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J Clin Oncol. 2008 Oct 1;26(28):4595-602. doi: 10.1200/JCO.2007.15.2058. Epub 2008 Jun 16.

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

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1
Division of Hematology and Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.

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.

PMID:
18559874
PMCID:
PMC2653131
DOI:
10.1200/JCO.2007.15.2058
[Indexed for MEDLINE]
Free PMC Article

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