Hypomethylating Agents in the Treatment of Myelodysplastic Syndromes and Myeloid Leukemia
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Epigenetic changes play an important role in cancer pathogenesis. Hypermethylation of DNA generally results in decreased expression of tumor suppressor genes and defective cell cycle control. This is a hallmark of myelodysplastic syndromes (MDS) and acute myeloid leukemia. Fortunately, epigenetic changes are potentially reversible and thus remain an attractive target for anticancer therapy. Inhibitors of DNA methyltransferase cause demethylation of DNA and exert their activity in myelodysplastic syndromes and acute myeloid leukemia with good safety profile. Decitabine and azacytidine are approved for treatment of patients with high-risk MDS. Demethylating agents seem to be the best choice for elderly patients with myelodysplastic syndromes and acute myeloid leukemia, even in case of high risk cytogenetic changes in the karyotype. The mechanisms of action, pharmacokinetics and antileukemic activity of azacytidine and decitabine are the subjects of this review.Keywords:
Decitabine
Azacitidine
Hypomethylating agent
Unprecedented progress continues to be made in the treatment strategies for the myelodysplastic syndromes (MDS). This review provides an introduction to DNA methyltransferase inhibitors. These agents include 5-azacytidine (azacitidine; AZA) and 5-aza-2'- deoxycytidine (decitabine; DAC). In particular, AZA was shown for the first time to significantly prolong the life expectancy of high-risk MDS patients in international multicenter clinical studies. The selection of responders and assessment of the long-term efficacy warrant further study. Keywords: MDS, DNA hypomethylation, epigenetic therapy, DNA methyltransferase inhibitors, azacitidine, decitabine, long-term efficacy, hematopoietic stem cell disorders, solid tumors, cytotoxic
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The hypomethylating agents (HMA) azacitidine and decitabine are both approved by the FDA for the treatment of myelodysplastic syndromes (MDS). Although heralded as a significant advancement, HMA lead to responses in less than half of patients and for those that respond most will relapse. As such, there is a crucial need to improve frontline therapy approaches. One promising strategy involves combining azacitidine or decitabine with investigational or existing therapies with the goal of achieving synergistic activity and better patient outcomes. The purpose of this paper is to critically review the efficacy and safety of reported HMA-based combination regimens in patients with higher-risk MDS.
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The hypomethylating agents azacitidine and decitabine are standard therapy for myelodysplastic syndromes (MDS), and are often used to treat patients with acute myeloid leukemia (AML) unlikely to benefit from cytotoxic chemotherapy. Switching hypomethylating agents after treatment failure is common, but this approach is not well studied. We retrospectively reviewed data on 25 patients with MDS, MDS/myeloproliferative neoplasm (MDS/MPN) or AML who were treated with decitabine after primary or secondary azacitidine failure at the University of Maryland Greenebaum Cancer Center. Five patients with MDS or MDS/MPN achieved stable disease with decitabine, but no patient achieved complete or partial remission or hematologic improvement. Most patients discontinued therapy due to disease progression or death after a median of 2 cycles and median survival was 5.9 months after decitabine initiation. Based on our data, decitabine therapy after azacitidine failure is of little benefit beyond disease stabilization in some patients.
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Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell disorders commonly characterized by a hypercellular and dysplastic bone marrow, cytopenias resulting from impaired peripheral blood cell production, and an increased risk of leukemic transformation. Currently, azacitidine, decitabine, and lenalidomide are approved by the US Food and Drug Administration for the treatment of MDS. The DNA methyltransferase (DNMT) inhibitors such as azacitidine and decitabine have demonstrated the ability to alter the natural history of disease and thus prolong time to leukemic transformation. In addition, azacitidine has shown the capacity to extend survival compared with the previous gold standard of conventional care regimens. Recently, decitabine has been shown to be well tolerated with a toxicity profile expected for this class of agent. Recent studies also suggest that decitabine may result in additional improvements in response. As more is learned about the mechanism of hypomethylating agents, new roles are emerging for decitabine in combination therapy for MDS. The third agent, lenalidomide, is a thalidomide analogue with significant activity in a subset of patients with low-risk MDS, anemia and chromosome 5 alterations. Several other agents are being evaluated in MDS. This review summarizes the existing clinical experience on DNMT inhibitors and other drugs for the treatment of MDS. (Korean J Med 76:121-125, 2009)
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Azacitidine and decitabine are hypomethylating agents that have dose-dependent epigenetic and cytotoxic effects and are widely used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this review, we discuss the path to regulatory approval of azacitidine and decitabine, highlighting the substantial efforts that have been made to optimize the dosing schedule and administration of these drugs, including the development of new, oral formulations of both agents. We also review novel combination strategies that are being investigated in ongoing clinical trials for patients with MDS and AML, as well as efforts to expand the current indications of these agents.
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The nucleoside analogs decitabine (5-AZA-dC) and azacitidine (5-AZA) have been developed as targeted therapies to reverse DNA methylation in different cancer types, and they significantly improve the survival of patients who are not suitable for traditional intensive chemotherapies or other treatment regimens. However, approximately 50% of patients have a response to hypomethylating agents (HMAs), and many patients have no response originally or in the process of treatment. Even though new combination regimens have been tested to overcome the resistance to 5-AZA-dC or 5-AZA, only a small proportion of patients benefited from these strategies, and the outcome was very poor. However, the mechanisms of the resistance remain unknown. Some studies only partially described management after failure and the mechanisms of resistance. Herein, we will review the clinical and molecular signatures of the HMA response, alternative treatment after failure, and the causes of resistance in hematological malignancies.
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Epigenetic changes play an important role in cancer pathogenesis. Hypermethylation of DNA generally results in decreased expression of tumor suppressor genes and defective cell cycle control. This is a hallmark of myelodysplastic syndromes (MDS) and acute myeloid leukemia. Fortunately, epigenetic changes are potentially reversible and thus remain an attractive target for anticancer therapy. Inhibitors of DNA methyltransferase cause demethylation of DNA and exert their activity in myelodysplastic syndromes and acute myeloid leukemia with good safety profile. Decitabine and azacytidine are approved for treatment of patients with high-risk MDS. Demethylating agents seem to be the best choice for elderly patients with myelodysplastic syndromes and acute myeloid leukemia, even in case of high risk cytogenetic changes in the karyotype. The mechanisms of action, pharmacokinetics and antileukemic activity of azacytidine and decitabine are the subjects of this review.
Decitabine
Azacitidine
Hypomethylating agent
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Citations (19)