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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4193-4201.
Prepublished online as a Blood First Edition Paper on August 20, 2008; DOI 10.1182/blood-2008-02-134411.
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Submitted February 6, 2008
Accepted August 1, 2008
An 86 probe set gene expression signature predicts survival in cytogenetically normal acute myeloid leukemia
Klaus H Metzeler, Manuela Hummel, Clara D. Bloomfield, Karsten Spiekermann, Jan Braess, Maria-Cristina Sauerland, Achim Heinecke, Michael Radmacher, Guido Marcucci, Susan P Whitman, Kati Maharry, Peter Paschka, Richard A Larson, Wolfgang E Berdel, Thomas Buchner, Bernhard Wormann, Ulrich Mansmann, Wolfgang Hiddemann, Stefan K Bohlander, and Christian Buske*
Laboratory of Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilians-University - Campus Grosshadern, Munich, Germany
Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany
Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States
Clinical Cooperative Group Leukemia, National Resource Center for Environment and Health, Munich, Germany
Department of Medical Informatics and Biomathematics, University of Muenster, Muenster, Germany
Cancer and Leukemia Group B (CALGB) Statistical Center, Durham, NC, United States
Department of Internal Medicine II, J.W. Goethe-University, Frankfurt am Main, Germany
Department of Medicine, The University of Chicago, Chicago, Illinois, United States
Department of Internal Medicine A, Hematology and Oncology, University of Muenster, Muenster, Germany
Department of Hematology and Oncology, Municipal Hospital, Branschweig, Germany
* Corresponding author; email: christian.buske{at}med.uni-muenchen.de.
Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes) which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P=0.002), EFS (HR, 1.73; P=0.001), and RFS (HR, 1.76; P=0.025). It kept its prognostic value in multivariable analyses adjusting for age, FLT3 ITD and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR, 4.11; P<0.001), EFS (HR, 2.90; P<0.001), and RFS (HR, 3.14, P<0.001) and retained its significance in a multivariable model for OS. In summary, we present a novel gene expression signature that offers additional prognostic information for patients with CN-AML. Both the AMLCG and the CALGB trials have been registered at ClinicalTrials.gov, AMLCG under identifier NCT00266136 and CALGB under identifier NCT00002925.
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