title: Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia.
abstract: Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than 'best supportive care'(BSC) in reducing transfusion frequency in 'low-risk' myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in 'high-risk' MDS or acute myeloid leukemia (AML) with 21-30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with >20% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS. Although azacitidine or decitabine are thus the standard to which newer therapies should be compared, here we discuss whether the improvement they afford in overall survival is sufficient to warrant a designation as a standard in treating individual patients. We also discuss pre- and post-treatment covariates, including assays of methylation to predict response, different schedules of administration, combinations with other active agents and use in settings other than active disease, in particular post HCT. We note that rational development of this class of drugs awaits delineation of how much of their undoubted effect in fact results from hypomethylation and reactivation of gene expression.
authors.affiliation: Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA. eestey@u.washington.edu
authors.forename: E H
authors.initials: EH
authors.lastname: Estey
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine