Objectives: Monitoring minimal residual disease (MRD) and timely intervention are effective strategies for preventing relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult acute myeloid leukemia (AML). The WT1 gene, a pan-leukemia marker, can be used as an indicator for MRD monitoring in AML patients. Currently, there is no unified standard for the intervention timing or treatment threshold based on WT1 gene detection after transplantation. This study aims to evaluate the clinical value of WT1 gene-guided preemptive therapy and further explore its optimal intervention threshold.
Methods: Data of adult AML patients with intermediate or high-risk cytogenetics who underwent allo-HSCT between January 2014 and June 2020 at the Department of Hematology, Xiangya Hospital, Central South University, were retrospectively collected. All patients had WT1 gene expression data within three years post-transplantation. We compared the outcomes of WT1-positive patients who received preemptive therapy with those who did not, and both groups with WT1-negative patients. The endpoints analyzed included cumulative incidence of relapse (CIR), disease-free survival (DFS) rate, overall survival (OS) rate, and non-relapse mortality (NRM) rate. Data of patients who did not receive any intervention were included to analyze factors that might influence prognosis. Univariate analysis was performed using factors such as age, gender, transplantation type,cytogenetic risk stratification, pre-transplant disease status, pre- and post-transplant WT1 levels, and donor gender; factors with P<0.10 in univariate analysis were further included in a Cox regression model for multivariate analysis. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off value of WT1 gene expression for predicting relapse.
Results: A total of 165 AML patients were included, of whom 86 had WT1 gene positivity within three years post-transplantation. Among these, 58 received preemptive therapy and 28 did not. Compared with WT1-negative patients, those WT1-positive patients who did not receive preemptive therapy had significantly higher 5-year CIR (42.9% vs 10.5%, P<0.001), lower 5-year DFS (50.0% vs. 80.7%, P=0.001), and lower 5-year OS (60.7% vs 82.8%, P=0.018), while the 5-year NRM rates were not significantly different (7.1% vs 8.9%, P=0.744). For patients who received preemptive therapy, no significant differences in these outcomes were observed (all P>0.05). Multivariate analysis revealed that post-transplantation WT1 gene positivity was a poor prognostic factor for AML patients (CIR: HR=6.24, P=0.000 1; DFS: HR=2.77, P=0.009 6). ROC curve analysis indicated that the area under the curve (AUC) for WT1 gene expression predicting post-transplantation relapse within 3 years was 0.727 (95% CI 0.582 to 0.873), with an optimal cut-off value of 122 copies, sensitivity of 60.0%, and specificity of 89.9%.
Conclusions: sequential monitoring of WT1 gene expression in intermediate- or high-risk AML patients after allo-HSCT within 3 years, with timely preemptive therapy for those who become WT1-positive, can effectively reduce relapse and improve prognosis. A WT1 gene expression level of 120 copies may be a more precise and reliable intervention threshold for preemptive therapy.
目的: 微量残留病(minimal residual disease，MRD)的监测与及时干预是预防成人急性髓系白血病(acute myeloid leukemia，AML)异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation，allo-HSCT)后复发的有效策略。泛白血病标志物WT1基因可作为AML患者MRD的监测指标。目前，临床上关于移植后基于WT1基因检测的抢先治疗的干预节点及干预时机尚无统一的标准。本研究旨在评估WT1基因指导的抢先治疗的临床价值，并进一步探讨其最佳干预节点。方法: 回顾性收集2014年1月至2020年6月间在中南大学湘雅医院血液科接受allo-HSCT的细胞遗传学风险为中危和高危成人AML患者的资料，所有患者均有移植后3年内的WT1基因表达检测数据。比较移植后接受抢先治疗的WT1基因阳性患者、未接受抢先治疗的WT1基因阳性患者之间，以及二者分别与移植后WT1基因阴性患者间终点指标[累积复发率(cumulative incidence of relapse，CIR)、无病生存(disease-free survival，DFS)率、总生存(overall survival，OS)率、非复发死亡(non-relapse mortality，NRM)率]的差异。纳入移植后未行干预的患者的数据，对可能影响预后的因素进行分析。将患者的年龄、性别、移植类型、细胞遗传学危险分层、移植前疾病状态、移植前WT1基因表达情况、移植后WT1基因表达情况、供者性别纳入单因素分析；进一步对单因素分析中P<0.10的因素纳入Cox回归模型进行多因素分析。采用受试者操作特征(receiver operating characteristic，ROC)曲线分析WT1基因表达水平预测复发的最佳截断值。结果: 共纳入165例AML患者，86例在移植后3年内出现WT1基因阳性，其中58例接受抢先治疗，28例未接受抢先治疗。与移植后WT1基因阴性患者相比，未接受抢先治疗的WT1基因阳性患者的5年CIR明显升高(42.9% vs 10.5%，P<0.001)、5年DFS率(50.0% vs 80.7%，P=0.001)与OS率(60.7% vs 82.8%，P=0.018)明显降低，5年NRM率差异无统计学意义(7.1% vs 8.9%，P=0.744)；而接受抢先治疗的WT1基因阳性患者的上述指标差异均无统计学意义(均P>0.05)。多因素分析结果显示移植后WT1基因阳性是AML患者移植后预后不良因素(CIR：HR=6.24，P=0.000 1；DFS率：HR=2.77，P=0.009 6)。ROC曲线分析结果显示3年内WT1基因表达预测移植后复发的曲线下面积为0.727(95% CI 0.582~0.873)，最佳截断值为122拷贝，敏感度为60.0%，特异度为89.9%。结论: 连续监测细胞遗传学中高危AML患者allo-HSC后3年内WT1基因的表达，并对出现WT1基因表达阳性的患者进行及时的抢先治疗，能有效减少该类患者移植后的复发，改善预后。以WT1基因表达水平120拷贝作为抢先治疗的节点可能更为精准和可靠。.
Keywords: WT1 gene; acute myeloid leukemia; hematopoietic stem cell transplantation; minimal residual disease; preemptive therapy.