DEVELOPMENT OF AUTOLOGOUS BMT PROGRAMS IN CML

使用强化全身准备治疗， 在无反应的CML患者中移植自体细胞 干扰素或不适合异基因骨髓移植， 在短期内产生的存活率与所观察到的相当， 在同种异体骨髓移植中， 阶段的疾病（70%的生存率在两年的后续行动），但 当自体移植的移植物 在疾病的加速和爆发危机阶段进行（35%）。 由于成功的主要决定因素似乎是是否有 二倍体自体细胞在移植时，我们已经添加了 按照降低白血病与正常的比率的程序， 用于移植的制剂中的细胞：初始常规剂量 化疗，主要采集外周血二倍体 恢复期早期的造血祖细胞群 从体内化学疗法，从体外方法， CD_（34）柱分级分离早期正常骨髓祖细胞 （CellPro）和单克隆抗体阴性选择技术， 从自体骨髓或外周血中选择性去除CML细胞 用于自体移植的制剂。 我们也 建议实施临床骨髓逆转录病毒标记， 程序，旨在帮助我们评估上述效率 选择性分离早期造血正常祖细胞的方法 不含Ph+细胞，来自自体骨髓和外周血。 的 标记程序将帮助我们独立评估的有效性， 预防治疗在消除全身性疾病和效率， 用于从自体细胞中去除CML细胞的程序， 强化治疗后自体移植。 这样才能 确定复发是否由留在系统中的CML细胞引起 循环与留在自体骨髓中的CML细胞， 清除后移植。 我们还计划推出一个 标记程序，其被设计为比较 外周血和骨髓细胞来重建正常的骨髓 在强化准备治疗后的功能。 该方案还将 使我们能够比较外周血中的Ph+细胞水平与 这可能会导致复发。 我们将研究 正常造血祖细胞的离体扩增方法 移植前。 我们将评估基因方法， CML患者中二倍体细胞的再生长，以及抑制白血病细胞。 这些研究将针对发展更有效的 使用自体骨诱导持久的细胞遗传学缓解的程序 骨髓移植用于不符合生物学条件的CML患者 治疗或同种异体骨髓移植。

The use of intensive systemic preparative therapy followed by transplantation of autologous cells in CML patients who were unresponsive to interferon or ineligible for allogeneic bone marrow transplantation has generated survivals in the short term which are equivalent to those seen in allogeneic bone marrow transplantation when delivered in the chronic phases of the disease (70% survival at two years of follow-up), but is associated with lower levels of survival when that autologous transplant is conducted in the accelerated and blast crisis phases of disease (35%. Since the major determinant of success appeared to be the availability of diploid autologous cells at the time of transplant, we have added the following procedures for reduction of the ratio of leukemic to normal cells in the preparations used for transplant: initial conventional dose chemotherapy, collection of predominantly peripheral blood diploid populations of hematopoietic progenitor cells early in the recovery phase from in vivo chemotherapy from ex vivo methods for positive selection of the early normal myeloid progenitor cells by CD34 column fractionation (CellPro), and monoclonal antibody negative selection techniques for the selective removal of CML cells from autologous marrow or peripheral blood preparations to be used for autologous transplantation. We are also proposing the implementation of a clinical marrow retroviral marking program, which is designed to help us evaluate the efficiency of the above methods to selectively isolate early hematopoietic normal progenitor cells free from Ph+ cells, from autologous marrow and peripheral blood. The marking program will help us independently evaluate the efficacy of preparative therapy in eradicating systemic disease and the efficiency of procedures used to remove CML cells from autologous cells used for autologous transplant after intensive therapy. In this way, we can determine if relapse arises from CML cells left in the systemic circulation versus CML cells left in the autologous marrow used for transplant following purging. We also are proposing to launch a double marking program which is designed to compare the reconstitutive capacity of peripheral blood versus marrow cells to reconstitute normal marrow function after intensive preparative therapy. This program will also allow us to compare the level of Ph+ cells in peripheral blood versus marrow which can contribute to relapse. We will study the utility of methods for ex vivo expansion of normal hematopoietic progenitor cells prior to transplant. We will evaluate genetic methods for promoting the regrowth of diploid cells in CML patients, and to suppress leukemic cells. These studies will be directed to the development of more effective programs for inducing durable cytogenetic remissions using autologous bone marrow transplantation for CML patients not eligible for biological therapy or allogenic bone marrow transplantation.