Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Blood. 2018 Mar 22;131(12):1372-1379. doi: 10.1182/blood-2017-11-815746. Epub 2018 Feb 2.
Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (T) to effector T cells (Ts). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Ts to Ts after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036.
急性移植物抗宿主病（aGVHD）后皮质类固醇耐药导致异基因造血细胞移植后发病率和死亡率高。目前用于治疗 SR-aGVHD 的免疫抑制疗法效果不佳，因为反应不佳或毒性过大，主要是感染。α-抗胰蛋白酶（AAT）是一种天然丰富的丝氨酸蛋白酶抑制剂，通过下调炎症和增加调节性（T）细胞与效应 T 细胞（Ts）的比例，能够抑制实验性 GVHD。在这项前瞻性多中心临床研究中，我们试图确定 AAT 给药治疗 SR-aGVHD 的安全性和反应率。40 名中位年龄为 59 岁的患者接受每周两次静脉内 AAT 治疗 4 周，作为 SR-aGVHD 的一线治疗。主要终点是总体缓解率（ORR），即第 28 天无进一步免疫抑制治疗的情况下，SR-aGVHD 患者完全（CR）或部分缓解的比例。治疗耐受性良好，无药物相关不良事件。治疗后观察到血清 AAT 水平显著升高。第 28 天的 ORR 和 CR 率分别为 65%和 35%，包括所有 aGVHD 靶器官的反应。在第 60 天，在没有干预性免疫抑制的情况下，73%的患者持续有反应。6 个月时感染性死亡率为 10%，最后一次 AAT 输注后 30 天内为 2.5%。与临床前数据一致，相关样本显示 AAT 治疗后激活 Ts 与 Ts 的比值增加。这些数据表明 AAT 是安全的，并且在治疗 SR-aGVHD 方面可能具有潜在疗效。该试验在 www.clinicaltrials.gov 上注册为 #NCT01700036。
