Project 3: Risk Adapted Clinical Trials of GVHD Treatment

项目3摘要 胃肠道（GI）移植物抗宿主病（GVHD）仍然是非复发性死亡的主要原因 (NRM)但GVHD症状的严重程度也可预测结果 因此，所有患者都接受了长时间的高剂量全身化疗， 类固醇，有些治疗不足，有些治疗过度。GVHD的类固醇治疗本身就是一个主要原因 发病率和并发症包括感染、身体功能下降和生活质量差 （QOL）。在当前周期中，我们开发并验证了MAGIC算法概率（MAP）， 将两种血清GI GVHD生物标志物结合成一个单一的值，用于测量GI隐窝的程度 损害MAP更准确地预测临床结局，如对治疗的反应和NRM 临床严重程度和阈值将患者分为高风险组或低风险组。患者 高危GVHD（占GVHD 35%）占NRM的75%。相比之下，我们的初步数据显示， 在第一次治疗期间表现出临床和生物标志物应答的低风险GVHD患者亚组 两周的治疗代表了超低风险人群，对类固醇有91%的反应， NRM。超低风险患者占所有GVHD的40%。我们的中心假设是生物标志物引导的， GVHD的风险适应性治疗将改善结果。我们将在两项临床试验中验证这一假设。 具体目标1利用了项目2中的发现，即RIPK 1的激活会破坏 在临床前模型中，肠干细胞及其抑制可以预防和逆转GI GVHD。在这 目的是，我们将进行一项多中心的2期临床试验，以测试添加RIPK 1抑制剂是否 对高危GVHD患者进行类固醇治疗可增加治疗反应率， NRM。在《特定目标2》中，我们将进行一项2期多中心临床试验， GVHD风险可以通过短暂暴露于类固醇而成功治疗。我们将使用实时临床和 生物标志物监测，以减少类固醇暴露超过50%。我们将量化这种方法的有效性 通过比较试验患者中严重感染的频率与 同期对照组。在一个子目标中，我们将测试我们的方法是否能改善生活质量， 通过病例与对照组患者报告的结果进行测量。因此，这两项试验使用 创新和互补，风险适应性治疗策略，以治疗高风险和低风险GVHD。 如果试验成功，我们将为绝大多数患者设计新的治疗方法， 发展GVHD，并将解决高风险GVHD的治疗不足以及过度- 治疗低风险GVHD。 .

PROJECT 3 ABSTRACT Gastrointestinal (GI) graft-vs-host disease (GVHD) remains the major cause of non-relapse mortality (NRM) after hematopoietic cell transplant but GVHD symptom severity at onset predicts outcomes too poorly to guide treatment and thus all patients are treated with prolonged courses of high dose systemic steroids, under treating some and over treating others. Steroid treatment for GVHD is itself a major cause of morbidity and complications include infections, reduced physical function, and poor quality of life (QOL). In the current cycle, we developed and validated the MAGIC algorithm probability (MAP), which combines two serum GI GVHD biomarkers into a single value that measures the extent of GI crypt damage. The MAP predicts clinical outcomes such as response to treatment and NRM more accurately than clinical severity alone and thresholds categorize patients into high or low risk groups. Patients with high risk GVHD (35% of GVHD) account for 75% of NRM. In contrast, our preliminary data show that a subset of patients with low risk GVHD who exhibit both clinical and biomarker responses during the first two weeks of treatment represent an ultra-low risk population with 91% response to steroids and 2% NRM. Ultra-low risk patients comprise 40% of all GVHD. Our central hypothesis is that biomarker-guided, risk adapted treatment of GVHD will improve outcomes. We will test this hypothesis in two clinical trials. Specific Aim 1 leverages the discovery in Project 2 that activation of RIPK1 causes destruction of intestinal stem cells and its inhibition can both prevent and reverse GI GVHD in preclinical models. In this Aim, we will conduct a multicenter Phase 2 clinical trial to test whether the addition of a RIPK1 inhibitor to steroid treatment in patients with high risk GVHD increases treatment response rates and decreases NRM. In Specific Aim 2 we will conduct a Phase 2 multicenter clinical trial that tests whether ultra-low risk GVHD can be successfully treated with a brief exposure to steroids. We will use real-time clinical and biomarker monitoring to reduce steroid exposure by more than 50%. We will quantify the efficacy of this approach by comparing the frequency of severe infections in trial patients to a well matched contemporaneous control cohort. In a subaim, we will test whether our approach improves QOL as measured by patient reported outcomes in cases compared to controls. These two trials thus use innovative and complementary, risk-adapted treatment strategies to treat both high and low risk GVHD. If the trials are successful, we will have devised new treatments for the large majority of patients who develop GVHD and will have addressed the under-treatment of high risk GVHD as well as the over- treatment of low risk GVHD. .