Hematopoietic Cell Therapy for Young Adults with Severe Sickle Cell Disease

儿童时期制定的支持性卫生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，从而提高了成年期的生存率。这在一定程度上改变了SCD的人口统计，包括越来越多患有慢性健康障碍的年轻人。虽然造血细胞移植（HCT）具有治疗潜力，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）分型技术和支持性护理的进展改善了HCT的结果，特别是在非亲属供体HCT之后。Busulfan， Fludarabine和抗胸腺细胞球蛋白的调节方案具有较低的毒性，并且对患有晚期髓系恶性肿瘤和重度地中海贫血的成人非亲属供体HCT有效。我们组织了一个由移植研究人员和成人镰状细胞提供者组成的跨学科小组，以验证来自hla相同的兄弟姐妹或无血缘关系的骨髓供者的HCT对患有严重SCD的年轻人是安全有效的假设。我们建议在一项试点调查中验证这一假设，这也将作为设计、组织和启动大型平行队列临床试验的中心计划机制，在该试验中，移植和支持治疗对成人重度SCD进行比较。因此，我们建议通过以下具体目的来研究成人重症镰状细胞病的HCT: 1。确定HCT治疗严重镰状细胞病的可行性和耐受性。2. 测量供体造血对终末器官功能的影响，并确定大型比较临床试验的样本量和临床终点。如果计划和启动成功，拟议的比较临床试验将是第一个比较HCT和支持治疗SCD的临床试验，并可能扩大成人重度SCD的治疗机会。

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.