Herrera Alex F, Kim Haesook T, Bindra Bhavjot, Jones Kyle T, Alyea Edwin P, Armand Philippe, Cutler Corey S, Ho Vincent T, Nikiforow Sarah, Blazar Bruce R, Ritz Jerome, Antin Joseph H, Soiffer Robert J, Koreth John
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Biol Blood Marrow Transplant. 2014 Nov;20(11):1737-43. doi: 10.1016/j.bbmt.2014.06.040. Epub 2014 Jul 10.
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 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/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 50 mg/day to 20 mg/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.
慢性移植物抗宿主病（GVHD）在异基因造血干细胞移植后会导致显著的发病率和死亡率。尽管疗效有限且存在长期毒性，但皮质类固醇仍是标准的初始治疗方法。基于我们使用硼替佐米有效预防急性GVHD的经验，我们推测蛋白酶体抑制将补充皮质类固醇的免疫调节作用，以改善慢性GVHD（cGVHD）的治疗结果。我们进行了一项硼替佐米联合泼尼松用于cGVHD初始治疗的单臂II期试验。在每35天周期的第1、8、15和22天，静脉注射硼替佐米，剂量为1.3mg/m²，共3个周期（15周）。泼尼松的剂量为0.5至1mg/kg/天，建议在第1周期后逐渐减量。所有22名入组参与者均可评估毒性；20名可评估反应。硼替佐米联合泼尼松治疗耐受性良好，有1例3级感觉性周围神经病变可能与硼替佐米有关。在可评估参与者中，第15周时的总体缓解率为80%，包括2例（10%）完全缓解和14例（70%）部分缓解。皮肤的器官特异性完全缓解率为73%，肝脏为53%，胃肠道为75%，关节、肌肉或筋膜受累为33%。第15周时泼尼松的中位剂量从50mg/天降至20mg/天（P<0.001）。硼替佐米和泼尼松联合用于cGVHD的初始治疗是可行的且耐受性良好。我们观察到硼替佐米和泼尼松联合治疗的缓解率很高；然而，在这项单臂研究中，我们无法直接衡量硼替佐米的影响。蛋白酶体抑制可能对cGVHD的治疗有益，应进一步评估。
