The Role of AMD3100 as a Preparative Regimen in Allogeneic Hematopoietic Cell Transplantation

Since the development of allogeneic hematopoietic cell transplantation (HCT), many advances have been made that allow HCT treatment to be utilized in a wider range of patients. In the face of all these developments, additional barriers to engraftment have emerged. In addition to the immune barrier, non-immune related barriers are thought to contribute to engraftment resistance. One physical barrier of HCT engraftment is a need for space in the host hematopoietic stem cell (HSC) niche. It has been suggested that donor cells must home to specific areas in the bone marrow, engraft, and proliferate in these spaces. If endogenous HSCs occupy the niche, it is hypothesized that incoming donor cells will not be able to engraft. AMD3100 is a small molecule antagonist of CXC chemokine receptor 4 (CXCR4) and functions to block CXCR4 and stromal cell-derived factor-1 (SDF-1) interactions. This blockade results in rapid mobilization of HSCs from niche spaces to peripheral blood. We hypothesize that AMD3100 creates space within the endogenous stem cell niche allowing for better engraftment of transplanted HSC donors. We found that subcutaneous injections of AMD3100 (5mg/kg) into C57/BL6-Rag2 common gamma chain-deficient mice induced mobilization of HSCs from bone marrow and absolute numbers of HSC in bone marrow reached a nadir four hours post-AMD3100 injection (2013±553 vs. 3765±392, p = 0.02, n = 4-6). AMD3100 pre-treated immunodeficient recipients were transplanted with a bolus dose of 6300 MHC-mismatched AKR/j HSCs. We also performed daily rounds of AMD3100 injections followed by low dose injections of 450 HSCs over the course of 14 days for a total transplant of 6300 cells. HSC bone marrow donor chimerism 12-weeks post-transplant was not increased in the bolus-transplanted animals (1.9±0.6% vs. 1.4±0.3%, p = 0.7, n = 5-9). Repeat-transplanted animals exhibited a slight increase in engraftment; however, this increase was not found to be statically significant (2.1±0.2% vs. 2.5±0.8%, p = 0.4, n = 4-5). These data demonstrate that while AMD3100 is effective as a HSC mobilizer, it is not effective in increasing engraftment potential of transplant recipients.