Over the past decade the use of mobilized peripheral blood has largely replaced bone marrow as a source of stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte Colony Stimulating Factor (G-CSF) with or without chemotherapy has become the standard of care for PBSC mobilization in the autologous transplant setting but is associated with both significant cost, moderate toxicities and significant rates of failure to achieve the minimum number of CD34/kg necessary for transplantation. A novel small molecule targeting the CXCR4/SDF-1 axis, AMD3100, has been recently tested in preclinical models and early clinical trials as a rapid stem cell mobilizing agent. Our group has performed many of the preclinical studies and clinical trials clearly establishing the role of AMD3100 as an effective and rapid stem cell mobilizing agent in man. We have extended these studies by testing subcutaneous (SC) AMD3100 as a single agent to mobilize stem cells for allogeneic stem cell transplantation from HLA-matched donors. In this proposal we propose to test the role of intravenous (IV) AMD3100 for mobilizing stem cells from allogeneic donors. First, we hypothesize that IV AMD3100 will mobilize more CD34 and more rapidly than SC AMD3100. Second, we predict that AMD3100 will mobilize phenotypically and functionally distinct subsets of CD34+ and T cell subsets compared to G-CSF. Third, we hypothesize that mobilization by IV AMD3100 will result in failure rates to achieve the minimum threshold CD34/kg necessary for allogeneic stem cell transplantation after a single aapheresis that are significantly less than SC AMD3100 and comparable to what is reported for G-CSF but with less side effects and in hours vs. days.
In Aim 1 we will perform a phase II trial in which patients with hematologic malignancies will be transplanted with stem cells from HLA-matched allogeneic donors mobilized with the optimal dose of IV AMD3100.
In Aim 2 we will characterize the CD34+ and CD34+ subsets mobilized by IV AMD3100 and CD34+ mobilized with G-CSF.
In Aim 3 we will characterize the T cells and T cell subsets mobilized by IV AMD3100 and T cells mobilized by G-CSF. We believe that the results of these studies will provide the foundation for future randomized trials comparing the clinical outcomes of patients transplanted with stem cell products mobilized by AMD3100 vs. G-CSF. Based on our preliminary data we believe that the clinical trial and the studies described in this proposal will pave the way for a paradigm shift in the standard of care for allogeneic stem cell transplantation via the generation of more effective allografts in less time with fewer toxicities to both donors and recipients.
We will use intravenous (IV) AMD3100, a rapid stem cell mobilizing agent, to mobilize human stem cells from normal donors for allogeneic stem cell transplantation. We will analyze the content of stem cells and T cells mobilized by IV AMD3100, and assess its safety profile in normal donors and the outcomes of recipients of these AMD3100-mobilized stem cell products. These studies will provide the foundation for generating improved stem cell allografts in less time and with improved safety to the donors and outcomes for the recipients compared to G-CSF.
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