[362] Wilms Tumor 1 (WT1) Gene Mutations Predict Poor Outcome in Adults with Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML): A Cancer and Leukemia Group B (CALGB) Study. Session Type: Oral Session

Peter Paschka, Guido Marcucci, Amy S. Ruppert, Krzysztof Mrózek, Susan P. Whitman, Kati Maharry, Christian Langer, Claudia D. Baldus, Bayard L. Powell, Maria R. Baer, Andrew J. Carroll, Michael A. Caligiuri, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; CALGB, Chicago, IL, USA

The WT1 gene on chromosome 11p13 encodes a zinc-finger protein regulating gene transcription. A recent study conducted on 70 CN-AML patients (pts) found that 7 (10%) harbored WT1 mutations (WT1mut) and suggested that WT1mut are associated with failure to achieve complete remission (CR) (Summers et al., Leukemia 2007;21:550). However, the prognostic impact of WT1mut remains to be elucidated in a larger set of homogeneously treated adults with de novo CN-AML and in the context of established prognostic molecular markers. We studied the prevalence and prognostic impact of WT1mut in 196 younger [<60 years (yrs)] adults with de novo CN-AML who were intensively treated on frontline CALGB protocols incorporating autologous stem cell transplantation for consolidation, i.e. 9621 or 19808. The median follow-up for pts alive was 4.2 yrs (range, 1.2-8.9 yrs). Diagnostic bone marrow and/or blood specimens were studied for WT1mut by denaturing high-performance liquid chromatography and DNA direct sequencing. The samples were also analyzed for FLT3-ITD, FLT3-TKD, MLL-PTD, NPM1 and CEBPA mutations, and ERG and BAALC expression levels. Twenty-one (11%) of the 196 pts had WT1mut [15 had WT1mut in exon 7 (WT1mut7), 5 WT1mut in exon 9 (WT1mut9) and 1 WT1mut in both exons]. WT1mut7 were frameshift or nonsense mutations predicted to result in a truncated WT1 protein; WT1mut9 were missense mutations leading to single amino-acid substitutions. At diagnosis, WT1mut pts had higher white blood cell counts (WBC; P=0.01), more frequently harbored FLT3-ITD (P=0.06) and were more often high ERG (P=0.01) and high BAALC (P=0.006) expressers than unmutated WT1 (WT1wt) pts. While CR rates were not significantly different between WT1mut and WT1wt pts (76% vs 84%, P=0.36), WT1mut pts had worse disease-free survival [(DFS); P<0.001; 3-yr DFS rates, 13% vs 50%; Figure A] and worse overall survival [(OS); P<0.001; 3-yr OS rates, 10% vs 56%; Figure B] than WT1wt pts. In a multivariable analysis, WT1mut independently predicted worse DFS (P=0.009) when controlling for CEBPA (CEBPAmut vs CEBPAwt, P=0.005) and FLT3-ITD/NPM1 risk status (FLT3-ITD-negative and NPM1mut vs all other combinations of FLT3-ITD and NPM1 mutation status, P<0.001). The risk of relapse was 2.9 times higher for WT1mut pts than for WT1wt pts (95% CI: 1.3-6.3). WT1mut also independently predicted worse OS (P<0.001), and conferred a 3.6 times higher risk of death compared with WT1wt pts (95% CI: 1.8-7.2), when controlling for CEBPA (P=0.02), FLT3-ITD/NPM1 risk status (P<0.001), and WBC (P=0.01). In conclusion, we show here for the first time, in a relatively large set of intensively treated younger CN-AML pts, that WT1mut independently predicts very poor outcome. We propose that in future trials, WT1mut analysis should be considered for molecularly-based risk assessment and risk-adapted treatment stratification of CN-AML pts.


Abstract #362 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Acute Myeloid Leukemia|WT1|Prognostic Factor
Disclosure: No relevant conflicts of interest to declare.

Monday, December 10, 2007 11:15 AM

Session Info:  Simultaneous Session: Gene Mutations in AML (11:00 a.m.-12:30 p.m.)