Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol

Marc R. Mansour, Maria L. Sulis, Veronique Duke, Letizia Foroni, Sarah Jenkinson, Kenneth Koo, Christopher G. Allen, Rosemary E. Gale, Georgina Buck, Sue Richards, Elisabeth M. Paietta, Jacob M. Rowe, Martin S. Tallman, Anthony H. Goldstone, Adolfo A. Ferrando, David C. Linch

Research output: Contribution to journalArticle

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Abstract

Purpose: Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Methods: NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome. Results: NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS;MUTv WT,51%v 27%, P=.10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72). Conclusion: NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.

Original languageEnglish (US)
Pages (from-to)4352-4356
Number of pages5
JournalJournal of Clinical Oncology
Volume27
Issue number26
DOIs
StatePublished - Sep 10 2009
Externally publishedYes

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Mutation
Threonine
Proline
Serine
Disease-Free Survival
United Kingdom
Glutamic Acid
High Pressure Liquid Chromatography
Pediatrics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. / Mansour, Marc R.; Sulis, Maria L.; Duke, Veronique; Foroni, Letizia; Jenkinson, Sarah; Koo, Kenneth; Allen, Christopher G.; Gale, Rosemary E.; Buck, Georgina; Richards, Sue; Paietta, Elisabeth M.; Rowe, Jacob M.; Tallman, Martin S.; Goldstone, Anthony H.; Ferrando, Adolfo A.; Linch, David C.

In: Journal of Clinical Oncology, Vol. 27, No. 26, 10.09.2009, p. 4352-4356.

Research output: Contribution to journalArticle

Mansour, MR, Sulis, ML, Duke, V, Foroni, L, Jenkinson, S, Koo, K, Allen, CG, Gale, RE, Buck, G, Richards, S, Paietta, EM, Rowe, JM, Tallman, MS, Goldstone, AH, Ferrando, AA & Linch, DC 2009, 'Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol', Journal of Clinical Oncology, vol. 27, no. 26, pp. 4352-4356. https://doi.org/10.1200/JCO.2009.22.0996
Mansour, Marc R. ; Sulis, Maria L. ; Duke, Veronique ; Foroni, Letizia ; Jenkinson, Sarah ; Koo, Kenneth ; Allen, Christopher G. ; Gale, Rosemary E. ; Buck, Georgina ; Richards, Sue ; Paietta, Elisabeth M. ; Rowe, Jacob M. ; Tallman, Martin S. ; Goldstone, Anthony H. ; Ferrando, Adolfo A. ; Linch, David C. / Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 26. pp. 4352-4356.
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title = "Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol",
abstract = "Purpose: Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Methods: NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome. Results: NOTCH1 and FBXW7 mutations were common (60{\%} and 18{\%}, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS;MUTv WT,51{\%}v 27{\%}, P=.10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49{\%} v 34{\%}, P = .20; FBXW7 MUT v WT, EFS 53{\%} v 41{\%}, P.72). Conclusion: NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.",
author = "Mansour, {Marc R.} and Sulis, {Maria L.} and Veronique Duke and Letizia Foroni and Sarah Jenkinson and Kenneth Koo and Allen, {Christopher G.} and Gale, {Rosemary E.} and Georgina Buck and Sue Richards and Paietta, {Elisabeth M.} and Rowe, {Jacob M.} and Tallman, {Martin S.} and Goldstone, {Anthony H.} and Ferrando, {Adolfo A.} and Linch, {David C.}",
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T1 - Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol

AU - Mansour, Marc R.

AU - Sulis, Maria L.

AU - Duke, Veronique

AU - Foroni, Letizia

AU - Jenkinson, Sarah

AU - Koo, Kenneth

AU - Allen, Christopher G.

AU - Gale, Rosemary E.

AU - Buck, Georgina

AU - Richards, Sue

AU - Paietta, Elisabeth M.

AU - Rowe, Jacob M.

AU - Tallman, Martin S.

AU - Goldstone, Anthony H.

AU - Ferrando, Adolfo A.

AU - Linch, David C.

PY - 2009/9/10

Y1 - 2009/9/10

N2 - Purpose: Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Methods: NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome. Results: NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS;MUTv WT,51%v 27%, P=.10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72). Conclusion: NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.

AB - Purpose: Notch pathway activation by mutations in either NOTCH1 and/or FBXW7 is one of the most common molecular events in T-cell acute lymphoblastic leukemia (T-ALL) and, in pediatric disease, predicts for favorable outcome. Their prognostic significance in adult T-ALL is unclear. We sought to evaluate the outcome according to mutation status of patients with adult T-ALL treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Methods: NOTCH1 and FBXW7 were screened by a combination of denaturing high-performance liquid chromatography and sequencing in 88 adult patients with T-ALL treated on the UKALLXII/ECOG E2993 protocol and compared with clinical characteristics and outcome. Results: NOTCH1 and FBXW7 mutations were common (60% and 18%, respectively) and were not associated with age or WBC count. NOTCH1 heterodimerization domain mutations were associated with FBXW7 mutations (P = .02), and NOTCH1 proline, glutamic acid, serine, threonine (PEST) rich domain and FBXW7 mutations were mutually exclusive. There were an equal number of high- and standard-risk patients in the NOTCH1 and FBXW7 mutated (MUT) groups. Patients wild type (WT) for both markers trended toward poorer event-free survival (EFS;MUTv WT,51%v 27%, P=.10; hazard ratio, 0.6). Analysis by each marker individually was not significantly predictive of outcome (NOTCH1 MUT v WT, EFS 49% v 34%, P = .20; FBXW7 MUT v WT, EFS 53% v 41%, P.72). Conclusion: NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.

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