Mount Sinai Core Clinical Consortium for the BMT Clinical Trials Network

摘要/摘要 西奈山骨髓移植CTN联盟结合了三大血液和骨髓移植(BMT) 中心(西奈山、范德比尔特和梅奥诊所；&gt；每年总计900个，包括250个同种异体 BMT)，在BMT CTN内拥有良好的生产力记录。我们的财团拥有 实现BMT CTN战略目标的重要优势，包括长期的科学 领导BMT CTN，对BMT CTN临床试验有很高的收益，有能力大量招募 在临床试验中代表人数不足的少数族裔，在非心脏移植方面的广泛专业知识 恶性血液疾病(特别是镰状细胞疾病)，以及一种高度创新的生物标志物 移植物抗宿主病(GVHD)是异基因骨髓移植的主要并发症。我们的 研究人员开发并验证了一种新的基于GVHD生物标记物的评分方法 根据患者在骨髓移植后7天采集的血液样本，将患者分为低 重度移植物抗宿主病风险和6个月无复发死亡率(NRM)的风险和高危人群。那一天 7分准确地分配风险，无论供者类型，人类白细胞抗原匹配程度，预适应方案， 年龄，或使用胸腺球蛋白，使其成为在多中心测试先发制人GVHD策略的理想选择 BMT CTN设置。在高危第7天评分的患者中，大多数死亡是由于类固醇 难治性胃肠道(GI)GVHD，即使症状在几周后才出现。因此，我们建议 一项先发制人的临床试验，以减少高危患者的激素难治性GVHD。我们期待着这样的结果 先发制人不会增加复发或其他原因的死亡，从而提高存活率。至 为了实现这一目标，我们建议先发制人地使用vedolizumab治疗高危患者， 以α4β7 T细胞为靶标并抑制其向胃肠道转运的单抗。韦多珠单抗 FDA是否已批准用于炎症性肠病，并已成功用于小型 激素难治性GI GVHD的骨髓移植患者数量。我们的建议的一个可取之处是 在最有可能发生激素难治性移植物抗宿主病的患者中测试这一策略需要的费用更少 受试者要检测一个有益的效果。我们的具体目标是：(1)积极参与BMT CTN 临床试验和委员会以及(2)先发制人地治疗生物标记物定义的高危患者 Vedolizumab可提高激素耐药的一年无移植物抗宿主病、无复发的存活率。 相关性：血液和骨髓移植临床试验网络进行临床试验 改善面临危及生命的疾病的患者的预后。西奈山BMT CTN财团 将通过招募患者参加BMT CTN临床试验来推进BMT CTN的使命 为BMT CTN提供科学领导。拟议的临床试验将减轻移植物抗宿主 疾病，最严重的骨髓移植并发症。

SUMMARY/ABSTRACT The Mount Sinai BMT CTN Consortium combines three large blood and marrow transplant (BMT) centers (Mount Sinai, Vanderbilt, and the Mayo Clinic; >900 total annual including >250 allogeneic BMT) with a strong track record of productivity within the BMT CTN. Our consortium possesses significant strengths to accomplish BMT CTN strategic goals including long-standing scientific leadership of the BMT CTN, high accrual to BMT CTN clinical trials, a proven ability to enroll large numbers of under-represented minorities in clinical trials, extensive expertise in transplant for non- malignant blood diseases (especially sickle cell disease), and a highly innovative, biomarker-based approach to graft versus host disease (GVHD), the principal complication of allogeneic BMT. Our investigators have developed and validated a novel GVHD-biomarker based score that stratifies patients on the basis of blood samples obtained seven days after BMT that separates patients into low risk and high risk groups for risk of severe GVHD and six month non-relapse mortality (NRM). The day 7 score accurately assigns risk regardless of donor type, degree of HLA-match, conditioning regimen, age, or use of thymoglobulin, making it ideal for testing a preemptive GVHD strategy in the multicenter BMT CTN setting. The majority of deaths in patients with a high risk day 7 score are due to steroid refractory gastrointestinal (GI) GVHD even though symptoms only occur weeks later. We thus propose a preemptive clinical trial to reduce steroid refractory GVHD in high risk patients. We expect such preemption will not increase relapse or deaths from other causes and thereby improve survival. To accomplish this goal, we propose to preemptively treat high risk patients with vedolizumab, a monoclonal antibody that targets α4β7+ T cells and inhibits their trafficking to the GI tract. Vedolizumab is FDA approved for inflammatory bowel disease and has already successfully been used in a small number of BMT patients with steroid refractory GI GVHD. A desirable attribute of our proposal is that testing this strategy in the patients most likely to develop steroid refractory GVHD will require fewer subjects to detect a beneficial effect. Our specific aims are: (1) To participate vigorously in BMT CTN clinical trials and committees and (2) To preemptively treat biomarker-defined high risk patients with vedolizumab to improve one-year steroid-refractory GVHD-free, relapse-free survival. RELEVANCE: The Blood and Marrow Transplant Clinical Trials Network conducts clinical trials to improve outcomes for patients facing life-threatening diseases. The Mount Sinai BMT CTN Consortium will advance the mission of the BMT CTN by enrolling patients onto BMT CTN clinical trials and providing scientific leadership to the BMT CTN. The proposed clinical trial will mitigate graft-versus-host disease, the most serious BMT complication.