MRD监测对儿童B系急性淋巴细胞性白血病疗效评估的意义

Clinical importance of minimal residual disease testing in the therapy of childhood B-cell acute lymphoblastic leukemia

目的研究监测微小残留白血病(MRD)在B系急性淋巴细胞白血病(ALL)患儿治疗中的作用。方法回顾性研究了2001年9月1日至2005年4月31日,采用ALL-XH-99方案治疗的B系ALL患儿中进行MRD监测的患儿共124例。用四色多参数流式细胞仪监测ALL患儿治疗过程中不同时间点的MRD。结果在124例进行过MRD监测的B系ALL患儿中,其中MRD<0.01%、0.01%～0.1%和>0.1%的分别有103例、13例和8例,其5年无复发生存率(RFS)分别为(88.9±3.9)%、(70.0±14.5)%和0%,而5年无事生存率(EFS)分别为(82.4±4.4)%、(21.2±18.0)%和0%,两者均P<0.01;将首次CR后半年内MRD检查分成阴性(<0.01%)和阳性两组,其5年RFS分别为(87.7±4.1)%和(58.3±14.2)%,(P<0.01);5年EFS分别为(80.7±4.6)%和(25.6±13.8)%(P<0.01);首次CR后半年以后MRD检查阴性和阳性两组的5年RFS分别为(92.0±3.6)%和(48.5±15.5)%(P<0.01)。多因素分析显示结果显示诱导缓解后MRD、泼尼松诱导窗口反应、第19天骨髓象是否达M-1级骨髓象和是否检出BCR-ABL或MLL-AF4融合基因对患儿治疗过程中是否发生复发有预后价值(P<0.05)。结论在B系ALL患儿治疗过程中,无论在诱导缓解达到CR时,还是在随后的治疗过程中,监测MRD水平对于评估ALL患儿疗效有重要意义。

Objective To study the role of minimal residual disease （MRD） in the evaluation of therapeutic effectiveness of childhood B-cell acute lymphoblastic leukemia （ALL）. Methods MRD testing was performed in 124 children with B-cell ALL, who were newly diagnosed and enrolled in the ALL-XH-99 treatment protocol from September 2001 to April 2005. MRD was determined by 4-color flow cytometry in the different time points during the treatment period. Results After induction therapy, 103, 13 and 8 patients showed MRD 〈 0.01% , 0. 01%4）. 1% and 〉 0. 1% , respectively. The 5-year relapse-free survival （RFS） in the patients with MRD 〈 0.01% , 0.01% -0. 1% and 〉 0.1% was 88.9 ±3.9%, 70.0 ±14.5% and 0% , respectively and the 5-year event-free survival （EFS） was 82.4 ± 4.4% , 21.2 ± 18.0% and 0% , respectively. There were significant differences in the RFS and EFS among the patients with different MRD levels （P 〈 0.01 ）. Within half a year after induction remission, the 5-year RFS in patients with MRD negative （ 〈0.01% ） and positive was 87.7±4.1% and 58.3 ± 14.2%, respectively （ P 〈 0.01 ） and the 5-year RFS was 80.7± 4.6% and 25.6 ± 13.8% , respectively （ P 〈 0.01 ）. After half a year with induction remission, the patients with MRD negative and positive also showed statistical differences in the 5-year RFS （92.0 ±3.6% vs 48.5 ± 15.5% ; P 〈 0.01 ） and EFS （85.6 ±4.5% vs 21.4 ± 11.0% ; P 〈 0.01 ）. Multivariate analysis confirmed that the MRD level after induction chemotherapy together with the reaction to prednisone, the bone marrow features on the 19th day of induction, and the fusion gene with BCR-ABL or MLL-AF4 had prognostic significance in childhood B-cell ALL. Conclusions The MRD level in the whole course of therapy is an important outcome indicator in childhood B cell ALL.