Division of Hematologic Malignancies, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA.
Haematologica. 2018 Mar;103(3):522-530. doi: 10.3324/haematol.2017.176859. Epub 2018 Jan 11.
Aprior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after human leukocyte antigen (HLA)-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft--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--host disease between conventional tacrolimus/methotrexate (A) bortezomib/tacrolimus/methotrexate (B), and bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors. The primary endpoint was grade II-IV acute graft--host 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 II-IV acute graft--host disease rates were similar (A 32.6%, B 31.1%, C 21%; =0.53 for A B, =0.16 for A C). The 2-year non-relapse mortality incidence was similar (A 14%, B 16%, C 6.4%; =0.62), as were relapse (A 32%, B 32%, C 38%; =0.74), chronic graft--host disease (A 59%, B 60% C 55%; =0.66), progression-free survival (A 54%, B 52%, C 55%; =0.95), and overall survival (A 61%, B 62%, C 62%; =0.98). Overall, the bortezomib-based regimens evaluated did not improve outcomes compared with tacrolimus/methotrexate therapy. .
前期 I/II 期试验表明，在 HLA 错配的减低强度预处理异基因造血干细胞移植后，硼替佐米/他克莫司/甲氨蝶呤预防方案可降低急性移植物抗宿主病（GVHD）的发生率，且具有较好的总生存率和无进展生存率。我们进行了一项开放标签的三臂 1:1:1 期 II 随机对照试验，比较了在缺乏 HLA 匹配相关供体的减低强度预处理异基因移植受者中，常规他克莫司/甲氨蝶呤（A）、硼替佐米/他克莫司/甲氨蝶呤（B）和硼替佐米/西罗莫司/他克莫司（C）三种方案的 II-IV 级急性 GVHD 发生率。主要终点是第 180 天的 II-IV 级急性 GVHD 发生率。138 例患者（A 组 46 例，B 组 45 例，C 组 47 例）的中位年龄为 64 岁（范围：24-75 岁），具有不同的恶性诊断和疾病风险（低危 14 例，中危 96 例，高危/极高危 28 例），接受了 7-8/8 HLA 错配（40 例）或匹配的无关供体（98 例）移植。幸存者的中位随访时间为 30 个月（范围：14-46 个月）。尽管早期免疫重建存在差异，但第 180 天 II-IV 级急性 GVHD 发生率相似（A 组 32.6%，B 组 31.1%，C 组 21%；A 与 B 组比较，=0.53；A 与 C 组比较，=0.16）。2 年非复发死亡率相似（A 组 14%，B 组 16%，C 组 6.4%；A 与 B 组比较，=0.62；A 与 C 组比较，=0.16），复发率相似（A 组 32%，B 组 32%，C 组 38%；A 与 B 组比较，=0.74；A 与 C 组比较，=0.16），慢性 GVHD 相似（A 组 59%，B 组 60%，C 组 55%；A 与 B 组比较，=0.66；A 与 C 组比较，=0.16），无进展生存率相似（A 组 54%，B 组 52%，C 组 55%；A 与 B 组比较，=0.95；A 与 C 组比较，=0.16），总生存率相似（A 组 61%，B 组 62%，C 组 62%；A 与 B 组比较，=0.98；A 与 C 组比较，=0.16）。总的来说，与他克莫司/甲氨蝶呤治疗相比，硼替佐米为基础的方案并未改善结局。
