MYCOPHENOLATE MOFETIL FOR THE TREATMENT OF REFRACTORY, ACUTE, CELLULAR RENAL-TRANSPLANT REJECTION

In a 6-month open label, randomized, multicenter trial, we compared th e efficacy and safety of mycophenolate mofetil (MMF) with high dose in travenous steroids (IVS) for the treatment of refractory, acute cellul ar rejection in recipients of first or second cadaveric or living-dono r renal allografts. A total of 150 patients were enrolled and randomiz ed in a 1-to-1 ratio to receive oral MMF 1.5 g twice daily (n=77) or i .v. methylprednisolone 5 mg/kg for 5 days (n=73), tapered over the sub sequent 5 days to 20 mg/day or the baseline dose of steroid given on t he day before the diagnosis of rejection. Patients in both groups gene rally received cyclosporine and maintenance doses of corticosteroids t hroughout the study period. The IVS group (but not the MMF group) was generally maintained on azathioprine, The primary efficacy variable wa s graft and patient survival at 6 months, Graft loss and death were re duced by 45% in the MMF treatment group; 19 patients (26.0%) in the NS group experienced graft loss or died, compared with 11 patients (14.3 %) in the MMF group (P=0.081, sequential probability ratio test analys is). In the IVS group, 64.4% of patients experienced either subsequent biopsy proven rejection, presumptive rejection (presumed rejection cl inically diagnosed but not biopsy proven and treated with a full cours e of immunosuppressive therapy), or treatment failure (premature termi nation for any reason, including death, graft loss, or an adverse even t) compared with 39.0% in the MMF group (P=0.001, Cochran-Mantel-Haens zel [CMH] general association test). One or more full courses of immun osuppressive treatment for subsequent rejection episodes were administ ered to 35.6% of patients in the IVS group and 24.7% of patients in th e MMF group. The number of patients who received full courses of corti costeroids for subsequent episodes of rejection was equal in the 2 gro ups, but the number of patients who received full courses of antilymph ocyte therapy was more than twice as great in the TVS group (n=18) com pared with the MMF group (n=8), Adverse events were reported in 74.6% of patients who received TVS and in 93.5% of patients who received MMF . A cerebral lymphoma developed in 1 patient in each group, and a lymp hopro-liferative disorder developed in 2 patients in the MMF group; in 1 of these patients, the lymphoproliferative disorder was subsequentl y determined to be present before study entry, Opportunistic infection s occurred in 35% of patients in each treatment group. The incidence o f cytomegalovirus (CMV) viremia/syndrome was comparable between groups , but tissue-invasive CMV was reported for 7 patients (9.1%) who recei ved MMF, compared with 1 patient (1.4%) who received IVS. At 12 months postenrollment, the cumulative proportions of patients who died or lo st their grafts were 31.5% in the IV steroid arm versus 18.2% for the MMF arm (P=0.042, CMH general association test, not adjusted for seque ntial monitoring). Thus, graft loss and death were reduced by 42% in t he MMF treatment group, In summary, MMF is a clinically promising immu nosuppressant and was effective for the treatment of refractory acute rejection with continuing administration for prophylaxis of subsequent rejection.