Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study

Abstract

Purpose: To analyze the prognostic impact of Wilms' tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC.

Results: Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITD(negative)/NPM1(mutated) as low risk v FLT3-ITD(positive) and/or NPM1(wild-type) as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count.

Conclusion: We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML.

Figures

Fig A1.

(A) Disease-free and (B) overall survival of patients with CN-AML according to the mutational WT1 status (ie, patients with WT1 mutations [WT1mut] v patients without WT1 mutations [WT1wt]) and the FLT3-ITD/NPM1 molecular-risk group (ie, high risk: patients with FLT3-ITD and/or wild-type NPM1; low risk: patients without FLT3-ITD and with NPM1 mutation).

Fig 1.

Coexistence of WT1 mutations with mutations in other genes, such as NPM1, FLT3 (ITD), CEBPA, FLT3 (TKD), and MLL (PTD) among 21 patients who harbored WT1 mutations. (*) Indicates the presence of the CEBPA polymorphism c.1175_1180dup in patient 3.

Fig 2.

(A) Disease-free and (B) overall survival of patients with CN-AML according to mutational WT1 status (ie, patients with WT1 mutations [WT1mut] v patients without WT1 mutations [WT1wt]).