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Calcineurin-inhibitor-based methotrexate and mycophenolate mofetil regimens as graft-versus-host disease prophylaxis after reduced intensity conditioning allogeneic transplantation

Sep 5, 2018

Saurabh Chhabraand colleagues conducted a retrospective study reviewing the impact of the combination of calcineurin inhibitor (CNI) and for example tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) on graft-versus-host disease (GvHD) and transplant outcomes in allogeneic stem cell transplant recipients. These two regimens have been extensively used for GvHD prophylaxis after reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT).

All patients (n = 1,564) in this study underwent RIC allo-HSCT for acute myeloid and lymphoid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS) between 2000 and 2013 using HLA-identical sibling or unrelated donor peripheral blood graft. CYSP or TAC with MTX or MMF was administered for GvHD prophylaxis. The primary endpoints of the study included grade II–IV and III–IV acute GvHD, chronic GvHD and overall survival rates. Patients were divided into four groups based on the regimen received: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP.

Key findings:

  • In unrelated-donor recipient patients, MMF-CYSP significantly associated with an increased risk of grade II–IV acute GvHD compared with MTX-TAC: relative risk (RR) = 1.78, P< 0.001
  • In unrelated-donor recipient patients, MMF-CYSP significantly associated with an increased risk of grade III–IV acute GvHD compared with MTX-TAC: RR = 1.93, P= 0.006
  • There was no significant difference in the cumulative incidences of grade II–IV and grade III–IV acute GvHD between the four cohorts in the matched sibling donor group
  • There was no significant difference found in the incidence of chronic GvHD between the four unrelated donor recipient groups
  • There was no significant difference found regarding the incidence of cGvHD between the four cohorts in the matched sibling donor group
  • Non-relapse mortality rates in unrelated-donor recipients receiving MMF-TAC were higher than in patients receiving MTX-TAC: HR = 1.48, P= 0.008
  • There was no significant difference in chronic GvHD rate, disease-free survival and overall survival between the four prophylaxis regimens

This study showed that MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP regimens yield equivalent benefits in terms of outcomes. Even with these beneficial clinical findings, with unrelated donor RIC allo-HCT, MMF-CYSP was found to be inferior compared with MTX-based regimens for acute GvHD prophylaxis, however, there were no differences in chronic GvHD and overall survival rates among these regimens. The clinical benefits in this cohort merit further study regarding these regimens with standardized dosing schedules and objective pharmacokinetic ranges using specific endpoints to confirm the findings of this study.

  1. Chhabra S . et al.Comparative analysis of calcineurin-inhibitor-based methotrexate and mycophenolate mofetil-containing regimens for prevention of Graft-versus-Host Disease after reduced intensity conditioning allogeneic transplantation. Biol Blood Marrow Transplant.  2018 Aug 25. DOI: 1016/j.bbmt.2018.08.018.[Epub ahead of print].