The Promising Strategy of Mycophenolate Mofetil Dosing to Prevent Moderate- to Severe-Acute Graft-Versus-Host Disease.

Abstract

To prevent acute graft-versus-host disease (GVHD) and graft failure, mycophenolate mofetil (MMF) has been employed as a substitute of methotrexate in allogeneic hematopoietic stem cell transplantation (all-SCT). However, the dosing strategy of MMF after all-SCT remains to be established.In this study, we investigated the optimal MMF dosing until day 30 based on pharmacokinetic studies in 28 Japanese allo-SCT patients. For better clinical outcomes of MMF, higher mycophenolic acid (MPA) plasma levels are proposed to be desirable. Therefore, the first 11 patients (group A) received MMF orally every 12 hours at an escalated dose from 15 mg/kg to 25 mg/kg (maximum total daily dose 3000 mg), according to real-time pharmacokinetic monitoring of the total MPA area under the curve (AUC). However, the dose escalation in each individual did not always increase the AUC. Then, MMF was given orally at a fixed dose of 1000 mg every 8 hours in the subsequent 17 patients (group B). The pharmacokinetic data revealed that the increase of dosing frequency could statistically keep higher MPA plasma levels, as reflected in concentration at steady state (Css: group A vs. group B; 1.12 vs. 2.18 μg/ml on day 16, P = 0.003) or trough value (Ctrough: 0.18 vs. 0.56 μg/ml on day 16, P = 0.019). These results indicate that MMF administration of every 8 hours would be better than that of every 12 hours even in the same total daily dose until day 30.We further assessed the safety and efficacy of extended MMF administration beyond day 30 retrospectively. Twenty-five patients ceased MMF at day 30, whereas 16 patients were subjected to extended regimen depending on the individual risk factors for GVHD (median dosing period 64.5 days, 50–94 days). No severe adverse events were observed in both groups. While the cumulative incidence (CI) of more than grade I acute GVHD at day 100 was comparable between the two groups (72.1 % vs. 62.5 %, P = 0.63, Figure 1A), the CI of grade II to IV acute GVHD was lesser in the latter group (42.3 % vs. 12.5 %, P = 0.045, Figure 1B).These results suggest that MMF should be administered every 8 hours until day 30 after allo-SCT, followed by extending MMF administration at least until day 60 as a preemptive therapy for moderate- to severe-acute GVHD. This strategy might be very useful for double UCB transplantation under non-myeloablative conditioning especially, because the transplantation is reported to develop severe acute GVHD frequently. [Display omitted]