A critical evaluation of the EFS endpoint in AML: Does induction treatment failure timing have a profound impact on study design and results?

IF 2.1 4区 医学 Q3 HEMATOLOGY Leukemia research Pub Date : 2024-03-01 DOI:10.1016/j.leukres.2024.107465
Yulia Sidi , Cassie Dong , Yujun Wu , Douglas V. Faller
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Abstract

Despite emerging novel therapies, treating acute myeloid leukemia (AML) remains challenging. Complexities persist in designing pivotal clinical trials and establishing acceptable endpoints for AML. Recent FDA guidance for drug and biological products development for AML outlines considerations for trial design. The guidance defines overall survival (OS) and event-free survival (EFS) as endpoints representing clinical benefit for AML therapies without curative intent. We highlight the EFS definition, particularly the assignment of day 1 as the event date for patients with induction treatment failures (ITFs), as recommended in the guidance. Through a comprehensive simulation study, our results show that the guidance EFS definition performs adequately with high complete remission (CR) rates but may pose challenges for low CR rates. When the experimental arm CR rate is 5% or less over the control, the use of the ITF events at day 1 for EFS definition leads to a critical power decrease, hampering the ability to predict survival benefit for a moderate OS duration. We further expand upon the EFS definition with the event date at ITF period end. Our goal is to inform investigators and regulatory agencies about the implications and limitations of various EFS definitions for future pivotal trials in AML.

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对急性髓细胞白血病 EFS 终点的批判性评估:诱导治疗失败时机是否会对研究设计和结果产生深远影响?
尽管新疗法层出不穷,但治疗急性髓性白血病(AML)仍然充满挑战。在设计关键性临床试验和建立急性髓细胞白血病可接受终点方面仍然存在复杂性。美国食品及药物管理局最近发布的急性髓细胞白血病药物和生物制品开发指南概述了试验设计的注意事项。该指南将总生存期(OS)和无事件生存期(EFS)定义为代表无治疗意图的急性髓细胞性白血病疗法临床获益的终点。我们强调了无事件生存期的定义,尤其是指南中推荐的将诱导治疗失败(ITF)患者的第 1 天指定为事件发生日。通过全面的模拟研究,我们的结果表明,指南中的 EFS 定义在完全缓解(CR)率较高的情况下表现良好,但在 CR 率较低的情况下可能会面临挑战。当实验臂 CR 率为对照组的 5%或更低时,使用第 1 天的 ITF 事件进行 EFS 定义会导致功率急剧下降,影响预测中等 OS 持续时间的生存获益的能力。我们使用 ITF 期末的事件日期进一步扩展了 EFS 定义。我们的目标是让研究者和监管机构了解各种 EFS 定义对未来急性髓细胞白血病关键性试验的影响和局限性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Leukemia research
Leukemia research 医学-血液学
CiteScore
4.00
自引率
3.70%
发文量
259
审稿时长
1 months
期刊介绍: Leukemia Research an international journal which brings comprehensive and current information to all health care professionals involved in basic and applied clinical research in hematological malignancies. The editors encourage the submission of articles relevant to hematological malignancies. The Journal scope includes reporting studies of cellular and molecular biology, genetics, immunology, epidemiology, clinical evaluation, and therapy of these diseases.
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