Treatment of Hematologic Malignancies with DNA Hypomethylating Agents
2014
The azanucleosides 5-azacytidine (5-aza, Vidaza) and its deoxyribonucleoside analog 5-aza-2′ deoxycytidine (decitabine), while first synthesized and shown to have/possess [besitzen] antileukemic activity in 1964, have only recently been approved for the treatment of myeloid neoplasias. Thus, they now provide a novel treatment standard for the mostly elderly patients with these diseases. Clinical development of clinically active low-dose schedules of these drugs has taken an arduous route, since for decades their in vivo mechanism of action (DNA hypomethylation) was not generally accepted. In turn, proof of their clinical activity even at low doses (together with the recent discovery of mutations of the DNMT3a gene in AML) has leaned credence to the fundamental role of DNA methylation abnormalities in cancer and the applicability of epigenetically active drugs to treat leukemias, preleukemias, and even solid tumors. This chapter provides a comprehensive overview of the clinical development of both drugs as single agents for MDS and AML and other hematopoietic malignancies. In addition, combination treatment with other epigenetically active agents is described, as well as innovative use before and after allogeneic blood stem cell transplantation.
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