Genetic and Epigenetic Determinants of Chemotherapy Resistance and Adverse Outcome in Elderly Patients With AML

OBJECTIVES:

• Delineate the spectrum of genetic and epigenetic lesions occurring in elderly patients with acute myeloid leukemia (AML).
• Determine the biological functions perturbed by these lesions.
• Identify and validate lesions or pathways that are most highly associated with chemo-sensitive and chemo-refractory disease, and with adverse outcome in elderly AML.
• Identify potential classifiers and biomarker lesions that we can then evaluate prospectively in the E2906 trial which is about to begin enrollment.

OUTLINE: DNA and RNA extracted from cell samples are analyzed for genetic and epigenetic expression by Agilent SureSelect sequencing, Illumina HiSeq2000 platform coding and sequencing, DNA methylation, and microarray assays. Results are then associated with patients' overall survival, progression-free survival, and complete response rate. Results are also analyzed assessing the prognostic relevance of known mutations and epigenetic alterations that have shown to have an impact on overall survival and response to therapy in younger patients with acute myeloid leukemia (AML) in E1900 including, but not limited to, FLT3, DNMT3A, IDH1, IDH2, TET2, ASXL1, WT1, and MLL, and 15-gene DNA methylation classifier, and with novel recurrent mutations identified by other AML-profiling efforts.