title: NOTCH1 mutations are associated with favourable long-term prognosis in paediatric T-cell acute lymphoblastic leukaemia: a retrospective study of patients treated on BCH-2003 and CCLG-2008 protocol in China.
abstract: Activating mutations of NOTCH1 are a common occurrence in T-cell acute lymphoblastic leukaemia (T-ALL), but its impact on T-ALL treatment is still controversial. In this study, the incidence, clinical features, and prognosis of 92 Chinese children with T-ALL treated using the Beijing Children's Hospital-2003 and Chinese Childhood Leukaemia Group-2008 protocols were analysed. NOTCH1 mutations were found in 42% of T-ALL patients and were not associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. However, proline, glutamate, serine, threonine (PEST)/transactivation domain (TAD) mutations were associated with younger age (15/16 mutant vs. 48/76 wild-type, P = 0·018) and more central nervous system involvement (4/16 mutant vs. 3/76 wild-type, P = 0·016); while heterodimerization domain (HD) mutations were associated with KMT2A-MLLT1 (MLL-ENL; 4/30 mutant vs. 1/62 wild-type, P = 0·037). Furthermore, prognosis was better in patients with NOTCH1 mutations than in those with wild-type NOTCH1 (5-year event-free survival [EFS] 92·0 ± 4·5% vs. 64·0 ± 7·1%; P = 0·003). Long-term outcome was better in patients carrying HD mutations than in patients with wild-type HD (5-year EFS 89·7 ± 5·6% vs. 69·3 ± 6·2%; P = 0·034). NOTCH1 mutations and MRD at day 78 were independent prognostic factors. These findings indicate that NOTCH1 mutation predicts a favourable outcome in Chinese paediatric patients with T-ALL on the BCH-2003 and CCLG-2008 protocols, and may be considered a prognostic stratification factor.
authors.affiliation: Beijing Key Laboratory of Paediatric Haematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Paediatrics, Haematology and Oncology Centre, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Liu
authors.forename: Rui-Dong
authors.initials: RD
authors.lastname: Zhang
authors.forename: Wei-Jing
authors.initials: WJ
authors.lastname: Li
authors.forename: Xiao-Xi
authors.initials: XX
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.forename: Min-Yuan
authors.initials: MY
authors.lastname: Wu
authors.forename: Hu-Yong
authors.initials: HY
authors.lastname: Zheng
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D018365:Neoplasm, Residual; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1
keywords: T cells; acute lymphoblastic leukaemia; clinical studies; paediatrics; prognostic factors