The ultimate goal of bringing most new drugs to the clinic in hematologic malignancy is to improve overall survival. However, the use of surrogate end points for overall survival is increasingly considered standard practice, because a well validated surrogate end point 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 end point 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 end point to demonstrate “efficacy”? Janus kinase (JAK) inhibitors for myelofibrosis (MF) 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 MF but no major leap forward to alter the natural history of the disease. We argue that the clinical development of novel agents for MF will be accelerated by moving away from using end points 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 end points, should replace established end points. Careful reanalysis of existing data and trials in progress is needed to identify the most useful surrogate end points for future MF trials and better serve patient interest.

中文翻译：

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确定骨髓纤维化临床试验中的疾病修饰潜力


将大多数新药引入血液系统恶性肿瘤临床的最终目标是提高总生存期。然而，使用替代终点计算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。已建立的例子包括监测慢性髓系白血病和急性白血病中的微小残留病，以及淋巴瘤中的代谢反应评估。然而，当临床试验终点不是疾病修饰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满足该终点以证明“疗效”时，会发生什么情况？用于骨髓纤维化 （MF） 的 Janus 激酶 （JAK） 抑制剂对减轻症状负担和脾肿大有特定影响，但对疾病自然病程的影响有限。自十多年前推出 ruxolitinib 以来，MF 的临床试验取得了适度的增量成功，但没有重大飞跃来改变疾病的自然史。我们认为，通过放弃使用专门用于测量 JAK 抑制剂有益作用的终点，将加速 MF 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减少，应取代已建立的终点。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的利益。