Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin
Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin
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DOI：
10.1182/bloodadvances.2020003336
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发表时间：
2020-12-22
期刊：
影响因子：
7.5
通讯作者：
Levine, John E.
中科院分区：
文献类型：
--
作者：
Gergoudis, Stephanie C.;DeFilipp, Zachariah;Levine, John E.
激素难治性(SR)急性移植物抗宿主病(GVHD)仍然是异基因造血细胞移植(HCT)后无复发死亡(NRM)的主要原因，但HCT前临床危险因素并不能准确预测其发生。西奈山急性GVHD国际联合会(MAGIC)算法概率(MAP)根据2个血清生物标记物、肿瘤形成抑制因子2和再生胰岛衍生3α的浓度来衡量肠隐窝损伤的程度，从而确定早在HCT后7天就有发生SR GVHD的高风险患者。我们对患移植物抗宿主病的高危患者进行了一项多中心概念验证“先发制人”治疗试验。α-1抗胰蛋白酶(AAT)是一种丝氨酸蛋白酶抑制剂，具有抗移植物抗宿主病活性。如果患者在HCT后第7天有高危MAP，或如果最初风险较低，在第14天重复测试时成为高危患者，则符合条件。30名高危患者接受每周两次的AAT治疗，共16剂，并将他们的结果与90名高危近同期的魔术对照组患者进行比较。AAT治疗耐受性好，毒副作用少，但SR GVHD的发生率(20%比14%，P=5.56)并未低于对照组。我们的结论是，基于生物标记物的实时风险分配在异基因HCT后早期是可行的，但AAT的剂量和治疗方案并没有改变SR急性GVHD的发生率。这项试验在www.Clinicaltrials.gov上注册为#NCT03459040。
Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3 alpha. We conducted a multicenter proof-of-concept "preemptive" treatment trial of alpha-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = 5.56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.