Efficacy of WT1 gene-guided pre-emptive therapy for prevention of relapse in acute myeloid leukemia after transplantation and its optimal intervention threshold.

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.