FK506 (TACROLIMUS) MONOTHERAPY FOR PREVENTION OF GRAFT-VERSUS-HOST DISEASE AFTER HISTOCOMPATIBLE SIBLING ALLOGENEIC BONE-MARROW TRANSPLANTATION

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activa tion of antigen-specific T lymphocytes, a major component in the patho genesis of graft-versus-host disease (GVHD). This study was designed t o obtain first estimates of the safety and efficacy of FK506 monothera py in the prevention of GVHD following HLA-identical sibling marrow tr ansplantation. Additionally, a subset of patients was studied to defin e the pharmacokinetic profile of FK506. Twenty-seven adult patients wi th leukemia or myelodysplasia received FK506 starting the day before t ransplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion . When clinically possible, FK506 was given orally in two divided dose s starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. Al l patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6-month study period. A se cond patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of dis tribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and b ioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed gr ade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indi cate that FK506 monotherapy has activity in preventing GVHD. Further s tudies of FK506 with lower doses to improve tolerability and in combin ation with other immunosuppressants to augment efficacy are warranted. (C) 1996 by The American Society of Hematology.