Project 3: Risk Adapted Clinical Trials of GVHD Treatment

项目3摘要 胃肠道移植物抗宿主病(GVHD)仍然是无复发死亡的主要原因 造血细胞移植后(NRM)，但GVHD症状严重程度也预示着预后 不利于指导治疗，因此所有患者都需要长时间的大剂量全身性治疗 类固醇，一些治疗不足，另一些治疗过度。激素治疗GVHD本身就是一个主要原因 发病率和并发症包括感染、身体功能减退和生活质量差 (QOL)。在当前周期中，我们开发并验证了魔术算法概率(MAP)，该算法 将两个血清GI GVHD生物标志物合并为单个值，以衡量GI隐窝的程度 损坏。MAP更准确地预测临床结果，如治疗反应和NRM 而不仅仅是临床严重程度和阈值将患者分为高风险组或低风险组。患有疾病的患者 高危GVHD(占GVHD的35%)占NRM的75%。相比之下，我们的初步数据显示， 低风险移植物抗宿主病患者的亚组，在第一次治疗中表现出临床和生物标记物反应 两周的治疗代表了对类固醇有91%和2%反应的超低风险人群 NRM。超低风险患者占所有移植物抗宿主病患者的40%。我们的中心假设是生物标记物引导的， GVHD的风险适应治疗将改善结果。我们将在两个临床试验中检验这一假设。 特定目标1利用项目2中的发现，即激活RIPK1会导致 在临床前模型中，肠道干细胞及其抑制物可预防和逆转GI GVHD。在这 目的：我们将进行一项多中心二期临床试验，以测试添加RIPK1抑制剂 对高危GVHD患者进行类固醇治疗可提高治疗应答率并降低 NRM。在特定的目标2中，我们将进行一项第二阶段多中心临床试验，测试超低剂量 风险GVHD可以通过短暂接触类固醇来成功治疗。我们将使用实时临床和 生物标志物监测，以减少50%以上的类固醇暴露。我们将量化这一方法的效果 通过比较试验患者和配对良好的患者严重感染的频率来确定方法 同期对照队列。在子目标中，我们将测试我们的方法是否像 以患者报告的结果来衡量病例与对照组的结果。这两项试验因此使用了 创新和互补的、适应风险的治疗策略，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，并将解决高危GVHD治疗不足以及过度 低危移植物抗宿主病的治疗。 。

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. .