Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol
- PMID: 19635999
- PMCID: PMC2744275
- DOI: 10.1200/JCO.2009.22.0996
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; 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.
Conflict of interest statement
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Figures
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References
-
- Hoelzer D, Thiel E, Loffler H, et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood. 1988;71:123–131. - PubMed
-
- Chessells JM, Hall E, Prentice HG, et al. The impact of age on outcome in lymphoblastic leukemia. MRC UKALL X and XA compared: A report from the MRC Paediatric and Adult Working Parties. Leukemia. 1998;12:463–473. - PubMed
-
- Moorman AV, Harrison CJ, Buck GAN, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): Analysis of cytogenetics data from patients treated on the Medical Research Council (MRC) UKALLXII/ Eastern Cooperative Oncology Group (ECOG) 2993 Trial. Blood. 2007;109:3189–3197. - PubMed
-
- Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269–271. - PubMed
-
- Mansour MR, Linch DC, Foroni L, et al. High incidence of NOTCH1 mutations in adult patients with T-cell acute lymphoblastic leukemia. Leukemia. 2006;20:537–539. - PubMed
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