Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands.
Leukemia. 2021 Mar;35(3):651-660. doi: 10.1038/s41375-021-01164-x. Epub 2021 Feb 15.
Precision medicine is gaining importance in the treatment of acute myeloid leukemia (AML). Objectively reviewing past and current knowledge aids guiding future research. Therefore, we provide a complete overview of all phase II and phase III trials investigating targeted therapies in AML and their primary endpoints over the past two decades in perspective of their clinical benefit. We assessed whether drugs were primarily designed to treat AML or were repurposed and how successful they were based on progression of distinct drugs from phase II to phase III to FDA-approval. Between January 2000 and September 2020, 167 agents with 96 targets were investigated in 397 phase II trials. Twenty-eight agents were steered towards phase III, after three phase II trials on average. Repurposed drugs less often advanced in clinical development than drugs primarily developed for AML. Composite responses were the most prevalent primary endpoints in phase II. Of the eight FDA-approved drugs, none investigated quality of life at time of approval, and three out of eight have yet to show benefit in overall survival. Returns on targeted therapy research remain lean for AML patients. Future trials should not overlook non-targeted agents and foremost study endpoints proven to predict patient well-being.
精准医学在急性髓系白血病（AML）的治疗中变得越来越重要。客观地回顾过去和现在的知识有助于指导未来的研究。因此，我们从临床获益的角度，全面概述了过去二十年中所有针对 AML 的靶向治疗的 II 期和 III 期试验及其主要终点。我们评估了这些药物是主要设计用于治疗 AML，还是重新用于其他疾病，以及它们基于从 II 期到 III 期到 FDA 批准的不同药物的进展情况，其成功率如何。在 2000 年 1 月至 2020 年 9 月期间，有 167 种药物针对 96 个靶点在 397 项 II 期试验中进行了研究。经过平均三次 II 期试验后，有 28 种药物进入 III 期研究。重新用于临床试验的药物比专门为 AML 开发的药物更不容易在临床开发中取得进展。复合反应是 II 期试验中最常见的主要终点。在 8 种获得 FDA 批准的药物中，没有一种在批准时研究生活质量，其中 3 种在总生存期方面尚未显示获益。针对 AML 患者的靶向治疗研究回报仍然微薄。未来的试验不应忽视非靶向药物，而应首先研究已证明可预测患者健康状况的终点。
