Abstract
Epigenetic changes play an important role in the development of acute myeloid leukemia (AML). Unlike gene mutations, epigenetic changes are potentially reversible, which makes them attractive for therapeutic intervention. Agents that affect epigenetics are the DNA methyltransferase inhibitors, azacitidine and decitabine. Because of their relatively mild side effects, azacitidine and decitabine are particularly feasible for the treatment of older patients and patients with co-morbidities. Both drugs have remarkable activity against AML blasts with unfavorable cytogenetic characteristics. Recent phase 3 trials have shown the superiority of azacitidine and decitabine compared with conventional care for older AML patients (not eligible for intensive treatment). Results of treatment with modifications of the standard azacitidine (seven days 75 mg/m2 SC; every four weeks) and decitabine (five days 20 mg/m2 IV; every four weeks) schedules have been reported. Particularly, the results of the 10-day decitabine schedule are promising, revealing complete remission (CR) rates around 45% (CR + CRi (i.e., CR with incomplete blood count recovery) around 64%) almost comparable with intensive chemotherapy. Application of hypomethylating agents to control AML at the cost of minimal toxicity is a very promising strategy to “bridge” older patients with co-morbidities to the potential curative treatment of allogeneic hematopoietic cell transplantation. In this article, we discuss the role of DNA methyltransferase inhibitors in AML.
Highlights
Epigenetic changes include, by definition, through mitosis and meiosis, heritable changes in gene expression that are not caused by changes in the primary DNA sequence [1]
10-day schedule were comparable with the reported complete remission (CR) rates with the seven-day schedule, this study suggest that prolonged administration of azacitidine seems to increase the hematological normalization (HN) rate compared with standard dosing
Leukemia Group (CELG) and the German myelodysplastic syndromes (MDS) Study Group, recently opened a prospective randomized trial to compare conventional intensive chemotherapy based on cytarabine combined with an anthracycline (“3 + 7”) with the hypomethylating agent, decitabine, to determine the optimal backbone for the treatment of older acute myeloid leukemia (AML) patients (NCT02172872)
Summary
Epigenetic changes include, by definition, through mitosis and meiosis, heritable changes in gene expression that are not caused by changes in the primary DNA sequence [1]. Epigenetic changes affect the spatial structure of the DNA that is coiled around histones. The best-known epigenetic changes are methylation and acetylation of amino acid residues in histones and methylation of cytosine (C) bases in areas of the genome rich in CpG dinucleotides (CpG islands). Methylation of cytosines, mediated by one of the DNA methyltransferases (DNMTs), results in silencing of gene expression. 12%–22%, 7%–23% and 15%–33%, respectively, of the AML patients [5,6] These genes are involved in DNA methylation, and their mutated variants may help elucidate the mechanisms of aberrant DNA methylation in AML blasts. Translocations (e.g., MLL (mixed lineage leukemia gene)) and mutations (e.g., ASXL1, UTX) in genes affecting histone modifications are frequently observed
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