Mycophenolate Mofetil: A Friend or a Foe with Post-Transplantation Cyclophosphamide and Tacrolimus Prophylaxis in HLA-Matched Donors?

Adapted from the haploidentical hematopoietic stem cell transplantation (HCT) literature, post-transplantation cyclophosphamide (PTCy) is being used increasingly with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac), and with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive and potentially antitumor and antimicrobial properties, MMF is an attractive drug; the benefit gained when it is used with PTCy/Tac remains unclear, however. To assess this, we compared PTCy/Tac (n = 242) and PTCy/Tac/MMF (n = 144) regimens in recipients of HLA-matched donor transplantation. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.6 to 2.8; P < .001), and steroid-refractory/dependent aGVHD (HR, 4.8; 95% CI, 2.4 to 9.6; P < .001), yet a significantly lower risk of relapse (HR, .5; 95% CI, .3 to .9; P = .009) and better progression-free survival (PFS) (HR, .7; 95% CI, .5 to .9; P = .04). There were no differences in the risk of grade III-IV aGVHD, chronic graft-versus-host disease (cGVHD), nonrelapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days and an elevated risk of bacterial infection. In an exploratory stool microbiome analysis (n = 16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism and understand its role with PTCy-based prophylaxis.