Adverse impact of a high CD4/CD8 ratio in the allograft may be overcome by methotrexate- but not mycophenolate- or post-transplant cyclophosphamide-based graft versus host disease prophylaxis.

Introduction: A high CD4/CD8 T cell ratio in hematopoietic stem cell transplant (HSCT) allografts was observed to predict graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) but has not been comparatively examined in settings of various GVHD-prophylaxis regimens.

Methods: This retrospective monocentric study included all consecutive HSCT performed with peripheral blood stem cells between January 2000 and June 2021. The impact of the graft CD4/CD8 ratio was analyzed in three cohorts with different GVHD-prophylaxis platforms.

Results: In the cyclosporine/mycophenolate-mofetil (CSA/MMF) cohort (n = 294, HLA-matched HSCT), a high (>75th percentile) CD4/CD8 ratio was associated with increased overall mortality (HR: 1.56; p = .01), increased NRM (HR: 1.85; p = .01) and GVHD-associated mortality (HR: 2.13; p = .005). In the post-transplant cyclophosphamide (PTCy)/tacrolimus/MMF cohort (n = 113, haploidentical-related or mismatched-unrelated HSCT), a high CD4/CD8 ratio was associated with increased overall mortality (HR 2.07; p = .04) and aGVHD3-4 (HR: 2.24; p = .02). By contrast, in the CSA/methotrexate (CSA/MTX) cohort (n = 185, HLA-matched HSCT) the CD4/CD8 ratio had no significant impact on any of the investigated endpoints.

Conclusion: A high CD4/CD8 ratio in the allograft has an adverse impact on GVHD and survival in CSA/MMF- and PTCy-based HSCT, while MTX-based prophylaxis may largely alleviate this important risk factor.