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

Journal article

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.

Authors: Mansour, MR; Sulis, M; Duke, V; Foroni, L; Jenkinson, S

• Publication status: Published
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• Volume: 27
• Issue: 26
• Pages: 4352-4356
• Publication date: 2009-09-01
• DOI: 10.1200/jco.2009.22.0996
• EISSN: 1527-7755
• ISSN: 0732-183X
• Language: English
• Keywords: Genotype; Ubiquitin-Protein Ligases; Treatment Outcome; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; F-Box Proteins; Gene Frequency; Male; Prognosis; Young Adult; Cell Cycle Proteins; Chromatography, High Pressure Liquid; Humans; Female; Adolescent; Middle Aged; Receptor, Notch1; Disease-Free Survival; Adult; Multivariate Analysis; Mutation; Follow-Up Studies; Great Britain; DNA Mutational Analysis