儿童急性淋巴细胞性白血病微小残留病监测的预后意义

目的 研究儿童急性淋巴细胞性白血病(ALL)化疗过程中,不同时间点监测的不同微小残留病(MRD)水平的预后意义.方法 对102例ALL患儿进行MRD监测研究,分别在患儿诱导化疗开始后第15天、第29天、第3个月、第6个月、第12个月进行MRD监测.根据患儿初诊时免疫表型特征,采用流式细胞术检测不同的四色单克隆抗体组合.常用的抗体组合包括CD45CD19CD34CD10和CD45CD19CD34CD20等.结果 102例ALL患儿的5年总体生存(OS)率和无事件生存(EFS)率分别为(86.9±3.4)%和(79.9±4.0)%,共12例患儿复发.在第15天、29天、3个月、6个月和12个月,分别有14.3%、43.9%、39.1%、39.7%和45.6%的患儿处于MRD阴性(MRD<10~(-4)).其中MRD水平能在1年内达到阴性的患儿的长期存活率明显高于MRD持续阳性的患儿[5年EFS:(92.5±3.2)% vs. (58.3±8.6)%,P<0.001].各时间点上,化疗后第15天时MRD≥10~(-2)[(79.8±10.3)% vs.(28.6±17.1)%,P<0.001]、第29天时MRD≥10~(-3)[(88.3±4.9)% vs.(51.3±14.4)%,P<0.003]、第3个月[(92.4±5.1)% vs.(65.5±7.5)%,P<0.015]、6个月[5-year EFS rates(96.3±3.6)% vs.(65.4±7.5)%,P<0.003]及第12个月[(100.0±0.0)% vs.(67.7±8.4)%,P<0.002]时MRD≥10~(-4)的患儿的5年EFS率明显较差.而第15天时MRD≥10~(-2)是独立的不良预后因素.结论 采用流式细胞术动态监测MRD水平能有效地评估ALL患儿的预后,而不同时间点上具有预后意义的MRD水平并不相同.

Monitoring of minimal residual disease in children with acute lymphoblastic leukemia and its prognostic significance

Objective Monitoring of minimal residual disease(MRD)is proven to be increasingly valuable for predicting relapse and outcome of childhood acute lymphoblastic leukemia(ALL)and is used to identify patients'risk groups in several current clinical trials.However,the limitation is that most studies focused on the cut-off value at 10~(-4) and the time point after induction.The aim of this study was to investigate the predictive values of different MRD levels detected at different chemotherapy phases in childhood ALL. Methods One hundred and two patients were enrolled in this study from January 2002 to December 2004 in our hospital. All the patients were treated with modified National Protocol of Childhood ALL in China,1997.MRD levels were detected on the 15th day,29th day,at 3 months,6 months and 12 months after initial chemotherapy.All samples were stained with a panel of four colour combinations of fluorochrome conjugated monoclonal antibodies according to the leukemia-associated immunophenotype (LAIP)defined at diagnosis and analyzed by multi-parametric flow cytometry.CD45CD19CD34CD10,CD45CD19CD34CD20 and CD45CDl9CD10CD20 were the most common combinations in B lineage ALL,while CD45CD2CD3CD7 and CD45CD2CD3CD34 were the most frequently used immunophenotypes for T lineage ALL The median follow-up time Was 63.3 months ranged from 40.6 to 87.5 months.Results Of the 102 patients,64 were male and 38 were female,with a median age of 5.7(0.2-14.8)years.Eighty-eight cases were diagnosed as B lineage ALL and the remaining 14 were T-ALL The 5-year overall survival (OS) rate and event free survival (EFS) rate for this cohort were(86.9±3.4)% and (79.9±4.0)%,respectively.Twelve patients underwent relapse.Among the 102 patients,14.3%had negative MRD(MRD <10~(-4)) on day 15,43.9%on day 29,39.1%,39.7%and 45.6% had negative MRD at the third,sixth and twelfth month after chemotherapy.Patients who could achieve negative MRD within one year had superior outcome to the others[5-year EFS rates:(92.5±3.2)% vs.(58.3±8.6)%,P<0.001].The EFS for patients based on MRD levels measured at different stages of therapy were compared by Kaplan-Meier analyses.MRD was predictive of outcome at all 5 time points at a range of thresholds.The optimum threshold,selected for each time point on the basis of log rank analysis,progressively dropped from 10~(-2) of day 15[5-year EFS rates(79.8±10.3)% vs.(28.6±17.1)%,P<0.001],to 10~(-3) of day 29 [5-year EFS rates(88.3±4.9)% vs.(51.3±14.4)%,P<0.003 ],to 10~(-4) at 3 [5-year EFS rates(92.4±5.1)% vs. (65.5±7.5)%,P<0.015],6[5-year EFs rates (96.3±3.6)% vs.(65.4±7.5)%,P<0.003 ] and 12 [ 5-year EFS rates(100.0±0.0)% vs.(67.7±8.4)%,P<0.002]months.And the hazard ratios for relapse and death at higher MRD level groups were 5.91(95% CI:1.9-18.9),5.02 (95%CI:1.5-16.5),5.21(95%CI:1.2-22.9)and 11.10(95%CI:1.5-84.5)on day 15,day 29,at month 3 and month 6,respectively.And MRD≥10~(-2) on day 15 was proven to be independent predictor by multivariate Cox proportional-hazards regression model. Conclusion Dynamic MRD detection by multi-parametric flow cytometry is highly predictive of outcome for childhood ALL,and the cut-off values at different time points were different.