Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
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DOI：
10.1200/jco.20.01086
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发表时间：
2021-06-10
影响因子：
45.3
通讯作者：
Kean, Leslie S.
中科院分区：
文献类型：
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作者：
Watkins, Benjamin;Qayed, Muna;Kean, Leslie S.
严重（3-4级）急性移植物抗宿主病（AGVHD）是非亲缘供者（URD）造血细胞移植（HCT）后死亡的主要原因，导致HLA不匹配移植后特别高的死亡率。目前还没有批准用于AGVHD预防的药物，这强调了对新型治疗方法的关键未满足需求。ABA 2是一项II期试验，旨在严格评估在基于钙调磷酸酶抑制剂（CNI）/甲氨蝶呤（MTX）的GVHD预防中加入阿巴西普的T细胞共刺激阻断的安全性、有效性和免疫学效果，以测试阿巴西普是否可以减少AGVHD。方法：ABA 2在两个分层下招募患有血液恶性肿瘤的成人和儿童：随机、双盲、安慰剂对照分层（8/8-HLA匹配的URD），比较CNI/MTX加阿巴西普与CNI/MTX加安慰剂，以及单臂分层（7/8-HLA不匹配的URD），比较CNI/MTX加阿巴西普与CNI/MTX CIBMTR对照。主要终点为+100天3-4级AGVHD，+180天无严重AGVHD生存期（SGFS）为关键次要终点。使用II期试验推荐的较高的1型错误（0.2）计算样本量，并基于预测阿巴西普将3-4级AGVHD从20%降低至10%（8/8 s）和30%降低至10%（7/8 s）。ABA 2入组了142名接受者（8/8，中位随访= 716天）和43名接受者（7/8，中位随访= 708天）。结果在8/8例中，阿巴西普组3-4级AGVHD为6.8%，安慰剂组为14.8%（P = 0.13，风险比= 0.45）。SGFS为93.2%（CNI/MTX+阿巴西普）与82%（CNI/MTX+安慰剂，P = 0.05）。在较小的7/8队列中，3-4级AGVHD为2.3%（CNI/MTX+阿巴西普，意向治疗人群），与CNI/MTX的非随机匹配队列（30.2%，P <0.001）相比，SGFS更好（97.7% v58.7%，P <0.001）。免疫学分析显示，阿巴西普治疗患者的T细胞活化得到控制。结论在URD HCT中加入阿巴西普是安全的，可减少AGVHD，改善SGFS。这些结果表明，阿巴西普可以大大改善AGVHD相关的移植结果，对HLA不匹配的HCT具有特别有益的影响。
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) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .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%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .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.