A Randomized Phase II Trial Comparing Tacrolimus and Mycophenolate Mofetil to Tacrolimus and Methotrexate for Acute Graft-versus-Host Disease Prophylaxis

Abstract

Tacrolimus (Tac) plus methotrexate (MTX) is a standard regimen for graft-versus-host disease (GVHD) prophylaxis. Mycophenolate mofetil (MMF) is sometimes used instead of MTX to minimize toxicity, despite the lack of controlled studies demonstrating efficacy. We conducted a single-center, randomized phase II trial comparing Tac + MMF to Tac + MTX. Intent-to-treat analyses included 42 patients randomized to Tac + MMF and 47 to Tac + MTX. Patient characteristics were not different between the study arms. Patients in the Tac + MMF arm were less likely to experience severe mucositis, require narcotic analgesia and parenteral nutrition, and had earlier hospital discharge. The Tac + MMF arm had the same time to neutrophil recovery, but earlier platelet recovery. The cumulative incidence of grade II-IV acute GVHD (aGVHD) at 100 days was similar (P = .8), but grade III-IV aGVHD was higher in the Tac + MMF arm (19% versus 4%; P = .03); this was predominantly seen in unrelated donor transplants (26% versus 4%; P = .04), and less in related donor transplants (11% versus 4%; P = n.s.). Moderate or severe chronic GVHD was similar (P = .71). There were no significant differences between the arms in relapse, nonrelapse mortality, or overall and relapse-free survivals. MMF was associated with less early toxicity than MTX but was not as effective in preventing severe aGVHD, especially in unrelated donor transplants.

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

“…Among MTX/TAC-treated patients, we anticipated a grade II-IV acute GVHD rate of 80%, based on that observed in MTX/TAC-treated patients in a recent, prospective clinical trial at our center. 19 Based on previously published results of a single-arm phase II SIR/TAC trial results in which the incidence of grade II-IV acute GVHD was approximately 20% in comparison to previously reported incidence of 40-50% following MTX/TAC, 4,5 our a priori hypothesis was that we would observe a 50% reduction in this primary endpoint. The trial design included a concurrent comparator to facilitate interpretation, as there is variation in reported baseline incidences of grade II-IV acute GVHD between centers.…”

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

“…We subsequently reported on our experience with CSA and MMF compared to CSA and MTX in a retrospective analysis spanning from 1999 to 2007, again demonstrating reductions in mucositis, time to engraftment, length of stay, as well as risk of chronic GVHD, without difference in survival or relapse [14]. A study comparing Tac and MMF to Tac and MTX in both sibling and unrelated donor myeloablative HCT also demonstrated no difference in 100 day incidence of grade 2-4 GVHD, with a significant reduction in toxicities, but a higher incidence of grade 3-4 GVHD, primarily in unrelated donor transplants [15]. Additional small retrospective studies evaluating MMF in myeloablative transplant recipients have also confirmed improved toxicity and GVHD incidence and survival outcomes that are comparable to MTX [16,17].…”

Folinic acid administration after MTX GVHD prophylaxis in pediatric allo-SCT

“…28 Given the randomized studies in adults demonstrating reduced mucositis when combining mycophenolate mofeteil (MMF) with CsA or tacrolimus rather than MTX, a question could be raised regarding the utility of maximizing strategies to enhance delivery of the full course of MTX. 29,30 However, the randomized trial with tacrolimus showed that MMF was less effective than MTX at reducing the risk of severe acute GVHD. 30 Furthermore, in vitro data demonstrate that MMF has substantially greater inhibition of natural killer cell proliferation and cytotoxic function than MTX, which may lead to a significant decrease in the GVL effect of natural killer cells.…”

“…29,30 However, the randomized trial with tacrolimus showed that MMF was less effective than MTX at reducing the risk of severe acute GVHD. 30 Furthermore, in vitro data demonstrate that MMF has substantially greater inhibition of natural killer cell proliferation and cytotoxic function than MTX, which may lead to a significant decrease in the GVL effect of natural killer cells. 31,32 Our study was the first to assess the use of FA for MTX-related toxicity in pediatric allo-SCT patients receiving CSA and MTX for GVHD prophylaxis.…”