期刊
LEUKEMIA
卷 27, 期 1, 页码 41-47出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.176
关键词
T-ALL; NOTCH1; FBXW7; risk stratification
资金
- Cancer Research UK
- UK Leukaemia and Lymphoma Research
- UK Children's Cancer and Leukaemia Group
- Department of Health's NIHR Biomedical Research Centre's funding scheme
- Medical Research Council [G0300130, MC_U137686856, G0500389] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10370] Funding Source: researchfish
- MRC [G0500389, MC_U137686856] Funding Source: UKRI
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. Leukemia (2013) 27, 41-47; doi:10.1038/leu.2012.176
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