TACROLIMUS - A NEW AGENT FOR THE PREVENTION OF GRAFT-VERSUS-HOST DISEASE IN HEMATOPOIETIC STEM-CELL TRANSPLANTATION

Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressiv e activity 100 times that of cyclosporine by weight. The molecular mec hanism of action is mediated,ia an inhibition of the phosphorylase act ivity of calcineurin by drug-immunophilin complex, resulting in the in hibition of IL-2 gene expression. There are emerging studies now showi ng significant efficacy of tacrolimus in GVHD prevention in both relat ed and unrelated donor transplantation. Three multicenter randomized s tudies comparing tacrolimus to cyclosporine have been completed, one e ach in related and unrelated donor transplantation: the remaining stud y involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute G VHD in patients mho received tacrolimus, One study in sibling donor tr ansplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclospori ne, but the survival was similar in patients with non-advanced disease , The remaining two studies, one in unrelated donors and the other com bining both related and unrelated donors did not show any survival dif ference between the tacrolimus and cyclosporine groups. in addition, t his review also highlights some of the critical questions regarding th e role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the s tarting i.v. dose of tacrolimus; (3) the suggested whole blood level o f tacrolimus and its effect on nephrotoxicity; and (4) whether tacroli mus should be used in patients with advanced malignancy. Future studie s using tacrolimus in combination with other immunosuppressants, and i ts use in patients with advanced malignancy will be warranted.