Submitted February 23, 2006
Accepted April 21, 2006
Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: A cancer and leukemia group B study
Michael D Radmacher, Guido Marcucci, Amy S Ruppert, Krzysztof Mrozek, Susan P Whitman, James W Vardiman, Peter Paschka, Tamara Vukosavljevic, Claudia D Baldus, Jonathan E Kolitz, Michael A Caligiuri, Richard A Larson, and Clara D Bloomfield*
Division of Hematology and Oncology, Department of Internal Medicine, Ohio State University,Columbus
Ohio Division of Hematology and Oncology, Department of Internal Medicine, Ohio State UnivUniversity
University of Chicago, Chicago, IL, USA
Charite, Campus Benjamin Franklin, Medizinische Klinik III, Berlin, Germany
North Shore University Hospital, Manhasset, NY
* Corresponding author; email: clara.bloomfield{at}osumc.edu.
Patients with acute myeloid leukemia (AML) and normal karyotype are classified in an intermediate-risk group, albeit this subset is heterogeneous for clinical outcome. A recent complementary-DNA microarray study identified a gene-expression signature that-- when used to cluster normal karyotype patients-- separated them into two prognostically relevant subgroups. We sought the first independent validation of the prognostic value of this signature. Using oligonucleotide microarrays to measure gene expression in samples from uniformly treated adults with karyotypically normal AML, we performed cluster analysis based on the previously identified signature. We also developed a well-defined classification rule using the signature to predict outcome for individual patients. Cluster analysis confirmed the prognostic utility of the signature: patient clusters differed in overall (P=0.001) and disease-free (P=0.001) survival. The signature-based classifier identified groups with differences in overall (P=0.02) and disease-free (P=0.05) survival. A strong association of the outcome classifier with the prognostically adverse FLT3 internal tandem duplication (FLT3 ITD) potentially explained the prognostic significance of the signature. However, in the subgroup of patients without FLT3 ITD there was a moderate difference in survival for the classifier-derived groups. Our analysis confirms the applicability of the gene-expression profiling strategy for outcome prediction in cytogenetically normal AML.
