Mobilized autologous peripheral blood stem cells (PBSC) have replaced bone marrow as the source of hematopoietic stem cells because of more rapid neutrophil and platelet recovery, largely due to a higher yield of CD34+ cells in PBSC grafts. Various mobilization strategies using myeloid growth factors, particularly G-CSF (filgrastim), have been used either alone or in combination with chemotherapy. However, up to 40% of patients will fail to mobilize an optimal CD34 cell dose (defined as e5x106/kg). Plerixafor, a small molecule CXCR4 antagonist, in combination with G-CSF has been shown to increase total CD34+ cells mobilized compared to G-CSF alone, and is approved by the Food and Drug Administration for PBSC mobilization in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). However, a significant disadvantage of plerixafor is cost; adding $25,567 per patient compared to G-CSF alone in NHL patients in a recent economic analysis. Furthermore, 14-24% of MM and NHL patients receiving plerixafor plus G-CSF still failed to collect e2x106 CD34+ cells/kg in four days of apheresis in large trials. Our group has a long standing interest in the roles of prostaglandin E2 (PGE2) and the cyclooxygenase (COX) pathway on hematopoiesis and HSC and HPC trafficking, We have recently defined a new role for PGE2 in the hematopoietic niche and shown that non- steroidal anti-inflammatory drugs (NSAID) that inhibit COX enzymes responsible for PGE2 synthesis significantly enhance the number of HSC and HPC in peripheral blood, and act synergistically with G-CSF to mobilize PBSC with superior engraftment potential. This proposal seeks to translate our preclinical findings to develop a novel, inexpensive and more efficacious PBSC mobilizing regimen. Specifically, we propose to:
Aim 1 Conduct a phase II clinical trial to assess the safety and efficacy of the combination of meloxicam and filgrastim for mobilizing autologous PBSC in patients with MM and NHL, hypothesizing that the combination of the FDA approved NSAID, meloxicam, and filgrastim will enhance the number of CD34+ cells collected in NHL and MM patients undergoing ASCT, and Aim 2 Utilize a molecular, phenotypic and functional approach to better understand the mechanism of action of NSAID on PBSC graft content and function, assessing the mobilized graft for CD34+ cells and their expression of CXCR4, and proliferation status, and immune cell content (Aim 2A), and performing gene expression microarrays and gene ontology enrichment analysis on CD34+ cells/HPC subsets to identify genes/biological pathways associated with NSAID-mediated change in HPC proliferative potential (Aim 2B). In the long-term, understanding these changes will allow us to more effectively bridge the differentiation gap post-transplant, and develop novel and potentially more efficacious and cost-effective mobilization regimens and strategies.
Mobilization and collection of sufficient blood stem cells from patients is critical for the success of autologous stem cell transplantation, which is the best treatment in many patients with hematological malignancies. However, up to 40% percent of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) fail to mobilize and collect an optimum number of stem cells for rapid and reliable engraftment using growth factors, including filgrastim. Plerixafor is a relatively an agent that has enhanced mobilization of stem cells when combined with filgrastim, but its main drawback is high cost. We have studied the effects of simple non- steroidal anti-inflammatory drugs (NSAID), which inhibit prostaglandins, on the bone marrow and blood forming stem cells. Our data in animal models indicate that NSAID can significantly enhance the mobilization of stem cells, yielding a graft with possible better engraftment potential. We propose a phase II clinical trial to translate our preclinical dat and develop a novel, inexpensive, and potentially more efficacious regimen for mobilization of stem cells, and include correlative studies that will help us to better understand the targeting of the bone marrow niche for improving stem cell mobilization.
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