The class of DNA methyltransferase inhibitors is represented by azacitidine and decitabine. Azacitidine is approved for the treatment of patients in both low- and high-risk subtypes of myelodysplastic syndrome (MDS), and decitabine is currently under review by the FDA. Azacitidine phase III trial data, based upon the Cancer and Leukemia Group B (CALGB) study 9221, showed durable clinical and symptomatic improvement in bone marrow function, a reduction in the risk of leukemic transformation, and significant improvements in the quality of life of patients treated with azacitidine compared with supportive care alone. This study also provided data suggestive of improvement in survival in MDS patients. The experience with decitabine comprises a number of phase I/II studies and a phase III trial yet to be published. While there is a strong base of experience supporting the efficacy of DNA methyltransferase inhibitors in the treatment of MDS, a number of practical issues need to be explored further. These include the optimization of the timing and duration of treatment, and the prediction of response to therapy. Along with current experience, future studies will lead to the development of treatment algorithms, strategies for selecting patients (e.g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS.

Azacitidine (Vidaza®, Pharmion Corp., Boulder, CO, USA) and decitabine (DacogenTM, SuperGen, Inc., Dublin, CA, USA, and MGI Pharma, Inc., Bloomington, MN, USA) are DNA methyltransferase (DNMT) inhibitors that have clinical activity in patients with myelodysplastic syndromes. Mechanism-based laboratory studies suggest that clinical optimization of therapy with DNMT inhibitors needs to include optimizing intracellular drug uptake and maximizing drug exposure over time while still using lower doses to avoid cytotoxicity. Clinical studies suggest that increased dose intensity and multiple cycles of administration substantially increase response rates. Other strategies for optimizing the efficacy of DNMT inhibitor therapy also include identification of patients that are best qualified for treatment, and defining in vivo mechanisms of patient responses. In the future, combination strategies to increase gene reactivation and to take advantage of increased expression of target genes may be critical for achieving optimal results.

A variety of epigenetic changes contribute to transcriptional dysregulation in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). DNA methyltransferase (DNMT) inhibitors—azacitidine and decitabine—have significant activity in the treatment of MDS. Despite marked activity in myeloid malignancy, monotherapy with DNMT inhibitors is limited by low complete and partial response rates (7–20%) and median response durations of 15 months. As with classical cytotoxic therapy, the targeting of biologic pathways and mechanisms may best be accomplished using a combination of agents offering complementary mechanisms and synergistic pharmacodynamic interactions. The goal of this approach is to improve response rates, quality, and duration, and to minimize adverse events. There are a number of new therapies under development for the management of MDS and AML. This review article touches on some of the more promising combination regimens in various phases of investigation. The treatment of MDS and AML is undergoing rapid evolution. Cytogenetic complete remission and prolonged survival represent important goals. Incremental improvements in disease state and quality-of-life issues are also important for patients. Given the overall failure of cytotoxic chemotherapy in the achievement of cures in MDS and MDS-related AML, the application of less toxic, biologically directed agents may represent a more promising approach to treatment. Combination therapies with DNMT inhibitors using optimal dosing regimens to focus on methylation reversal with lower doses over longer periods of time, rather than direct cytotoxic effects, are beginning to suggest promising results in MDS and AML.

DNA methyltransferase (DNMT) inhibitors, azacitidine (Vidaza®, Pharmion, Boulder, CO, USA) and decitabine (DacogenTM; SuperGen Inc, Dublin, CA, USA, and MGI Pharma Inc, Bloomington, MN, USA), have had a significant impact on the treatment paradigm of myelodysplastic syndromes (MDSs), previously managed mainly by supportive care and hematopoietic-stem-cell transplantation. The positive clinical experience seen in MDS to date coupled with the persistent challenges faced in the treatment of other hematologic malignancies has served as the impetus for further exploration of the therapeutic value of DNMT inhibitors beyond MDS. In that respect, the majority of data for these agents are in the setting of acute myelogenous leukemia (AML). Experience with these agents in patients with refractory anemia with excess blasts in transformation (reclassified by the World Health Organization as AML) was also reported in the clinical trials submitted to the FDA for approval of azacitidine for MDS. Some use has also been described in chronic myelogenous leukemia and acute lymphocytic leukemia. Further studies are needed to clarify the appropriate dose and the number and duration of cycles in the treatment of leukemias, and to identify ideal candidates for therapy, explore the role of DNMT inhibitors in combination with other agents, especially histone deacetylase inhibitors, delineate differences between the commercially available agents, and establish the long-term safety of these agents. To this end, experience with DNMT inhibitors in hematologic malignancies other than MDS is reviewed in an effort to better understand the therapeutic potential of these agents and to define areas of future exploration in these settings.