A TOXICITY STUDY OF TRIMETREXATE USED IN COMBINATION WITH CYCLOSPORINE AS ACUTE GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS IN HLA-MISMATCHED, RELATED DONOR BONE-MARROW TRANSPLANTS

This study evaluated the acute toxicity of trimetrexate (TMTX) used in combination with cyclosporine (CsA) for prevention of acute graft-ver sus-host disease (GVHD) in patients undergoing allogeneic marrow trans plantation from HLA-mismatched, related donors. TMTX has a mechanism o f action similar to that of methotrexate (MTX); however, unlike MTX, T MTX is not primarily dependent on renal excretion. Patients were condi tioned for transplant with cyclophosphamide, anti-thymocyte globulin, and total body irradiation. TMTX, 10 mg/m(2) i.v., was administered on days 1, 3, 6, 11, 18, 25, 32, and 39 after transplant. CsA, 1.5 mg/kg i.v., was administered every 12 hr beginning on day -1. Eleven patien ts with hematologic malignancies or aplastic anemia (median age = 34 y r) received TMTX. Toxicity assessed included nausea, vomiting, fever, rash, time to myeloid and platelet engraftment, mucositis, and hepatic and renal dysfunction. Toxicity of TMTX was not different from that o bserved with MTX in a similar patient population. One patient died on day 16 before engraftment, The other 10 patients all engrafted and all developed acute GVHD at a median time of 11 days after transplant, Th e major manifestation of acute GVHD was in the skin, and all but one p atient responded to primary therapy with corticosteroids. Seven patien ts have survived a median of 447 days after transplant. No significant toxicity from TMTX was observed. Further trials are warranted to defi ne the role of TMTX in marrow transplantation.