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Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial

Jenkinson, S; Koo, K; Mansour, MR; Goulden, N; Vora, A; Mitchell, C; Wade, R; ... Gale, RE; + view all (2013) Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial. Leukemia , 27 (1) pp. 41-47. 10.1038/leu.2012.176.

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Abstract

Activating mutations in the NOTCH1 pathway are frequent in pediatric T-cell acute lymphoblastic leukemia (T-ALL) but their role in refining risk stratification is unclear. We screened 162 pediatric T-ALL patients treated on the MRC UKALL2003 trial for NOTCH1/FBXW7 gene mutations and related genotype to response to therapy and long-term outcome. Overall, 35% were wild-type (WT) for both genes (NOTCH1 WT FBXW7 WT), 38% single NOTCH1 mutant (NOTCH1 Single FBXW7 WT), 3% just FBXW7 mutant (NOTCH1 WT FBXW7 MUT) and 24% either double NOTCH1 mutant (NOTCH1 Double FBXW7 WT) or mutant in both genes (NOTCH1 MUT FBXW7 MUT), hereafter called as NOTCH1±FBXW7 Double. There was no difference between groups in early response to therapy, but NOTCH1±FBXW7 Double patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1 WT FBXW7 WT patients (71% versus 40%, P=0.004). Outcome improved according to the number of mutations, overall survival at 5 years 82%, 88% and 100% for NOTCH1 WT FBXW7 WT, NOTCH1 Single FBXW7 WT and NOTCH1±FBXW7 Double patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7 Double patients were classified as high risk (slow response and/or MRD positive), only two had disease progression and all remain alive. Patients with double NOTCH1 and/or FBXW7 mutations have a very good outcome and should not be considered for more intensive therapy in first remission, even if slow early responders or MRD positive after induction therapy. © 2013 Macmillan Publishers Limited All rights reserved.

Type: Article
Title: Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial
DOI: 10.1038/leu.2012.176
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
URI: http://discovery.ucl.ac.uk/id/eprint/1499995
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