Törlén Johan, Ringdén Olle, Garming-Legert Karin, Ljungman Per, Winiarski Jacek, Remes Kari, Itälä-Remes Maija, Remberger Mats, Mattsson Jonas
Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Haematologica. 2016 Nov;101(11):1417-1425. doi: 10.3324/haematol.2016.149294. Epub 2016 Aug 4.
Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades II-IV (41% vs. 51%; P=0.19) or grades III-IV (13% vs. 7%; P=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; P=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; P<0.01). No significant differences in incidence of oropharyngeal mucositis, time to full donor chimerism, or number of cytomegalovirus infections were seen between the two treatment arms, and transplant-related toxicities were equally distributed. Triglyceride (P=0.005) and cholesterol (P=0.009) levels were higher in tacrolimus/sirolimus patients. Transplant-related mortality (18% vs. 12%; P=0.40) and 5-year overall survival (72% vs. 71%; P=0.71) were similar. Five-year relapse-free survival in patients with malignant diagnoses was 65% in the cyclosporine/methotrexate group and 63% in the tacrolimus/sirolimus group (P=0.73). We conclude that tacrolimus/sirolimus remains a valid and safe alternative to cyclosporine/methotrexate as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation, with comparable transplant-related outcomes. The trial was registered at clinicaltrials.gov identifier: 00993343.
改善移植物抗宿主病的预防措施仍然是异基因造血干细胞移植的一个重要目标。基于西罗莫司可能具有的优势特性的报道，我们在一项前瞻性、开放性、随机试验中，比较了环孢素和甲氨蝶呤的标准方案（n = 106）与他克莫司和西罗莫司联合方案（n = 103）用于异基因造血干细胞移植后移植物抗宿主病的预防效果。假设是他克莫司/西罗莫司方案将导致较少的急性移植物抗宿主病并降低移植相关死亡率。两组之间II - IV级（41%对51%；P = 0.19）或III - IV级（13%对7%；P = 0.09）急性移植物抗宿主病的累积发生率无显著差异。中性粒细胞植入时间（18天对17天；P = 0.24）相似，但环孢素/甲氨蝶呤组患者的血小板植入时间更长（14天对12天；P < 0.01）。两个治疗组在口咽黏膜炎发生率、完全供体嵌合时间或巨细胞病毒感染数量方面无显著差异，且移植相关毒性分布均匀。他克莫司/西罗莫司组患者的甘油三酯（P = 0.005）和胆固醇（P = 0.009）水平较高。移植相关死亡率（18%对12%；P = 0.40）和5年总生存率（72%对71%；P = 0.71）相似。恶性诊断患者的5年无复发生存率在环孢素/甲氨蝶呤组为65%，在他克莫司/西罗莫司组为63%（P = 0.73）。我们得出结论，作为异基因造血干细胞移植后移植物抗宿主病的预防措施，他克莫司/西罗莫司仍然是环孢素/甲氨蝶呤的一种有效且安全的替代方案，移植相关结果相当。该试验在clinicaltrials.gov上注册的标识符为：00993343。
