The role of azacitidine in the treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia. Supportive care including transfusions and growth factors remained the mainstay of treatment for decades; however, further understanding of the biology behind these diseases led to the investigation of novel agents. As hypermethylation of tumor suppressor genes, such as p15, was believed to play a key role in the pathogenesis of these diseases, hypomethylating agents were investigated. Azacitidine is one of two hypomethylating agents used in the treatment of MDS, and the first approved by US FDA. In preclinical studies, azacitidine demonstrated hypomethylating/differentiating activity with low concentration, whereas high concentration was associated with cytotoxic effects. In clinical trials, azacitidine not only improved the cytopenias associated with MDS but also delayed leukemic transformation, improved quality of life and improved overall survival in many patients so treated. Azacitidine was the first agent noted to change the natural history of the disease. Further studies are underway evaluating the role of azacitidine pre- and post-transplantation, in combination with other agents, as well as in treatment of acute myeloid leukemia patients who are not good candidates for intensive chemotherapy. Azacitidine is also likely to be studied in the treatment of other malignant conditions. Although both subcutaneous and intravenous administrations have been approved, oral azacitidine is presently under investigation.