ALLOGENEIC BONE MARROW TRANSPLANTATION FOR CML

慢性粒细胞白血病是一种治疗后有可能治愈的疾病 同种异体骨髓移植 的主要失败 慢性期疾病患者的治疗是移植物抗宿主 疾病和CMV感染。 患者失败的主要原因 晚期疾病是移植物抗宿主病，CMV感染， 复发 此外，一旦移植后复发， 选择是有限的。 在这个项目中，我们将研究三种创新的方法， CML患者的异基因骨髓移植; 预防HLA相合患者的移植物抗宿主病 供体、次全T细胞耗竭和移植后强化 免疫抑制用于GVHD预防，用于不匹配或 用于移植治疗早期或晚期疾病的无关供体，以及 塞替派、白消安和环磷酰胺的组合用于患有 有HLA相同供体的晚期CML患者。 细胞遗传学，荧光， 费城染色体的原位杂交， P210、罕见免疫表型流式细胞术、bcr-abl的3SR测定 在3-6个月时进行bcr-abl聚合酶链反应 间隔，以确定哪种测试最能预测复发后 移植 BrdU/原位杂交将专门用于 检查残留的Ph阳性细胞是否增殖。 将使用聚合酶链反应检测片段长度多态性 以评估各种谱系中的残留宿主细胞， 混合嵌合体与复发、感染、排斥反应或 GVHD。 还将对患者进行连续研究，以重建 免疫系统通过流式细胞术测量淋巴细胞亚群， 非特异性体外免疫反应试验， 对CML细胞和P210蛋白的活性，以及对 针对CMV的特异性反应。 对于复发的患者， 移植，干扰素-α，白细胞介素-2和 将评估CD 8耗尽的供体淋巴细胞的输注，以确定 其有效性和耐受性。 临床研究的结果将决定是否 这些创新的方法是有效的治疗患者， 慢性粒细胞白血病，实验室研究将提供 进一步深入了解这一过程的生物学， 可以制定战略。

Chronic myelogenous leukemia is a potentially curable disease when treated with allogeneic bone marrow transplantation. The major failures of treatment for patients with chronic phase disease are graft-versus-host disease and CMV infection. The major reasons for failure for patients with advanced disease are graft-versus-host disease, CMV infection, and relapse. Moreover, once relapse has occurred after transplantation, options are limited. In this project, we will investigate three innovative approaches to allogeneic marrow transplantation for patients with CML; CD8-depletion for prevention of graft-versus-host disease for patients with HLA-identical donors, subtotal T-cell depletion and intensive posttransplant immunosuppression for GVHD prophylaxis for patients with mismatched or unrelated donors for transplantation for early or advanced disease, and a combination of thiotepa, busulfan, and cyclophosphamide for patients with advanced CML who have HLA-identical donors. Cytogenetics, fluorescence in situ hybridization for the Philadelphia chromosome, western blot assay for the P210, flow cytometry for rare immunophenotypes, 3SR assay for bcr-abl and polymerase chain reaction for bcr-abl will be done at 3-6 month intervals to determine which test is best predictive of relapse after transplantation. BrdU/in situ hybridization specifically will be used to investigate whether residual Ph positive cells are proliferating. Polymerase chain reaction for fragment length polymorphisms will be used to assess residual host cells in various lineages to determine the relationship of mixed chimerism with relapse, infection, rejection, or GVHD. Patients will also be studied serially for reconstitution of the immune system by measurement of lymphocyte subsets by flow cytometry, nonspecific test of immune responsiveness in vitro, in vitro tests of activity against CML cells and the P210 protein, and for development of specific responses against CMV. For patients who relapse after transplantation, the combination of interferon-alpha, interleukin-2 and infusion of CD8-depleted donor lymphocytes will be evaluated to determine its efficacy and tolerability. The results of the clinical investigations will determine whether or not these innovative approaches are effective treatments for patients with chronic myelogenous leukemia, and the laboratory studies will provide further insight into the biology of the process so that future treatment strategies may be developed.