Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3mg/m2 i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15weeks). Prednisone was dosed at .5 to 1mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50mg/day to 20mg/day at week 15 (P<.001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated.
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Conflict of Interest Disclosure: This manuscript describes the off-label use of bortezomib. This study was sponsored, in part, by Millenium Pharmaceuticals, Inc. J.K. has received honoraria from OptumHealth , has served as an advisor/consultant for Takeda Pharmaceuticals, Spectrum Pharmaceuticals, and Eleven Biotherapeutics, and has received research funding from Millennium Pharmaceuticals , Otsuka Pharmaceuticals , and Prometheus Laboratories . C.S.C has received consulting honoraria and research funding from Millenium Pharmaceuticals, Inc. J.H.A. and R.J.S have served as consultants for Millenium Pharmaceuticals, Inc .
The authors thank the study's registered nurses, Susan Stephenson and Mildred Pasek; the stem-cell transplantation program nurse practitioners, Melissa Cochran, Amy Joyce, Bonnie Dirr, and Katherine Stephans; and all the study participants. This study was supported in part by Millennium Pharmaceuticals, Inc. and by the National Institutes of Health/National Cancer Institute ( P01 CA142106 , R01 CA183559 ). J.K. is a Clinical Research Scholar of the Leukemia and Lymphoma Society.
- Chronic graft-versus-host disease
- Graft-versus-host disease
- Hematopoietic stem cell transplantation
- Proteasome inhibition