摘要目的 评价根据骨髓微小残留病(MRD)检测调整儿童急性淋巴细胞白血病(ALL)危险度分组的意义.方法 前瞻性选取2008年4月至2011年8月于中国医学科学院血液病医院就诊并采用CCLG-2008方案系统治疗的初诊标危、中危ALL患儿共285例,其中男179例(62.8％)、女106例(37.2％),年龄5.3(0.5 ～14.0)岁.无需涉及MRD调整危险度分组已定义为高危组的初诊ALL患儿不在本研究范围.根据初次于本院确诊并入组的时间分组:Ⅰ组:2008年4月至2009年12月的初诊,共126例,均按CCLG-2008方案设定的危险度分组进行划分及治疗,且未根据骨髓MRD水平调整危险度分组及治疗方案;Ⅱ组:2010年1月至2011年8月初诊患儿,共159例,除按CCLG-2008方案设定的危险度分组进行划分及治疗外,在治疗过程中将根据不同时期(诱导治疗的第33天以及整体治疗的第12周)MRD的水平调整其危险度分组及治疗方案.两组患儿均采用四色荧光抗体标记的流式细胞仪进行MRD检测.组间比较采用t或x2检验,生存曲线采用Kaplan-Meier分析,多因素分析采用Cox回归分析.结果 本组285例患儿中B细胞型268例(94.0％),T细胞型17例(6.0％);中枢神经系统(CNS)1状态232例(81.4％),CNS 2状态48例(16.8％),CNS 3状态5例(1.8％).Ⅰ组标危78例(61.9％),中危48例(38.1％);Ⅱ组调整前标危109例(68.6％),中危50例(31.4％),调整后标、中、高危比例分别为:53.5％(85例)、39.6％(63例)和6.9％(11例).285例患儿均随访2.5年,总复发率为7.4％(21例),Ⅰ组和Ⅱ组分别为12.7％(16例)和3.1％(5例)(P=0.009);败血症、侵袭性真菌感染、坏死性小肠炎等较为严重感染的发生率为32.3％(92/285),Ⅰ组和Ⅱ组分别为28.6％(36/126)和35.2％ (56/159) (P =0.392);总病死率为6.7％(19/285),Ⅰ组和Ⅱ组分别为10.3％(13/126)和3.8％ (6/159) (P =0.044).应用Kaplan-Meier法单因素分析两组患儿2.5年总生存期、无事件生存期(EFS)及无病生存期(DFS):Ⅰ组均低于Ⅱ组(均P＜0.05).Cox多元回归法多因素分析患儿2.5年总生存期、EFS及DFS,在排除了年龄、性别、初始白细胞计数、血红蛋白、血小板、幼稚细胞比例、初始骨髓幼稚细胞比例、融合基因、染色体核型等众多影响因素后,应用MRD进行调整危险度分组及治疗有利于延长患儿的总生存期、EFS及DFS(均P＜0.05).调整后的危险度分组越高其预后越差(均P＜0.05).结论应 用MRD调整危险度分组没有增加患儿严重感染的发生率,但有利于降低患儿的复发率及病死率,提高总生存期、EFS及DFS.

abstractsObjective To estimate the significance of the adjustment of acute lymphoblastic leukemia (ALL) risk group by monitoring minimal residual disease(MRD).Method Totally 285 children ALL patients who were diagnosed and systematically treated according to CCLG-2008 in Institute of Hematology and Blood Diseases Hospital,CAMS and PUMC,from April 2008 to August 2011 were prospectively selected.Among these cases,62.8％ (n =179) were boys and 37.2％ (n =106) were girls and the median age was 5.3 (0.5-14.0).The patients who were at high-risk group initially were excluded.The grouping of eases:the patients were divided into two groups according to the dates of initial diagnosis.Group Ⅰ had 126 patients who were initially diagnosed between April 2008 and December 2009 in whom therapeutic regimen was not adjusted by reassignment of risk group by MRD.Group Ⅱ had 159 patients who were initially diagnosed between January 2010 and August 2011 whose therapeutic regimen was adjusted by reassignment of risk group by MRD at specific time (33rd day of induction chemotherapy and 12 weeks after the beginning of chemotherapy).MP-FCM Coulter FC-500 was used in the detection of MRD.Result Among these 285 patients,94.0％ (n =268) were diagnosed as B-lineage acute lymphoblastic leukemia and 6.0％ (n =17) were T-lineage acute lymphoblastic leukemia.In group Ⅰ,61.9％ (n =78) patients belonged to low-risk group,38.1％ (n =48) median-risk; in group Ⅱ,before the adjustment,the rates of the low-risk group and median-risk group were 68.6％ (n =109)and 31.4％ (n =50),respectively,while after the adjustment they were altered to 53.5％ (n =85)and 39.6％ (n =63),furthermore 6.9％ (n =11)patients went into the high-risk group.Both groups were followed up for 2.5 years after their diagnoses,the disease of 7.4％ (n =21) patients relapsed,and the rates of two groups were 12.7％ (n =16) and 3.1％ (n =5) respectively,P =0.009.The rate of serious infection (such as sepsis,pulmonary infection) of all these patients was 32.3％ (92/285),there was no significant difference between the two groups [28.6％ (36/126) vs.35.2％ (56/159),P =0.392].The mortality of all these patients was 6.7％ (19/285),and that of group Ⅰ was higher than that of group Ⅱ [10.3％ (13/126)vs.3.8％ (6/159),P =0.044].The 2.5 years overall survival (OS),event-free survival (EFS) and disease-free survival (DFS) of group Ⅰ were all lower than those of group Ⅱ in Kaplan-Meier survivorship analysis (all P ＜ 0.05).The two groups were followcd up for 2.5 years after their diagnoses,after elimination of the confounding influence of sex,age,FAB subtype,WBC count,ratio of blast cells in bone marrow at diagnosed,chromosome karyotype and fusion gene,reassignment of risk group by MRD was used to calculate the OS,EFS and DFS of ALL patients (all P ＜ 0.05).After the adjustment the risk group was more significant in the assessment of prognosis.Conclusion The reassignment of risk group in low and median risk groups children with acute lymphoblastic leukemia by MRD did not increase the rate of serious infection but could reduce the relapse rate and mortality,and was beneficial to increase the patients' OS,EFS and DFS.