Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 27, Issue 26, Pages 4352-4356Publisher
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2009.22.0996
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Funding
- United Kingdom Medical Research Council
- Leukemia Research Fund
- National Institutes of Health [R01CA120196, R01CA129382]
- WOLF Foundation
- Leukemia and Lymphoma Society [1287-08, 6237-08]
- Charlotte Geyer Foundation
- Leukemia & Lymphoma Society Scholar
- MRC [G0500389, MC_U137686856] Funding Source: UKRI
- Medical Research Council [G0500389, MC_U137686856] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10370] Funding Source: researchfish
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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; MUTvWT, 51% v27%, 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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