Immunosuppressive agents in hematopoietic stem cell transplantation

Abstract

A prior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after HLA-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft versus host disease incidence, with promising overall and progression-free survival. We performed an open-label 3-arm 1:1:1 phase II randomized-controlled-trial comparing grade II-IV acute graft versus host disease between conventional tacrolimus/methotrexate (A) versus bortezomib/tacrolimus/methotrexate (B); and versus bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors. Primary endpoint was grade II-IV acute graft versus host disease incidence rate by day+180. 138 patients (A 46, B 45, C 47) with median age 64 years (range, 24-75), varying malignant diagnoses and disease risk (Low 14, Intermediate 96, High/Very High 28) received 7-8/8 HLA-mismatched (40) or matched unrelated donor (98) grafts. Median follow-up in survivors was 30 months (range, 14-46). Despite early immune reconstitution differences, d+180 grade II-IV acute graft versus host disease rates were similar (A 32.6%, B 31.1%, C 21%; p=0.53 for A vs. B, p=0.16 for A vs. C). 2-year non-relapse mortality incidence was similar (A 14%, B 16%, C 6.4%; p=0.62), as were relapse (A 32%, B 32%, C 38%; p=0.74), chronic graft versus host disease (A 59%, B 60% C 55%; p=0.66), progression-free (A 54%, B 52%, C 55%; p=0.95) and overall survival (A 61%, B 62%, C 62%; p=0.98). Overall, the bortezomib-based regimens evaluated did not improve outcomes compared with tacrolimus/methotrexate. Study identifier: NCT01754389 (http://www.ClinicalTrials.gov)