Wilms' tumor gene 1 is an independent prognostic factor for pediatric acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation

Abstract

Background: Sequential monitoring of Wilms' tumor gene 1 (WT1) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) could predict relapse in adult acute myeloid leukemia (AML). However, the prognostic role of WT1 in pediatric AML after allo-HSCT is unclear. Thus, we determined to see whether sequential monitoring of WT1 after allo-HSCT could predict relapse in AML children.

Methods: Pediatric AML patients receiving allo-HSCT from January 21, 2012 to December 20, 2018 at the Peking University Institute of Hematology were included in this study. WT1 expression level was determined by TaqMan-based reverse transcription-polymerase chain reaction. WT1 sequential monitoring was performed 1, 2, 3, 4.5, 6, 9, and 12 months post-transplantation and at 6-month intervals thereafter. The primary end point was relapse. The secondary end points included disease-free survival (DFS), overall survival (OS), and non-relapse mortality (NRM). Kaplan-Meier analysis was used for DFS and OS estimates, while competing risk analysis was used for estimating relapse and NRM.

Results: Of the 151 consecutive patients included, the median age was 10 years (range, 1-17). The optimal cutoff value of WT1 within 1 year after allo-HSCT to predict relapse was 0.8% (80 WT1 copies/10⁴ ABL copies), with a sensitivity of 60% and specificity of 79%. Compared with WT1 expression < 0.8%, WT1 expression ≥0.8% indicated significantly higher 5-year cumulative incidence of relapse (CIR, 35.1% vs. 11.3%; P = 0.001), lower 5-year disease-free survival (DFS, 60.4% vs. 80.8%; P = 0.009), and lower 5-year overall survival (OS, 64.9% vs. 81.6%; P = 0.038) rates. Multivariate analyses showed that WT1 was an independent risk factor for relapse (HR 2.89; 95% confidence interval (CI), 1.25-6.71; P = 0.014). Both the CIR (5-year CIR: 8.3% vs. 11.3%; P = 0.513) and DFS (5-year DFS: 91.7% vs. 80.8%; P = 0.208) were comparable between patients achieving minimal residual disease (MRD) negativity after preemptive interferon-α (IFN-α) treatment and those without MRD after allo-HSCT, which were better than those of MRD-positive patients without preemptive therapies.

Conclusions: Sequential monitoring of WT1 could predict relapse in pediatric AML after allo-HSCT. WT1-directed immunotherapy may have the potential to prevent relapse and improve survival.

Keywords: Acute myeloid leukemia; Allogeneic hematopoietic stem cell transplantation; Pediatric; Relapse; Wilms’ tumor gene 1.

Fig. 1

WT1 expression at different points after allo-HSCT in patients maintaining CR without interventions (n = 81). Horizontal bars show the median values of WT1 at each time point

Fig. 2

The outcomes of patients without preemptive interventions according to WT1 after allo-HSCT (n = 96): a relapse, b non-relapse mortality, c disease-free survival, and d overall survival

Fig. 3

The relapse of patients according to MRD status after allo-HSCT. a 2-year CIR in patients without any preemptive interventions (n = 96): WT1+ alone vs. MRD-: 28.4% vs. 9.2%, P = 0.032; MRDco+ vs. MRD-: 57.1% vs. 9.2%, P < 0.001; WT1+ alone vs. MRDco+: 28.4% vs. 57.1%; P = 0.168. b 5-year CIR in all patients (n = 151): WT1+ alone vs. MRD-: 29.8% vs. 11.3%, P = 0.013; MRDco+ vs. MRD-: 55.8% vs. 11.3%, P < 0.001; WT1+ alone vs. MRDco+: 29.8% vs. 55.8%, P = 0.060

Fig. 4

The outcomes of patients according to preemptive IFN-α treatment. a 5-year CIR: MRD- after IFN vs. MRD-: 8.3% vs. 11.3%, P = 0.513; MRD- after IFN vs. MRD+ without intervention: 8.3% vs. 36.2%, P = 0.024; MRD- vs. MRD+ without intervention: 11.3% vs. 36.2%, P = 0.004. b 5-year DFS: MRD- after IFN vs. MRD-: 91.7% vs. 80.8%, P = 0.208; MRD- after IFN vs. MRD+ without intervention: 91.7% vs. 59.9%, P = 0.014; MRD- vs. MRD+ without intervention: 80.8% vs. 59.9%, P = 0.019