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

S. Jenkinson, K. Koo, M. R. Mansour, N. Goulden, A. Vora, C. Mitchell, R. Wade, S. Richards, J. Hancock, A. V. Moorman, D. C. Linch, R. E. Gale

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)41-47
Number of pages7
JournalLeukemia
Volume27
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • FBXW7
  • NOTCH1
  • T-ALL
  • risk stratification

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Jenkinson, S., Koo, K., Mansour, M. R., Goulden, N., Vora, A., Mitchell, C., Wade, R., Richards, S., Hancock, J., Moorman, A. V., Linch, D. C., & Gale, R. E. (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), 41-47. https://doi.org/10.1038/leu.2012.176