MIDAS: MIcroangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation

MIDAS：接受干细胞移植的成人的微血管病、内皮损伤

• 批准号: 10685361
• 负责人: Sumithira Vasu
• 金额: $ 74.31万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685361
• 关键词: Acute Graft Versus Host Disease; Address; Adult; Age; Allogenic; Area; Biological; Biological Markers; Blood Banks; Caring; Cell Therapy; Cells; Child; Clinical; Clinical Data; Clinical Markers; Clinical Research; Cohort Studies; Collaborations; Complement; Complement Activation; Complication; Consensus; Data; Development; Diagnosis; Diagnostic; Early Diagnosis; Elderly; Eligibility Determination; Endothelium; Enrollment; Etiology; Event; Financial cost; Flare; Frequencies; Functional disorder; Future; Health; Hematopoietic Stem Cell Transplantation; Hemolytic Anemia; Hospitalization; Immunosuppression; Incidence; Infection; Injury; Institution; Intensive Care Units; Interferons; Interruption; Intervention; Knowledge; Length; Life; Measures; Modality; Monitor; Mononuclear; Neurologic Symptoms; Ohio; Organ; Outcome; Pathogenesis; Patient risk; Pediatric cohort; Persons; Phenotype; Plasma; Population; Predisposition; Prevention; Procedures; Prospective Studies; Prospective cohort; Publications; Publishing; Rehabilitation therapy; Renal function; Reporting; Resolution; Risk Factors; Role; Sampling; Series; Serum; Stem cell transplant; Testing; Therapeutic; Therapeutically Targetable; Time; Toxic effect; Transplant Recipients; Transplantation; Universities; Work; cell growth; chemotherapy; clinical database; clinical diagnosis; clinical phenotype; clinical risk; cohort; conditioning; diagnostic strategy; evidence based guidelines; graft vs host disease; hematopoietic cell transplantation; high risk; high risk population; improved; indexing; individual patient; inhibitor; interest; kidney dysfunction; mortality; new therapeutic target; novel therapeutic intervention; older patient; organ injury; post-transplant; prospective; routine screening; screening; screening guidelines; thrombotic; transplant centers

MIDAS: Microangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation ABSTRACT Hematopoietic cell transplant-associated thrombotic microangiopathy (HCT-TMA) is a clinical diagnosis based on consensus criteria and associated with high mortality rates (80%). Approximately 9,000 hematopoietic cell transplant (HCT) procedures are performed in the U.S. annually, and reported frequencies of HCT-TMA are highly variable due to lack of routine screening. HCT-TMA is a morbid and potentially life-threatening complication of HCT including microangiopathic hemolytic anemia, renal dysfunction and neurological symptoms. The initiating event of HCT-TMA appears to be endothelial injury, and extensive data indicate decline in endothelial health as people age suggesting that HCT-TMA might be more frequent or severe in older persons. Preliminary data indicate a bimodal distribution of HCT-TMA in adults, with a peak early after transplantation, which is well described in children, but a second later peak 3-6 months after transplant, sometimes associated with a flare of graft versus host disease (GVHD) during taper of immune suppression. There is no reported prospective study of HCT-TMA in adults thus risk factors and outcomes are currently unknown. This is a key gap in current knowledge and we plan to address this gap in our proposal. The need for a prospective adult cohort study of HCT-TMA is urgent as older patients are increasingly eligible for HCT. This study will define clinical phenotypes, risk factors, and possible therapeutic strategies for HCT-TMA. Our overarching hypothesis is that “The etiology and risk factors for HCT-TMA are different in adults than children, and that these differences importantly modify potential diagnostic and therapeutic strategies”. We propose to identify strategies that will define HCT recipients with increased susceptibility to HCT-TMA occurring early after transplantation, and later after establishment of GVHD. Identifying endothelial injury occurring post-HCT at the earliest possible time will allow for prompt clinical intervention and interruption of the cycle of endothelial injury and complement activation. The centers participating in this study are ideal for this work because they are large transplant centers with a strong track record of successful clinical research and study enrollment with a long-standing interest in HCT- TMA, evidenced by previous publications in the area. We will use our prospectively generated, well-annotated clinical database to test hypotheses regarding pathophysiology, for example, that GVHD is a major contributor to HCT-TMA by examining clinical risk factors and biomarkers of endothelial injury. We will measure the financial cost of HCT-TMA, late organ toxicity and will formulate and test a predictive index for HCT-TMA to target monitoring and treatment to highest-risk individuals. In summary, this study will provide essential data to identify persons at highest risk of HCT-TMA to allow testing of future clinical interventions such as studies of endothelial protecting agents and complement or interferon inhibitors for HCT-TMA and development of evidence-based guidelines for screening and diagnosis of HCT-TMA in adults.

MIDAS：接受干细胞移植的成人的微血管病变、内皮损伤 抽象的 造血细胞移植相关血栓性微血管病（HCT-TMA）是一种基于临床诊断的疾病 与高死亡率 (80%) 相关的标准和共识。 美国每年都会进行移植 (HCT) 手术，报告的 HCT-TMA 频率为 由于缺乏常规筛查，HCT-TMA 具有高度可变性，是一种病态且可能危及生命的疾病。 HCT 并发症包括微血管病性溶血性贫血、肾功能障碍和神经系统疾病 HCT-TMA 的起始事件似乎是内皮损伤，大量数据表明其下降。 随着人们年龄的增长，内皮健康状况也会发生变化，这表明 HCT-TMA 在老年人中可能更频繁或更严重。 初步数据表明，成人中 HCT-TMA 呈双峰分布，移植后早期达到峰值， 这在儿童中得到了很好的描述，但第二个高峰出现在移植后 3-6 个月，有时与 免疫抑制逐渐减弱期间出现移植物抗宿主病 (GVHD) 尚无报道。 成人 HCT-TMA 的前瞻性研究目前尚不清楚危险因素和结果，这是一个关键差距。 根据目前的知识，我们计划在我们的提案中解决这一差距，需要一个未来的成人队列。 随着老年患者越来越适合 HCT，HCT-TMA 的研究迫在眉睫。这项研究将定义临床。 HCT-TMA 的表型、危险因素和可能的治疗策略是： “成人 HCT-TMA 的病因和危险因素与儿童不同，这些差异 “修改潜在的诊断和治疗策略”。 定义 HCT 受者在移植后早期和后期对 HCT-TMA 的易感性增加 建立 GVHD 后，尽早识别 HCT 后发生的内皮损伤。 允许及时进行临床干预并中断内皮损伤和补体激活的循环。 参与这项研究的中心是这项工作的理想选择，因为它们是大型移植中心，拥有 拥有成功临床研究和研究注册的良好记录，对 HCT 有着长期的兴趣- TMA，该领域以前的出版物证明了我们将使用我们预期生成的、注释良好的。 临床数据库，用于测试有关病理生理学的假设，例如 GVHD 是一个主要因素 通过检查内皮损伤的临床风险因素和生物标志物来衡量 HCT-TMA 的财务状况。 HCT-TMA 的成本、晚期器官毒性，并将制定和测试 HCT-TMA 目标的预测指数 总之，这项研究将为识别高危人群提供必要的数据。 HCT-TMA 风险最高的人可以测试未来的临床干预措施，例如内皮细胞研究 HCT-TMA 的保护剂和补体或干扰素抑制剂以及基于证据的开发 成人 HCT-TMA 筛查和诊断指南。

项目成果

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and C

协调移植相关血栓性微血管病的诊断标准和预后评估的定义：代表欧洲血液和骨髓移植学会、美国移植学会和 C 学会的报告

• 发表时间: 2023-03
• 作者: Schoettler, M L;Carreras, E;Cho, B;Dandoy, C E;Ho, V T;Jodele, S;Moissev, I;Sanchez;Srivastava, A;Atsuta, Y;Carpenter, P;Koreth, J;Kroger, N;Ljungman, P;Page, K;Popat, U;Shaw, B E;Sureda, A;Soiffer, R;Vasu, S
• 通讯作者: Vasu, S