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

Department of Pediatrics, Columbia University, New York, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 08/2009; 27(26):4352-6. DOI: 10.1200/JCO.2009.22.0996
Source: PubMed

ABSTRACT 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.
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.
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).
NOTCH1 and FBXW7 mutant-positive patients do not fare sufficiently well to warrant an individualized treatment approach in future studies.

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Available from: Rosemary E Gale, Jan 17, 2014
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    • "A similar result was obtained in the analysis of 141 adult T-ALL patients treated in either the Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) (n = 87) and GRAALL-2003 (n = 54) trials, in which NOTCH1 or FBXW7 mutations correlated with favorable outcome [Asnafi et al. 2009]. However, analysis of a series of T-ALL patients treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/ Eastern Cooperative Oncology Group (ECOG) E2993 protocol found no significant association between NOTCH1 and FBXW7 mutations and prognosis [Mansour et al. 2009]. Similarly, while NOTCH1 and FBXW7 mutations are associated with favorable early response to treatment in pediatric T-ALL, this early advantage did not ultimately translate to long-term outcome in DCOG or COALL protocols and in the EORTC 58881 and 58951 clinical trials [Clappier et al. 2010; Zuurbier et al. 2010]. "
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    • "However on modern, more intensive treatment protocols, patients with this translocation have become classified as intermediate risk in terms of stratification for treatment. Similarly the prognosis of T-ALL with acquired mutations in the NOTCH1 pathway is strongly linked to the treatment protocol (Breit et al, 2006; Zhu et al, 2006; Larson Gedman et al, 2009; Mansour et al, 2009). At present we are witnessing a major shift in the prognostic association of BCR-ABL1 fusion gene – a genetic aberration that used to be a 'hallmark' of high-risk leukaemia. "
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    • "At the same time, in a detailed analysis of the MRC UKALL XII/ECOG E2993 study, the patients with the wild type for both NOTCH1 and FBXW7 exhibited a trend towards a poorer event-free survival. However, the analysis of each marker individually was not significantly predictive of the outcome, making it impossible to conclude that each marker was a potential target for therapeutic stratification (Mansour et al, 2009). It must be emphasized, however, that it is possible that differing therapeutic strategies, such as higher doses of asparaginase, vincristine and prednisone in the GRAALL study, may, at least partly, account for differences in the results of these two major studies. "
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