Optimum Use of Tacrolimus in the Prophylaxis of Graft Versus Host Disease

Transplantation of haemopoietic stem cells containing immunocompetent cells invariably leads to the development of graft versus host disease (GVHD) in the recipients unless immunosuppressive prophylaxis is administered for approximately 6 months. Despite the availability of immunosuppressive drugs such as cyclosporin, GVHD remains the most important cause of morbidity and mortality in haemopoietic stem recipients. Tacrolimus (FK506), a macrolide lactone isolated from the fermentation broth of Streptomyces tsukubiensis, has been introduced as an agent with greater activity than cyclosporin for GVHD prophylaxis. Several pilot studies using tacrolimus for prophylaxis of acute GVHD have shown promising results leading to 3 major pivotal trials. These studies were nonblinded randomised trials comparing the combination of tacrolimus and methotrexate with cyclosporin and methotrexate in both matched sibling and unrelated donor transplants for the prevention of acute GVHD. All 3 trials showed a significantly lower incidence of acute GVHD in the tacrolimus arm when compared to the cyclosporin arm. The overall and disease-free survival of patients with non-advanced malignancies was similar between the 2 groups. In one matched sibling study, the overall and disease-free survival in high-risk advanced disease patients who received tacrolimus was poorer than in the cyclosporin recipients. However, a recent matched case controlled study using the International Bone Marrow Transplant Registry database confirmed that the poorer survival outcome of the tacrolimus recipients was due to adverse influence of baseline prognostic factors in the tacrolimus group. The toxicity profile of tacrolimus is similar to that of cyclosporin with the exception that the incidence of hirsutism and hypertension is less frequent in tacrolimus recipients. The nephrotoxicity associated with tacrolimus is dose related. Logistic regression analysis indicated that whole blood tacrolimus concentrations greater than 20 ng/ml were associated with significant nephrotoxicity. The current recommended therapeutic concentration range in whole blood is 10 to 20 ng/ml. Some studies found equal efficacy with a therapeutic range of 5 to 15 ng/ml. This review addresses many details on the practical management of adverse effects, dosage and drug interactions.