Hematopoietic Cell Therapy for Young Adults with Severe Sickle Cell Disease

描述（由申请人提供）：摘要在儿童时期采取的支持性医疗保健措施成功地预防了镰状细胞病（SCD）的严重感染和许多其他危及生命的并发症，从而提高了成年后的生存率。这在一定程度上改变了SCD的人口统计数据，包括越来越多的患有慢性健康障碍的年轻人。虽然造血细胞移植（HCT）具有治愈潜力，但很少有SCD患者接受HCT治疗，部分原因是这种治疗的毒性。最近，人类白细胞抗原（HLA）分型技术和支持性治疗的进步改善了HCT的结果，特别是在无关供体HCT后。白消安，氟达拉滨和抗胸腺细胞球蛋白的预处理方案具有降低的毒性特征，并且在患有晚期骨髓恶性肿瘤和重型地中海贫血的成人中的无关供体的HCT中似乎有效。我们组织了一个由移植研究者和成人镰状细胞提供者组成的跨学科小组，以检验来自HLA相同的兄弟姐妹或无关骨髓供体的HCT在患有严重SCD的年轻人中安全有效的假设。我们建议在一项试点研究中检验这一假设，该研究也将作为设计、组织和启动一项大型平行队列临床试验的中央规划机制，在该试验中，将对严重SCD成人的移植和支持治疗进行比较。因此，我们建议通过以下具体目标来研究严重镰状细胞病成人的HCT：1。确定HCT在患有严重镰状细胞病的年轻人中的可行性和耐受性。2.测量供体造血对终末器官功能的影响，并确定更大规模比较临床试验的样本量和临床终点。如果成功计划和启动，拟议的比较临床试验将是第一个比较HCT和SCD支持治疗的试验，并可能扩大严重SCD成人的治疗机会。 公共卫生相关性：镰状细胞病在成年期迅速发展，导致各种器官损伤和过早死亡，并且没有良好的治疗方法可用于预防疾病的进展。虽然骨髓移植在儿科患者中是有效的，但它在疾病管理中的地位尚不清楚，并且尚未在成人中进行系统研究。我们建议对16-40岁的患者进行BMT的试点多中心研究，以确定这种治疗的安全性和耐受性，并促进大规模试验的计划，以确定BMT在镰状细胞病成人中的位置。

DESCRIPTION (provided by applicant): Abstract Supportive health care measures instituted during childhood successfully prevent serious infections and many other life-threatening complications of sickle cell disease (SCD), resulting in improved survival to adulthood. This has, in part, shifted the demographics of SCD to include a growing proportion of young adults with chronic health impairments. While hematopoietic cell transplantation (HCT) has curative potential, very few individuals with SCD are treated by HCT, due in part to the toxicity of this treatment. Recently, advances in Human Leukocyte Antigen (HLA) typing techniques and supportive care have improved outcomes of HCT, particularly after unrelated donor HCT. A conditioning regimen of Busulfan, Fludarabine and anti-thymocyte globulin has a reduced toxicity profile and appears effective in HCT from unrelated donors in adults who have advanced myeloid malignancies and thalassemia major. We have organized an interdisciplinary group of transplant investigators and adult sickle cell providers to test the hypothesis that HCT from an HLA-identical sibling or unrelated marrow donor is safe and effective in young adults with severe SCD. We propose to test this hypothesis in a pilot investigation, which will also serve as a central planning mechanism for designing, organizing and launching a large parallel cohort clinical trial in which transplantation and supportive treatment for adults with severe SCD will be compared. Thus, we propose to investigate HCT in adults with severe sickle cell disease by the following specific aims: 1. Determine the feasibility and tolerability of HCT in young adults with severe sickle cell disease. 2. Measure the impact of donor hematopoiesis on end-organ function and define the sample size and clinical endpoints of a larger comparative clinical trial. If successfully planned and initiated, the proposed comparative clinical trial would be the first to compare HCT and supportive care for SCD, and could broaden the therapeutic opportunities for adults with severe SCD. PUBLIC HEALTH RELEVANCE: Sickle cell disease progresses rapidly during adulthood leading to damage to various organs and premature mortality and there are no good treatments available to prevent the progression of disease. While bone marrow transplantation is known to be effective in pediatric patients, it's place in the management of the disease is unclear and has not been systematically studied in adults. We propose to conduct a pilot multi-center study of BMT for patients 16-40 years of age to determine the safety and tolerability of this treatment and facilitate the planning of a large scale trial to determine place of BMT in adults with sickle cell disease.