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Methylation inhibitor therapy in the treatment of myelodysplastic syndrome

Nature Clinical Practice Oncology volume 2, pages S12–S23 (2005)Cite this article

Abstract

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.

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Figure 1: CALGB (Cancer and Leukemia Group B) 9221: Median time to transformation to acute myeloid leukemia or death in patients with myelodysplastic syndrome treated with azacitidine or given best supportive care.
Figure 2: CALGB (Cancer and Leukemia Group B) 9221: Survival from landmark data according to crossover status (Kaplan–Meier method).
Figure 3: CALGB (Cancer and Leukemia Group B) 9221: Fatigue, dyspnea, and physical functioning, as recorded on the EORTC (European Organization for Research and Treatment of Cancer) questionnaire, of patients with myelodysplastic syndrome who crossed over from supportive care to treatment with azacitidine (5-Aza-C) (n = 30).
Figure 4: CALGB (Cancer and Leukemia Group B) 9221: Physiological distress and well-being, as measured by the Mental Health Inventory (MHI), of patients who crossed over from supportive care to treatment with azacytidine (5-Aza-C) (n = 30).
Figure 5: Mechanism of action of DNA methyltransferase inhibitors and their incorporation into DNA.

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Authors and Affiliations

  1. Division of Hematology/Oncology and Director of the Myelodysplastic Syndrome/Myeloproliferative Disease Center at the Mount Sinai School of Medicine, Associate Professor of Medicine, New York, NY, USA

    Lewis R Silverman

  2. Professor of Haematology and Head of the Department of Haematology at King's College London and King's College Hospital NHS Trust, London, UK

    Ghulam J Mufti

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Correspondence to Ghulam J Mufti.

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Silverman, L., Mufti, G. Methylation inhibitor therapy in the treatment of myelodysplastic syndrome. Nat Rev Clin Oncol 2 (Suppl 1), S12–S23 (2005). https://doi.org/10.1038/ncponc0347

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