Busulfan conditioning: optimization, kinetics, genomics

描述（由申请人提供）：同种异体移植可以治愈，但大多数患者复发或死于治疗相关的并发症。本提案的目的是开发一种更有效、毒性更小的移植预处理方案。我们计划通过完成以下具体目标来实现这一目标：1.建立静脉注射白消安（Busulfex）联合氟达拉滨作为体内T细胞去除移植预处理方案的最大耐受剂量：Bu广泛用于异基因移植预处理。其剂量限制性毒性为肝静脉闭塞病（VOD）。VOD的风险与BU ADC相关，但也受其他药物（如环磷酰胺、甲氨蝶呤）和程序（如T细胞耗竭）的影响。我们假设，当BU剂量达到目标并且VOD的其他风险因素最小化时，最大AUC将增加。我们计划进行一项IV BU（Busulfex）和氟达拉滨联合Alemtuzumab GVHD预防的剂量递增研究。个体化给药以达到预定目标AUC，从而达到可预测的全身暴露量，将基于试验剂量的药代动力学分析。2.评价剂量递增BuFluCampath预处理后的无病生存期和总生存期。先前的研究表明BU浓度和复发之间呈反比关系。我们假设BU AUC增加将导致疾病控制的改善。确定最大AUC后，将在高危AML和MDS患者的前瞻性II期研究中研究疗效。3.探讨谷胱甘肽S-转移酶（GSTA 1）和谷胱甘肽S-转移酶（GSTM 1）基因多态性及酶水平对BU药代动力学和毒性的影响。BU代谢主要由谷胱甘肽S-转移酶A1和M1介导。我们推测BU代谢和毒性的变化是由于GST多态性。我们建议评估GSTA 1和GSTM 1的多态性和活性，并将其与BU代谢和毒性相关。4.探讨GST在白血病细胞中的表达与白血病细胞凋亡的关系。GST基因型与移植结局我们推测白消安耐药与白血病细胞GST表达有关，而GST表达又与GST基因型部分相关。我们建议研究GST在白血病细胞中的表达，并将GST表达与基因型和对移植的反应相关联。这些研究是探索性的。

DESCRIPTION (provided by applicant): Allo transplant can result in cure, but the majority of pts relapse or die from treatment related complications. The objective of this proposal is the development of a more effective and less toxic transplant conditioning regimen. We plan to achieve this objective by completing the following specific aims : 1.To establish the maximally tolerated dose of intravenous busulfan (Busulfex) in combination with fludarabine as conditioning regimen for transplantation with in-vivo T-cell depletion: Bu is widely used in the conditioning for allogeneic transplantation. Its dose limiting toxicity is hepatic veno-occlusive disease (VOD). The risk for VOD is related to BU ADC, but is also influenced by other medications (e.g. cyclophosphamide, methotrexate) and procedures (e.g. T-cell depletion). We hypothesize that the maximum AUC will be increased when BU doses are targeted and other risk factors for VOD minimized. We plan a dose escalation study of IV BU (Busulfex) and fludarabine in combination with alemtuzumab GVHD prophylaxis. Individualized dosing to achieve a pre-defined target AUC, and thus predictable systemic exposure, will be based on pharmacokinetic analysis of a test dose. 2. To evaluate disease free and overall survival after dose escalated BuFluCampath conditioning. Prior studies indicate an inverse relationship between BU concentration and recurrence. We hypothesize that increased BU AUC will result in improvement in disease control. After the maximum AUC has been established, the efficacy will be studied in a prospective phase II study of patients with high risk AML and MDS. 3.To evaluate the effect of GSTA1 and GSTM1 polymorphisms and enzyme levels on kinetics and toxicity of BU. BU metabolism is mainly mediated by glutathione S-transferases A1 and M1. We hypothesize that variations in BU metabolism and toxicity are due to GST polymorphisms. We propose to evaluate polymorphisms and activity of GSTA1 and GSTM1 and to correlate them with BU metabolism and toxicity. 4. To study the relation between GST expression in leukemia cells. GST genotype and outcome of transplant. We hypothesize that resistance to busulfan is related to GST expression in leukemia cells, which in turn is partially related to GST genotype. We propose to study expression of GST's in leukemia cells and to correlate GST expression with genotype and with response to transplant. These studies are exploratory.