微量残留病在儿童B系急性淋巴细胞白血病危险分层及预后中的临床意义

Clinical Significance of Minimal Residual Disease in Risk Stratification and Prognosis of Childhood B-lineage Acute Lymphoblastic Leukemia

目的:探讨儿童B系急性淋巴细胞性白血病(B-ALL)治疗过程中不同时间点的微量残留病(minimal residual disease,M RD)水平在B-ALL危险分层及临床预后中的意义。方法:回顾性分析我院2008年8月1日至2013年1月1日以流式细胞术监测3个不同时间点(即诱导化疗第15天、第33天和治疗第12周)的380例BALL患儿骨髓M RD与5年无事件生存(EFS)率和总生存(OS)率的关系。结果:患儿的年龄、初诊白细胞数、染色体、MLL、BCR/ABL、预处理反应、第33天骨髓MRD与患儿的5年EFS率密切相关。多参数流式细胞术检测MRD有标记和MRD无标记与患儿5年EFS率之间差异无统计学意义(P=0.564);且各免疫表型与5年EFS率之间的差异也无统计学意义(P=0.84)。第15天MRD>10^(-2)(P=0.004)、第33天MRD>10^(-3)(P<0.001)、第12周M RD>10^(-3)(P<0.001)的患儿5年EFS率及总生存率减低与不良预后明显相关。第33天MRD<10^(-4)(阴性)、10^(-4)-10^(-3)、10^(-3)-10^(-2)、≥10^(-2)的5年EFS率分别为86.6±2.7%、77.5±4.9%、70.1±8.0%、44.8±9.9%(P<0.001);5年OS率分别为89.5±2.7%、80±4.9%、76.0±7.8%、53.2±10.1%(P<0.001)。结论:第33天M RD≥10^(-2)是B-ALL患儿5年EFS率和OS率显著减低的高危因素。缓解后动态监测MRD水平有助于预测B-ALL复发。

Objective： To explore clinical significance of monitoring the level of minimal residual disease （MRD） at different time point in the risk stratification and prognosis of Childhood B - lineage Acute Lymphoblastic Leukemia. Methods： Three hundred and eighty cases of children＇s B-ALL from Augest 2008 to January 2013 in our hospital were enrolled in this study. MRD levels were detected at day 15, day 33 and week 12 after initial chemotherapy. The event- free survival（ EFS ） and overall survival （OS） were measured on the basis of MRD levels at different stages of chemotherapy and were compared by Kaplan Meier analyses. Results：The patient＇s age, initial white blood cell count, chromosome, MLL, BCR/ABL, pretreatment reaction, bone marrow MRD at days 33 were closely related with the 5 - year EFS rate. Multiparameter flow cytometry showed the marked MRD and unmarked MRD were not significantly different between their 5 - year EFS rate（ P 〉 0.05 ）, and the every immune phenotype was also no significantly different between the 5 -year EFS rate（P 〉0.05）. The children with MRD〉10 -2 at day 15（P 〈0.01 ）, MRD〉10 -3 at day 33 （ P 〈 0. 01 ） and MRD〉 10 -3 on week 12 （ P 〈 0. 01 ） have a decreased 5 - year EFS rate and overall survival, which related with poor prognosis obviously. The 5 -year EFS rates at the MRD 〈 10 -4 （negative）, 10^（-4）-10^（-3）、10^（-3）-10^（-2）、≥10^（-2）atday33 were 86.6±2.7%、77.5±4.9%、70.1±8.0%、44.8±9.9%（P〈0.001） with significant difference respectively; the 5 - year OS rate was 89.5±2.7%、80±4.9%、76.0±7.8%、53.2±10.1%（P〈0.001） with statistically significant difference （ P 〈 0.01 ）. Conclusion： The MRD i〉 10 - 2 at day 33 is a high risk factor for significant reduction of the 5 - year EFS rate and the 5 - year OS rate of children with B-ALL. Thus, dynamic monitoring the MRD level can predict relapse of B-ALL after remission.