Calcineurin activity as a functional index of immunosuppression after allogeneic stem-cell transplantation

Background. The authors have previously shown that mononuclear cells derived from patients with resistant chronic graft-versus-host-disease (GVHD) express high calcineurin (CN) activity, suggesting that in vitro assessment of CN activity may be a useful index to estimate the degree of immunosuppression afforded by cyclosporine A (CsA). The goal of this study was to assess CN activity during the first 2 months after allogeneic stem-cell transplantation (SCT) and to correlate its evolution with the occurrence of acute GVHD. Methods. Thirty-one allogeneic SCT recipients were enrolled during a 21-month period. All received GVHD prophylaxis with CsA (2 mg/kg/day) and methotrexate (on days 1, 3, and 6). CN activity was measured before transplant, and then once weekly, for at least 2 months. Results. Eighteen patients developed acute grade 11 or higher GVHD at a median time of 22.5 days and were treated with steroids. CN activity was significantly increased in these 18 patients when compared with 13 patients who did not develop GVHD. Analysis involving the receiver operating characteristic curve demonstrated that acute grade 11 or higher GVHD can be predicted with a sensitivity of 89% and a specificity of 54% with the use of a cutoff value of 28 pmol RII/mg proteins/min of CN activity. Conclusions. CN activity appears to be a promising therapeutic test to predict acute GVHD after allogeneic SCT. This functional assessment of the in vivo efficacy of CsA opens new insights for CsA dose adjustment-in particular, the administration of its most efficient dose instead of its maximal tolerated dose, as is currently performed.