93例儿童急性B淋巴细胞白血病IKZF1基因缺失的临床研究

Clinical study on deletion of IKZF1 gene in 93 children with B-cell acute lymphoblastic leukemia

目的探讨IKZF1基因缺失对儿童急性B淋巴细胞白血病(B-ALL)复发及预后的影响,为合并IKZF1基因缺失B-ALL患儿的化疗方案选择和强度调整提供理论依据。方法选择2014年6月至2016年11月于昆明医科大学附属儿童医院血液肿瘤科初诊并可获得足量骨髓DNA样本的93例B-ALL患儿为研究对象。根据患儿IKZF1基因表达情况,将其分为IKZF1基因缺失组(n=18)和IKZF1基因未缺失组(n=75)。计算IKZF1基因缺失发生率。采用χ^2检验或Fisher确切概率法比较2组患儿性别、年龄、初诊时白细胞计数、早期治疗反应,初诊时中枢神经系统(CNS)分级、微小残留病(MRD)分组,危险度分组、是否复发及生存状态的构成比。采用Kaplan-Meier法计算两组患儿的2年无病生存(DFS)和总体生存(OS)率,分别绘制生存曲线。本研究样本收集均征得患儿监护人的知情同意,并签署知情同意书。本研究遵循的程序符合昆明医科大学附属儿童医院制定的伦理学标准(批准文号:CCCG-ALL-2015),得到该委员会的批准。结果① IKZF1基因缺失发生率为19.4%(18/93)。② 2组患儿性别、年龄、初诊时CNS分级、早期治疗反应及危险度分组的构成比分别比较,差异均无统计学意义(P>0.05)。IKZF1基因缺失组初诊时白细胞计数≥50×10^9/L及MRD分组为高危的患儿比例分别为38.9%(7/18)和27.8%(5/18),显著高于IKZF1非缺失组患儿的13.3%(10/75)和8.0%(6/75),2组分别比较,差异均有统计学意义(χ^2=4.75,P=0.019; χ^2=4.72,P=0.009)。IKZF1基因缺失组患儿的复发率为33.3%(6/18),显著高于IKZF1非缺失组的9.3% (7/75),2组比较,差异亦有统计学意义(χ^2=6.95,P=0.008)。③ IKZF1基因缺失组患儿2年DFS、OS率分别为(72.7±13.4)%和(81.8±11.6)%,显著低于IKZF1非缺失组患儿的(92.3±3.0)%和(94.4±2.8)%,并且差异均有统计学意义(P<0.05)。结论IKZF1基因缺失是导致B-ALL患儿复发的高危预测因素之一。应将IKZF1基因缺失作为一项危险因素,用于指导B-ALL患儿危险分层,以便调整化疗方案及强度,改善预后。

Objective To study the effect of IKZF1 gene deletion on the relapse and prognosis of children with B-cell acute lymphoblastic leukemia (B-ALL) , and provide a theoretical basis for the selection and intensity adjustment of chemotherapy in B-ALL children with IKZF1 gene.Methods From June 2014 to November 2016, a total of 93 children with B-ALL were included in the study. They were newly diagnosed in the Department of Hematology Oncology, Children′s Hospital of Kunming Medical University, and able to provide sufficient bone marrow DNA samples.They were divided into IKZF1 gene deletion group(n=18) and IKZF1 gene non-deletion group (n=75). The incidence of IKZF1 gene deletion was calculated. The gender, age, number of white blood cells count, early treatment response, central nervous system (CNS) classification, minimal residual disease(MRD) grouping, risk grouping, recurrence and survival constituent ratioes were compared between two groups. The 2-year disease-free survival (DFS) and overall survival(OS) rates of the two groups were calculated by Kaplan-Meier method, and the survival curves were plotted. The samples collection of this study were agreed from the guardians, and they signed the informed consent forms. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Kunming Medical University (approval No. CCLG-ALL-2015).Results ① The incidence of IKZF1 gene deletion was 19.4% (18/93). ② There were no significant differences in gender, age, CNS classification, early treatment response and risk grouping between the two groups (P>0.05). The proportion of children with white blood cell count ≥50×10^9/L and high-risk MRD in the IKZF1 gene deletion group were 38.9% (7/18) and 27.8% (5/18), respectively, which were significantly higher than those of IKZF1 non-deletion group with 13.3% (10/75) and 8.0% (6/75), respectively, and the differences were statistically significant (χ^2=4.75, P=0.019; χ^2=4.72, P=0.009). The recurrence rate of the IKZF1 gene deletion group was 33.3% (6/18), which was significantly higher than that of the IKZF1 non-deletion group with 9.3%(7/75), and the difference was also statistically significant (χ^2=6.95, P=0.008). ③ The 2-year DFS and OS rates in the IKZF1 gene deletion group were (72.7±13.4)% and (81.8±11.6)%, respectively, which were significantly lower than those of IKZF1 non-deletion group with (92.3±3.0)% and (94.4±2.8)%, and the differences were significant (P<0.05).Conclusions Deletion of the IKZF1 gene is one of the high-risk predictors of recurrence in children with B-ALL. It should be used as a risk factor to guide the risk stratification of B-ALL children in order to adjust the intensity of chemotherapy method and improve their prognosis.