Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Semin Oncol. 2011 Oct;38(5):682-92. doi: 10.1053/j.seminoncol.2011.04.011.
Hypomethylating agents such as 5-azacytidine or decitabine have been a major breakthrough in the treatment of patients with myelodysplastic syndromes (MDS). They have been shown to improve transfusion requirements and to change the natural history of the disease. However, with increasing cumulative clinical experience, it has become apparent that these agents are not curative and have their own shortcomings. There is a subgroup of patients who do not respond to frontline therapy and a large, growing cohort of patients that lose response or progress while on hypomethylating agent-based therapy. There are no standard treatment options in this arena and it is therefore a focus of significant research interest. Since the mechanisms of resistance to hypomethylating agents are not known, selection of therapy is largely empiric but must take into account the age, comorbidities, and performance status of the patient, as well as the characteristics of the disease at the time of treatment failure. Higher intensity approaches and allogeneic stem cell transplant can yield improved response rates and long-term disease control but should be limited to a selected cohort of patients who can tolerate the treatment-related morbidities. For the majority of patients who likely will be better candidates for lower intensity therapy, several novel, investigational approaches are becoming available. Among these are newer nucleoside analogues, inhibitors of protein tyrosine kinases, molecules that interact with redox signaling within the cell, immunotherapy approaches, and others. Patients with MDS whose disease has failed to respond to hypomethylating agent therapy should be referred for clinical trials when available. As we learn more about the patterns and mechanisms of failure, the next challenge will be to determine which therapies are suitable for each individual patient.
低甲基化剂，如 5-氮杂胞苷或地西他滨，在治疗骨髓增生异常综合征（MDS）患者方面取得了重大突破。它们已被证明可以改善输血需求并改变疾病的自然病程。然而，随着临床经验的不断积累，很明显这些药物并非治愈性的，并且存在自身的缺点。有一部分患者对一线治疗没有反应，而很大一部分正在接受低甲基化剂治疗的患者则会失去反应或进展。在这一领域没有标准的治疗选择，因此它是一个重要的研究重点。由于尚不清楚对低甲基化剂产生耐药的机制，因此治疗选择在很大程度上是经验性的，但必须考虑到患者的年龄、合并症和身体状况以及治疗失败时疾病的特征。更高强度的方法和同种异体干细胞移植可以提高缓解率和长期疾病控制率，但应限于能够耐受治疗相关并发症的选定患者群体。对于大多数可能更适合低强度治疗的患者，几种新的、正在研究的方法正在出现。其中包括新型核苷类似物、蛋白酪氨酸激酶抑制剂、与细胞内氧化还原信号相互作用的分子、免疫治疗方法等。对于那些对低甲基化剂治疗无反应的 MDS 患者，应在有临床试验时将其转介至临床试验。随着我们对失败模式和机制的了解不断增加，下一个挑战将是确定哪些疗法适合每个患者。
