Nonmyeloablative Hematopoietic Cell Allotransplants

项目1：非清髓性异基因造血细胞移植 我们建议继续探索异基因造血的非清髓性预适应方案。 细胞移植在恶性血液病及感染患者中的应用 人类免疫缺陷病毒1型(HIV1)。建议的主要养生法已从 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，在很大程度上可以 由于缺乏严重的与方案有关的毒性反应，在门诊护理环境中使用。后者 这一特征使我们能够忽略目前存在的年龄和共病限制。 消融疗法。考虑到这一点，以及大多数候选人的患者确诊时的中位年龄 疾病的年龄从65岁到70岁不等，可通过异体基因治疗和潜在治愈的患者数量 Hct已大大增加。前两个特定目标将调查人类白细胞抗原相合和 不匹配的捐赠者。虽然重点是无关的HCT，但几项议定书也将包括相关的捐赠者。 两个方案是前瞻性随机试验，一个是关于预防急性移植物抗宿主病，另一个是关于结果 适用于接受清髓性或非清髓性调理的骨髓性恶性肿瘤患者。几个 疾病特异性方案将评估非清髓性HCT方法对慢性粒细胞白血病患者的价值 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 骨髓瘤和HIV1/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特异性共病指数。几乎所有的研究都在进行中 在一个多机构联盟的赞助下，该联盟包括17个国外的学术中心 西雅图，弗雷德·哈钦森癌症研究中心作为协调中心。 与公共健康的相关性：这些拟议的研究旨在提高异基因药物的安全性 HCT，一种已经用于每年治疗数千名患者的疗法。这个项目的成功将扩大 同种异体血细胞移植在老年患者和其他患者中的应用 更多的医疗问题。此外，建议的治疗方案允许“最纯粹的移植物与... 肿瘤效应，除了密集的条件作用，并提供了一个很好的基础上添加 疾病特有的模式。最后，共病数据可能会变得和定义癌症一样重要 诊断、分期、缓解状态和其他更常见的变量预测患者的反应和 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.