CHEMOTHERAPY PROGRAMS TO GENERATE DIPLOID CELLS FOR AUTOLOGOUS BMT

生成用于自体 BMT 的二倍体细胞的化疗程序

• 批准号: 6237057
• 负责人: HAGOP KANTARJIAN
• 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/6237057
• 关键词: artificial immunosuppression; autologous transplantation; biological response modifiers; biomarker; bone marrow purging; bone marrow transplantation; cell population study; chromosome translocation; chronic myelogenous leukemia; combination chemotherapy; cytogenetics; diploidy; flow cytometry; fluorescent dye /probe; harringtonines; hematopoiesis; hematopoietic stem cells; human therapy evaluation; human tissue; in situ hybridization; interferon alpha; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; polymerase chain reaction; prognosis

Interferon therapy can induce cytogenetic remissions which last for years in 26% of early chronic phase CML patients, but the remissions are produced only after long periods of daily therapy, often requiring months to years to achieve major or complete cytogenetic remission. In contrast, intensive but not ablative does of combination chemotherapy (such as Daunomycin Ara-C) rapidly produce major cytogenetic remissions in 30% of patients, but these remissions do not last for more than a few months. We have embarked upon a program to develop chemotherapy based alternatives for the therapy of CML patients who are interferon-resistant and do not have allograft donors. The goal of this program is to use chemotherapy to generate diploid (normal) cells for use in autologous bone marrow transplantation. To accomplish this, we have searched for forms of chemotherapy which are associated with more durable periods of myelosuppression than is the case with conventional dose chemotherapy, but are less toxic than standard chemotherapy. We also are collecting peripheral blood cells in the early stages of hematopoietic recovery at a time when diploid cells dominate the progenitor population. In addition, we use ex vivo fractionation of early hematopoietic progenitor cells to obtain populations of autologous marrow and peripheral blood which are enriched in diploid cells. We infuse these fractionated autologous cells, which are enriched in diploid cells, following systemic intensive therapeutic regimens which are ablative. We have developed very promising early clinical results with the chemotherapeutic agent, homoharringtonine (HHT), which are using in untreated patients. The myelosuppressive effect of HHT is more durable than that seen with conventional forms of chemotherapy. HHT produces major cytogenetic remissions in 33% of the early chronic phase patients treated. In addition, the clinical experience so far accumulated with the autologous transplant program suggests that chemotherapy with the combinations of fludarabine, Ara-C and mitoxantrone (FAM) or Daunomycin high dose Ara-C (DARAC) followed by CD34 selection, and autologous bone marrow transplant with the autologous cells selected ex vivo can produce major or complete cytogenetic remissions in interferon-resistant late chronic phase patients so treated, and that minor cytogenetic remissions with this program can be achieved even with accelerated phase or blast crisis patients. The PCR assay, the rare immunophenotype assay, and the metaphase FISH assay are used to measure response, and to optimize the formulation of this therapy so as to promote the collection of autologous diploid cells on the maximum number of diploid cells. We also hope to attempt to identify surrogate molecular endpoints for prolonged remission duration or survival. The work proposed in this project is designed to increase the number of patients who are eligible for autologous marrow transplants. Dr. Gehan and Terry Smith will work with us on this program and all clinical and laboratory programs to evaluate the correlations between laboratory data and clinical outcome in the therapeutic programs.

干扰素治疗可诱导持续数年的细胞遗传学缓解 26% 的早期慢性期 CML 患者出现这种情况，但缓解率是 仅在长时间的日常治疗后产生，通常需要数月 数年才能实现主要或完全细胞遗传学缓解。 相比之下， 强化但非消融剂量的联合化疗（例如 Daunomycin Ara-C）可迅速使 30% 的患者获得主要的细胞遗传学缓解 患者，但这些缓解不会持续超过几个月。 我们 已开始实施一项开发基于化疗的替代方案的计划 用于治疗对干扰素有抵抗力且不耐受的 CML 患者 有同种异体移植供体。 该计划的目标是使用化疗 产生用于自体骨髓的二倍体（正常）细胞 移植。 为了实现这一目标，我们寻找了各种形式 化疗与更持久的周期相关 与常规剂量化疗相比，骨髓抑制效果更好，但是 比标准化疗的毒性更小。 我们也在征集 造血恢复早期的外周血细胞 二倍体细胞在祖细胞群中占主导地位的时间。 此外， 我们使用早期造血祖细胞的离体分离 获得自体骨髓和外周血群体 富含二倍体细胞。 我们输注这些分离的自体细胞， 经过全身强化后，富含二倍体细胞 消融性治疗方案。 我们已经开发出非常有前途的 化疗药物高三尖杉酯碱的早期临床结果 （HHT），用于未经治疗的患者。 骨髓抑制作用 HHT 比传统形式的 HHT 更耐用 化疗。 HHT 在 33% 的患者中产生主要的细胞遗传学缓解 治疗早期慢性期患者。 此外，临床上 迄今为止在自体移植项目中积累的经验 建议采用氟达拉滨、Ara-C 和 米托蒽醌 (FAM) 或道诺霉素高剂量 Ara-C (DARAC)，随后使用 CD34 选择并用自体细胞进行自体骨髓移植 选择的离体可以产生主要或完全的细胞遗传学缓解 干扰素耐药的慢性期晚期患者接受如此治疗，并且 即使使用该程序也可以实现轻微的细胞遗传学缓解 加速期或急变危象患者。 PCR检测，罕见 免疫表型测定和中期 FISH 测定用于测量 反应，并优化该疗法的配方，以促进 收集最大数量的自体二倍体细胞 二倍体细胞。 我们也希望尝试鉴定替代分子 延长缓解持续时间或生存的终点。 拟议的工作 该项目旨在增加接受治疗的患者数量 适合自体骨髓移植。 格汉博士和特里·史密斯 将与我们合作开展该项目以及所有临床和实验室项目 评估实验室数据和临床结果之间的相关性 在治疗计划中。