Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation

Abstract

With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative HLA-haploidentical (NMA haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Early discontinuation of immunosuppression may reduce the risk of relapse and improve immune reconstitution, but may increase the risk of GVHD. We conducted a prospective trial of NMA haplo BMT for patients with hematologic malignancies (median age, 61 years), evaluating the safety of early discontinuation of tacrolimus. All patients received T cell-replete bone marrow followed by high-dose PTCy, mycophenolate mofetil, and tacrolimus. Tacrolimus was prespecified to stop without taper at day +90, +60, or +120, contingent on having ≥5% donor T cells, no relapse, and no grade II-IV acute or significant chronic GVHD. Safety stopping rules were based on ≥5% graft failure, ≥10% nonrelapse mortality (NRM), or a ≥20% combined incidence of severe acute and chronic GVHD from the tacrolimus stop date through day +180. Of the 47 patients in the day +90 arm, 23 (49%) stopped tacrolimus as planned. Of the 55 patients in the day +60 arm, 38 (69%) stopped as planned. Safety stopping criteria were not met. In both arms, at day +180, the probability of grade II-IV acute GVHD was <40%, that of grade III-IV acute GVHD was <8%, and that of NRM was <5%. The 1-year probabilities of chronic GVHD and NRM were <15% and <10%, respectively, in both arms. The 1-year GVHD-free relapse-free survival was higher in the day 60 arm. Thus, stopping tacrolimus as early as day +60 is feasible and carries acceptable risks after NMA haplo BMT with PTCy. This approach may facilitate post-transplantation strategies for relapse reduction.

Trial registration: ClinicalTrials.gov NCT01342289.

Keywords: Cyclophosphamide; Graft-versus-host disease; Haploidentical; Immunosuppression; Nonmyeloablative; Tacrolimus.

Conflict of interest statement

Conflict of interest statement: There are no conflicts of interest to report.

Copyright © 2018. Published by Elsevier Inc.

Figures

Figure 1

Safety outcomes of NMA, HLA-haploidentical BMT according to planned duration of tacrolimus. Cumulative incidences by competing-risk analysis of (A) grade II-IV acute GVHD, (B) grade III-IV acute GVHD, (C) any chronic GVHD, and (D) NRM. Point estimates and confidence intervals are provided in Table 3. The graphs represent all patients with the planned duration of tacrolimus (Tac), regardless of the actual duration.

Figure 2

Efficacy of NMA, HLA-haploidentical BMT according to planned duration of tacrolimus. (A) Cumulative incidence of relapse by competing-risk analysis. (B) PFS. (C) OS. (D) GFRS. Point estimates and confidence intervals are provided in Table 3. The median follow-up was 48 months for the day +90 cohort and 18 months for the day +60 cohort.