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.

项目概要/摘要 许多儿童和年轻成人患者需要进行同种异体造血细胞移植 (HCT) 治疗癌症以外的致命疾病。通常治疗的非恶性疾病 同种异体 HCT 包括严重先天性免疫缺陷、先天性代谢缺陷、骨髓衰竭 疾病和血液病，如地中海贫血和镰状细胞病。 降低强度训练（RIC）和降低毒性训练（RTC）方案通常是 用于患有非恶性疾病的患者。 RIC 和 RTC 方案通常含有阿仑单抗（alemtuzumab）， 针对 CD52 的人源化单克隆抗体。 CD52 由大多数表达 淋巴细胞和一些其他白细胞。阿仑单抗包含在 RIC 和 RTC 方案中 2 主要原因。阿仑单抗通过消耗受体淋巴细胞来预防移植排斥 包括可能将同种异体移植物识别为外来物的 T 细胞。阿仑单抗还可以减少移植物 与宿主疾病相比，因为阿仑单抗可能通过施用 造血干细胞移植物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至关重要 生存。 我们不知道阿仑单抗的最佳给药方式。我们之前曾报道过，最佳的周 移植物给药当天（第 0 天）阿仑单抗浓度为 0.2-0.6 mcg/mL 降低移植失败和移植物抗宿主病的风险。该范围内的水平也优化 免疫能力早日恢复。能够给予阿仑单抗剂量非常重要，以便大多数患者 在这个理想的目标浓度窗口内达到第 0 天的浓度。 我们进行了详细的阿仑单抗药代动力学 (PK) 研究并制定了群体 PK 模型以允许制定精确剂量策略。我们应用了这种精确剂量策略 在对12名患者进行的试点可行性研究中取得了良好的结果。我们正在请求当前的资金 申请支持儿科和青少年中阿仑单抗精准给药的更大规模 II 期研究 患有非恶性疾病的成年患者。我们将评估我们的目标定位方法是否成功 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、移植失败和移植物抗宿主病的临床结果。