Severe canine hereditary hemolytic anemia treated by nonmyeloablative marrow transplantation.
Severe hemolytic anemia in Basenji dogs secondary to pyruvate kinase (PK) deficiency can be corrected by marrow allografts from healthy littermates after a conventional high-dose myeloablative conditioning regimen. The nonmyeloablative conditioning regimen used here, which consisted of a sublethal dose of 200 cGy total body irradiation before and immunosuppression with mycophenolate mofetil and cyclosporine after a dog leukocyte antigen (DLA)-identical littermate allograft, has been found to be effective in establishing stable mixed donor/host hematopoietic chimerism in normal dogs. We explored the feasibility of nonmyeloablative marrow allografts for the treatment of canine PK deficiency and studied the effect of stable allogeneic mixed hematopoietic chimerism on the natural course of the disease. Five affected dogs received transplants, of which 3 dogs had advanced liver cirrhosis and myelofibrosis. Both complications were presumed to be due to iron overload. All 5 dogs showed initial engraftment. Two rejected their grafts after 6 weeks but survived with completeautologous marrow recovery and return of the disease. One died from liver failure on day 27 with 60% donor engraftment. Two dogs have shown sustained mixed donor/host chimerism for more than a year with 85% and 12% donor hematopoietic cells, respectively. Overall clinical response correlated with the degree of donor chimerism. The dog with the low degree of chimerism achieved partial resolution of hemolysis, but the disease symptoms persisted as manifested by increasing iron overload resulting in progression of marrow and liver fibrosis. The dog with the high degree of donor chimerism achieved almost complete resolution of hemolysis with a decrease of marrow iron content and resolution of marrow fibrosis. These observations suggest that mixed hematopoietic chimerism can be relatively safely established in dogs with PK deficiency even in the presence of advanced liver cirrhosis. However, although effective in correcting or delaying the development of myelofibrosis, a low degree of mixed chimerism was not sufficient to prevent continued hemolysis of red blood cells of host origin. Complete donor chimerism appears necessary to achieve a long-term cure.
Zaucha
J A
JA
Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle 98109-1024, USA.
Yu
C
C
Lothrop
C D
CD
Nash
R A
RA
Sale
G
G
Georges
G
G
Kiem
H P
HP
Niemeyer
G P
GP
Dufresne
M
M
Cao
Q
Q
Storb
R
R
D000745:Anemia, Hemolytic, Congenital / Q000628:therapy*; D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004285:Dogs; D019653:Myeloablative Agonists / Q000494:pharmacology; D014184:Transplantation, Homologous
D019653:Myeloablative Agonists