Hematopoietic Cell Therapy for Young Adults with Severe Sickle Cell Disease

描述(申请人提供)：摘要儿童时期制定的支持性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存活率。这在一定程度上改变了SCD的人口结构，将越来越多的患有慢性健康损害的年轻人包括在内。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)分型技术的进步和支持性治疗改善了HCT的预后，特别是在无血缘关系的供者HCT之后。一种由白花丹、氟达拉滨和抗胸腺细胞球蛋白组成的调节方案具有较低的毒性，对患有晚期髓系恶性肿瘤和重型地中海贫血的成年人的无关捐赠者的HCT似乎有效。我们组织了一个由移植研究人员和成人镰刀细胞提供者组成的跨学科小组来测试这一假设，即来自HLA相合兄弟姐妹或无关骨髓捐赠者的HCT在患有严重SCD的年轻人中是安全有效的。我们建议在一项试点研究中验证这一假设，这也将作为设计、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，将比较成人严重SCD患者的移植和支持性治疗。因此，我们建议通过以下特定目的来研究成人重症镰状细胞病患者的HCT：1.确定在患有严重镰状细胞疾病的年轻人中实施HCT的可行性和耐受性。2.测量供者造血对终末器官功能的影响，并确定更大的对照临床试验的样本量和临床终点。如果成功规划和启动，拟议的对比临床试验将是第一个比较HCT和支持治疗SCD的试验，并可能扩大患有严重SCD的成年人的治疗机会。

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.