Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-vs-host disease prevention.

Tacrolimus (Tac)/methotrexate (MTX) is standard graft-versus-host disease (GVHD) prophylaxis, however, associated with several toxicities. Tac, reduced dose ("mini")-MTX, mycophenolate mofetil (MMF) has been used, but never compared to standard MTX. We performed a randomized trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX/MMF) for GVHD prevention after allogeneic hematopoietic cell transplantation (HCT). Patients (pts) receiving first myeloablative HCT using an 8/8 HLA-matched donor were eligible. Primary endpoints were incidence of acute (a)GVHD, mucositis, and engraftment. Secondary endpoints included chronic (c)GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Ninety-six pts were randomized to Full-MTX (N=49) or Mini-MTX (N=47). The majority (86%) used bone marrow grafts. There was no significant difference in day 100 grade 2-4 aGVHD (28% Mini-MTX/MMF vs 27% Full-MTX, P=0.41), however higher grade 3-4 aGVHD (13% vs 4%, P=0.07) with Mini-MTX/MMF. Mini-MTX/MMF pts had lower grade 3-4 mucositis (57% vs 82%, P=0.010), and faster neutrophil engraftment (median 15 vs 17 days, P<0.001). There were no significant differences in moderate-severe cGVHD at 1 year (23% vs 20%, P=0.14) or infections. Mini-MTX/MMF pts experienced less nephrotoxicity (2% vs 26%, P<0.001) and less respiratory failure (6% versus 18%, P=0.03). There was no difference in 1-year relapse (19% vs 21%, P=0.89) or OS (72% vs. 71%, P=0.08), and Mini-MTX/MMF was associated with lower but non-significant NRM (11% vs 22%), P=0.06. Compared to Full-MTX, Mini-MTX/MMF was associated with no difference in grade 2-4 aGVHD and a more favorable toxicity profile. The higher severe aGVHD warrants additional study to further optimize this regimen.