Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (Non-Hodgkin's) lymphoma
Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (Non-Hodgkin's) lymphoma
复制标题
DOI：
10.1158/1078-0432.ccr-05-2730
复制
发表时间：
2006-10-01
影响因子：
11.5
通讯作者：
Grant, Steven
中科院分区：
文献类型：
--
作者：
Roberts, John D.;Smith, Mitchell R.;Grant, Steven
目的：临床前研究提示苔藓抑素1可能增强氟达拉滨治疗血液系统恶性肿瘤的疗效。我们进行了一项I期研究，以确定11期研究中使用苔藓抑素1和氟达拉滨的适当时间表和剂量。实验设计：慢性淋巴细胞白血病（CLL）或惰性淋巴瘤患者每天接受氟达拉滨治疗5天，并在氟达拉滨治疗前后连续输注单剂量苔藓虫素1 24小时。在连续患者中逐步增加剂量，直到根据剂量限制性毒性事件确定每个序列的推荐II期剂量。结果：苔藓虫抑制素1与全剂量氟达拉滨（25mg /m(2) /d × 5）可安全耐受。苔藓抑素1 II期推荐剂量为50 μ g/m(2)，这两个序列，苔藓抑素1 ->氟达拉滨和氟达拉滨->苔藓抑素1。该组合对慢性淋巴细胞白血病和惰性淋巴瘤均有活性，在以前接受过氟达拉滨治疗的患者中也有反应。相关研究不支持苔藓抑素1通过下调靶细胞中蛋白激酶C而增强氟达拉滨活性的假设。结论：苔藓虫素1可与全剂量氟达拉滨联合用药，且在既往治疗后疾病持续的患者中，联合用药具有中等疗效。鉴于抗cd20单克隆抗体利妥昔单抗等单克隆抗体在治疗CLL和无痛性淋巴瘤中的活性，褐虫抑制素1和氟达拉滨与利妥昔单抗联合的概念值得未来考虑。
Purpose: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase 11 studies.Experimental Design: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events.Results: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m(2) /d x 5). The recommended bryostatin 1 phase II dose is 50 mu g/m(2) for both sequences, bryostatin 1 --> fludarabine and fludarabine --> bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells.Conclusions: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.