诱导缓解第33天MRD与IKZFl基因型对于儿童急性B淋巴细胞白血病生存率的影响

Effects of minimal residual disease level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia

目的研究诱导缓解第33天微小残留病(MRD)与IKZF1基因型对于儿童急性B淋巴细胞白血病(B-ALL)生存率的影响。方法以第一疗程化疗获得完全缓解且有完整随访信息的152例初诊B-ALL患为研究对象。采用流式细胞术检测化疗第33天MRD,并分为3组:残留白血病细胞<10-4者为MRD标危组(60例),10-4≤MRD<10-2为MRD中危组(55例),MRD≥10-2为MRD高危组(37例)。应用巢式RT-PCR检测化疗前所有患儿的IKZF1基因型。分析诱导缓解第33天MRD及IKZF1基因型对B-ALL患儿无复发生存率的影响。结果 152例初诊B-ALL患儿有7种常见IKZF1基因亚型:IK1、IK2/3、IK4、IK6、IK8、IK9和IK10,其中130例表达IKZF1基因功能亚型、22例为IKZFl基因功能缺失亚型。随访期间26例(17%)患儿复发,以高危患儿复发率最高(P<0.05),而标危、中危组复发率的差异无统计学意义(P>0.05)。IKZFl基因功能缺失亚型阳性患儿的累计复发率高于IKZFl基因功能亚型阳性的患儿(P<0.01)。MRD标危、中危、高危患儿的预计5年无复发生存率分别为(94.2±2.9)%、(86.7±3.8)%和(56.2±4.5)%,三组间的差异均有统计学意义(P<0.05)。IKZFl基因功能亚型阳性患儿的5年无复发生存率高于功能缺失亚型阳性患儿(P<0.01)。MRD标危组IKZFl基因功能亚型阳性患儿的预计5年无复发生存率与功能缺失亚型阳性患儿的差异无统计学意义(P>0.05),中危组和高危组中IKZFl基因功能亚型阳性患儿的预计5年无复发生存率均高于功能缺失亚型阳性患儿(P<0.05)。结论 IKZFl基因功能缺失亚型阳性的B-ALL患儿复发率高,尤其是化疗第33天MRD≥10-4的IKZF1基因功能缺失亚型阳性B-ALL患儿。

Objective To study the effects of minimal residual disease（MRD） level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia（B-ALL）. Methods A total of 152 children with newly-diagnosed B-ALL who had complete remission after the first cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups： standard-risk（SR） group（MRD 10-4; n=60）, intermediate-risk（IR） group（10-4≤ MRD〈 10-2; n=55）, and high-risk（HR） group（MRD ≥10-2; n=37）. Nested RT-PCR was used to determine the IKZF1 genotype of all children before chemotherapy. The effects of MRD level on day 33 of remission induction and IKZF1 genotype on the recurrence-free survival（RFS） of children with B-ALL were analyzed. Results There were 7 common IKZF1 subtypes in all the 152 children with B-ALL： IK1, IK2/3, IK4, IK6, IK8, IK9, and IK10. Of the 152 children, 130 had functional subtypes of IKZF1 and 22 had non-functional subtypes of IKZF1. During the follow-up period, relapse occurred in 26（17%） children, and the recurrence rate was highest in the HR group（P〈0.05）. However, there was no significant difference in the recurrence rate between the SR group and the IR group（P〉0.05）. The cumulative recurrence rate of the children with non-functional subtypes of IKZF1 was significantly higher than that of those with functional types of IKZF1（P〈0.01）. The predicted 5-year RFS rates in the SR, IR, and HR groups were（94.2±2.9）%,（86.7±3.8）%, and（56.2±4.5）% respectively（P〈0.05）. The 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1（P〈0.01）. There was no significant difference in the predicted 5-year RFS rate between the children with functional subtypes of IKZF1 and those with non-functional subtypes of IKZF1 in the SR group（P〉0.05）. However, the predicted 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with nonfunctional subtypes of IKZF1 in the IR group and the HR group（P〈0.05）. Conclusions B-ALL children with nonfunctional subtypes of IKZF1 have a high recurrence rate, and the recurrence rate will be even higher in B-ALL children with non-functional subtypes of IKZF1 and MRD ≥10-4 on day 33 of chemotherapy.