Reducing the Toxicity of BMT in Sickle Cell Anemia

降低 BMT 对镰状细胞性贫血的毒性

• 批准号: 6792011
• 负责人: ROBERT IANNONE
• 金额: $ 13.07万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792011
• 关键词: FK506; antineoplastics; bone marrow transplantation; clinical research; clinical trials; cyclophosphamide; disease /disorder prevention /control; dosage; fludarabine; graft versus host disease; histocompatibility; human subject; human therapy evaluation; immunopharmacology; immunosuppressive; mycophenolate mofetil; patient oriented research; radiation therapy; siblings; sickle cell anemia; tissue mosaicism; transplant rejection; transplantation immunology; whole body irradiation effect

DESCRIPTION (provided by applicant): The main objective of the research proposal is to reduce the toxicity of bone marrow transplantation (BMT) for sickle cell disease (SCD) in order to extend this potentially curative therapy to more patients. Despite current therapies, SCD is associated with substantial morbidity and mortality. Myeloablative BMT can cure SCD but its application is limited by a 5-10% mortality risk, a 10% failure rate, graft-versus-host disease (GVHD) and the risk of gonadal and endocrine dysfunction. Nonmyeloablative BMT (NST) can result in mixed hematopoietic chimerism, stable co-existence of host and donor marrow, and may be less toxic than myeloablative BMT. Because normal red blood cells (RBCs) survive much longer than sickle RBCs, a low-level of normal donor chimerism may substantially reduce the fraction of sickle cells in the circulation and prevent their pathologic effects. There is limited experience, however, with NST in patients with SCD. We have studied animal models of mixed chimerism to treat SCD, tested novel NST regimens for inducing donor-specific tolerance and reducing GVHD, and piloted a clinical trial of NST in patients with SCD. Six of seven patients treated had initial donor engraftment and toxicities were mild and reversible, however, all patients experienced late graft failure. We now hypothesize that HLA-identical sibling bone marrow will engraft in >80% of patients with SCD who receive pre-transplantation fludarabine and low-dose total body irradiation, with or without cyclophosphamide (Cy), followed by post-transplantation Cy, tacrolimus and mycophenolate mofetil. We will study in-vitro anti-donor reactivity as a predictor of rejection, track other factors associated with engraftment and GVHD, assess immune reconstitution after NST, and evaluate the effect of this treatment on multiple clinical parameters. I was recently recruited to the Children's Hospital of Philadelphia to establish a clinical research program in BMT for non-malignant diseases, emphasizing SCD. My objective is to become an independent clinical scientist by obtaining formal instruction and conducting mentored patient-oriented research on reducing the toxicity of BMT for SCD. I have a strong mentoring committee composed of scientists with expertise in clinical trial development, SCD, BMT, biostatistics, bioethics and transplant biology. As part of my training, I will obtain a Master's Degree in Clinical Research through the Center for Clinical Epidemiology and Biostatistics.

描述（由申请人提供）：该研究计划的主要目标是降低骨髓移植（BMT）治疗镰状细胞病（SCD）的毒性，以便将这种潜在的治愈疗法推广到更多患者。尽管有目前的治疗方法，SCD 仍然与大量的发病率和死亡率相关。清髓性 BMT 可以治愈 SCD，但其应用受到 5-10% 的死亡风险、10% 的失败率、移植物抗宿主病 (GVHD) 以及性腺和内分泌功能障碍的风险的限制。非清髓性 BMT (NST) 可导致混合造血嵌合、宿主和供体骨髓稳定共存，并且可能比清髓性 BMT 毒性更低。由于正常红细胞 (RBC) 的存活时间比镰状红细胞长得多，因此低水平的正常供体嵌合可能会大大减少循环中镰状细胞的比例，并防止其病理效应。然而，在 SCD 患者中使用 NST 的经验有限。我们研究了治疗 SCD 的混合嵌合动物模型，测试了用于诱导供体特异性耐受和减少 GVHD 的新型 NST 方案，并在 SCD 患者中进行了 NST 临床试验。接受治疗的七名患者中有六名进行了初始供体移植，毒性轻微且可逆，但所有患者均经历了晚期移植失败。我们现在假设，>80% 的 SCD 患者接受移植前氟达拉滨和低剂量全身放疗（联合或不联合环磷酰胺 (Cy)），然后接受移植后 Cy、他克莫司和吗替麦考酚酯，HLA 相同的同胞骨髓将被移植。我们将研究体外抗供体反应性作为排斥反应的预测因子，追踪与植入和 GVHD 相关的其他因素，评估 NST 后的免疫重建，并评估这种治疗对多种临床参数的影响。 我最近被费城儿童医院招募，负责建立针对非恶性疾病的 BMT 临床研究项目，重点关注 SCD。我的目标是通过获得正式指导并进行指导性的以患者为导向的研究来降低 BMT 对 SCD 的毒性，成为一名独立的临床科学家。我有一个强大的指导委员会，由在临床试验开发、SCD、BMT、生物统计学、生物伦理学和移植生物学方面具有专业知识的科学家组成。作为培训的一部分，我将通过临床流行病学和生物统计学中心获得临床研究硕士学位。