Mycophenolate Mofetil versus Methotrexate for Prevention of Acute Graft-Versus-Host Disease: Results of a Systematic Review Limited to Prosepective Randomized Controlled Studies

Morbidity and mortality due to acute and subsequently chronic graft-versus-host disease (GVHD) remains a serious limitation to wider applicability of T-cell replete allogeneic HCT for otherwise incurable hematologic diseases. Developing active regimens for acute GVHD (aGVHD) prophylaxis is necessary due to current absence of effective treatments for severe aGVHD, particularly if refractory to corticosteroids. Both mycophenolate mofetil (MMF) and methotrexate (MTX) based regimens have been used clinically to prevent aGVHD. However, conflicting results have been noted when comparing, directly or indirectly, MMF-based against MTX-based regimens for prevention of aGVHD.

A systematic literature search was performed using MEDLINE and Cochrane's CENTRAL databases. All prospective-randomized controlled trials (RCT) comparing MMF-based regimens versus MTX-based regimens for prevention of aGVHD were eligible for inclusion and analysis. Our primary outcomes were overall survival (OS) and incidence of grade II-IV aGVHD. Our secondary outcomes were time-to-neutrophil engraftment, time-to-platelet engraftment, incidence of chronic GVHD (cGVHD), incidence of severe mucositis, frequency of pain control requirement, frequency of total parenteral nutrition (TPN) use, relapse rate, and incidence of non-relapse mortality (NRM). Pooling of data from similar outcomes was done using the random-effects model.

Three studies enrolling 174 patients (MMF= 95; MTX= 79) were included in this systematic review. Pooled analysis shows that use of MMF, for aGVHD prophylaxis, results in significantly faster platelet engraftment (pooled hazard ratio (HR)= 0.87 (95%CI, 0.81,0.93; p<0.0001)) reported in 2 studies (129 patients), a lower incidence of severe mucositis (pooled risk ratio (RR)=0.48 (95%CI, 0.33, 0.71; p=0.0002)) reported in 3 studies (174 patients), and less use of TPN (pooled RR=0.48 (95%CI, 0.26, 0.90; p=0.02)) reported in 2 studies (129 patients) or narcotics for pain control (pooled risk ratio=0.76 (95%CI, 0.63, 0.91; p=0.002)) reported in 2 studies (129 patients) compared to MTX. There was no difference, however, between MMF and MTX in OS (pooled HR=0.73 (95%CI, 0.45, 1.17; p=0.19)) reported in 2 studies (129 patients), incidence of grade II-IV aGVHD (pooled RR=1.31 (95%CI, 0.85, 2.03; p=0.22)) reported in 3 studies (174 patients), incidence of cGVHD (pooled RR=0.92 (95%CI, 0.65, 1.30; p=0.62)) reported in 2 studies (129 patients), time to neutrophil engraftment (pooled HR=0.77 (95%CI, 0.51, 1.17; p=0.23)) reported in 2 studies (129 patients), relapse risk (pooled RR=0.84 (95%CI, 0.52,1.38; p=0.50)) reported in 2 studies (129 patients), or NRM (RR=1.21 (95%CI, 0.62, 2.36; p=0.57)) reported in one study (89 patients).

Critical appraisal of available published evidence appears limited/weak to recommend one particular agent, MMF or MTX, to combine with a calcineurin inhibitor as the favored aGVHD prophylaxis regimen. A large randomized controlled trial that compares MMF and MTX is required to address this issue. But, identifying the most optimal dose(s) and schedule(s) of administration of MMF and MTX is required in advance.

No relevant conflicts of interest to declare.