Prognostic Impact of WT1 Mutation on AML of Different Risk Groups Based on 2022 European Leukemianet (ELN) Risk Classification

Background The Wilms tumor 1 (WT1) gene, located on chromosome 11p13 exists in multiple isoforms. It has been implicated in the regulation of cell survival, proliferation and differentiation, and may function both as a tumor suppressor and an oncogene. Approximately 15% of acute myeloid leukemia (AML) patients carry WT1 mutations, and WT1 mutation have been shown to be independent predictor of worse clinical outcome in some but not all adult AML studies. Some studies suggested that NPM1-AML & AML with CEBPA double-mutation accompanied with WT1 mutation can alter their original favorable prognosis. Recently, a revised European LeukemiaNet (ELN) genetic risk classification has been published and the prognostic significance of WT1 mutation in three risk groups according to this 2022 ELIN risk classification is still unclear.

Objective To investigate the prognostic significance of WT1 gene mutations in acute myeloid leukemia (AML) patients with different risk of the 2022-ELN risk classification.

Methods 502 patients de novo AML diagnosed between March 2015 and July 2021 who underwent next-generation sequencing (NGS) tests and had MICM precise typing at the Peking University Institute of Hematology were enrolled in this study. The patients received chemotherapy ± hematopoietic stem cell transplantation (HSCT), and they were stratified into three groups according to the 2022 version of ELN-AML risk stratification.

Results Among 502 patients, a total of 71 (14.1%) patients carried WT1 mutations, of which 57 patients had mutations at a single locus, 8 patients had mutations at double sites, 5 patients had co-mutations at 3 sites in the WT1 gene, and 1 patient had mutations at 4 sites. Comparing the incidence of AML-related mutations between the WT1 mutation group and the wild-type group, the results showed that the concomitant rate of NPM1 mutations was lower in the WT1 mutation group than in the WT1 wild-type group (14.1% vs 27.1%, p=0.028), and the concomitant rate of CEBPA-bZIP mutations was higher in the WT1 mutation group than in the WT1 wild-type group (29.6% vs 10.9%, p<0.001). The concomitant rate of CEBPA double mutation was also higher in the WT1 mutation group than in the WT1 wild-type group (29.6% vs 10.4%, p<0.001), and the concomitant rate of GATA2 mutation was higher in the WT1 mutation group than in the WT1 wild-type group (14.1% vs. 4.4%, p=0.004). In addition, the WT1 gene expression level (WT1/ABL1) was higher in the WT1 mutation group than in the WT1 wild group at diagnosis (22.0% vs 13.5%, p=0.004). All patients were further divided into 6 groups based on 2022 ELIN risk classification and whether they received HSCT. There were 158 (31.5%) patients in the low-risk chemotherapy group, 73 (14.5%) in the low-risk transplantation group, 72 (14.3%) in the intermediate-risk chemotherapy group, 58 (11.6%) in the intermediate-risk transplantation group, 78 (15.5%) in the high-risk chemotherapy group, and 63 (12.5%) in the high-risk transplantation group. Univariate and multivariate COX regression analyses were performed including WT1 mutation, FAB classification, age, sex, and karyotype stratification indicators. In 58 patients who were intermediate-risk and received HSCT, patients with WT1 mutation resulted in higher cumulative incidence of relapse(CIR) in compared with those without WT1 mutation (52.3% vs 33.5%, HR=9.28, p<0.001). In the remaining 5 groups of patients, WT1 mutation seemed have no significant effect on overall survival(OS), event-free survival (EFS), or CIR in patients (p-values were all less than 0.05).

Conclusion Among intermediate-risk AML patients in the 2022 version of ELN stratification who received transplantation, the CIR after transplantation was higher in AML patients with WT1 mutation. It seemed that WT1 mutation was an independent risk factor for post-transplantation recurrence, and allogeneic HSCT cannot efficiently overcome the poor prognosis of WT1 mutation in the intermediate-risk group. Intermediate-risk AML with WT1 mutations still requires more active strategies to prevent relapse. Of course, the impact of WT1 mutation on prognosis needs to be further confirmed by expanding the sample size.

No relevant conflicts of interest to declare.