CHEMOTHERAPY PROGRAMS TO GENERATE DIPLOID CELLS FOR AUTOLOGOUS BMT

干扰素治疗可诱导持续数年的细胞遗传学缓解 在26%的早期慢性期CML患者中， 只有经过长时间的日常治疗，通常需要数月 至数年，以实现主要或完全的细胞遗传学缓解。 与此相反， 强化但非消融剂量的联合化疗（如 柔红霉素Ara-C）在30%的患者中迅速产生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 已经开始了一项开发基于化疗的替代方案的计划 用于治疗对干扰素耐药的CML患者， 有同种异体移植供体。 这个项目的目标是使用化疗， 产生用于自体骨髓的二倍体（正常）细胞 移植 为了做到这一点，我们已经寻找了各种形式的 化疗，这与更持久的时期， 骨髓抑制比常规剂量化疗的情况下，但 比标准化疗毒性小 我们也在收集 外周血细胞在造血恢复的早期阶段， 二倍体细胞在祖细胞群体中占主导地位的时间。 此外，本发明还提供了一种方法， 我们使用早期造血祖细胞的体外分级分离， 获得自体骨髓和外周血的群体， 富含二倍体细胞。 我们将这些分离的自体细胞， 这些细胞富含二倍体细胞， 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 的HHT是更持久的比看到与传统形式的 化疗 HHT在33%的患者中产生主要的细胞遗传学缓解。 早期慢性期患者接受治疗。 此外，临床 自体移植项目迄今积累的经验 表明氟达拉滨、阿糖胞苷和 米托蒽醌（FAM）或柔红霉素高剂量阿糖胞苷（DARAC），然后是CD 34 选择，并使用自体细胞进行自体骨髓移植 选择的离体可以产生主要的或完全的细胞遗传学缓解， 干扰素抗性晚期慢性期患者， 轻微的细胞遗传学缓解与此计划可以实现，即使与 加速期或急变期患者。 PCR检测，罕见的 免疫表型测定和中期FISH测定用于测量 反应，并优化这种疗法的配方，以促进 收集自体二倍体细胞的最大数量 二倍体细胞 我们还希望尝试识别替代分子， 延长缓解持续时间或生存期的终点。 工作提出的 在这个项目中，目的是增加病人的数量， 适合自体骨髓移植 Gehan博士和Terry Smith 我将与我们合作，在这个项目和所有的临床和实验室项目 评价实验室数据与临床结局之间的相关性 在治疗项目中。

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.