Gao Chao, Liu Shu-Guang, Zhang Rui-Dong, Li Wei-Jing, Zhao Xiao-Xi, Cui Lei, Wu Min-Yuan, Zheng Hu-Yong, Li Zhi-Gang
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.
Br J Haematol. 2014 Jul;166(2):221-8. doi: 10.1111/bjh.12866. Epub 2014 Apr 2.
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.
NOTCH1激活突变在T细胞急性淋巴细胞白血病（T-ALL）中很常见，但其对T-ALL治疗的影响仍存在争议。本研究分析了92例使用北京儿童医院-2003方案和中国儿童白血病协作组-2008方案治疗的中国儿童T-ALL患者的发病率、临床特征和预后。42%的T-ALL患者存在NOTCH1突变，且与临床特征、泼尼松反应以及第33天和第78天的微小残留病（MRD）无关。然而，脯氨酸、谷氨酸、丝氨酸和苏氨酸（PEST）/反式激活结构域（TAD）突变与年龄较小（16例突变型中的15例 vs. 76例野生型中的48例，P = 0.018）以及更多的中枢神经系统受累相关（16例突变型中的4例 vs. 76例野生型中的3例，P = 0.016）；而异二聚化结构域（HD）突变与KMT2A-MLLT1（MLL-ENL）相关（30例突变型中的4例 vs. 62例野生型中的1例，P = 0.037）。此外，NOTCH突变患者的预后优于野生型NOTCH1患者（5年无事件生存率[EFS]为92.0±4.5% vs. 64.0±7.1%；P = 0.003）。携带HD突变患者的长期预后优于野生型HD患者（5年EFS为89.7±5.6% vs. 69.3±6.2%；P = 0.034）。NOTCH1突变和第78天的MRD是独立的预后因素。这些发现表明，在BCH-2003和CCLG-2008方案治疗的中国儿童T-ALL患者中，NOTCH1突变预示着良好的预后，可被视为一种预后分层因素。
