Nonmyeloablative Hematopoietic Cell Allotransplants

项目1：非清髓性造血细胞同种异体移植 我们建议继续探索异基因造血的非清髓性预处理方案 细胞移植（HCT）治疗恶性血液病患者和感染者 人类免疫缺陷病毒 1 (HIV1)。提议的主要方案是从 临床前犬模型，使用移植后免疫抑制来增强植入和控制 移植物抗宿主病（GVHD），依靠移植物抗肿瘤效应来根除癌症，并且很大程度上可以通过 由于缺乏与治疗方案相关的严重毒性，因此在门诊护理环境中进行。后者 特征使我们能够忽略目前骨髓细胞存在的年龄和合并症限制。 消融疗法。考虑到这一点以及大多数候选患者诊断时的中位年龄这一事实 疾病年龄范围为 65-70 岁，可通过同种异体治疗和潜在治愈的患者数量 HCT 大大提高。前两个具体目标将研究 HLA 匹配和 HCT 捐赠者不匹配。虽然重点是不相关的 HCT，但一些方案也将包括相关的捐赠者。 两项方案是前瞻性随机试验，一项是关于预防急性 GVHD，另一项是关于结果 适用于接受清髓性或非清髓性调理的骨髓恶性肿瘤患者。几个 疾病特异性方案将评估非清髓性 HCT 方法对患有以下疾病的患者的价值： 慢性粒细胞白血病、Ph1急性淋巴细胞白血病、慢性淋巴细胞白血病、多发性白血病 骨髓瘤和 HIV1/AIDS 患者。第三个目标将验证新的预测价值 在一项多中心研究中制定了 HCT 特异性合并症指数。几乎所有的研究都正在进行中 在一个多机构联盟的支持下，该联盟包括 17 个国外学术中心 西雅图，弗雷德·哈钦森癌症研究中心作为协调中心。 与公共卫生的相关性：这些拟议的研究旨在提高同种异体的安全性 HCT 是一种每年已用于治疗数千名患者的疗法。该项目的成功将扩大 同种异体 HCT 的应用显着增加，允许将其用于老年患者和其他患有 额外的医疗问题。此外，所提出的方案允许最纯粹地确定移植物与- 除了强化调理外，肿瘤效应还提供了良好的基础 特定疾病的模式。最后，合并症数据可能会变得与定义癌症一样重要 诊断、分期、缓解状态和其他更熟悉的变量来预测患者的反应和 结果。

Project 1: Nonmyeloablative Hematopoietic Cell Allotransplants We propose to continue exploring nonmyeloablative conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) in the treatment of patients with malignant blood disorders and those infected with human immunodeficiency virus 1 (HIV1). The principal regimens proposed have been translated from a preclinical canine model, use postgrafting immunosuppression to both enhance engraftment and control graft-vs-host disease (GVHD), rely on graft-vs-tumor effects for eradicating cancer, and can largely be administered in the ambulatory care setting owing to lack of serious regimen-related toxicities. The latter characteristic has enabled us to ignore the age and comorbidity limitations currently existing for myelo- ablative regimens. Given that and the fact that median ages at diagnoses for patients with most candidate diseases range from 65-70 years, the number of patients treatable and potentially curable by allogeneic HCT has been greatly increased. The first two Specific Aims will investigate HCT from HLA-matched and mismatched donors. While the focus is on unrelated HCT,several protocols will also include related donors. Two protocols are prospective randomized trials, one on prevention of acute GVHD, and one on outcomes for patients with myeldid malignancies given either myeloablative or nonmyeloablative conditioning. Several disease-specific protocols will assess the value of the nonmyeloablative HCT approach for patients with chronic myelocytic leukemia, Ph1+ acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, and patients with HIV1/AIDS. The third Aim will validate the prognostic value of a newly developed HCT-specific comorbidity index in a multi-center study. Almost all studies are being conducted under the auspices of a multi-institutional consortium which includes 17 academic centers outside of Seattle, and in which the Fred Hutchinson Cancer Research Center serves as the coordinating center. Relevance to Public Health: These proposed studies are aimed at increasing the safety of allogeneic HCT, a therapy already used to treat thousands of patients each year. Success in this project will broaden considerably the application of allogeneic HCT by allowing its use in elderly patients and others with additional medical problems. Further, the proposed regimen allows for'the purest determination of graft-vs- tumor effects, apart from intensive conditioning, and provides an excellent foundation on which to add disease-specific modalities. Finally, comorbidity data will likely become as important as defining cancer diagnosis, stage, remission status, and other more familiar variables in predicting patient response and outcome.