Originally published as JCO Early Release 10.1200/JCO.2009.22.0996 on July 27 2009

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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

From the Department of Haematology, Cancer Institute, and University College London Hospital; Imperial College, Hammersmith Hospital Campus, London; Clinical Trial Service Unit, Oxford, United Kingdom; Department of Pediatric Oncology, Columbia University Medical Center; Institute for Cancer Genetics and Department of Pathology, Columbia University Medical Center, New York; Our Lady of Mercy Cancer Center, New York Medical College, Bronx, NY; Rambam Medical Center and Technion, Israel Institute of Technology, Haifa, Israel; and Northwestern University Feinberg School of Medicine, Chicago, IL.

Corresponding author: Marc Mansour, MBChB, Department of Haematology, University College London, UCL Cancer Institute, WC1E 6BT, United Kingdom; e-mail: m.mansour{at}ucl.ac.uk.

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.

Supported by the United Kingdom Medical Research Council (M.R.M.), Leukemia Research Fund (R.E.G. and D.C.L.), and National Institutes of Health (Grants No. R01CA120196 and R01CA129382 to A.F.); the WOLF Foundation (A.F.); the Leukemia and Lymphoma Society (Grants No. 1287-08 and 6237-08 to A.F.); and the Charlotte Geyer Foundation (A.F.). A.F. is a Leukemia & Lymphoma Society Scholar.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00002514 [ClinicalTrials.gov] .

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