Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Curr Opin Hematol. 2018 Mar;25(2):146-153. doi: 10.1097/MOH.0000000000000400.
Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndromes (MDS). Although these agents induce responses in up to 40% of patients, most patients ultimately experience loss of response. The purpose of this review is to provide an overview of the different therapies under development for MDS after HMA therapy.
Recent advances in the understanding of MDS pathogenesis have led to the development of new potential therapies after HMA failure. Newer HMAs, less susceptible to in-vivo deamination, such as guadecitabine or ASTX727 have shown activity. Alterations of immune checkpoints in MDS have led to multiple clinical trials evaluating the activity of monoclonal antibodies targeting these proteins (pembrolizumab, nivolumab, ipilimumab). Different combinations and new formulations of cytotoxic agents, such as clofarabine or CPX-351, are newer options for specific subsets of patients. Finally, targeted agents inhibiting multiple kinases (rigosertib), BCL2 (venetoclax) or mutant IDH1 (ivosidenib), IDH2 (enasidenib), FLT3 (sorafenib, midostaurin) or spliceosome components (H3B-8800) are other novel options.
Despite the poor prognosis associated with HMA failure, clinical trials, new cytotoxic agents and allogeneic stem-cell transplantation, can offer therapeutic opportunities for these patients for whom there is no standard of care.
低甲基化药物（HMAs）是骨髓增生异常综合征（MDS）患者的标准治疗方法。尽管这些药物在多达 40%的患者中诱导反应，但大多数患者最终会失去反应。本综述的目的是概述 HMA 治疗后 MDS 正在开发的不同治疗方法。
对 MDS 发病机制的理解的最新进展导致了 HMA 失败后新的潜在治疗方法的发展。新型 HMAs，如更不易受体内脱氨影响的 guadecitabine 或 ASTX727，已显示出活性。MDS 中免疫检查点的改变导致了多项临床试验评估针对这些蛋白的单克隆抗体的活性（pembrolizumab、nivolumab、ipilimumab）。不同的细胞毒性药物组合和新制剂，如氯法拉滨或 CPX-351，是特定患者亚组的新选择。最后，靶向抑制多个激酶（rigosertib）、BCL2（venetoclax）或突变 IDH1（ivosidenib）、IDH2（enasidenib）、FLT3（sorafenib、midostaurin）或剪接体成分（H3B-8800）的药物也是其他新的选择。
尽管 HMA 失败后预后较差，但临床试验、新型细胞毒性药物和同种异体干细胞移植可为这些无标准治疗方法的患者提供治疗机会。
