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

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.