Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results.

Aprior phase trial of bortezomib/tacrolimus/methotrexate prophylaxis after human leukocyte antigen (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 three-arm 1:1:1 phase II randomized controlled trial comparing grade II-IV acute graft-versushost 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. The primacy endpoint was grade IIIV acute graftversushost disease incidence rate by day +180. One hundred and thirty-eight patients (A 46, B 45, C 47) with a median age of 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, day +180 grade IIIV acute graftversus -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). The 2year nonrelapse 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 graftversushost disease (A 59%, B 60% C 55%; P=0.66), progressionfree survival (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 therapy.