Azanucleoside DNA Methyltransferase Inhibitor Drugs: Update on Clinical Applications in Myelodysplastic Syndromes and Acute Myeloid Leukemia

The cytidine analog 5-azacytidine (5-aza, Vidaza) and its deoxyribonucleoside analog 5-aza-2'-deoxycytidine (decitabine, Dacogen), while first synthesized and shown to have interesting antileukemic activity in 1964, have only recently been FDA and EMA approved for the treatment of myelodysplastic syndromes (MDS; 5-aza by FDA and EMA, decitabine by FDA) and acute myeloid leukemia (AML) of older patients unfit for intensive chemotherapy (EMA). These drugs therefore constitute a novel treatment standard for the mostly elderly patients with these hematologic malignancies. The clinical development of active, low-toxic schedules of these drugs (favoring DNA hypomethylation over immediate cytotoxicity) has taken an arduous route: for decades, this mechanism of action was not generally accepted. However, eventually, the proof of their clinical activity even at low doses-together with the recent discovery of recurrent somatic mutations of multiple epigenetic modifier genes in AML-has in turn lent credence to the fundamental role of DNA methylation abnormalities in cancer in general. This chapter provides an update of the clinical development and current state of both drugs as single agents for MDS, AML, and other hematopoietic malignancies, particularly as a novel, well-tolerated treatment option for older and unfit patients with comorbidities. In addition, combination treatments with other epigenetically active agents are described, and direct comparisons between the two drugs are reviewed. Finally, an integrated treatment approach is emerging where leukemia and MDS patients fit for allogeneic blood stem cell transplantation are being "bridged" to this curative treatment by hypomethylating treatment as a milder, better-tolerated alternative to standard, aggressive chemotherapy.