Absence of biallelic TCRγ deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia

Alejandro Gutierrez, Suzanne E. Dahlberg, Donna S. Neuberg, Jianhua Zhang, Ruta Grebliunaite, Takaomi Sanda, Alexei Protopopov, Valeria Tosello, Jeffery Kutok, Richard S. Larson, Michael J. Borowitz, Mignon L. Loh, Adolfo A. Ferrando, Stuart S. Winter, Charles G. Mullighan, Lewis B. Silverman, Lynda Chin, Stephen P. Hunger, Stephen E. Sallan, A. Thomas Look

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Abstract

Purpose: 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. Patients and 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 TCRγ 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. Conclusion: Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRγ 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.

Original languageEnglish
Pages (from-to)3816-3823
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number24
DOIs
Publication statusPublished - Aug 20 2010

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Treatment Failure
Induction Chemotherapy
Pediatrics
Comparative Genomic Hybridization
DNA-Directed DNA Polymerase
V(D)J Recombination
Polymerase Chain Reaction
DNA
Thymocytes
Complementary Therapies
Survivors
Clinical Trials
Survival
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Gutierrez, A., Dahlberg, S. E., Neuberg, D. S., Zhang, J., Grebliunaite, R., Sanda, T., ... Look, A. T. (2010). Absence of biallelic TCRγ deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. Journal of Clinical Oncology, 28(24), 3816-3823. https://doi.org/10.1200/JCO.2010.28.3390

Absence of biallelic TCRγ deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. / Gutierrez, Alejandro; Dahlberg, Suzanne E.; Neuberg, Donna S.; Zhang, Jianhua; Grebliunaite, Ruta; Sanda, Takaomi; Protopopov, Alexei; Tosello, Valeria; Kutok, Jeffery; Larson, Richard S.; Borowitz, Michael J.; Loh, Mignon L.; Ferrando, Adolfo A.; Winter, Stuart S.; Mullighan, Charles G.; Silverman, Lewis B.; Chin, Lynda; Hunger, Stephen P.; Sallan, Stephen E.; Look, A. Thomas.

In: Journal of Clinical Oncology, Vol. 28, No. 24, 20.08.2010, p. 3816-3823.

Research output: Contribution to journalArticle

Gutierrez, A, Dahlberg, SE, Neuberg, DS, Zhang, J, Grebliunaite, R, Sanda, T, Protopopov, A, Tosello, V, Kutok, J, Larson, RS, Borowitz, MJ, Loh, ML, Ferrando, AA, Winter, SS, Mullighan, CG, Silverman, LB, Chin, L, Hunger, SP, Sallan, SE & Look, AT 2010, 'Absence of biallelic TCRγ deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia', Journal of Clinical Oncology, vol. 28, no. 24, pp. 3816-3823. https://doi.org/10.1200/JCO.2010.28.3390
Gutierrez, Alejandro ; Dahlberg, Suzanne E. ; Neuberg, Donna S. ; Zhang, Jianhua ; Grebliunaite, Ruta ; Sanda, Takaomi ; Protopopov, Alexei ; Tosello, Valeria ; Kutok, Jeffery ; Larson, Richard S. ; Borowitz, Michael J. ; Loh, Mignon L. ; Ferrando, Adolfo A. ; Winter, Stuart S. ; Mullighan, Charles G. ; Silverman, Lewis B. ; Chin, Lynda ; Hunger, Stephen P. ; Sallan, Stephen E. ; Look, A. Thomas. / Absence of biallelic TCRγ deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 24. pp. 3816-3823.
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abstract = "Purpose: 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. Patients and 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 TCRγ 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. Conclusion: Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRγ 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.",
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AU - Gutierrez, Alejandro

AU - Dahlberg, Suzanne E.

AU - Neuberg, Donna S.

AU - Zhang, Jianhua

AU - Grebliunaite, Ruta

AU - Sanda, Takaomi

AU - Protopopov, Alexei

AU - Tosello, Valeria

AU - Kutok, Jeffery

AU - Larson, Richard S.

AU - Borowitz, Michael J.

AU - Loh, Mignon L.

AU - Ferrando, Adolfo A.

AU - Winter, Stuart S.

AU - Mullighan, Charles G.

AU - Silverman, Lewis B.

AU - Chin, Lynda

AU - Hunger, Stephen P.

AU - Sallan, Stephen E.

AU - Look, A. Thomas

PY - 2010/8/20

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N2 - Purpose: 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. Patients and 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 TCRγ 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. Conclusion: Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCRγ 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.

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