Hematopoietic Transplantation for AML

造血移植治疗 AML

• 批准号: 7270268
• 负责人: RICHARD E. CHAMPLIN
• 金额: $ 35.14万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270268
• 关键词: AMD3100; AML/MDS; Acute Myelocytic Leukemia; Allogenic; Blood; Busulfan; Busulfan/Fludarabine; CXCR4 gene; Clinical Trials; Clofarabine; Correlative Study; Daily; Dose; Drug Kinetics; Dysmyelopoietic Syndromes; Evaluation; Goals; Grant; Hematopoietic; Human; Immune; Intravenous; Mediating; Modality; Modeling; Mus; Outcome; Patients; Pharmacogenetics; Rate; Relapse; Resistance; Risk; Signal Transduction; Stem cell transplant; Supportive care; Testing; Translations; Transplantation; Treatment Protocols; base; cytotoxicity; graft vs host disease; graft vs leukemia effect; improved; inhibitor/antagonist; leukemia; mortality; novel; novel strategies; purine analog; response

Allogeneic stem cell transplantation is an important treatment modality for AML. We and others have established that the benefit relates both to cytoreduction by the preparative regimen and the immune mediated graft-vs-leukemia (GVL) effect. Transplant results have improved over the last 3 decades, primarily related to improvements in supportive care. Unfortunately there has been little improvement in reducing the risk of leukemia relapse post transplant. The goal of this current proposal is to improve leukemia free survival by evaluation of novel approaches to improve the antileukemia cytoreduction by the preparative regimen and a novel strategy to reduce GVHD while retaining GVL. In the previous grant period, we demonstrated that the combination of intravenous busulfan and fludarabine is an effective preparative regimen for allogeneic stem cell transplantation with a low rate of treatment related mortality. This proposal seeks to further improve these results by optimizing the pharmacokinetics of busulfan (aim 1), combining the CXCR4 inhibitor AMD3100 with this regimen to provide synergistic antileukemia cytotoxicity (aim2) and favorably modulating GVHD and GVL effects with novel triterpenoids CDDO and CDDO-Me (aim 3). Specific Aims: Aim 1A) To optimize the antileukemia cytoreduction from the preparative regimen. We will test the hypothesis that administration of busulfan (Bu) given in a pharmacokinetically adjusted dose to yield a blood daily ADC of 6,000 uMol-min is superior to a fixed dose of 130 mg/m^ in this regimen to improve leukemia- free survival in patients with acute myelogenous leukemia and myelodysplastic syndrome. Correlative studies will examine pharmacogenetic predictors of response and resistance. 1B) A mechanistically based study will evaluate combination of clofarabine with busulfan and fludarabine with a goal of further improving leukemia-free survival. Aim 2) To test the hypothesis that the addition of AMD3100, a CXCR4 inhibitor, will improve the antileukemia effect of high dose busulfan-fludarabine with allogeneic stem cell transplantation for treatment of AML/MDS. Correlative studies will examine CXCR4 expression and related signaling on outcome. Aim 3) To test the hypothesis that post transplant treatment with CDDO and CDDO-Me will reduce GVHD while maintaining the antileukemia effect of allogeneic stem cell transplantation, thereby improving leukemia- free survival. This will be initially studied in a murine model (Aim 3A), with translation to a human clinical trial (Aim 3B).

异基因造血干细胞移植是治疗急性髓细胞白血病的重要手段。我们和其他人已经 确定了益处与制备方案的细胞减少和免疫治疗有关， 介导的移植物抗白血病（GVL）效应。在过去的30年里，移植结果有所改善，主要是 与支持性护理的改善有关。不幸的是，在减少 移植后白血病复发的风险。目前这项提案的目标是改善无白血病 通过评价新的方法来提高制备性抗白血病细胞减少的生存率 方案和新的策略，以减少GVHD，同时保留GVL。在上一个资助期，我们 表明静脉内白消安和氟达拉滨的组合是一种有效的制备 异基因干细胞移植的治疗方案，治疗相关死亡率低。这项建议 通过优化白消安的药代动力学（aim 1），结合 CXCR 4抑制剂AMD 3100与该方案一起提供协同抗白血病细胞毒性（aim 2）， 用新的三萜类化合物CDDO和CDDO-Me有利地调节GVHD和GVL效应（目的3）。 具体目标： 目的1A）优化制备性抗白血病细胞减灭方案。我们将测试 假设以药物动力学调整剂量给予白消安（Bu）以产生血液 在该方案中，6，000 uMol-min的每日ADC上级130 mg/m2的固定剂量，以改善白血病。 急性髓性白血病和骨髓增生异常综合征患者的无瘤生存率相关 研究将检查反应和抗性的药物遗传学预测因子。1B）基于机械的 研究将评估氯法拉滨与白消安和氟达拉滨的组合， 无白血病生存率 目的2）验证CXCR 4抑制剂AMD 3100对白血病细胞的抗白血病作用 大剂量白消安-氟达拉滨联合异基因造血干细胞移植治疗AML/MDS疗效观察 相关研究将检查CXCR 4表达和相关信号对结果的影响。 目的3）验证移植后CDDO和CDDO-Me治疗可减少GVHD的假设 同时保持异基因干细胞移植的抗白血病作用，从而改善白血病， 自由生存。这将首先在小鼠模型（Aim 3A）中进行研究，然后转化为人类临床试验 (Aim 3B）。