Gatza Erin, Braun Thomas, Levine John E, Ferrara James L M, Zhao Shuang, Wang Tianyi, Chang Lawrence, Harris Andrew, Pawarode Attaphol, Kitko Carrie, Magenau John M, Yanik Gregory A, Couriel Daniel R, Goldstein Steven, Connelly James, Reddy Pavan, Paczesny Sophie, Choi Sung Won
Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
Biol Blood Marrow Transplant. 2014 Sep;20(9):1426-34. doi: 10.1016/j.bbmt.2014.05.023. Epub 2014 Jun 2.
Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375.
1级急性移植物抗宿主病（GVHD）的临床诊断标志着造血干细胞移植（HSCT）后GVHD可能进展且致命病程的开始。然而，针对早期GVHD的干预性研究尚缺。我们开展了一项单臂前瞻性II期试验，以检验这一假设：用依那西普和局部用皮质类固醇治疗新诊断的1级急性GVHD可在28天内降低进展至2至4级的发生率。研究患者（n = 34）的中位年龄为51岁（范围10至67岁），接受了无关供者（n = 22）或相关供者（n = 12）的HSCT。研究患者接受依那西普（0.4mg/kg，最大剂量25mg/剂）治疗，每周2次，共4至8周。34例患者中有10例（29%）在28天内进展至2至4级急性GVHD。1年时2至4级和3至4级急性GVHD的累积发生率分别为41%和3%。2年时非复发死亡率为19%，总生存率为63%。在同期对照队列中，研究期间诊断为1级急性GVHD并接受局部用皮质类固醇但未接受依那西普治疗的患者，28例中有12例（43%）在28天内进展至2至4级GVHD，1年时2至4级GVHD和3至4级GVHD的发生率分别为61%（41%对61%，P = 0.08）和18%（3%对18%，P = 0.05）。与同期对照患者相比，接受依那西普治疗的患者在1级急性GVHD诊断后28天，GVHD血浆生物标志物抑制肿瘤形成2（P = 0.06）和再生胰岛衍生3-α（P = 0.01）的升高也较少。由于入组不佳，本研究提前终止。未来需要进行前瞻性研究，以识别有迅速进展为更严重GVHD风险的1级急性GVHD患者，并建立1级急性GVHD治疗的共识。本试验已在ClinicalTrials.gov注册，编号NCT00726375。
