ALLOGENEIC BONE MARROW TRANSPLANTATION FOR CML

该项目包括五个目标，旨在测试假设，提高 异基因血液和骨髓移植的结果。项目 提出了改进制备的治疗指数的创新， 方案，优化同种异体移植物的组成， 在预防严重移植物抗白血病的同时， 宿主疾病在目标1中，我们检验了持久缓解可以 通过诱导移植物抗白血病作为主要治疗来实现 CML和这种策略是否可以提高无病生存率。目标2我们 扩展我们对白消安静脉注射制剂的开发并进行测试 静脉注射白消安和环磷酰胺的准备方案是否 通过药代动力学进行剂量指导可以改善 慢性期患者与匹配的同胞供体。在目标3中，我们扩展 我们先前的研究证实了用CD8耗竭的GVL诱导是有效的 供体淋巴细胞输注，并确定最佳生物剂量 进一步研究的目标是诱导移植物完全缓解， 抗宿主病我们将继续比较它们的功效与 未分级淋巴细胞用于诱导GVL。在目标4中，我们翻译 在项目4和6中制定的创新办法， 临床试验，检测胸苷激酶转导的供体 淋巴细胞输注可消除供体淋巴细胞输注后的GVHD 并评估巨剂量T细胞去除造血干细胞的疗效 HLA半相合供者的移植。目标5：我们 将评估地西他滨作为骨髓抑制剂在 晚期CML患者和匹配同胞的准备方案 供体

This project includes five aims directed to testing hypotheses improving the outcome of allogeneic blood and marrow transplantation. The project addresses innovations to improve the therapeutic index of the preparative regimen, optimize the composition of the allograft and enhance the development of graft versus leukemia while preventing severe graft versus host disease. In Aim 1, we test the hypothesis that durable remissions can be achieved by induction of graft-versus-leukemia as primary treatment for CML and whether this strategy can improve disease free survival. Aim 2 we extend our development of an intravenous formulation of busulfan and test whether a preparative regimen of IV busulfan and cyclophosphamide with dose guiding by pharmacokinetics can improve leukemia free survival for chronic phase patients with matched sibling donors. In Aim 3, we extend our prior studies demonstrating effective GVL induction with CD8 depleted donor lymphocyte infusions and determine the optimal biologic dose for further study with a goal of inducing complete remission with graft- versus-host disease. We will go on to compare their efficacy versus unfractionated lymphocytes for induction of GVL. In Aim 4, we translate innovative approaches being developed in projects 4 and 6 into human clinical trials, testing whether thymidine kinase transduced donor lymphocyte infusions can abrogate GVHD after donor lymphocyte infusions and to evaluate the efficacy of megadose T-cell depleted blood stem cell transplantation for patients with HLA-haploidentical donors. In Aim 5, we will evaluate the efficacy of decitabine as a myelosuppressive agent in preparative regimens for patients with advanced CML and a matched sibling donor.