TREATMENT POOR HEMATOPOIETIC STEM CELL MOBILIZATION WITH G-CSF & ALBUTEROL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 11/8/2007 应用粒细胞集落刺激因子(G-CSF)动员外周血造血干细胞(PBSC)是获取造血干/祖细胞(HSPC)进行自体移植的首选方法，与骨髓采集相比，它对患者具有更高的安全性和舒适度。然而，在接受恶性血液病自体移植的患者中，通过这种方法获得的外周血干细胞数量往往不足，需要重复采集。Paul Frenette博士的实验室最近发现，完整的外周交感神经系统对G-CSF诱导的PBSC动员至关重要，其机制是抑制成骨细胞的功能及其随后表达的CXCL12(SDF-1)，这是一种以HSPC上表达的CXCR4为配体的趋化因子。CXCL12-CXCR4轴的破坏已被证明足以诱导PBSC动员。Frenette博士的研究小组还显示，给予β-受体阻滞剂(心得安)可显著降低G-CSF诱导的HSPC动员，而给予？2肾上腺素能激动剂(克伦特罗)可增强G-CSF诱导的PBSC动员。 基于小鼠的这项工作，我们提出了以下具体目标： 1)启动一项I/II期临床L研究，在初始采集周期不足的患者中进行第二次外周血干细胞动员，在标准的G-CSF动员方案中加入β2肾上腺素能激动剂沙丁胺醇，以获得更高数量的HSPC，通过外周血和采集的产品中CD34+和CD34+CD38-细胞的数量来衡量。比较的基线将是在初始采集周期中收集的CD34+细胞的数量。 2)评价粒细胞集落刺激因子(G-CSF)对人PBSC动员后交感神经系统的影响。 有两个重要的长期目标。其一是避免需要重复采集HSPC，因为需要重复放置中心线、全身麻醉和骨髓采集，以及移植日期的延迟，这会对患者造成负面影响。根据动员不良的预测因素，如年龄和既往化疗，HSPC捐献者可以在最初的采集周期接受沙丁胺醇，以实现足够的PBSC采集。其次，如果G-CSF动员是通过刺激交感神经系统发生的这一假设得到证实，这可能会导致更具特异性的PBSC动员药物的开发，因为G-CSF可以导致衰弱的副作用，如骨痛，很少有更严重的毒性，如脾破裂，以及危及生命的镰状细胞疾病患者的血管闭塞。 研究设计为沙丁胺醇将以剂量递增的策略给予，标准动员方案为G-CSF(10微克/公斤/天，共5天)。在第1级，沙丁胺醇将与第5剂G-CSF同时开始；在第2级，与第3次G-CSF同时开始；在第3级，与第1次G-CSF同步开始。外周血干细胞采集将于G-CSF第5天开始。主要的结果衡量标准是第一次和第二次收集周期之间的比较，第一次收集的前两天的CD34+产品总产率。 为了确定G-CSF是否通过刺激交感神经系统发挥PBSC动员作用，研究对象连续采集3个时间点的尿液和外周血：基线(动员前)、开始沙丁胺醇当天和收集第1天，测定去甲肾上腺素(NE)和去甲肾上腺素(NE)的主要神经元代谢物二羟基苯甘醇(DHPG)水平。主要的结果衡量指标是基线时与动员时相比的血浆NE和DHPG水平。 假设： 1.在外周血干细胞(PBSC)采集患者的G-CSF动员方案中加入B_2肾上腺素能激动剂沙丁胺醇是安全的，并增加了采集的造血干/祖细胞(HSPC)的数量。 2.粒细胞集落刺激因子对人PBSC动员后交感神经系统的兴奋作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 11/8/2007 Peripheral blood hematopoietic stem cell (PBSC) mobilization using granulocyte colony-stimulating factor (G-CSF) is the preferred method to obtain hematopoietic stem and progenitor cells (HSPC) for autologous transplantation due to its higher level of safety and comfort for the patient compared to bone marrow harvest. In patients undergoing autologous transplant for hematologic malignancy, however, the numbers of peripheral blood stem cells obtained by this method are frequently inadequate, requiring repeat collections. The laboratory of Dr. Paul Frenette has recently shown that an intact peripheral sympathetic nervous system is crucial for G-CSF induced PBSC mobilization, with the mechanism being inhibition of osteoblast function and their subsequent expression of CXCL12 (SDF-1), a chemokine whose ligand is CXCR4 expressed on HSPC. Disruption of this CXCL12-CXCR4 axis has been previously shown to be sufficient to induce PBSC mobilization. Dr. Frenette's group also showed that administration of a ?-blocker (propranolol) significantly reduced G-CSF induced HSPC mobilization and that administration of a ?2 adrenergic agonist (clenbuterol) enhanced G-CSF induced PBSC mobilization. Based on this work in mice, we propose the following specific aims: 1) To initiate a Phase I/II clinica l study examining, in patients undergoing a second PBSC mobilization for an inadequate initial collection cycle, the utility of adding the ?2 adrenergic agonist albuterol to a standard G-CSF mobilization regimen in order to obtain a higher number of HSPC, as measured by the number of CD34+ and CD34+CD38- cells in the peripheral blood and collected product. The baseline for comparison will be the number of CD34+ cells collected with the initial collection cycle. 2) To evaluate whether G-CSF can stimulate sympathetic nervous system activity in humans undergoing G-CSF induced PBSC mobilization. There are two important long-term objectives. One is to avoid the need for repeat HSPC collections, which negatively affects patients due to the need for repeat central line placement, general anesthesia with a bone marrow harvest, and delay of the transplantation date. Based on predictive factors for a poor mobilization, such as age and prior chemotherapy, HSPC donors could receive albuterol during an initial collection cycle to achieve an adequate PBSC collection. Secondly, if the hypothesis that G-CSF mobilization occurs through stimulation of the sympathetic nervous system is verified, this could lead to the development of more specific agents for PBSC mobilization, as G-CSF can cause debilitating side effects such as bone pain, rarely more serious toxicities such as splenic rupture, and life-threatening vaso-occlusion in patients with sickle cell disease. The research design is that the albuterol will be administered in a dose-escalation strategy with a standard mobilization regimen of G-CSF (10 ug/kg/day for 5 days). In Level 1, albuterol will be initiated coincident with the 5th dose of G-CSF; in Level 2, with the 3rd dose of G-CSF; and in Level 3, with the 1st dose of G-CSF. Peripheral blood stem cell collection will begin on the 5th day of G-CSF. The primary outcome measure is comparison between the initial and second collection cycles of the total CD34+ product yield of the 1st two days of collection. In order to determine if G-CSF induced PBSC mobilization acts through stimulation of the sympathetic nervous system, urine and peripheral blood will be collected from study subjects at 3 consecutive time points: at baseline (prior to mobilization), on the day of starting albuterol, and on the 1st day of collection to measure levels of norepinephrine (NE) and dihydroxyphenylglycol (DHPG), the principal neuronal metabolite of NE. The primary outcome measure is plasma NE and DHPG levels at baseline compared to during mobilization. Hypotheses: 1. Addition of the B2 adrenergic agonist albuterol to the G-CSF mobilization regimen of patients undergoing peripheral blood stem cell (PBSC) collection is safe and increases the number of hematopoietic stem and progenitor cells (HSPC) collected. 2. G-CSF stimulates sympathetic nervous system activity in humans undergoing G-CSF induced PBSC mobilization.