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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

Lookup NU author(s): Dr Sarah Jenkinson, Professor Anthony Moorman

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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. Leukemia (2013) 27, 41-47; doi:10.1038/leu.2012.176


Publication metadata

Author(s): Jenkinson S, Koo K, Mansour MR, Goulden N, Vora A, Mitchell C, Wade R, Richards S, Hancock J, Moorman AV, Linch DC, Gale RE

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2013

Volume: 27

Issue: 1

Pages: 41-47

Print publication date: 01/01/2013

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/leu.2012.176

DOI: 10.1038/leu.2012.176


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