Tacrolimus and Reduced-Dose Methotrexate Combined With Mycophenolate Mofetil to Prevent Graft-Versus-Host Disease

Open-label, phase 3, prospective randomized trial 

Compared with a full dose of tacrolimus-methotrexate (full-MTX), which is the standard-of-care, tacrolimus and a reduced-dose of methotrexate (mini-MTX) combined with mycophenolate mofetil (MMF) demonstrated a more favorable toxicity profile, with no difference in grade 2 to 4 acute GVHD, according to a phase 3 trial evaluating methods of GVHD prevention after allogeneic hematopoietic cell transplantation (HCT). 

“The use of a calcineurin inhibitor, most commonly tacrolimus, in combination with methotrexate, has been a standard practice over the past 3 decades for GVHD prevention,” explains Betty K Hamilton, MD, Cleveland Clinic, Cleveland, Ohio. “This approach, however, is associated with several toxicities; although several alternative approaches to GVHD prevention have been investigated, they have all failed to significantly improve transplant outcomes.”

Tacrolimus and methotrexate continues to be the standard GVHD prophylaxis; however, as Dr Hamilton and colleagues noted, it is associated with several toxicities. Study authors initiated a 
a randomized trial comparing tacrolimus and full-MTX with tacrolimus and mini-MTX plus MMF  for GVHD prevention after allogeneic hematopoietic cell transplantation.  

For this study, 96 patients receiving first myeloablative HCT using an 8/8 HLA-matched donor were eligible. The primary end points were incidence of acute GVHD (aGVHD), mucositis, and engraftment. The secondary end points included chronic GVHD (cGVHD), organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). 

Patients were randomly assigned to receive either tacrolimus and full-MTX (n = 49; full-MTX arm) or tacrolimus and mini-MTX plus MMF (n = 47; mini-MTX/MMF arm). The majority (86%) used bone marrow grafts. There was no significant difference in grade 2 to 4 acute GVHD (27% in the full-MTX arm vs 28% in the mini-MTX/MMF arm; P = .41); however there was a higher incidence of grade 3 to 4 acute GVHD in the mini-MTX/MMF arm (4% vs 13%; P = .07). Patients in the mini-MTX/MMF arm had lower grade 3 or 4 mucositis and faster engraftment. There were no differences in moderate-to-severe chronic GVHD at 1 year or infections. Notably, patients receiving mini-MTX/MMF experienced less nephrotoxicity and respiratory failure. 

Study authors found there was no difference in the 1-year relapse (21% vs 19%; P = .89) and OS (71% vs 72%; P = .08). Also, the mini-MTX/MMF arm was associated with lower, but nonsignificantly reduced NRM (22% vs 11%; P = .06). Compared with the full-MTX arm, the mini-MTX/MMF arm demonstrated no difference in grade 2 to 4 acute GVHD, and a more favorable toxicity profile. 

“Although there remains a continued need to optimize GVHD prevention to mitigate severe GVHD and disease relapse, this study demonstrates that a [tacrolimus]/mini-MTX/MMF regimen is a safe and effective alternative to standard [tacrolimus]/MTX in myeloablative related and unrelated donor transplant,” Hamilton and authors concluded.

“The higher, severe acute GVHD warrants further study to optimize this regimen,” they added. 

Source:

Hamilton BK, Rybicki LA, Li H, et al. Tacrolimus/methotrexate vs tacrolimus/reduced-dose methotrexate/mycophenolate for graft-versus-host disease prevention. Blood Advances. Published online August 22 2023. doi:10.1182/bloodadvances.2023010310