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Acute Leukemias

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

Leukemia volume 27, pages 41–47 (2013)Cite this article

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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 (NOTCH1WTFBXW7WT), 38% single NOTCH1 mutant (NOTCH1SingleFBXW7WT), 3% just FBXW7 mutant (NOTCH1WTFBXW7MUT) and 24% either double NOTCH1 mutant (NOTCH1DoubleFBXW7WT) or mutant in both genes (NOTCH1MUTFBXW7MUT), hereafter called as NOTCH1±FBXW7Double. There was no difference between groups in early response to therapy, but NOTCH1±FBXW7Double patients were more likely to be associated with negative minimal residual disease (MRD) post-induction than NOTCH1WTFBXW7WT 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 NOTCH1WTFBXW7WT, NOTCH1SingleFBXW7WT and NOTCH1±FBXW7Double patients, respectively (log-rank P for trend=0.005). Although 14 NOTCH1±FBXW7Double 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.

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Acknowledgements

We are grateful to the clinical investigators who entered and managed patients in the trial. Primary childhood leukemia samples used in the study were provided by the Leukaemia and Lymphoma Research Childhood Leukaemia Cell Bank working with the laboratory teams in the Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK; Molecular Biology Laboratory, Royal Hospital for Sick Children, Glasgow, UK; Molecular Haematology Laboratory, Royal London Hospital, London, UK; and Molecular Genetics Service and Sheffield Children’s Hospital, Sheffield, UK. This work was supported by Cancer Research UK, UK Leukaemia and Lymphoma Research, and the UK Children’s Cancer and Leukaemia Group, and was undertaken at UCL which receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme.

AUTHOR CONTRIBUTIONS

SJ, KKK and MRM performed experiments; RW and SR analyzed data; REG and DCL designed the study; AV, NG and CM are the trial co-investigators; JH is the trial MRD co-ordinator; AVM provided data; SJ, DCL and REG wrote the manuscript with contributions from other authors as appropriate.

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Author notes

  1. M R Mansour

    Present address: 8Current address: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston and Harvard Medical School, Boston, MA, USA,

Authors and Affiliations

  1. Department of Haematology, UCL Cancer Institute, London, UK

    S Jenkinson, K Koo, M R Mansour, D C Linch & R E Gale

  2. Department of Haematology, Great Ormond Street Hospital, London, UK

    N Goulden

  3. Department of Haematology, Sheffield Children’s Hospital, Sheffield, UK

    A Vora

  4. Paediatric Oncology, John Radcliffe Hospital, Oxford, UK

    C Mitchell

  5. Clinical Trial Service Unit, Oxford, UK

    R Wade & S Richards

  6. Bristol Genetics Laboratory, Southmead Hospital, Bristol, UK

    J Hancock

  7. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

    A V Moorman

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Jenkinson, S., Koo, K., Mansour, M. et al. Impact of NOTCH1/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial. Leukemia 27, 41–47 (2013). https://doi.org/10.1038/leu.2012.176

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