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.
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