Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
The University of Queensland, Brisbane, Queensland, Australia.
Bioessays. 2021 Oct;43(10):e2100125. doi: 10.1002/bies.202100125. Epub 2021 Aug 31.
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.
DNA 低甲基化剂（HMA）阿扎胞苷（AZA）和地西他滨（DAC）可改善骨髓增生异常综合征（MDS）患者的生存率和输血独立性，并为不适合强化化疗的老年 AML 患者提供低强度细胞毒治疗，特别是与新型药物联合使用时。AZA 和 DAC 的作用机制依赖于活跃的 DNA 复制，因此只有在多个周期的治疗后才能观察到患者的反应。尽管延长剂量可能提供最佳的治疗方案，但由于药物的注射剂型的限制，其只能间歇性治疗。最近，AZA 的口服剂型在 AML 化疗后作为维持治疗时，显著改善了患者的无复发生存（RFS）和总生存（OS）。此外，DAC 和 AZA 与其他药物联合使用时，对改善老年 AML 患者的生存均有显著疗效。这些最近令人兴奋的结果改变了老年 AML 患者的治疗模式。有鉴于此，我们回顾了 HMA 作用机制、探索剂量和方案的临床试验，以及最近增强疗效的 HMA 联合治疗的最新知识。
