Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

Abstract

Summary:Tacrolimus (FK506) is a macrolide lactone with potent immunosuppressive activity 100 times that of cyclosporine by weight. The molecular mechanism of action is mediated via an inhibition of the phosphorylase activity of calcineurin by drug-immunophilin complex, resulting in the inhibition of IL-2 gene expression. There are emerging studies now showing significant efficacy of tacrolimus in GVHD prevention in both related and unrelated donor transplantation. Three multicenter randomized studies comparing tacrolimus to cyclosporine have been completed, one each in related and unrelated donor transplantation; the remaining study involved both related and unrelated donor transplantation. All three studies showed a significantly lower incidence of grade II-IV acute GVHD in patients who received tacrolimus. One study in sibling donor transplantation showed that patients with advanced disease who received tacrolimus had a poorer survival than patients who received cyclosporine, but the survival was similar in patients with non-advanced disease. The remaining two studies, one in unrelated donors and the other combining both related and unrelated donors did not show any survival difference between the tacrolimus and cyclosporine groups. In addition, this review also highlights some of the critical questions regarding the role of this agent in allogeneic stem cell transplantation: (1) the contribution of methotrexate in combination with tacrolimus; (2) the starting i.v. dose of tacrolimus; (3) the suggested whole blood level of tacrolimus and its effect on nephrotoxicity; and (4) whether tacrolimus should be used in patients with advanced malignancy. Future studies using tacrolimus in combination with other immunosuppressants, and its use in patients with advanced malignancy will be warranted.

Chronic graft-versus-host disease manifesting as polymyositis: an uncommon presentation

“…Cyclosporine and steroids are well-described treatment options for patients with myositis in post transplant, as well as idiopathic cases. There is very limited experience with the use of tacrolimus, 28,32 but in this case report it was effective in combination with steroids. The duration of immunosuppressive 545 Table 1 Treatment results for polymyositis associated with chronic GVHD *NR = no response on one patient who received no treatment, and one received ATG alone without steroids; PR = partial response; CR = complete response; R = primary resistant to steroids; FT = failure to taper; ATG = antithymocyte globulin; IVIG = intravenous immunoglobulin; AZA = azathioprine; CsA = cyclosporine; MTX = methotrexate; NA = information not available.…”

“…HLA DRw52 is present in 75% of patients with idiopathic polymyositis and in Ͼ90% of patients with idiopathic polymyositis with anti-Jo-1 antibody. [29][30][31][32] HLA B8, DR3 (DRb*0301) and DQA1*0501 have also been reported more frequently in patients with idiopathic polymyositis. 12 Interestingly, our two patients had HLA DRw52.…”

Tacrolimus compared with cyclosporine A after haploidentical T-cell replete transplantation with post-infusion cyclophosphamide

“…4 FK is a calcineurin inhibitor that is almost 100-fold more potent than cyclosporine A (CyA) in its inhibitory activity and more active in clinical trials. [5][6][7] In this retrospective study, we analyzed 100 patients grafted with haplo HSCT with PT-Cy and receiving FK or CyA.…”

Twice daily i.v. bolus tacrolimus infusion for GVHD prophylaxis in children undergoing stem cell transplantation

“…2 It has significant efficacy in preventing GVHD in both related and unrelated donor hematopoietic stem cell transplantation (HSCT). 3,4 In two randomized human trials, tacrolimus in combination with standard dose MTX was associated with a significantly lower incidence of acute GVHD (aGVHD) compared with cyclosporine (CSP) and MTX combination. 4,5 Currently in the HSCT setting, the recommended method of administration of i.v.…”