Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.
Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.
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DOI：
10.1056/nejmoa2027372
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发表时间：
2021-01-07
期刊：
影响因子：
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通讯作者：
Zhang S
中科院分区：
文献类型：
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作者：
Farag SS;Abu Zaid M;Schwartz JE;Thakrar TC;Blakley AJ;Abonour R;Robertson MJ;Broxmeyer HE;Zhang S
二肽基肽酶4 （DPP-4，又称CD26）是一种表达于T细胞上的跨膜受体，在激活T细胞中具有共刺激功能。在小鼠模型中，下调CD26可预防移植物抗宿主病（GVHD），但保留移植物抗肿瘤作用。西格列汀抑制DPP-4是否可以预防同种异体干细胞移植后急性GVHD尚不清楚。我们进行了一项两期2期临床试验，以测试西格列汀联合他克莫司和西罗莫司是否会在第100天将II至IV级急性GVHD的发生率从30%降低到不超过15%。患者接受清髓调节，然后进行动员外周血干细胞移植。西格列汀从移植前一天开始至移植后第14天，每12小时口服600 mg。共有36名患者接受了匹配的亲属或非亲属供体的移植，他们的中位年龄为46岁（范围为20至59岁）。36例患者中有2例在第100天发生急性GVHD；II至IV级GVHD的发生率为5%(95%可信区间[CI]， 1至16)，III或IV级GVHD的发生率为3% （95% CI， 0至12）。1年未复发死亡率为零。复发和慢性GVHD的1年累积发生率分别为26% （95% CI, 13 - 41）和37% （95% CI, 22 - 53）。1年无gvhd、无复发生存率为46% （95% CI, 29 - 62）。毒性作用与接受同种异体干细胞移植的患者相似。在这项非随机试验中，西格列汀联合他克莫司和西罗莫司在清髓异基因造血干细胞移植后第100天发生II至IV级急性GVHD的发生率较低。（由国家心脏，肺和血液研究所资助；ClinicalTrials.gov号码，NCT02683525。）
Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.)
影响因子：
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作者：
Sadeghi B;Al-Hashmi S;Hassan Z;Rozell B;Concha H;Lundmark C;Grönvik KO;Abedi-Valugerdi M;Hassan M
通讯作者：
Hassan M