Precision Alemtuzumab Therapy in Allogeneic HCT

项目摘要/摘要 许多儿童和青年患者需要异基因造血细胞移植(HCT)来治疗 治疗癌症以外的致命疾病。通常用来治疗的非恶性疾病 异基因红细胞移植包括严重的先天免疫缺陷、先天代谢缺陷、骨髓衰竭 疾病，以及血液病，如地中海贫血和镰状细胞病。 低强度调理(RIC)和减毒调理(RTC)方案是常见的 适用于非恶性疾病患者。RIC和RTC方案通常包含alemtuzumab，a 针对CD52的人源化单抗。CD52由大多数人表达 淋巴细胞和其他一些白细胞。Alemtuzumab包括在RIC和RTC方案中，共2个疗程 主要原因。Alemtuzumab通过耗尽淋巴细胞受体来预防移植物排斥反应 包括可能识别异体移植物为异体的T细胞。Alemtuzumab还可以减少移植物 对宿主疾病的治疗，因为alemtuzumab可能通过给药在裂解水平上徘徊 造血干细胞移植，并导致移植的淋巴细胞耗尽。充分预防 移植物衰竭和移植物抗宿主病是确保成功的结果和患者的关键 生死存亡。 我们不知道给阿仑珠单抗服药的最佳方式。我们之前已经报道过，最佳周期- 移植物给药当天(第0天)移植用阿伦珠单抗浓度为0.2-0.6mcg/ml 降低移植物衰竭和移植物抗宿主病的风险。在此范围内的级别也会优化 早期免疫恢复。重要的是能够给阿伦图珠单抗注射，这样大多数患者 在这个理想的目标浓度窗口内实现0天浓度。 我们已经进行了详细的alemtuzumab药代动力学(PK)研究，并开发了一种人群PK 模型，以允许开发精确的配药策略。我们应用了这种精确的剂量策略 在12例患者的试点可行性研究中取得了良好的效果。我们正在申请目前的资金 应用Alemtuzumab支持更大规模的儿童和青年阿伦图珠单抗精确剂量II期研究 非恶性疾病的成人患者。我们将评估我们的方法在目标定位方面的成功 患者在第0天达到0.2-0.6mcg/mL的理想治疗浓度窗口，以及对 免疫重建、移植物衰竭和移植物抗宿主病的临床结果。

Project Summary/Abstract Many pediatric and young adult patients require an allogeneic hematopoietic cell transplant (HCT) for treatment of deadly diseases besides cancer. Non-malignant disorders which are often treated with allogeneic HCT include severe inborn errors of immunity, inborn errors of metabolism, marrow failure disorders, and hematologic conditions such as thalassemia and sickle cell disease. Reduced intensity conditioning (RIC) and reduced toxicity conditioning (RTC) regimens are commonly used for patients with non-malignant disorders. RIC and RTC regimens usually contain alemtuzumab, a humanized monoclonal antibody that is directed against CD52. CD52 is expressed by the majority of lymphocytes and some other white blood cells. Alemtuzumab is included in RIC and RTC regimens for 2 main reasons. Alemtuzumab prevents graft rejection by depleting the recipient of lymphocytes including T cells which may recognize the allogeneic graft as foreign. Alemtuzumab also reduces graft versus host disease because alemtuzumab may linger at lytic levels through the administration of the hematopoietic stem cell graft and result in lymphocyte depletion of the graft. Adequate prevention of graft failure and graft versus host disease is essential to ensure successful outcomes and patient survival. We do not know the best way to dose alemtuzumab. We have previously reported that optimal peri- transplant alemtuzumab concentrations of 0.2-0.6mcg/mL on the day of graft administration (Day 0) reduce the risks of graft failure and graft versus host disease. Levels within this range also optimize early immune recovery. It is important to be able to dose alemtuzumab so that the majority of patients achieve Day 0 concentrations within this ideal target concentration window. We have performed detailed alemtuzumab pharmacokinetic (PK) studies and developed a population PK model to allow a Precision Dosing strategy to be developed. We applied this Precision Dosing strategy in a pilot feasibility study of 12 patients with good results. We are requesting funding in this current application to support a larger phase II study of Precision Alemtuzumab Dosing in pediatric and young adult patients with non-malignant disorders. We will evaluate the success of our approach in targeting patients to the ideal therapeutic concentration window of 0.2-0.6mcg/mL on Day 0 and the impact on the clinical outcomes of immune reconstitution, graft failure, and graft versus host disease.