Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Department of Pediatrics, University of Washington, Seattle, WA.
J Clin Oncol. 2022 Apr 10;40(11):1174-1185. doi: 10.1200/JCO.21.01755. Epub 2022 Jan 10.
Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (T) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of T-depletion of peripheral blood stem-cell (PBSC) grafts.
One hundred thirty-eight patients with acute leukemia received T-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of T. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD.
cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years.
Depletion of T from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.
移植物抗宿主病(GVHD)会导致异基因造血细胞移植后发病率和死亡率升高。幼稚 T 细胞(T 细胞)在小鼠模型中会引发严重的 GVHD。我们评估了外周血干细胞(PBSC)移植物 T 细胞耗竭的三项 II 期临床试验中的慢性 GVHD(cGVHD)和其他结局。
138 例急性白血病患者在高剂量或中剂量全身照射和化疗预处理后,接受 HLA 匹配的亲缘或无关供体的 T 细胞耗竭 PBSC。GVHD 预防采用他克莫司,联合或不联合甲氨蝶呤或霉酚酸酯。患者接受 CD34 选择的 PBSC 和定义剂量的 T 细胞耗竭的记忆 T 细胞。中位随访时间为 4 年。对三项试验累积数据的分析的主要结局是 cGVHD。
cGVHD 非常罕见且轻微(3 年累积发生率总,7%[95%CI,2 至 11%];中度,1%[95%CI,0 至 2%];重度,0%)。3 级和 4 级急性 GVHD(aGVHD)分别为 4%(95%CI,1 至 8)和 0%。2 级 aGVHD 的累积发生率很高(95%CI,64%至 79%),主要为 1 期上消化道 GVHD。匹配亲缘供体和匹配无关供体移植物受者的 3 级 aGVHD 发生率相似(5%[95%CI,0 至 9]和 4%[95%CI,0 至 9])和 cGVHD(7%[95%CI,2 至 13]和 6%[95%CI,0 至 12])。3 年时,总生存、无 cGVHD 生存、无复发生存、复发和非复发死亡率分别为 77%(95%CI,71%至 85%)、68%(95%CI,61%至 76%)、23%(95%CI,16%至 30%)和 8%(95%CI,3%至 13%)。
从 PBSC 同种异体移植物中耗竭 T 细胞可导致严重急性和任何 cGVHD 的发生率非常低,而复发或非复发死亡率没有明显增加,这使这种新型移植物工程策略有别于其他造血细胞移植方法。