Clinical and molecular landscapes of steroid-refractory graft-versus-host disease following hematopoietic stem cell transplantation: a narrative review

Gunning, Thomas S.1,*; Cucchiara, Jack1; Golalipour, Elahe2; Ghanny, Steven1,2,3

1Hackensack Meridian School of Medicine, Nutley, NJ, USA

2Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA

3Department of Pediatrics, Hackensack University Medical Center, Hackensack, NJ, USA

*Correspondence to: Thomas S. Gunning, MPH, Thomas.Gunning@hmhn.org.

Abstract

Allogeneic hematopoietic stem cell transplantation is a highly effective stem cell-based therapy, but graft-versus-host disease remains a major post-transplant complication. While first-line graft-versus-host disease treatment involves high-dose corticosteroids, up to half of patients go on to develop steroid-refractory graft-versus-host disease, where graft-versus-host disease symptoms persist or worsen despite steroid treatment. This review provides an update on the clinical and molecular landscapes of steroid-refractory graft-versus-host disease, examining the challenges in diagnosis, management, and general understanding of steroid-refractory graft-versus-host disease pathophysiology. Progression to steroid-refractory graft-versus-host disease confers a poor prognosis and is associated with increased morbidity. There are multiple mechanisms that drive steroid-refractory graft-versus-host disease, which include the overactivation of T-cell and B-cell mechanisms, a heightened inflammatory state, and cell-intrinsic factors that mediate steroid responses. Current treatment options beyond corticosteroids include JAK pathway inhibition, mesenchymal stem cell therapy, extracorporeal photopheresis, and additional therapies currently under investigation in clinical trials. Potential avenues for future directions must aim to improve patient outcomes and post-transplant survivorship. Through comprehensive elucidation of the molecular mechanisms underlying steroid-refractory graft-versus-host disease, the development of mechanism-based, regenerative medicine-targeted therapeutic strategies, and the optimization of clinical trial design, it is anticipated that the prognosis and quality of life for patients with steroid-refractory graft-versus-host disease will be significantly improved. From a clinical standpoint, these advancements are expected to catalyze a transition from empirical to more personalized, mechanism-directed therapies, ultimately providing more durable and effective treatment options for patients with steroid-refractory graft-versus-host disease.

异基因造血干细胞移植后类固醇难治性移植物抗宿主病（SR-GvHD）的临床和分子特征：叙述性综述

摘要

异基因造血干细胞移植是一种高效的干细胞疗法，但移植物抗宿主疾病仍是移植后的主要并发症。虽然移植物抗宿主病的一线治疗包括大剂量皮质类固醇，但多达一半的患者会发展成类固醇难治性移植物抗宿主病，即尽管接受了类固醇治疗，移植物抗宿主病症状仍然持续或恶化。此综述介绍了类固醇难治性移植物抗宿主病的最新临床和分子图谱，探讨了诊断、管理方面的挑战以及对类固醇难治性移植物抗宿主病病理生理学的一般理解。类固醇难治性移植物抗宿主病的进展预后不良，发病率也随之升高。导致类固醇难治性移植物抗宿主病的机制有多种，其中包括 T 细胞和 B 细胞机制过度激活、炎症状态加剧以及介导类固醇反应的细胞内在因素。除皮质类固醇外，目前的治疗方案还包括 JAK 通路抑制、间充质干细胞疗法、体外光子疗法，以及目前正在临床试验中研究的其他疗法。未来发展方向的潜在途径必须以改善患者预后和移植后存活率为目标。通过全面阐明类固醇难治性移植物抗宿主疾病的分子机制，开发基于机制的再生医学靶向治疗策略，以及优化临床试验设计，预计类固醇难治性移植物抗宿主疾病患者的预后和生活质量将得到显著改善。从临床角度看，这些进展有望促进从经验疗法向更个性化、机制导向型疗法过渡，最终为类固醇难治性移植物抗宿主病患者提供更持久、更有效的治疗方案。