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J Clin Oncol. 2009 Sep 10;27(26):4352-6. doi: 10.1200/JCO.2009.22.0996. Epub 2009 Jul 27.

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

Author information

1
Department of Haematology, University College London, UCL Cancer Institute, WC1E 6BT, United Kingdom. m.mansour@ucl.ac.uk

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; MUT v 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00002514.

PMID:
19635999
PMCID:
PMC2744275
DOI:
10.1200/JCO.2009.22.0996
[Indexed for MEDLINE]
Free PMC Article

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