Nonmyeloablative Hematopoietic Cell Allotransplants

非清髓性造血细胞同种异体移植

• 批准号: 8558867
• 负责人: Rainer F. Storb
• 金额: $ 31.41万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8558867
• 关键词: Acute Graft Versus Host Disease; Acute Myelocytic Leukemia; Age; Allogenic; Ambulatory Care; Antibodies; Calcineurin inhibitor; Canis familiaris; Cells; Chronic; Collaborations; Comorbidity; Cyclosporine; Diagnosis; Disease; Dose; Elderly; Engraftment; Enrollment; Graft vs Tumor Effect; Hematologic Neoplasms; Hematopoietic; Hodgkin Disease; Immune; Immune system; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; Individual; Instruction; Length of Stay; Malignant Neoplasms; Modeling; Mycophenolate; Outcome; Patients; Pharmaceutical Preparations; Phase; Population; Protocols documentation; Randomized; Regimen; Relapse; Research; Sirolimus; Small-Cell Lymphoma; Tacrolimus; Time; Toxic effect; Transplantation; Transplantation and Immune System; Tumor Burden; Whole-Body Irradiation; adult leukemia; allotransplant; arm; base; conditioning; design; fludarabine; graft vs host disease; hematopoietic cell transplantation; immune function; improved; pre-clinical; prevent; tumor

PROJECT SUMMARY (See instructions): Project 2: Nonmyeloablative Hematopoietic Cell Allotransplants This project investigates allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning to treat patients with advanced hematological malignancies who are elderly and/or have cormobidities precluding high-dose HCT. Conditioning involves fludarabine (FLU) and 2 Gy total body irradiation (TBI), which lack serious toxicities. Post-grafting immunosuppresssion with mycophenolate motetil and a calcineurin inhibitor both aids engraftment and controls graft-vs.-host disease (GVHD). Graft-vs-tumor (GVT) effects are used to eradicate cancer. Avoiding toxicities has enabled us to surmount age and comorbidity limitations associated with myeloablative regimens. For these reasons and given that median ages of patients at diagnoses of most candidate diseases range from 65-70 years, the number of patients treatable by allogeneic HCT has greatly increased. To date, >1,600 patients have been enrolled on our nonmyeloablative protocols. This project will focus on relapse and acute GVHD. Specific Aim 1 consists of phase l/ll disease-specific protocols aimed at reducing relapse for patients with chronic lymphocytic lymphoma, acute myelocytic leukemia, and Hodgkin lymphoma. Seventy percent of patients who relapse do so Within the first year. We hypothesize that early relapse is due to blunting of GVT effects by early posttransplant immune compromise. Later, the immune system recovers as immunosuppressive drugs are being tapered or discontinued, thereby allowing powerful GVT effects to develop. The protocols intend to control tumor burden with specific drugs or an antibody-drug conjugate given after HCT, thereby bridging the early, immunocompromised post-transplant period without relapse until immune function recovers and GVT effects occur. Specific Aim 2 focuses on reducing acute GVHD. Aim 2a will use donor statin treatment to prevent acute GVHD among HLA-matched related recipients. Aim 2b is based on a just concluded, 3-arm, randomized, phase 11 study involving 208 HLA-matched unrelated recipients, which showed a significant reduction in acute GVHD with added sirolimus; Protocol 2448 is a phase 111 study comparing MMF/CSP/sirolimus to MMF/CSP. Aim 2c, HLA-mismatched grafts, will investigate the addition of sirolimus to MMF/CSP. Project 2 is a close collaboration with Project 1 to explore to what extent HLA typing can be refined, thereby extending donor options. A unique aspect of this project is that most of the proposed trials are conducted within a consortium that includes 23 academic centers outside of Seattle.

项目摘要（参见说明）： 项目 2：非清髓性造血细胞同种异体移植 该项目研究非清髓性预处理后的同种异体造血细胞移植 (HCT)，以治疗老年晚期血液恶性肿瘤患者和/或患有无法进行高剂量 HCT 的合并症的患者。调理包括氟达拉滨 (FLU) 和 2 Gy 全身照射 (TBI)，这些药物没有严重的毒性。使用霉酚酸酯和钙调神经磷酸酶抑制剂进行移植后免疫抑制既有助于移植又控制移植物抗宿主病 (GVHD)。移植物抗肿瘤（GVT）效应用于根除癌症。避免毒性使我们能够克服与清髓治疗方案相关的年龄和合并症限制。由于这些原因，并且考虑到大多数候选疾病诊断时患者的中位年龄为 65-70 岁，可通过同种异体 HCT 治疗的患者数量大大增加。迄今为止，已有超过 1,600 名患者参加了我们的非清髓方案。该项目将重点关注复发和急性 GVHD。具体目标 1 由 l/ll 期疾病特异性方案组成，旨在减少慢性淋巴细胞淋巴瘤、急性髓细胞白血病和霍奇金淋巴瘤患者的复发。百分之七十的患者会在第一年内复发。我们推测早期复发是由于移植后早期免疫损害减弱了 GVT 的影响。随后，随着免疫抑制药物逐渐减少或停药，免疫系统会恢复，从而产生强大的 GVT 效应。该方案旨在通过 HCT 后给予的特定药物或抗体药物偶联物控制肿瘤负荷，从而弥补移植后早期免疫功能低下的时期，而不会复发，直到免疫功能恢复和 GVT 效应发生。具体目标 2 侧重于减少急性 GVHD。目标 2a 将使用供体他汀类药物治疗来预防 HLA 匹配的相关受者中的急性 GVHD。目标 2b 基于一项刚刚结束的 3 臂、随机、11 期研究，涉及 208 名 HLA 匹配的无关受者，该研究显示添加西罗莫司后急性 GVHD 显着降低；方案 2448 是一项比较 MMF/CSP/西罗莫司与 MMF/CSP 的 111 期研究。目标 2c，HLA 不匹配的移植物，将研究在 MMF/CSP 中添加西罗莫司。项目 2 是与项目 1 的密切合作，旨在探索 HLA 分型可以改进到什么程度，从而扩大捐赠者的选择。该项目的一个独特之处在于，大多数拟议的试验都是在一个由西雅图以外的 23 个学术中心组成的联盟内进行的。