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 language | English (US) |
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Pages (from-to) | 41-47 |
Number of pages | 7 |
Journal | Leukemia |
Volume | 27 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2013 |
Externally published | Yes |
Keywords
- FBXW7
- NOTCH1
- T-ALL
- risk stratification
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research