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.

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

“…Hypermethylation of epigenetic regions of DNA and consequent alterations in expression of genes associated with normal cell cycling, apoptosis, and tumor suppression, are implicated in the pathogenesis of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) 4. Azacitidine mechanisms of action have not been fully elucidated, but it is thought to reduce DNA methylation upon incorporation into DNA, alter protein expression upon incorporation into RNA, and exert direct cytotoxic effects on abnormal hematopoietic cells in bone marrow 1, 2, 3…”

Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group

“…Not surprisingly, a complex karyotype thus scores in the very highrisk cytogenetic groups of AML and MDS [2][3][4][5]. Notably, it recently became apparent that clofarabine and the DNA hypomethylating agents azacytidine and decitabine (DAC) have marked activity in complex-karyotype AML [6][7][8][9] and MDS [10][11][12][13][14][15][16]. However, it is unclear why these drugs differ from cytarabine and other cytotoxic agents in that regard.…”

“…However, it is unclear why these drugs differ from cytarabine and other cytotoxic agents in that regard. Equally notable was the recurrent observation of activity of DAC [13,[15][16][17][18] and azacytidine [10,19] in MDS/AML patients with sole monosomy 7-also a robust clinical result but as yet lacking a mechanistic explanation. A monosomy might be only one of several abnormalities and may not exhibit prognostic impact itself [20,21].…”

Identification of differentially methylated markers among cytogenetic risk groups of acute myeloid leukemia

“…1 AML patients have benefited from treatment with hypomethylating agents such as azacitidine and decitabine, although not all respond equally. 2 Previous studies showed associations of certain methylation patterns with specific chromosome abnormalities and gene mutations and suggested a prognostic significance to these patterns. [3][4][5][6][7][8][9][10][11][12] However, it remains unclear if DNA methylation profiles differ according to AML cytogenetic risk group, the principal predictor of outcome in AML.…”