Prevention of graft-versus-host disease by immunosuppressive agents after transplantation of DLA-nonidentical canine marrow.

Dogs given 9.2 Gy of total body irradiation (TBI) followed by hematopoietic grafts from DLA-nonidentical unrelated or littermate donors and no postgrafting immunosuppression all develop acute graft-versus host disease (GVHD) and die within 3 weeks of grafting. Over a period of 10 years, the present study evaluated various immunosuppressive drugs either alone or in combination and compared their effectiveness to that of methotrexate (MTX) in preventing acute GVHD and prolonging survival. Among the single agents tested, 6-mercaptopurine and azathioprine resulted in a slight but significant prolongation of survival compared to controls, but they were less effective than MTX. Procarbazine and cytosine arabinoside were ineffective. Drugs tested in combination included MTX, cyclophosphamide, 6-mercaptopurine, azathioprine, cyclosporin, procarbazine, prednisone and antithymocyte globulin. Drug combinations, while effective in delaying the onset of GVHD, were associated with hematopoietic and other toxicities, which made their use impractical. Administration of MTX twice weekly proved to be no better than once weekly administration. Prednisone administered for the first 4 days after grafting in addition to MTX resulted in a modest improvement in survival. High-dose MTX (200 mg/kg) followed by leukovorin rescue resulted in severe early toxicity, both gastrointestinal and hematopoietic; however, some of those dogs which survived the early postgrafting period became stable long-term survivors. Most single agents tested in the present study proved to be either ineffective or were inferior to MTX in their ability to prevent GVHD. None of the drug combinations tested was as effective as the one involving MTX/cyclosporin reported previously.