急性淋巴细胞白血病克隆异质性特征及相关临床分析

Clonal heterogeneity and its prognostic significance in acute lymphoblastic leukemia

目的探讨克隆异质性在急性淋巴细胞白血病(ALL)患者中的特征及临床价值。方法回顾性分析2016年1月至2019年6月,河南省肿瘤医院血液科就诊的170例ALL初诊患者的临床资料,其中男93例、女77例,中位年龄17(2~80)岁。采用高通量测序技术靶向检测52种ALL相关基因,将检出的基因突变位点根据变异等位基因频率(VAF)及同期流式细胞学结果进行克隆异质性分析,并分析其与临床特征间的关系以及预后价值。结果121例(71.2%,121/170)患者检出基因突变,其中18例(52.9%,18/34)急性T淋巴细胞白血病患者可检出2个及以上的克隆,而仅有23例(16.9%,23/136)急性B淋巴细胞白血病患者可检出多克隆(P<0.01)。基因突变相关克隆异质性分析显示,NOTCH1突变患者出现2个及以上克隆的比例较高(13/19)(P<0.01)。生存分析结果显示,携带3个及以上克隆患者的无事件生存(EFS)明显低于其他患者(χ2=10.330,P=0.016),而在儿童患者中,携带多个克隆患者的总生存期和EFS均低于其他患者(总生存期:χ2=7.974,P=0.047;EFS:χ2=10.860,P=0.013)。结论ALL作为一种高度异质性血液肿瘤,克隆异质性与其来源不同的淋巴细胞谱系以及发病年龄密切相关,可进一步揭示疾病本质,评估预后风险。

Objective To explore the characteristics and clinical significance of clonal heterogeneity in patients with acute lymphoblastic leukemia(ALL).Methods From January 2016 to June 2019,170 newly diagnosed ALL patients were enrolled in the Department of Hematology,Henan Cancer Hospital,including 93 males and 77 females,with a median age of 17(2-80)years.Fifty-two ALL-related genes were detected by high-throughput sequencing technique.The clonal heterogeneity of mutations was analyzed according to the variant allele frequency(VAF)and the results of flow cytometry.The prognostic value of mutations was also evaluated.Results Gene mutations were detected in 121(71.2%,121/170)patients,of which 2 or more clones were detected in 18(52.9%,18/34)T-cell acute lymphoblastic leukemia patients,while only 23(16.9%,23/136)B-cell acute lymphoblastic leukemia patients were positive of multiple mutations(P<0.01).Gene mutation-related clonal heterogeneity analysis showed that 2 or more clones were frequent in patients with NOTCH1 mutations(13/19 patients)(P<0.01).Event free survival(EFS)in patients with 3 or more clones was significantly lower than other patients(χ2=10.330,P=0.016).Child ALL patients had similar result,that multiple clones predicted lower overall survival(OS)and EFS(OS:χ2=7.974,P=0.047;EFS:χ2=10.860,P=0.013).Conclusion Clonal heterogeneity in ALL patients is closely related to the different origin of lymphocyte lineages and the age of onset,which may reveal the nature of the disease and predict the clinical outcome.