硬化性慢性移植物抗宿主病（scGVHD）以皮肤纤维化的进行性和对现有治疗的频繁无反应为特征。异常的Hedgehog信号在皮肤成纤维细胞中的活化被认为与scGVHD有关。在这里，我们报告了两个I/II期研究（NCT03415867，GETH-TC；NCT04111497，FHD）中格拉斯地吉布（glasdegib）作为一种新的治疗药物在难治性scGVHD中的结果。纳入具有经过≥1线治疗后仍然活跃的scGVHD患者（FHD）或经过≥2线治疗后仍然活跃的scGVHD患者（GETH-TC）。主要终点为GETH-TC试验中限制毒性（DLT）和MTD，以及FHD试验中的安全性和耐受性措施。格拉斯地吉布以每日一次的28天为周期给予。根据2014年NIH cGVHD标准评估反应。并进行了相关研究以评估与纤维细胞独立的免疫机制对临床活性的作用。招募了20名（GETH-TC）和15名（FHD）患者。在GETH-TC试验中，治疗后出现II级及以上不良事件（AE）包括肌肉痉挛（85%）、脱发（50%）和味觉障碍（35%）。有2名患者出现DLT（G3级肌肉痉挛），而MTD则被确定为50毫克。在FHD试验中，III级肌肉痉挛是最常见的不良事件（33%）。在12个月时，GETH-TC试验中的皮肤/关节scGVHD总体反应率为65%（全部为部分反应），而FHD队列中为47%（6个部分反应，1个完全反应）。未发现与反应相关的免疫机制。格拉斯地吉布在难治性scGVHD患者中表现出有希望的疗效，但由肌肉痉挛引起的耐受性有限。©2023年美国癌症研究协会。

Sclerotic chronic GVHD (scGVHD) is characterized by progressive skin fibrosis and frequent refractoriness to available therapies. Aberrant activation of Hedgehog signaling in dermal fibroblasts has been implicated in scGVHD. Here, we report the results of two phase I/II studies (NCT03415867, GETH-TC; NCT04111497, FHD) that evaluated glasdegib, a smoothened antagonist, as a novel therapeutic agent in refractory scGVHD.Adult patients with active scGVHD after ≥1 (FHD) or ≥2 (GETH-TC) lines of therapy were enrolled. Primary endpoints were dose-limiting toxicity (DLT) and MTD in the GETH-TC trial, and safety and tolerability measures in the FHD trial. Glasdegib was administered once daily in 28-day cycles. Responses were scored per 2014 NIH cGVHD criteria. Correlative studies were performed to evaluate the role of fibroblast-independent immune mechanisms on clinical activity.Twenty (GETH-TC) and 15 (FHD) patients were recruited. Treatment-emergent grade (G) ≥2 adverse events (AE) in the GETH-TC trial included muscle cramps (85%), alopecia (50%), and dysgeusia (35%). Two patients experienced a DLT (G3 muscle cramps), and the MTD was established at 50 mg. G3 muscle cramps were the most frequently reported AE (33%) in the FHD trial. At 12-months, the skin/joint scGVHD overall response rate was 65% (all partial responses) in the GETH-TC trial and 47% (6 partial responses, 1 complete response) in the FHD cohort. No immune correlates of response were identified.Glasdegib demonstrated promising responses in patients with refractory scGVHD, but tolerability was limited by muscle cramping.©2023 American Association for Cancer Research.