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Review
. 2008 Nov;20(6):705-10.
doi: 10.1097/CCO.0b013e328313699c.

Demethylating agents in myeloid malignancies

Guillermo Garcia-Manero  1
Affiliations
Review

Demethylating agents in myeloid malignancies

Guillermo Garcia-Manero. Curr Opin Oncol. 2008 Nov.

Abstract

Purpose of review: Two demethylating agents are approved in myelodysplastic syndromes (MDS): 5-azacitidine and 5-aza-2'-deoxycitidine (decitabine). These drugs are structurally related and induce DNA hypomethylation. Aberrant DNA methylation is associated with gene silencing. It is proposed that hypomethylating agents work by inducing reexpression of epigenetically silenced genes. Here, we provide an up-to-date summary of the clinical experience with these drugs.

Recent findings: 5-Azacitidine and decitabine were approved in the United States based on clinical responses, but no effect on survival was documented. Recent results from a phase III study have indicated that treatment of patients with higher risk MDS with 5-azacitidine results in significant improvement in overall survival. Results of a randomized survival study of decitabine should be available in 2008. Reports of combination epigenetic therapies (a hypomethylating agent with a histone deacetylase inhibitor) indicate that these have significant activity in patients with MDS/acute myelogenous leukemia. Randomized studies are testing the concept that the combinations are superior to single-agent therapy.

Summary: Demethylating agents are the standard of care for patients with higher risk MDS and the only agent known to improve the natural history of MDS. Further work in new combination therapies may result in further advances in the care of patients with MDS.

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References

    1. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet. 2000;1:11–19. - PubMed
    1. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692. - PMC - PubMed

    2. This is an excellent state of the art review on the epigenetics of cancer.

    1. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–2440. - PubMed
    1. Kantarjian HM, O’Brien S, Cortes J, et al. Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98:522–528. - PubMed
    1. Fenaux P, Mufti G, Santini V, et al. Azacitidine treatment prolongs overall survival in higher risk MDS patients compared with conventional care regimens: Results of the AZA-001 phase III study. Blood. 2007;110:250a.

    2. Although this is currently in abstract form, it is expected to be published by the end of the year. This is the first randomized study to show a significant effect on survival by any therapy MDS. Fundamental study in the field.

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