Adapting Cyclosporine to Calcineurin Activity Rather Than to Cyclosporine Blood Levels: Toward a Functional Management of Graft-Versus-Host Disease Prophylaxis.

Abstract

We have previously shown [1] that a calcineurin activity (CA) < 28 pmol RII/mg proteins/min was significantly associated with the absence of acute GVHD after allogeneic stem cell transplant (SCT). The CA is poorly correlated with cyclosporine (CsA) trough level which is not a good marker of CsA efficacy. Therefore, the in vitro assessment of CA could help in adapting the cyclosporine doses for GVHD prophylaxis, better than blood CsA levels. Objective: The aim of this prospective study was to evaluate the feasibility of adapting the CsA doses to the values of in vitro CA either until GVHD occurs, or until day 100, whichever occurs first.Methods: CA assessment methods in PBMC of transplant patients and monoclonal CsA level measurement methods were previously reported [1]. CA and CsA levels were measured once a week from d0–d15, twice a week from d16–d35, then once a week up to d100. The CsA doses were adapted in order to maintain a CA < 28 from transplant by 20% progressive changes of the CsA daily dose. Adaptation was stopped in case of clinical CsA blood levels ≥ 600 ng/ml, creatinine clearance < 40 ml/mn, serum bilirubin > 40 m/L, or severe clinical toxicity.Patients: 39 adult patients with malignant hemotologic diseases (acute leukemia: 28; chronic leukemia: 4; others: 4) or aplastic anemia (3), and undergoing myeloablative SCT were included (HLA-id donor: 20; unrelated donor: 19). GVHD prophylaxis consisted in short course Methotrexate and CsA (initial dose: 3 mg/kg IV).Results: Out of 39 patients, 2 were adapted until d100 and did not develop GVHD; 27 were adapted without CsA toxicity until they developed GVHD (grade I: n=2; grade II: n=18; grade III–IV: n=7). In 10 (26%) patients, adaptation was stopped before d100, due to neurologic (n=1), renal (n=2) or liver (n=2) toxicity, severe nausea (n=1), investigator decision (n=1) or protocol violation (no CsA increase despite high CA and no CsA toxicity: n=3).Conclusion: Our study shows that CsA dose adaptation is feasible on the basis of CA regular assessment within the safety limits defined in our protocole. This adaptation is, however, limited by CsA toxicity, due to the need to significantly increase the CsA dose to get a CA < 28 pmol in 26% of the patients. A prospective controlled study is needed to compare the routine use of CA to the use of CsA blood levels for managing CsA doses in GVHD prophylaxis.