将大多数血液恶性肿瘤新药引入临床的最终目标是提高总体生存率。然而，使用替代终点来衡量总生存期越来越被认为是标准做法，因为经过充分验证的替代终点可以加速结果评估并促进更好的临床试验设计。既定的例子包括监测慢性粒细胞白血病和急性白血病的微小残留病，以及淋巴瘤的代谢反应评估。然而，当临床试验终点不是疾病缓解潜力的良好替代指标，成为根深蒂固的预期结果，并且预期或需要新药达到该终点以证明“功效”时，会发生什么？用于骨髓纤维化的 JAK 抑制剂对减轻症状负担和脾肿大具有特定影响，但对该疾病的自然史影响有限。自十多年前推出鲁索替尼以来，骨髓纤维化的临床试验取得了一定的成功，但在改变该疾病的自然史方面没有取得重大飞跃。我们认为，通过不再使用专门用于测量 JAK 抑制剂有益效果的终点，将会加速骨髓纤维化新药的临床开发。我们建议相关疾病负担的具体措施，例如由分子终点确定的突变负担的减少，应取代既定的终点。需要对现有数据和正在进行的试验进行仔细的重新分析，以确定未来 MF 试验最有用的替代终点，并更好地服务于患者利益。版权所有 © 2024 美国血液学会。

The ultimate goal of bringing most new drugs to the clinic in hematological malignancy is to improve overall survival. However, the use of surrogate endpoints for overall survival is increasingly considered standard practice, since a well validated surrogate endpoint can accelerate the outcome assessment and facilitate better clinical trial design. Established examples include monitoring minimal residual disease in chronic myeloid leukemia and acute leukemia, and metabolic response assessment in lymphoma. However, what happens when a clinical trial endpoint that is not a good surrogate for disease-modifying potential becomes ingrained as an expected outcome, and new agents are expected or required to meet this endpoint to demonstrate "efficacy"? JAK inhibitors for myelofibrosis have a specific impact on reducing symptom burden and splenomegaly, but limited impact on the natural history of the disease. Since the introduction of ruxolitinib more than a decade ago there has been modest incremental success in clinical trials for myelofibrosis, but no major leap forward to alter the natural history of the disease. We argue that the clinical development of novel agents for myelofibrosis will be accelerated by moving away from using endpoints that are specifically tailored to measure the beneficial effects of JAK inhibitors. We propose that specific measures of relevant disease burden, such as reduction in mutation burden as determined by molecular endpoints, should replace established endpoints. Careful re-analysis of existing data and trials in progress is needed to identify the most useful surrogate endpoints for future MF trials and better serve patient interest.Copyright © 2024 American Society of Hematology.