AMD3100 (Plerixafor) As A Single-Dose Stem Cell Mobilizing Agent In Vascularized Composite Tissue Allograft (VCA) Transplantation In A Canine Model
Bruce J. Swearingen, Jr., MD1,2, Scott S. Graves, PhD2,3, Rainer Storb, MD2,3, David W. Mathes, MD1,2.
1University of Colorado School of Medicine, Aurora, CO, USA, 2Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 3University of Washington Medical Center, Seattle, WA, USA.
Vascularized Composite Allograft (VCA) transplantation is a clinical reality but limited by toxicities of chronic immunosuppression and rejection. Current clinical tolerance protocols rely on recipient conditioning and donor cell mobilization that limits use to living donor transplants. We sought to design a clinically relevant protocol applicable to cadaveric organs. We have previously demonstrated stem cell engraftment using AMD3100 (Plerixafor) as a single dose agent for stem cell mobilization in a haploidentical canine model. We wanted to increase clinical relevance by testing our existing non-myeloablative stem cell canine VCA transplant model to full DLA-mismatched, unrelated canine donor-recipient pairs.
8 DLA haploidentical, related canine recipients (Group I) and 4 full DLA-mismatched, unrelated canine recipients (Group II) received conditioning with 350-450cGy TBI, AMD3100-mobilized donor stem cells + Bone Marrow (BM) infusion and simultaneous VCA transplantation with a short course of immunosuppression (MMF: 56 days/CSP: 70 days. Sirolimus 28 days added as third agent for Group II). CD34+ hematopoietic progenitor cells were quantified via flow cytometry. Peripheral blood chimerism was evaluated by PCR techniques weekly. VCA graft survival was followed clinically and histologically.
All 12 canines tolerated the conditioning regimen. Stem cell engraftment and donor chimerism was seen in all dogs. Mean COBE apheresis count was 3.98x10^8 cells/kg and mean BM aspirate count was 1.56x10^8 cells/kg across both groups (12 dogs). Outcomes were varied. In Group I there was evidence of an acute rejection episode (self-limited) in 1 dog. Evidence of GVHD (skin, liver) was seen in 3 dogs and pulmonary hemorrhage noted in 3 dogs. In Group II there was no evidence of acute rejection, however GVHD (skin, liver) was seen in 2 dogs. 2 dogs were lost post-transplant to complications of intussusception while still seemingly tolerant to the VCA.
This study demonstrates proof of principle for AMD3100 as a single-dose stem cell mobilizing agent for a clinically relevant tolerance protocol in both related haplotype and in mismatched, unrelated donor-recipient pairs. Use of AMD3100 led to stem cell engraftment in all animals transplanted with evidence of acute rejection in the VCA in only one canine. AMD3100 use limited by thrombocytopenia in our previous studies continue to appear be resolved with the addition of BM Aspirate in this model. Continued experiments should allow for longer-term follow up in future canine recipients that should optimistically not experience bowel complications or GVHD.
Back to 2018 Program