Work

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

Year: 2009

Type: article

Abstract: We conducted a single institution, randomized, controlled trial comparing tacrolimus + MTX (TAC/MTX) to tacrolimus + MMF (TAC/MMF). Eligible patients (pts) were to receive T-replete peripheral blood HCT from 10/10 or 9/10 HLA matched donors. Randomization was stratified based on conditioning regimen intensity. 92 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 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 and tapered after 6 months. MTX was given IV at doses of 15mg/m2 day +1 and 10mg/m2 on days +3, +6 and +11. MMF was dosed at 15 mg/kg every 12 hours (up to 3g/d) IV beginning day 0, switched to PO and continued for 12 months. Acute GVHD (aGVHD) was graded weekly by standard criteria; chronic GVHD (cGVHD) 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 cumulative incidences of grade 2–4 and 3–4 aGVHD were 79% and 4% in the TAC/MTX arm and 76% and 14% in the TAC/MMF arm (MITT; p = 0.84 and 0.1, respectively). The cumulative incidence of moderate or severe cGVHD at 6 months was 22% in the TAC/MTX arm and 26% in the TAC/MMF arm (MITT; p = 0.88). 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). The cumulative incidence of relapse was 33% in TAC/MTX arm compared to 18% for the TAC/MMF pts (p = 0.06). Overall survival was similar between groups (p = 0.76; 62% TAC/MTX vs. 66% TAC/MMF at 1 year). We conclude that MMF was no better than MTX in preventing GVHD and may perhaps be less effective in preventing more severe forms of aGVHD. Given the direction of effect we observed in severe aGVHD, it is unlikely that a larger trial would show benefit for this endpoint. There was a strong suggestion that relapse was more frequent after MTX than MMF. The beneficial effect of MMF on relapse was offset by the early increase in nonrelapse mortality, so that overall survival was unaffected.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2008.12.271