Purpose of Review

To discuss novel targeted therapies under investigation for treatment of myelodysplastic neoplasms (MDS).

Recent Findings

Over the last few years, results of phase 3 trials assessing novel therapies for high-risk MDS have been largely disappointing. Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. However, early phase trials of BCL-2, TIM3, and CD47 inhibitors have shown exciting data and are currently under phase 3 investigation. Moreover, combination of hypomethylating agents (HMA) with novel therapies targeting the mutational (IDH, FLT3, spliceosome complex) or immune (PD-1/PDL-1, TIM-3, IRAK-4) pathways are being investigated in early phase clinical trials and have shown adequate safety and promising efficacy.

Summary

Myelodysplastic neoplasms (MDS) are a group of hematopoietic neoplasms defined by cytopenias and morphological dysplasia. They are characterized by clonal proliferation of aberrant hematopoietic stem cells caused by recurrent genetic abnormalities. This leads to ineffective erythropoiesis, peripheral blood cytopenias, abnormal cell maturation, and a high risk of transformation into acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, it is not a suitable option for majority patients due to their age, comorbidities, and the high rate of treatment-related complications. HMAs remain the only FDA-approved treatment option for high-risk MDS. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.

中文翻译：

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骨髓增生异常性肿瘤的治疗靶点：超越低甲基化药物

审查目的

讨论正在研究的用于治疗骨髓增生异常性肿瘤 (MDS) 的新型靶向疗法。

最近的发现

在过去几年中，评估高危 MDS 新疗法的 3 期试验结果大多令人失望。Pevonedistat（NEDD-8 抑制剂）和 APR-246（TP53 再激活剂）均未达到试验终点。然而，BCL-2、TIM3 和 CD47 抑制剂的早期试验已经显示出令人振奋的数据，目前正在进行 3 期研究。此外，低甲基化剂 (HMA) 与针对突变（IDH、FLT3、剪接体复合物）或免疫（PD-1/PDL-1、TIM-3、IRAK-4）通路的新疗法的组合正在早期临床研究中试验并显示出足够的安全性和有前途的疗效。

概括

骨髓增生异常性肿瘤 (MDS) 是一组由血细胞减少和形态发育不良定义的造血系统肿瘤。它们的特征是由反复发生的遗传异常引起的异常造血干细胞的克隆增殖。这会导致红细胞生成无效、外周血细胞减少、细胞成熟异常以及转化为急性髓性白血病 (AML) 的高风险。异基因造血干细胞移植是唯一的治愈性疗法；然而，由于大多数患者的年龄、合并症和治疗相关并发症发生率高，它不是适合大多数患者的选择。HMAs 仍然是 FDA 批准的高风险 MDS 的唯一治疗选择。由于对 HMA 的不耐受、原发性和继发性耐药，在为 MDS 患者开发安全有效的新疗法方面，存在大量未满足的需求。在这篇综述中，我们重点关注目前治疗高危 MDS 的管理策略和正在开发的新疗法。