The Ohio State University Blood and Marrow Transplant Research Consortium

俄亥俄州立大学血液和骨髓移植研究联盟

基本信息

批准号：
10187635
负责人：
Sumithira Vasu
金额：
$ 17.72万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-26 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187635
关键词：
AMD3100 Acute Address Adult Allogenic Allografting B-Lymphocytes Base Sequence Benign Blood Bone Marrow Bone Marrow Transplantation CD34 gene CXCR4 gene Cell Transplantation Cells Clinical Trials Network Collaborations Conduct Clinical Trials Data Dendritic Cells Disease Engraftment Funding Future Genes Granulocyte Colony-Stimulating Factor Hematology Hematopoietic Immune Immune System Diseases Immune system Immunity Infection Kinetics Lead Leadership Longevity Macrophage Colony-Stimulating Factor Malignant - descriptor Malignant Neoplasms Methods Mission Morbidity - disease rate Natural Killer Cells Ohio Opportunistic Infections Outcome Patients Phenotype Plague Process Productivity Quality of life Randomized Recovery Relapse Reporting Research Research Personnel Safety Science Siblings Source T-Lymphocyte Testing Therapeutic immunosuppression Toxic effect Transplant Recipients Transplantation Universities Work base chronic graft versus host disease curative treatments donor stem cell experience graft failure graft vs host disease hematopoietic cell transplantation high risk immune reconstitution improved member novel novel strategies older patient peripheral blood phase 2 study phase III trial preference primary endpoint reconstitution secondary endpoint success symposium transplant centers

项目摘要

Project Summary While HCT offers potentially curative therapy to patients with a variety of benign and malignant diseases, both acute and chronic graft versus host disease (GVHD) continue to plague the field and often limit the longevity and quality of life of our patients. While either bone marrow (BM) or mobilized peripheral blood (MPB) are suitable sources of donor hematopoietic cells, this network established in BMT CTN 0201 that granulocyte colony stimulating factor (G-CSF) MPB is associated with a higher risk of chronic GVHD (cGVHD) and worse quality of life following unrelated donor HCT compared to BM. Similar results have been demonstrated in recipients of MPB from matched siblings. The Ohio State Blood and Marrow Transplant Research Consortium (OSUBMT- RC) is comprised of five highly experienced transplant centers with a well-established track record of productivity conducting clinical trials. Our consortium proposes a novel approach to limiting GVHD following HCT by establishing a new standard for the procurement of donor hematopoietic cells for transplantation. The OSUBMT- RC PI has pioneered a novel method to procure donor cells for HCT using the CXCR4 antagonist plerixafor without G-CSF. Plerixafor mobilizes CD34+ cells and other immune cells for transplantation far more rapidly than G-CSF (1 vs 5 days), with less toxicity to the donor. Grafts procured following plerixafor alone (P-MPB) promote full engraftment and based on a recent multi-center phase II study led by the PI, appear to reconstitute immunity faster than G-MPB and may cause less chronic GVHD (cGVHD). These advantages appear to be particularly striking in older patients receiving reduced intensity allografts. Based on these data, we hypothesize that P-MPB will become a suitable and possibly preferable alternative method to procure MPB for HCT due to the combination of better convenience and less toxicity for donors and less GVHD combined with better immune reconstitution in recipients. We propose to test these hypotheses with the following specific aims: Aim 1: We will conduct a randomized Phase II study of P-MPB versus G-MPB in recipients of matched sibling donor allografts with cGVHD-free, relapse free survival as the primary endpoint. Aim 2: We will test the hypothesis that immune reconstitution is improved with P-MPB versus G-MPB through correlative phenotypical, functional, and gene sequence based studies of T, B, NK, and dendritic cells procured from allograft recipients following HCT The proposed study addresses several key priorities of the BMT CTN established at the 2014 State of the Science Symposium and if promising will pave the way for a future definitive Phase III trial that could radically improve our process for collecting allografts from donors.

项目概要虽然 HCT 为患有各种良性和恶性疾病的患者提供了潜在的治疗方法，但急性和慢性移植物抗宿主病（GVHD）继续困扰着该领域，并常常限制寿命和我们患者的生活质量。虽然骨髓 (BM) 或动员外周血 (MPB) 都适合供体造血细胞的来源，该网络在 BMT CTN 0201 中建立，粒细胞集落刺激因子 (G-CSF) MPB 与慢性 GVHD (cGVHD) 的较高风险和较差的移植质量相关。与 BM 相比，无关捐赠者 HCT 后的生活。类似的结果已在接受者中得到证实来自匹配兄弟姐妹的 MPB。俄亥俄州血液和骨髓移植研究联盟 (OSUBMT- RC）由五个经验丰富的移植中心组成，具有良好的生产力记录进行临床试验。我们的联盟提出了一种限制 HCT 后 GVHD 的新方法：建立移植用供体造血细胞采购的新标准。 OSUBMT- RC PI 开创了一种使用 CXCR4 拮抗剂 plerixafor 获取 HCT 供体细胞的新方法没有 G-CSF。 Plerixafor 动员 CD34+ 细胞和其他免疫细胞进行移植的速度远远快于 G-CSF（1 天 vs 5 天），对供体的毒性较小。单独使用普乐沙福 (P-MPB) 后获得的移植物促进完全植入并基于最近由 PI 领导的多中心 II 期研究，似乎可以重建免疫力比 G-MPB 更快，并且可能减少慢性 GVHD (cGVHD)。这些优点看起来特别在接受强度降低的同种异体移植的老年患者中尤为明显。根据这些数据，我们假设 P-MPB 由于以下原因，将成为为 HCT 采购 MPB 的合适且可能更好的替代方法更好的便利性和对捐献者更低的毒性以及更少的 GVHD 与更好的免疫相结合在接受者中重构。我们建议通过以下具体目标来检验这些假设：目标 1：我们将在匹配的接受者中进行 P-MPB 与 G-MPB 的随机 II 期研究以无 cGVHD、无复发生存为主要终点的同胞供体同种异体移植物。目标 2：我们将检验 P-MPB 与 G-MPB 相比免疫重建得到改善的假设通过基于 T、B、NK 和树突的相关表型、功能和基因序列研究 HCT 后从同种异体移植受者处获取的细胞拟议的研究涉及 2014 年国情咨文建立的 BMT CTN 的几个关键优先事项科学研讨会如果有希望的话将为未来最终的第三阶段试验铺平道路，该试验可以从根本上解决改进我们从捐赠者那里收集同种异体移植物的流程。