Time-restricted versus standard-duration immunosuppression after allogeneic hematopoietic stem cell transplantation: Results of the prospective randomized HOVON-96 trial.

Cyclosporine A combined with mycophenolate mofetil (CsA/MMF) has become an established regimen for the prevention of graft-versus-host disease (GVHD) following non-myeloablative (NMA) allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the optimal duration of immunosuppression (IS) has not yet been defined and overtreatment is of concern. We hypothesized that time-restricted IS with CsA/MMF would increase the proportion of patients with non-severe GVHD compared to standard-duration IS, thereby resulting in reduction of the relapse rate and improvement of progression-free survival (PFS) and overall survival (OS). In a prospective randomized, multicenter, phase III trial, patients were allocated (1:1) to standard or time-restricted IS. A total of 389 patients were randomized, of whom 369 were transplanted (184 vs. 185 patients). The primary endpoint, the proportion of patients with non-severe GVHD defined as acute GVHD grades I-II without gut involvement or chronic GVHD not requiring systemic treatment within 180 days posttransplant, was 23% after standard-duration IS versus 24% after time-restricted IS (odds ratio: 1.02; 95% confidence interval (CI) 0.63-1.66,  = 0.92). The cumulative incidence of grade III-IV acute GVHD at 6 months posttransplant was not significantly different (14% vs. 18%;  = 0.20). The two-year cumulative incidence of chronic extensive GVHD was 50% versus 46% ( = 0.62). There were no significant differences in the rates of relapse/progression, non-relapse mortality, PFS, OS, and GVHD-free, relapse-free survival. Time-restricted IS with CsA/MMF did not increase the proportion of patients with non-severe GVHD, and secondary outcomes were not different compared to standard-duration IS following NMA-matched alloHSCT.