Mount Sinai Core Clinical Consortium for the BMT Clinical Trials Network

总结/摘要 西奈山BMT CTN联盟结合了三个大型血液和骨髓移植（BMT） 中心（Mount Sinai、范德比尔特和马约诊所;每年总计> 900例，包括> 250例同种异体移植 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战略目标的显著优势，包括长期的科学研究 BMT CTN的领导地位，BMT CTN临床试验的高应计率，经证实的招募大规模 在临床试验中代表性不足的少数民族的数量，在移植方面的广泛专长， 恶性血液病（特别是镰状细胞病），以及一种高度创新的，基于生物标志物的 移植物抗宿主病（GVHD）是同种异体骨髓移植的主要并发症。我们 研究人员已经开发并验证了一种新的基于GVHD生物标志物的评分， 根据BMT后7天获得的血液样本，将患者分为低 风险和高风险组的严重GVHD风险和6个月非复发死亡率（NRM）。一天 无论供体类型、HLA匹配程度、预处理方案， 年龄，或使用胸腺球蛋白，使其成为在多中心试验中测试先发制人的GVHD策略的理想选择。 BMT CTN设置。第7天评分为高风险的患者中的大多数死亡是由于类固醇 难治性胃肠道（GI）GVHD，即使症状仅在数周后发生。因此，我们建议 一项先发制人的临床试验，以减少高危患者中类固醇难治性GVHD。我们期待这样的 预防不会增加复发或其他原因导致的死亡，从而提高生存率。到 为了实现这一目标，我们建议预先用Vedolizumab治疗高危患者， 靶向α 4 β 7 + T细胞并抑制其运输至胃肠道的单克隆抗体。vedolizumab 是FDA批准的炎症性肠病，并已成功地用于小 患有类固醇难治性GI GVHD的BMT患者数量。我们建议的一个可取之处是， 在最有可能发展为类固醇难治性GVHD的患者中测试这种策略将需要更少的 受试者检测有益效果。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）抢先治疗生物标志物定义的高风险患者， Vedolizumab改善1年类固醇难治性无GVHD、无复发生存期。 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BMT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.