Prolonged allogeneic marrow engraftment following nonmyeloablative conditioning using 100 cGy total body irradiation and pentostatin before and pharmacological immunosuppression after transplantation.
In a canine model of dog leukocyte antigen (DLA)-identical nonmyeloablative marrow transplantation including postgrafting immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF), engraftment was only transient with 100 cGy total body irradiation (TBI) conditioning, indicating suboptimal pretransplant immunosuppression. In contrast, grafts after 200 cGy TBI were durable in 11/12 recipients. We hypothesized that addition of pentostatin before transplantation could, in part, substitute for 100 cGy TBI. Pharmacokinetic studies showed pentostatin significantly inhibited adenosine deaminase in canine lymphocytes. Eight dogs were conditioned with 6x4 mg/m pentostatin and 100 cGy TBI, whereas two dogs received 3x4 mg/m pentostatin plus 100 cGy TBI. All were given MMF/CSP posttransplant. All showed initial engraftment; four remained stable mixed chimeras for >32 weeks. The median duration of engraftment was 13 (range 9 to >39) weeks, which was significantly longer than in six historical controls conditioned with 100 cGy TBI alone (median 10, range 3-12 weeks) (P=0.01).
Panse
Jens P
JP
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Storb
Rainer
R
Storer
Barry
B
Santos
Erlinda B
EB
Wentzel
Collette
C
Sandmaier
Brenda M
BM
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D016572:Cyclosporine / Q000627:therapeutic use; D004285:Dogs; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008231:Lymphopenia / Q000139:chemically induced; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D015649:Pentostatin / Q000627:therapeutic use*; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D058892:Adenosine Deaminase Inhibitors; D007166:Immunosuppressive Agents; D015649:Pentostatin; D016572:Cyclosporine; D009173:Mycophenolic Acid