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（HIV 1）。所提出的主要方案是从一个 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），依赖于移植物抗肿瘤效应来根除癌症，并且可以在很大程度上被 由于缺乏严重的方案相关毒性，因此在门诊护理环境中给药。后者 这一特征使我们能够忽略目前存在的年龄和合并症限制， 消融疗法考虑到这一点，以及大多数候选人的诊断年龄中位数 疾病范围从65-70岁，可治疗的患者数量和通过同种异体移植可能治愈的患者数量。 HCT大大增加。前两个特定目的将研究HLA匹配的HCT， 不匹配的捐赠者虽然重点是无关的HCT，但几个方案也将包括相关供体。 两个方案是前瞻性随机试验，一个是关于急性GVHD的预防，另一个是关于结局 用于接受清髓性或非清髓性预处理的骨髓恶性肿瘤患者。几 疾病特异性方案将评估非清髓性HCT方法对以下患者的价值： 慢性粒细胞白血病，Ph 1+急性淋巴细胞白血病，慢性淋巴细胞白血病，多发性 骨髓瘤和HIV 1/AIDS患者。第三个目标将验证一个新的 在一项多中心研究中开发了HCT特异性合并症指数。几乎所有的研究都是在 在一个多机构联盟的赞助下，该联盟包括17个学术中心， 西雅图，其中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移植的安全性。 HCT是一种每年已经用于治疗数千名患者的疗法。该项目的成功将扩大 通过允许其用于老年患者和其他患有 更多的医疗问题。此外，所提出的方案允许“最纯粹地确定移植物与 肿瘤的影响，除了密集的空调，并提供了一个很好的基础上，添加 疾病特异性模式。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预测患者反应的变量， 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.