Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.

中文翻译：

---

依鲁替尼治疗既往治疗失败后的慢性移植物抗宿主病


慢性移植物抗宿主病（cGVHD）是同种异体干细胞移植的严重并发症，皮质类固醇治疗失败后几乎没有有效的选择。 B 细胞和 T 细胞在 cGVHD 的病理生理学中发挥作用。依鲁替尼抑制 B 细胞中的布鲁顿酪氨酸激酶和 T 细胞中的白细胞介素 2 诱导型 T 细胞激酶。在临床前模型中，依鲁替尼降低了 cGVHD 的严重程度。这项多中心、开放标签研究评估了依鲁替尼治疗对含皮质类固醇疗法反应不足的活动性 cGVHD 患者的安全性和有效性。先前 1 至 3 次治疗失败的 42 名患者每天接受依鲁替尼（420 毫克）治疗，直至 cGVHD 进展。主要疗效终点是基于 2005 年美国国立卫生研究院标准的 cGVHD 反应。中位随访时间为 13.9 个月，最佳总体缓解率为 67%； 71% 的缓解者表现出持续缓解≥20 周。观察所评估的相关器官的反应。大多数患有多个cGVHD器官受累的患者出现多器官反应。应答者的中位皮质类固醇剂量从基线时的每天 0.29 毫克/公斤减少到第 49 周时的每天 0.12 毫克/公斤； 5 名响应者停止使用皮质类固醇。最常见的不良事件是疲劳、腹泻、肌肉痉挛、恶心和瘀伤。随着依鲁替尼治疗时间的推移，与炎症、纤维化和 cGVHD 相关的可溶性因子的血浆水平显着降低。依鲁替尼在既往接受过 1 次 cGVHD 治疗的患者中产生了具有临床意义的缓解，且安全性可接受。基于这些结果，依鲁替尼在美国被批准用于治疗 1 种或多种全身治疗失败后患有 cGVHD 的成年患者。该试验已在 www.clinicaltrials 上注册。政府编号为#NCT02195869。