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

用 G-CSF 治疗造血干细胞动员不良

• 批准号: 7953715
• 负责人: Patricia Ann Shi
• 金额: $ 0.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953715
• 关键词: Adrenergic Agonists; Adverse effects; Affect; Age; Albuterol; Autologous; Autologous Transplantation; Bone Marrow; Bone Pain; CD34 gene; CXCL12 gene; CXCR4 gene; Cells; Clenbuterol; Clinical Research; Collecting Cell; Collection; Computer Retrieval of Information on Scientific Projects Database; Development; Dose; Funding; General Anesthesia; Grant; Granulocyte Colony-Stimulating Factor; Harvest; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Human; Institution; Laboratories; Lead; Life; Ligands; Measures; Methods; Mus; Neurons; Norepinephrine; Osteoblasts; Outcome Measure; Patients; Peripheral; Peripheral Blood Stem Cell; Phase; Plasma; Predictive Factor; Prior Chemotherapy; Propranolol; Research; Research Design; Research Personnel; Resources; Safety; Sickle Cell Anemia; Source; Splenic Rupture; Stem cells; Stromal Cell-Derived Factor 1; Study Subject; Sympathetic Nervous System; Time; Toxic effect; Transplantation; Treatment Protocols; United States National Institutes of Health; Urine; Work; base; chemokine; peripheral blood; primary outcome; stem

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 2007年11月8日 外周血造血干细胞（PBSC）使用粒细胞菌落刺激因子（G-CSF）动员是获得造血干细胞和祖细胞（HSPC）的首选方法，因为与骨骼骨髓相比，患者的安全性和舒适度更高，因此自体移植的自体移植。 但是，在接受自体移植的血液系统恶性肿瘤的患者中，通过这种方法获得的外周血干细胞的数量通常不足，需要重复收集。 保罗·弗雷尼特（Paul Frenette）博士的实验室最近表明，完整的外围交感神经系统对于G-CSF诱导的PBSC动员至关重要，其机制是抑制成骨细胞功能的机制及其随后表达CXCL12（SDF-1）（SDF-1）的表达，其趋化因子的趋化因子是其在HSPC上表达的cxcr4的趋化因子。 以前已证明该CXCL12-CXCR4轴的破坏足以诱导PBSC动员。 弗雷尼特（Frenette）博士的小组还表明，施用a-blocker（普萘洛尔）显着降低了G-CSF诱导的HSPC动员，并且给药2？2肾上腺素能激动剂（Clenbuterol）增强了G-CSF诱导的PBSC动员。 根据小鼠的这项工作，我们提出以下具体目的： 1）在接受第二次PBSC动员初始收集周期的患者中进行I/II期临床研究研究，添加？2肾上腺素能的激动剂白丁醇的实用性是为了获得CD34+和CD34+ CD38的数量，以获得更高的HSPC，以获得更高的HSPC，以获得更高的HSPC。 比较的基线将是与初始收集周期收集的CD34+细胞的数量。 2）评估G-CSF是否可以刺激接受G-CSF诱导PBSC动员的人类的交感神经系统活性。 有两个重要的长期目标。 一种是避免需要重复HSPC收集，这会对患者产生负面影响，这是由于需要重复中心线的放置，骨髓收获的全身麻醉以及移植日期的延迟。 基于动员不良的预测因素，例如年龄和先前的化学疗法，HSPC捐赠者可以在初始收集周期中接受沙丁胺醇，以获得足够的PBSC收集。 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. 研究设计是，Albuterol将以剂量降低策略的速度进行管理，并具有标准动员G-CSF（10 ug/kg/day 5天）的标准动员方案。 在第1级中，沙丁胺醇将与G-CSF的第5剂量相吻合；在第2级，G-CSF的第三剂量；在第3级中，第一个剂量的G-CSF。 外周血干细胞收集将在G-CSF的第5天开始。 主要结局指标是比较第1天收集的总CD34+产品产量的初始收集周期和第二个收集周期之间的比较。 为了确定G-CSF诱导的PBSC动员是否通过刺激交感神经系统来起作用，尿液和外周血将连续3个时间点从研究受试者中收集：基线（在动员之前），在开始启动Albuterol的那天，以及在启动Albutolol的那天，以及在收集的第一天，以测量无脑磷脂（Neylcine）（Neylcly）（Neyly）（neyly）（Neyly）（Neyly）（Neyly）（neyly）（Neyly）（Neyy） （DHPG），NE的主要神经元代谢产物。 与动员期间相比，基线时的血浆NE和DHPG水平是血浆NE和DHPG水平。 假设： 1。在接受周围血液干细胞（PBSC）收集的患者的G-CSF动员方案中添加B2肾上腺素能量的白化醇是安全的，并且增加了收集的造血干细胞和祖细胞（HSPC）的数量。 2。G-CSF刺激正在接受G-CSF诱导PBSC动员的人类的交感神经系统活性。