DEVELOPMENT OF AUTOLOGOUS BMT PROGRAMS IN CML

CML 自体 BMT 项目的开发

• 批准号: 6237062
• 负责人: ALBERT B DEISSEROTH
• 金额: $ 11.66万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-12 至 1998-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237062
• 关键词: CD antigens; autologous transplantation; biomarker; bone marrow purging; bone marrow transplantation; cell population study; cell sorting; chromosome translocation; chronic myelogenous leukemia; cytogenetics; diploidy; genetic transduction; hematopoiesis; hematopoietic stem cells; human therapy evaluation; human tissue; neoplasm /cancer classification /staging; neoplasm /cancer remission /regression; neoplastic cell; polymerase chain reaction; tissue /cell culture

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.

使用密集的全身制备疗法，然后使用 无反应性的CML患者自体细胞的移植 干扰素或不符合同种骨髓移植的条件 在短期内生成的生存，等同于所见 在同种异体骨髓移植中进行慢性移植 该疾病的阶段（在随访两年中生存70％），但为 自体移植时与较低的生存水平相关 在疾病的加速和爆炸危机阶段进行（35％。 由于成功的主要决定因素似乎是可用的 二倍体自体细胞在移植时，我们添加了 遵循降低白血病与正常比率的程序 用于移植的制剂中的细胞：初始常规剂量 化学疗法，主要是外周血二倍体的收集 恢复阶段早期造血祖细胞的种群 从体内化学疗法中的体内化学疗法来阳性选择 CD34色谱柱分馏的早期正常髓样祖细胞 （CellPro）和单克隆抗体负选择技术 选择性去除自体骨髓或外周血中的CML细胞 用于自体移植的准备工作。 我们也是 提议实施临床骨髓逆转录病毒标记 计划，旨在帮助我们评估上述效率 选择性隔离早期造血正常祖细胞的方法 没有pH+细胞，自体骨髓和外周血。 这 标记程序将帮助我们独立评估 消除全身性疾病的准备疗法和 用于从用于自体单元中删除CML单元的程序 强化治疗后自体移植。 这样，我们可以 确定复发是否来自全身剩余的CML单元 循环与CML细胞留在自体骨髓中 清除后移植。 我们还建议发起双重 旨在比较重构容量的标记程序 外周血与骨髓细胞的重建正常骨髓 强化准备疗法后的功能。 该程序也将 允许我们比较外周血中的pH+细胞水平 骨髓可能有助于复发。 我们将研究 正常造血祖细胞的体内扩展的方法 移植之前。 我们将评估促进的遗传方法 CML患者中二倍体细胞的再生，并抑制白血病细胞。 这些研究将针对更有效的发展 使用自体骨诱导耐用细胞遗传学的程序 CML患者未符合生物学的CML患者的骨髓移植 治疗或同种骨髓移植。