A Randomized, Controlled Trial of Graft-Versus-Host Disease (GVHD) Prophylaxis Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate: Analysis of GVHD, Relapse and Survival.

The selective IMPDH inhibitor, mycophenolate mofetil (MMF), has entered the clinic with the promise to provide potent immune suppression without the side effects of methotrexate (MTX) or other broad-spectrum immunosuppressants. The use of MMF in the prevention of GVHD after hematopoietic cell transplantation (HCT) has been increasing worldwide, but only one small controlled study comparing cyclosporine + MMF to cyclosporine + MTX has been conducted to date. We compared GVHD prophylaxis with tacrolimus + MTX (TAC/MTX) to tacrolimus + MMF (TAC/MMF) in a single institution, randomized, controlled trial. Eligible patients were to receive T-replete peripheral blood HCT from 10/10 or 9/10 HLA-A, B, C, DRB1 and DQB1 matched donors, and have no contraindications to the use of TAC, MTX, or MMF. Randomization was stratified based on conditioning regimen intensity. Ninety-two pts were randomized, 45 to TAC/MMF and 47 to TAC/MTX and were all included in the intent-to-treat (ITT) analysis. Two pts were not transplanted and one pt withdrew consent prior to transplant. These pts were all randomized to TAC/MMF and excluded in the modified ITT (MITT) analysis. Pts received TAC 0.03 mg/kg/24hr as a continuous IV infusion beginning day -3 with doses adjusted to maintain whole blood levels of 5–15ng/ml. Pts were converted to PO therapy as tolerated and tapered after 6 months in the absence of GVHD. MTX was given IV at doses of 15mg/m² day +1 and 10mg/m² on days +3, +6 and +11. In pts with renal insufficiency, MTX doses were adjusted per pts’ pretransplant creatinine clearance. MMF was dosed at 15 mg/kg every 12 hours (up to 3g/d) IV beginning day 0, switched to PO as tolerated and continued for 12 months. Acute GVHD was graded weekly by Thomas’ criteria, modified per ASBMT consensus criteria; chronic GVHD was scored monthly based on NIH consensus criteria. The groups were balanced with respect to age, diagnosis, disease risk, recipient/donor CMV status, conditioning regimen, donor type and relation. The incidences of grade 2–4 and 3–4 acute GVHD were 79% and 4% in the TAC/MTX arm and 79% and 17% in the TAC/MMF arm (p=1.0 and 0.08, respectively). The incidence of moderate or severe chronic GVHD was 55% in the TAC/MTX arm and 59% in the TAC/MMF arm (p=0.91). By ITT analysis, the cumulative incidence of non-relapse mortality suggested an early difference in favor of TAC/MTX, but at 2 years it was 28% for TAC/MTX arm compared to 32% for the TAC/MMF arm (p=0.41; MITT p=0.33). The cumulative incidence of relapse was 33% in TAC/MTX arm compared to 18% (ITT; 16% MITT) for the TAC/MMF pts (p=0.06; p=0.04 MITT). Overall survival was similar between groups in both the ITT (p=0.76; 62% TAC/MTX vs. 66% TAC/MMF at 1 year) and MITT analysis (p=0.75; 62% TAC/MTX vs. 66% TAC/MMF at 1 year). We conclude that MMF was no better than MTX in preventing acute or chronic GVHD and may perhaps be less effective in preventing more severe forms of acute GVHD. Given the direction of effect we observed in severe acute GVHD, it is unlikely that a larger trial would show benefit for this endpoint. There was a strong suggestion that relapse of malignancy was more frequent after MTX than MMF, apparently in relation to the drug interference with the graft-vs.-leukemia effect. The beneficial effect of MMF on relapse was offset by the early increase in nonrelapse mortality, so that overall survival was unaffected.