Precision Alemtuzumab Therapy in Allogeneic HCT

同种异体 HCT 中的精准阿仑单抗治疗

• 批准号: 10682496
• 负责人: PARINDA A. MEHTA
• 金额: $ 30.09万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682496
• 关键词: Acute Graft Versus Host Disease; Age; Allogeneic Bone Marrow Transplantation; Allogenic; Body Surface Area; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CDW52 gene; Cell Count; Childhood; Chimerism; Clinical; Clinical Trials; Data; Development; Disease; Dose; Drug Kinetics; Electronics; Enrollment; Ensure; Evaluation; Failure; Feasibility Studies; Funding; Graft Rejection; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hereditary Disease; Immune; Immunity; Inborn Errors of Metabolism; Incidence; Individual; Infection; Infusion procedures; Institution; Intervention; Leukocytes; Lymphocyte; Lymphocyte Depletion; Lytic; Malignant - descriptor; Malignant Neoplasms; Marrow; Mediating; Modeling; Monitor; Monte Carlo Method; Non-Malignant; Outcome; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Physicians; Pilot Projects; Population; Preparation; Prevention; Procedures; Public Health; Radiation Toxicity; Recommendation; Recovery; Regimen; Reporting; Risk; Sample Size; Scheme; Sickle Cell Anemia; Subgroup; T cell reconstitution; T-Lymphocyte; Technology; Testing; Thalassemia; Therapeutic; Therapeutic Effect; Time; Toxic effect; Toxicity due to chemotherapy; Transplant Recipients; Transplantation; Weight; Work; age group; alemtuzumab; conditioning; curative treatments; dashboard; falls; graft failure; graft vs host disease; hematopoietic cell transplantation; high risk; humanized monoclonal antibodies; immune reconstitution; improved; interest; interpatient variability; models and simulation; mortality; novel; pharmacokinetic model; phase 2 study; post-transplant; prevent; programs; simulation; standard of care; success; therapeutic target; tool; transplantation therapy; user-friendly; web-based tool; young adult

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.

项目摘要/摘要 许多儿科和年轻患者需要同种异体造血细胞移植（HCT） 除了癌症以外，致命疾病的治疗。通常接受的非恶性疾病 同种异体HCT包括严重的先天免疫力，天生的新陈代谢错误，骨髓衰竭 疾病和血液学疾病，例如thalassycal和镰状细胞疾病。 降低的强度调节（RIC）和毒性调节降低（RTC）通常是 用于非恶性疾病的患者。 RIC和RTC方案通常包含Alemtuzumab，A 针对CD52的人源化单克隆抗体。 CD52由大多数 淋巴细胞和其他一些白细胞。 RIC和RTC方案中包括Alemtuzumab 2 主要原因。 alemtuzumab通过耗尽淋巴细胞的接受者来防止移植物排斥 包括可能将同种异体移植物识别为外国的T细胞。 Alemtuzumab也减少了移植 与宿主疾病相对于宿主疾病，因为alemtuzumab可能通过给药 造血干细胞移植物，导致移植物的淋巴细胞耗竭。充分预防 移植失败，移植与宿主疾病对于确保成功的结果和患者至关重要 生存。 我们不知道剂量alemtuzumab的最佳方法。我们以前已经报道了最佳周期 移植当天（第0天）的移植Alemtuzumab浓度为0.2-0.6mcg/ml 降低移植失败和移植与宿主疾病的风险。此范围内的级别也优化 早期免疫恢复。重要的是要剂量alemtuzumab，以便大多数患者 在此理想的目标浓度窗口内实现第0天的浓度。 我们已经进行了详细的Alemtuzumab药代动力学（PK）研究并开发了人群PK 允许制定精确给药策略的模型。我们应用了这种精确的给药策略 在一项针对12例效果良好的患者的初步可行性研究中。我们在此电流中要求资金 用于支持小儿和年轻的精确alemtuzumab剂量的大型II期研究 非恶性疾病的成年患者。我们将评估我们的方法的成功 在第0天，患者达到0.2-0.6mcg/ml的理想治疗浓度窗口，对 免疫重建，移植失败以及移植物与宿主疾病的临床结果。