The conundrum of drug development in higher-risk MDS: lessons learned from recently failed phase 3 clinical trials.

Many attempts using HMA-based combinations have failed to improve upon HMA monotherapy.

许多使用基于HMA的联合疗法的尝试未能在HMA单药治疗的基础上取得改善。

Although promising efficacy was observed in early-phase clinical trials with several agents, subsequent randomized phase 3 trials failed to confirm improvements in complete response rates or overall survival. In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax.

尽管早期临床试验中观察到几种药物的疗效令人鼓舞，但随后的随机III期试验未能证实完全缓解率或总生存的改善。在这篇综述中，我们讨论了从最近报道的关于阿扎胞苷联合eprenetapopt (APR-246)、magrolimab、pevonedistat、sabatolimab、tamibarotene和venetoclax的负面试验中学到的教训。

First, we make a case for emphasizing biological classification rather than disease risk status alone to select patients for HR-MDS trials.

首先，我们主张强调生物学分类而不是单纯依据疾病风险状态来选择高危骨髓增生异常综合征(HR-MDS)试验的患者。

Second, we argue that patients with TP53-inactivated MDS and chronic myelomonocytic leukemia should be treated in dedicated clinical trials.

其次，我们认为应将TP53失活的骨髓增生异常综合征（MDS）和慢性粒单核细胞白血病患者纳入专门的临床试验中进行治疗。

Alternatively, if TP53-inactivated MDS is included in HR-MDS trials, then randomization stratification by TP53 inactivation status should be considered.

另外，如果TP53失活的骨髓增生异常综合征（MDS）被纳入高危骨髓增生异常综合征（HR-MDS）的试验中，那么在随机分组时应考虑按TP53失活状态进行分层。

Third, we caution against ignoring signals of excessive toxicity and premature discontinuation of investigational agent observed in early-phase trials.

第三，我们提醒注意，不应忽视在早期试验中观察到的过度毒性信号和研究药物的过早停用。

Fourth, we show that the International Working Group (IWG) 2006 response criteria, long used in HR-MDS trials, can both overestimate and underestimate the true therapeutic benefit.

第四，我们展示了国际工作组（IWG）2006年响应标准，该标准在高危骨髓增生异常综合征（HR-MDS）试验中长期使用，可能会高估和低估真正的治疗益处。

Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS.

相反，我们主张使用2023年国际工作组（IWG）的反应标准，以更好地捕捉高危骨髓增生异常综合征（HR-MDS）中临床上有意义的益处。

Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials.

最后，我们强调科学界需要以高效和迅速的方式获取失败的III期试验中的患者级数据和样本，以指导后续试验的开发。