title: FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation.
abstract: FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses 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. All 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 second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.
authors.affiliation: Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX 75146, USA
authors.forename: J W
authors.initials: JW
authors.lastname: Fay
authors.forename: J R
authors.initials: JR
authors.lastname: Wingard
authors.forename: J H
authors.initials: JH
authors.lastname: Antin
authors.forename: R H
authors.initials: RH
authors.lastname: Collins
authors.forename: L A
authors.initials: LA
authors.lastname: Piñeiro
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: R
authors.initials: R
authors.lastname: Saral
authors.forename: B E
authors.initials: BE
authors.lastname: Bierer
authors.forename: D
authors.initials: D
authors.lastname: Przepiorka
authors.forename: W E
authors.initials: WE
authors.lastname: Fitzsimmons
authors.forename: R M
authors.initials: RM
authors.lastname: Maher
authors.forename: D J
authors.initials: DJ
authors.lastname: Weisdorf
mesh_terms: D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000706:statistics & numerical data; D056486:Chemical and Drug Induced Liver Injury; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000517:prevention & control*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015994:Incidence; D007674:Kidney Diseases / Q000139:chemically induced; D007938:Leukemia / Q000401:mortality / Q000628:therapy; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000401:mortality / Q000628:therapy; D009679:Nuclear Family; D010298:Parity; D012449:Safety; D016019:Survival Analysis; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus