Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA.
J Clin Oncol. 2012 Sep 10;30(26):3202-8. doi: 10.1200/JCO.2012.42.0984. Epub 2012 Aug 6.
HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation.
We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up.
The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8(+) T-cell and natural killer cell reconstitution, was enhanced with bortezomib.
A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.
HLA 不相合无关供者（MMUD）造血干细胞移植（HSCT）与移植物抗宿主病（GVHD）增加和生存受损相关。在减低强度预处理（RIC）中，体外或体内 T 细胞耗竭（如抗胸腺细胞球蛋白）均不能明显改善结局。蛋白酶体抑制剂硼替佐米具有免疫调节特性，可能有利于控制 T 细胞丰富的 HLA 不相合移植中的 GVHD。
我们进行了一项前瞻性的 I/II 期试验，在接受血液恶性肿瘤 MMUD RIC HSCT 的患者中，在输注外周血干细胞后，每天给予一次硼替佐米，共 3 天（+1、+4 和+7 天），联合标准他克莫司和甲氨蝶呤，作为 GVHD 预防方案。我们报告了 45 例研究患者的结果：40 例（89%）为 1 个位点和 5 例（11%）为 2 个位点不匹配（HLA-A、-B、-C、-DRB1 或-DQB1），中位随访时间为 36.5 个月（范围 17.4 至 59.6 个月）。
180 天累积 2 至 4 级急性 GVHD 的发生率为 22%（95%CI，11%至 35%）。1 年慢性 GVHD 的累积发生率为 29%（95%CI，16%至 43%）。2 年非复发死亡率（NRM）和复发的累积发生率分别为 11%（95%CI，4%至 22%）和 38%（95%CI，24%至 52%）。2 年无进展生存率和总生存率分别为 51%（95%CI，36%至 64%）和 64%（95%CI，49%至 76%）。接受硼替佐米治疗的 HLA 不相合患者的 NRM、急性和慢性 GVHD 发生率以及生存情况与本机构同期接受 HLA 匹配 RIC HSCT 的患者相似。硼替佐米增强了免疫恢复，包括 CD8+T 细胞和自然杀伤细胞的重建。
一种新的短疗程硼替佐米为基础的 GVHD 方案可以消除 MMUD RIC HSCT 的生存损害，增强早期免疫重建，并且似乎适合前瞻性随机评估。
