Originally published as JCO Early Release 10.1200/JCO.2007.10.8720 on June 18 2007

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High Expression Levels of the ETS-Related Gene, ERG, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Guido Marcucci, Kati Maharry, Susan P. Whitman, Tamara Vukosavljevic, Peter Paschka, Christian Langer, Krzysztof Mrózek, Claudia D. Baldus, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield

From the Division of Hematology and Oncology, Department of Internal Medicine, and Division of Human Cancer Genetics, Department of Microbiology, Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Cancer and Leukemia Group B (CALGB) Statistical Center, Duke University Medical Center, Durham, NC; Department of Hematology and Oncology, Charité University Hospital, Berlin, Germany; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL; Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Medicine, North Shore University Hospital, Manhasset, NY; and the Department of Medicine, University of Chicago, Chicago, IL

Address reprint requests to Guido Marcucci, MD, The Ohio State University, The Comprehensive Cancer Center, A433B Starling-Loving Hall, 320 W 10th Ave, Columbus OH 43210; e-mail: guido.marcucci{at}osumc.edu

Purpose To validate ERG overexpression as an adverse predictor and assess its prognostic value in the context of other molecular markers in cytogenetically normal (CN) -acute myeloid leukemia (AML).

Patients and Methods Seventy-six adult patients with primary CN-AML, younger than 60 years and treated on Cancer and Leukemia Group B (CALGB) trial 19808, were evaluated for ERG expression by quantitative reverse transcriptase polymerase chain reaction. They were then combined with 72 patients enrolled onto CALGB 9621 for analyses that included other molecular markers.

Results Similar to patients enrolled onto CALGB 9621, high ERG expressers on CALGB 19808 had fewer complete remissions (CRs; P = .03) and worse event-free survival (EFS; P = .016) than low ERG expressers. In the combined set, high expressers (n = 55) had fewer CRs (P = .004) and shorter EFS (P < .001) than low expressers (n = 93). High ERG predicted failure to achieve CR (P = .004) after adjusting for BAALC expression (P = .04) and age (P = .008), and EFS (P = .004) after adjusting for FLT3 internal tandem duplication (ITD; P < .001). Among patients without FLT3-ITD (FLT3-ITD negative), only high ERG predicted shorter EFS (P = .001). Among NPM1-mutated (NPM1 positive) patients, high ERG predicted shorter EFS (P = .003), after adjusting for FLT3-ITD (P < .001). When all three markers were considered together, in the favorable FLT3-ITD–negative/NPM1-positive subset, high ERG was the only factor predicting shorter EFS (P = .002).

Conclusion We validated ERG overexpression as an adverse predictor in CN-AML. Moreover, by using ERG expression levels, we improved the previously proposed molecular-risk classification of CN-AML based on the presence or absence of FLT3-ITD and NPM1 mutations, given that we identified subsets with different outcome among FLT3-ITD–negative, NPM1-positive, and FLT3-ITD–negative/NPM1-positive patients.

published online ahead of print at www.jco.org on June 18, 2007.

Supported by National Cancer Institute (Bethesda, MD) Grants No. CA101140, CA77658, CA102031, CA31946, CA09512, CA16058, CA98933, CA90469, CA96887, and CA089341, and the Coleman Leukemia Research Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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