WT-1基因在急性髓系白血病预测分子学复发的分界值测定及其对预后的影响

朱化超; 贺鹏程; 习杰英; 任娟; 李淼静; 陈颖; 王晓宁; 张海玲; 张梅

doi:10.13201/j.issn.1004-2806.2020.09.008

WT-1基因在急性髓系白血病预测分子学复发的分界值测定及其对预后的影响

- 西安交通大学第一附属医院血液内科(西安, 710061)
基金项目:
陕西省重点研发计划项目(No:2020SF-176)

详细信息

通讯作者: 张梅,E-mail:zhangmei@medmail.com.cn

中图分类号: R733.71

收稿日期: 2020-07-14

Determination of the cut-off value of WT-1 for predicting molecular recurrence in patients with acute myeloid leukemia and its influence on prognosis

- Department of Hematology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China

More Information

Corresponding author: ZHANG Mei, E-mail: zhangmei@medmail.com.cn

Received Date: 14 July 2020

摘要

摘要: 目的:通过急性髓系白血病(AML)相关基因检测和受试者特征曲线(ROC)确定WT-1基因预测分子学复发的分界值,并验证该分界值是否与AML患者预后相关。方法:回顾性分析70例AML患者,应用多参数流式细胞法(MFC)测定异常免疫表型、RQ-PCR法或基因测序法测定白血病相关基因表达、同时测定WT-1基因水平。根据巩固治疗期间是否达到微小残留病灶(MRD)阴性将其分为MRD阴性(MFC阴性和白血病相关基因阴性)和MRD阳性[MFC阳性和(或)白血病相关基因阳性]两组,依据ROC曲线计算2组之间WT-1分界值。然后应用该WT-1分界值将患者分为WT-1(-)和WT-1(+)两组,应用 Kaplan-Meier 法进行评估预后,观察2组患者的累积复发率和无疾病生存期是否存在统计学差异。结果:使用ROC曲线分析得到WT-1分界值为3.68×10^-3,其特异度为87.6%,敏感度为41.7%,约登指数为0.293。巩固治疗1个疗程后,根据该分界值将70例患者分为WT-1(-)组46例(≤3.68×10^-3)和WT-1(+)组17例(>3.68×10^-3),7例失访。2组3年累积复发率分别为26.08%(12/46)和94.12%(16/17)(P<0.001),中位无疾病生存期分别为28个月和10个月,Log-rank检验2组间比较差异有统计学意义(P<0.001)。结论:应用AML相关基因检测和ROC曲线,可以确定不同实验室的WT-1分界值;巩固化疗后WT-1阴性的患者与WT-1阳性患者相比,复发率低,无疾病生存期延长。
- 急性髓系白血病 /
- WT-1基因 /
- 微小残留病 /
- 分子学复发
Abstract: Objective: To determine the cut-off value of Wilms' tumor gene 1 (WT-1) for predicting molecular recurrence by acute myeloid leukemia (AML)-related genes and receiver operating characteristic (ROC) curve,and verify whether the cut-off value is related to the prognosis of AML patients.Method: A retrospective analysis of 70 patients with AML was performed.We used multiparameter flow cytometry (MFC) to determine abnormal immune phenotypes,RQ-PCR or gene sequencing to determine leukemia-related gene and WT-1 gene quantification.The patients were divided into two groups:MRD negative (both MFC and leukemia-related gene negative) and MRD positive (MFC or leukemia related gene positive).We used the ROC curve to determine WT-1 cut-off value.The patients were divided into two groups by the WT-1 cut-off value and the Kaplan-Meier method was used to evaluate the prognosis.We observed whether the cumulative relapse rate and disease-free survival between the two groups was significantly different.Result: The cut-off value of WT-1 (WT-1/ABL) was 3.68×10^-3.The specificity was 87.6%,the sensitivity was 41.7%,and the Youden index was 0.293.After the first consolidation therapy,70 patients were divided into 46 cases in WT-1 (-) group (≤3.68×10^-3) and 17 cases in WT-1 (+) group (>3.68×10^-3),7 cases were lost to follow-up.The three-year cumulative recurrence rate of the two groups was 26.08% (12/46) vs 94.12% (16/17) (P<0.001),and the median disease-free survival was 28 months vs 10 months in WT-1(-) group and WT-1(+) group.The Log-rank test showed a significant difference between the two groups (P<0.001).Conclusion: WT-1 cut-off value can be determined by AML-related gene quantification and ROC curves in different laboratories,which is related to the prognosis of patients.Patients obtained WT-1(-) [HK]
- acute myeloid leukemia /
- Wilms' tumor gene 1 /
- minimal residual disease /
- molecular relapse

HTML全文

参考文献(17)

[1]	Dohner H,Weisdorf DJ,Bloomfield CD.Acute Myeloid Leukemia[J].N Engl J Med,2015,373:1136-1152.
[2]	Israyelyan A,Goldstein L,Tsai W,et al.Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation[J].Bone Marrow Transplant,2015,50:26-33.
[3]	Hao Y,Cheng Y,Wu Q,et al.Combined usage of Wilms' tumor gene quantitative analysis and multiparameter flow cytometry for minimal residual disease monitoring of acute myeloid leukemia patients after allogeneic hematopoietic stem cells transplantation[J].Exp Ther Med,2018,15:1403-1409.
[4]	Malagola M,Skert C,Borlenghi E,et al.Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients[J].Cancer Med,2016,5:265-274.
[5]	Duléry R,Nibourel O,Gauthier J,et al.Impact of Wilms' tumor 1 expression on outcome of patients undergoing allogeneic stem cell transplantation for AML[J].Bone Marrow Transplant,2017,52:539-543.
[6]	Dohner H,Estey E,Grimwade D,et al.Diagnosis and management of AML in adults:2017 ELN recommendations from an international expert panel[J].Blood,2017,129:424-447.
[7]	Daver N,Schlenk RF,Russell NH,et al.Targeting FLT3 mutations in AML:review of current knowledge and evidence[J].Leukemia,2019,33:299-312.
[8]	尤亚红.WT1基因异常表达在血液系统疾病中的意义[J].临床血液学杂志,2018,31(7):570-572.
[9]	Marjanovic I,Karan-Djurasevic T,Ugrin M,et al.Use of Wilms Tumor 1 Gene Expression as a Reliable Marker for Prognosis and Minimal Residual Disease Monitoring in Acute Myeloid Leukemia With Normal Karyotype Patients[J].Clin Lymphoma Myeloma Leuk,2017,17:312-319.
[10]	张玉玲,李海亮.WT1基因与造血系统肿瘤研究现状[J].临床血液学杂志,2017,30(5):395-398.
[11]	Qin Y,Wang Y,Zhu H,et al.Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation[J].Chin J Cancer,2016,35:46.
[12]	Cho BS,Min GJ,Park SS,et al.WT1 Measurable Residual Disease Assay in Patients With Acute Myeloid Leukemia Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation:Optimal Time Points,Thresholds,and Candidates[J].Biol Blood Marrow Transplant,2019,25:1925-1932.
[13]	Løvvik Juul-Dam K,Guldborg Nyvold C,Valerhaugen H,et al.Measurable residual disease monitoring using Wilms tumor gene 1 expression in childhood acute myeloid leukemia based on child-specific reference values[J].Pediatr Blood Cancer,2019,66:e27671.
[14]	Candoni A,De Marchi F,Zannier ME,et al.High prognostic value of pre-allogeneic stem cell transplantation minimal residual disease detection by WT1 gene expression in AML transplanted in cytologic complete remission[J].Leuk Res,2017,63:22-27.
[15]	Zhao XS,Yan CH,Liu DH,et al.Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity[J].Ann Hematol,2013,92:1111-1119.
[16]	Tomlinson B,Lazarus HM.Enhancing acute myeloid leukemia therapy-monitoring response using residual disease testing as a guide to therapeutic decision-making[J].Expert Rev Hematol,2017,10:563-574.
[17]	Liu H,Wang X,Zhang H,et al.Dynamic changes in the level of WT1 as an MRD marker to predict the therapeutic outcome of patients with AML with and without allogeneic stem cell transplantation[J].Mol Med Rep,2019,20:2426-2432.