Novel therapeutic strategies using hypomethylating agents in the treatment of myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm with high rates of leukemic transformation. MDS had been an intractable disease for which the mainstream of therapeutic approach was best supportive care. Recently, however, treatment of hematological malignancies has benefited from advances in molecular targeted drug discovery such as the revolutionary drug imatinib for chronic myeloid leukemia, and from the reappraisal of forgotten drugs such as thalidomide for multiple myeloma. Two azanucleotide drugs, azacitidine (AZA) and decitabine, were created as anti-neoplastic drugs in the 1960s with little success. In the 1980s, they were reassessed as hypomethylating agents (HMAs), and the introduction of low-dose schedules of them has shown dramatic effects in the delay of leukemic evolution for high-risk MDS. AZA was approved in Japan in March 2011 and has become a standard drug of choice in the treatment of high-risk MDS. Its position as a treatment for low-risk MDS remains to be established. Only half of patients with high-risk MDS can gain benefit from AZA. For example, those with complex karyotypes experience only a limited extension in survival. In addition, AZA resistance develops sooner or later. To achieve a more sustained disease control of high-risk MDS, the combined use of HMAs with other therapeutic approaches will be inevitable. Clinical trials of histone deacetylase inhibitors, lenalidomide, thrombopoietin agonists, or anticancer drugs in combination with HMAs are ongoing. In addition, HMAs are being used as a bridging therapy prior to allogeneic stem cell transplantation (AHSCT) and the salvage therapy of relapsed disease after AHSCT. Thus, HMAs will continue to be key drugs for the management of MDS.