Precision Alemtuzumab Therapy in Allogeneic HCT

项目总结/摘要 许多儿童和年轻成人患者需要同种异体造血细胞移植（HCT）， 治疗癌症以外的致命疾病。非恶性疾病，通常用 异基因HCT包括严重的先天性免疫缺陷、先天性代谢缺陷、骨髓衰竭 疾病和血液学病症如地中海贫血和镰状细胞病。 降低强度预处理（RIC）和降低毒性预处理（RTC）方案通常是 用于非恶性疾病患者。RIC和RTC方案通常含有阿仑单抗， 人源化单克隆抗体，其针对CD 52。CD 52由大多数人表达。 淋巴细胞和其他白色血细胞。Alemtuzumab包含在RIC和RTC方案中， 主要原因。Alemtuzumab通过消耗受体淋巴细胞来预防移植物排斥反应 包括可将同种异体移植物识别为外来的T细胞。Alemtuzumab还可减少移植物 因为Alemtuzumab在给药期间可能停留在裂解水平， 这导致造血干细胞移植物中的淋巴细胞减少并导致移植物的淋巴细胞耗竭。充分预防 移植失败和移植物抗宿主病对于确保成功的结果和患者 生存 我们不知道给药Alemtuzumab的最佳方式。我们以前曾报道过，最佳选择- 移植物给药当天（第0天）的移植物Alemtuzumab浓度为0.2- 0.6 mcg/mL 降低移植失败和移植物抗宿主病的风险。在此范围内的水平也优化 早期免疫恢复重要的是能够给药Alemtuzumab，以便大多数患者 在该理想目标浓度窗口内达到第0天浓度。 我们进行了详细的Alemtuzumab药代动力学（PK）研究，并开发了群体PK 模型，以便制定精确给药策略。我们采用了这种精确给药策略 在12名患者的试点可行性研究中取得了良好的效果。我们正在申请资金， 申请支持在儿童和年轻人中进行的Alemtuzumab精密度给药的大型II期研究 患有非恶性疾病的成年患者。我们将评估我们的方法是否成功， 患者在第0天达到理想治疗浓度窗0.2- 0.6 mcg/mL， 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.