Abstract
Risk-adjusted treatment stratification in T-cell acute lymphoblastic leukemias (T-ALLs) is currently based only on early response to chemotherapy. We investigated the prognostic implication of hyperactivation of NOTCH pathway resulting from mutations of NOTCH1 or FBXW7 in children with T-ALL enrolled in EORTC-CLG trials. Overall, 80 out of 134 (60%) patients were NOTCH+ (NOTCH1 and/or FBXW7 mutated). Although clinical presentations were not significantly associated with NOTCH status, NOTCH+ patients showed a better early response to chemotherapy as compared with NOTCH− patients, according to the rate of poor pre-phase ‘responders’ (25% versus 44%; P=0.02) and the incidence of high minimal residual disease (MRD) levels (11% (7/62) versus 32% (10/31); P=0.01) at completion of induction. However, the outcome of NOTCH+ patients was similar to that of NOTCH− patients, with a 5-year event-free survival (EFS) of 73% and 70% (P=0.82), and 5-year overall survival of 82% and 79% (P=0.62), respectively. In patients with high MRD levels, the 5-year EFS rate was 0% (NOTCH+) versus 42% (NOTCH−), whereas in those with low MRD levels, the outcome was similar: 76% (NOTCH+) versus 78% (NOTCH−). The incidence of isolated central nervous system (CNS) relapses was relatively high in NOTCH1+ patients (8.3%), which could be related to a higher propensity of NOTCH+ leukemic blasts to target the CNS.
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Acknowledgements
This publication was supported by Grant Nos. 5U10 CA11488-20 through 5U10 CA11488-39 from the National Cancer Institute (Bethesda, MD, USA), by TéléVie (Grant No. 7.4561.01), and by a donation from the Vlaamse Liga Tegen Kanker, the Belgian Federation against Cancer, the Kinderkankerfonds from Belgium, La Ligue Nationale Contre le Cancer from France and the EORTC Charitable Trust. Its content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute. We wish to thank the physicians who referred the patients reported in this paper and biologists who provided cytological, immunophenotypic and karyotype data. We particularly thank Marleen Bakkus (AZ-VUB, Brussels) for MRD studies, and Séraphine Rossi (EORTC headquarters, Brussels) for data management.
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Clappier, E., Collette, S., Grardel, N. et al. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia 24, 2023–2031 (2010). https://doi.org/10.1038/leu.2010.205
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DOI: https://doi.org/10.1038/leu.2010.205
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