewis B
LB
Chin
Lynda
L
Hunger
Stephen P
SP
Sallan
Stephen E
SE
Look
A Thomas
AT
D000293:Adolescent; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D019675:Genes, T-Cell Receptor gamma; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D012074:Remission Induction; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D017211:Treatment Failure