Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, and Emory University, Atlanta, GA.
Emory University, Atlanta, GA.
J Clin Oncol. 2021 Jun 10;39(17):1865-1877. doi: 10.1200/JCO.20.01086. Epub 2021 Jan 15.
Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.
ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).
In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) ( = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, < .001), and the SGFS was better (97.7% 58.7%, < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
严重（3-4 级）急性移植物抗宿主病（AGVHD）是异基因供体（URD）造血细胞移植（HCT）后死亡的主要原因，尤其是在 HLA 错配移植后死亡率特别高。目前尚无预防 AGVHD 的批准药物，这突显了对新型治疗药物的迫切需求。ABA2 是一项 II 期试验，严格评估了添加 T 细胞共刺激阻断剂阿巴西普与钙调神经磷酸酶抑制剂（CNI）/甲氨蝶呤（MTX）为基础的 GVHD 预防药物联合应用的安全性、有效性和免疫效应，以测试阿巴西普是否能降低 AGVHD 的发生。
ABA2 纳入了两种分层的血液系统恶性肿瘤成人和儿童患者：一项随机、双盲、安慰剂对照分层（8/8-HLA 匹配 URD），比较 CNI/MTX 加阿巴西普与 CNI/MTX 加安慰剂，以及一项单臂分层（7/8-HLA 错配 URD），比较 CNI/MTX 加阿巴西普与 CNI/MTX CIBMTR 对照。主要终点是第+100 天 3-4 级 AGVHD，第+180 天严重 AGVHD 无复发生存率（SGFS）是关键次要终点。根据建议的 II 期试验较高的Ⅰ型错误率（0.2）计算了样本量，这是基于预测阿巴西普将 3-4 级 AGVHD 从 20%降低到 10%（8/8s）和 30%降低到 10%（7/8s）。ABA2 共纳入了 142 例受者（8/8s，中位随访时间=716 天）和 43 例受者（7/8s，中位随访时间=708 天）。
在 8/8s 中，3-4 级 AGVHD 为 6.8%（阿巴西普）与 14.8%（安慰剂）（=0.13，风险比=0.45）。SGFS 为 93.2%（CNI/MTX 加阿巴西普）与 82%（CNI/MTX 加安慰剂，=0.05）。在较小的 7/8 队列中，3-4 级 AGVHD 为 2.3%（CNI/MTX 加阿巴西普，意向治疗人群），与 CNI/MTX 的非随机匹配队列（30.2%，<0.001）相比，这一结果有显著改善，并且 SGFS 更好（97.7%与 58.7%，<0.001）。免疫分析显示阿巴西普治疗患者的 T 细胞激活得到控制。
在 URD HCT 中添加阿巴西普是安全的，可降低 AGVHD 发生率，并提高 SGFS。这些结果表明，阿巴西普可能显著改善 AGVHD 相关的移植结果，特别是对 HLA 错配 HCT 具有有益的影响。
