阿巴西普阻断共刺激用于预防急性移植物抗宿主病的 II 期临床试验。

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.

机构信息

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, and Emory University, Atlanta, GA.

Emory University, Atlanta, GA.

出版信息

J Clin Oncol. 2021 Jun 10;39(17):1865-1877. doi: 10.1200/JCO.20.01086. Epub 2021 Jan 15.

DOI:10.1200/JCO.20.01086

PMID:33449816

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8260909/

Abstract

PURPOSE

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.

METHODS

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).

RESULTS

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.

CONCLUSION

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.

摘要

目的

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。

方法

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）。

结果

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。