多参数流式细胞术动态监测儿童B系急性淋巴细胞白血病微量残留病的临床意义

摘要本研究旨在探讨儿童B系急性淋巴细胞白血病（B-ALL）化疗过程中监测不同时间点微量残留病（MRD）水平的临床意义。回顾性分析我院2008年8月至2011年9月以流式细胞术监测3个时间点（即诱导化疗第15天、第33天和治疗第12周）的206例B-ALL患儿骨髓的MRD。结果表明：①206例B-ALL患儿中196例诱导化疗后迭完全缓解（CR）（CR率95．1％），其1年与3年无事件生存（EFS）率分别为（92．7±1．8）％和（78．7±3．7）％，其中标危、中危、高危组的3年EFS率分别为（85．6±4．9）％、（82．1±5．8）％和（58．1±9．2）％，3组比较有明显统计学差异（P〈0．001）；②各时间点上MRD分析显示：MRD水平越高，患儿的3年EFS率越低，其中第15天MRD≥10^-2组、第33天和第12周MRD≥10^-3组的患儿预后明显不佳；多因素分析显示，第12周MRD≥10^-3为独立的不良预后因素；第12周MRD〈10^-3的3年EFS率为（86．3±4．1）％，MRD≥10^-3的3年EFS率为（55．8±9．1）％，差异有统计学意义（P〈0．05）；③在化疗第33天MRD阴性（MRD〈10^-4）的98例患儿中有8例复发（复发率为8．2％），在这98例惠儿中有39例在第12周时转为阳性（MRD≥10^-4），其中5例复发；在第12周时MRD仍为阴性的59例中有3例复发；在第33天MRD阳性的108例患儿中有19例复发（复发率为17．6％），复发率在MRD阳性和阴性两组间差异有统计学意义（P〈0．05）。结论：B-ALL患儿治疗过程中以流式细胞术动态监测MRD可有效地评估治疗反应、判断预后、预测复发及指导化疗方案的调整，其中第15天、第33天及第12周的MRD分别以10^-2、10^-3、10^-3为区分危险度最佳界值，第12周MRD≥10^-3为独立的不良预后因素。

Clinical Significance of Dynamic Monitoring the Minimal Residual Disease in Childhood B-lineage Acute Lymphoblastic Leukemia by Multiparameter Flow Cytometry

This study was aimed to explore the clinical significance of monitoring level of minimal residual disease （MRD） at different time point in B-lineage childhood acute lymphoblastic leukemia （B-ALL）. Two hundred and six childrens with B-ALL were enrolled in this study from Augest 2008 to September 2011 in our hospital. MRD levels were detected by flow cytometry at day 15, 33 and week 12 after initiai chemotherapy. The event-free survival （EFS） for patients based on MRD levels measured at different stages of chemotherapy were compared by Kaplan Meier analyses. The results showed that out of 206 cases 196 cases achieved complete remission （CR） after induction therapy （ CR rate 95.1% ）, the 1- and 3-year EFS rate were （92.7 ± 1.8） % and （78.7 ± 3.7 ） %, respectively, and the 3-year EFS rate was （ 85.6 ± 4.9） % in standard risk group, （82.1 ± 5.8 ） % in intermediate risk group and （58.1 ± 9.2） % in high risk group, there was significant statistical difference between above menthoned 3 groups （ P 〈 0.001 ）. The MRD analysis at different time points showed that the higher the MRD level, the lower the 3-year EFS rate of childrens with ALL, in which the 3-year EFS rate of MRD ≥10^-2 at day 15, MRD ≥ 10^-3 at day 33 and MRD ≥ 10^-3 at week 12 were significantly lower. The MRD ≥ 10^-3 at week 12 was proven to be an independent predictor by multivariate Cox proportional-hazards regression model. The 3-year EFS rate for patients with MRD 〈 10^-3 and MRD ≥10^-3 at week 12were （86.3 ±4.1 ） % vs（55.8 ±9.1 ） % （P 〈0.05） ; 8 relapsed among 98 cases with negative MRD（ MRD 〈 10^-4 ） at day 33, 19 relapsed among 108 cases with positive MILD at day 33 between the two groups for recurrence rate has significant difference （P 〈 0.05）. It is concluded that dynamically monitoring MRD by multi-parameter flow cytometry can precisely evaluate treatment response, judge treatment outcome and predict relapse in childhood B-ALL. The MRD 10^-2 at day 15, MRD 10^-3 at day 33 and MRD 10^-3 at week 12 should be considered as the best cut-off. MRD≥10-3 at week 12 was proven to be an independent factor of poor prognosis.