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

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 TALL 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 ¼ 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 ¼ 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.