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.

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 11/8/2007 使用粒细胞集落刺激因子（G-CSF）的外周血造血干细胞（PBSC）动员是获得用于自体移植的造血干细胞和祖细胞（HSPC）的首选方法，因为与骨髓收获相比，其对患者的安全性和舒适度更高。 然而，在接受自体移植治疗恶性血液病的患者中，通过这种方法获得的外周血干细胞数量往往不足，需要重复收集。 Paul Frenette博士的实验室最近表明，完整的外周交感神经系统对于G-CSF诱导的PBSC动员至关重要，其机制是抑制成骨细胞功能及其随后的CXCL 12（SDF-1）表达，CXCL 12是一种趋化因子，其配体是HSPC上表达的CXCR 4。 先前已显示该CXCL 12-CXCR 4轴的破坏足以诱导PBSC动员。 Frenette博士的研究小组还表明，阻滞剂（普萘洛尔）显着减少G-CSF诱导的HSPC动员和管理的？2肾上腺素能受体激动剂（克仑特罗）增强G-CSF诱导的PBSC动员。 基于在小鼠中的这项工作，我们提出了以下具体目标： 第一章 启动I/II期临床 l研究检查，在接受第二次PBSC动员的患者不充分的初始收集周期，增加的效用？2肾上腺素能激动剂沙丁胺醇与标准G-CSF动员方案相比，以获得更高数量的HSPC，如通过外周血和收集的产物中的CD 34+和CD 34 + CD 38-细胞数量测量的。 用于比较的基线将是初始采集周期采集的CD 34+细胞数量。 （二） 评价G-CSF是否能刺激接受G-CSF诱导的PBSC动员的人的交感神经系统活动。 有两个重要的长期目标。 一个是避免重复HSPC采集的需要，由于需要重复中心静脉导管放置、全身麻醉和骨髓采集以及移植日期延迟，HSPC采集对患者产生负面影响。 基于动员不良的预测因素，如年龄和既往化疗，HSPC供体可在初始采集周期接受沙丁胺醇，以实现充分的PBSC采集。 其次，如果G-CSF动员通过刺激交感神经系统发生的假设得到证实，这可能导致开发更特异的PBSC动员剂，因为G-CSF可导致使人衰弱的副作用，如骨痛，很少更严重的毒性，如脾破裂，以及镰状细胞病患者危及生命的血管闭塞。 研究设计是沙丁胺醇将以剂量递增策略与标准G-CSF动员方案（10 ug/kg/天，持续5天）一起给药。 在水平1中，沙丁胺醇将与第5次G-CSF给药同时开始;在水平2中，与第3次G-CSF给药同时开始;在水平3中，与第1次G-CSF给药同时开始。 外周血干细胞采集将在G-CSF第5天开始。 主要结局指标是比较第一个和第二个采集周期采集前两天的总CD 34+产物产量。 为了确定G-CSF诱导的PBSC动员是否通过刺激交感神经系统起作用，将在3个连续时间点从研究受试者中采集尿液和外周血：基线（动员前）、沙丁胺醇开始治疗当天和采集第1天，以测量去甲肾上腺素（NE）和二羟基苯乙二醇（DHPG）（NE的主要神经元代谢物）的水平。 主要结果测量是基线时与动员期间相比的血浆NE和DHPG水平。 假设条件： 1. 在接受外周血干细胞（PBSC）采集的患者的G-CSF动员方案中添加B2肾上腺素能激动剂沙丁胺醇是安全的，并可增加采集的造血干细胞和祖细胞（HSPC）数量。 2. 在经历G-CSF诱导的PBSC动员的人中，G-CSF刺激交感神经系统活性。