JCO：硼替佐米有助于预防移植物抗宿主病

根据一篇于2012年8月6日在线发表在Journal of Clinical Oncology期刊上的研究论文，患有血液恶性肿瘤的病人接受来自HLA错配的非亲缘供者(HLA-mismatched unrelated donor, MMUD)的低强度预处理(reduced-intensity conditioning, RIC)的造血干细胞移植(hematopoietic stem cell transplantation, HSCT)之后，短期预防性的基于硼替佐米(bortezomib)的治疗以便降低移植物抗宿主病(graft-versus-host disease, GVHD)的发病率，可能能够给他们带来益处。

来自美国哈佛医学院达纳-法伯癌症研究所(Dana-Farber Cancer Institute)的研究员John Koreth博士和同事们开展一项前瞻性I/II期临床试验。这项临床试验涉及45名接受过MMUD RIC HSCT的病人。

这45名临床试验参与者随后接受短期的GVHD预防治疗，即在接受外周血干细胞输注和甲氨蝶呤(methotrexate)和他克莫司(tacrolimus)治疗之后的第一天、第四天和第七天服用硼替佐米。

研究人员发现，在180天之后，二到四级GVHD的累积性发病率(cumulative incidence)为22%，而一年的慢性GVHD累积性发病率为29%。2年后，病人肿瘤复发的死亡率为38%，而没有肿瘤复发的死亡率为11%。2年后，病人的无恶化存活率(progression-free surviva)和总存活率(overall survival)分别为51%和64%。没有肿瘤复发的死亡率、急性GVHD和慢性GVHD发病率以及存活率都与那些同时接受HLA匹配的RIC HSCT病人相类似。

论文作者们写道，“总之，对接受HLA错配的RIC移植的病人而言，短期的基于硼替佐米的GVHD预防治疗似乎是安全的和有效的，因为这会提高他们的存活率。重要的是，基于硼替佐米的MMUD移植获得的临床结果能够与HLA匹配的移植相比拟，而且还伴随着多种免疫重建参数的改善。”

本文编译自Bortezomib beneficial in graft-versus-host disease prophylaxis

doi: 10.1200/JCO.2012.42.0984
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Bortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation

John Koreth⇓, Kristen E. Stevenson, Haesook T. Kim, Sean M. McDonough, Bhavjot Bindra, Philippe Armand, Vincent T. Ho, Corey Cutler, Bruce R. Blazar, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz and Edwin P. Alyea III

Purpose 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. Patients and Methods 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. Results 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. Conclusion 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.