The DNA hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) improve survival and transfusion independence in myelodysplastic syndrome (MDS) and enable a low intensity cytotoxic treatment for aged AML patients unsuitable for intensive chemotherapy, particularly in combination with novel agents. The proposed mechanism of AZA and DAC relies on active DNA replication and therefore patient responses are only observed after multiple cycles of treatment. Although extended dosing may provide the optimal scheduling, the reliance of injectable formulation of the drug limits it to intermittent treatment. Recently, an oral formulation of AZA demonstrated significantly improved patient relapse free survival (RFS) and overall survival (OS) when used as maintenance after chemotherapy for AML. In addition, both DAC and AZA were found to be highly effective to improve survival in elderly patients with AML through combination with other drugs. These recent exciting results have changed the therapeutic paradigm for elderly patients with AML. In light of this, we review current knowledge on HMA mechanism of action, clinical trials exploring dosing and scheduling, and recent HMA combination therapies to enhance efficacy.

中文翻译：

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优化急性髓系白血病和骨髓增生异常综合征的 DNA 低甲基化治疗

DNA 低甲基化剂 (HMA) 阿扎胞苷 (AZA) 和地西他滨 (DAC) 可提高骨髓增生异常综合征 (MDS) 的存活率和输血独立性，并能够对不适合强化化疗的老年 AML 患者进行低强度细胞毒性治疗，尤其是与新型药物联合使用。AZA 和 DAC 的拟议机制依赖于活跃的 DNA 复制，因此只有在多个治疗周期后才能观察到患者的反应。尽管延长给药时间可以提供最佳的时间安排，但对药物注射剂的依赖限制了它的间歇性治疗。最近，当用作 AML 化疗后的维持治疗时，AZA 的口服制剂显示出显着改善的患者无复发生存 (RFS) 和总生存 (OS)。此外，发现 DAC 和 AZA 通过与其他药物联合使用对提高老年 AML 患者的生存率非常有效。这些最近令人兴奋的结果改变了老年 AML 患者的治疗范式。有鉴于此，我们回顾了当前关于 HMA 作用机制的知识、探索给药和时间安排的临床试验以及最近的 HMA 联合疗法以提高疗效。