Innovative approaches in acute graft-versus-host disease: emerging therapeutics and novel clinical trial design

Acute graft-versus host disease (aGVHD) is a major early complication of allogeneic hematopoietic cell transplantation and is associated with substantial morbidity and mortality, particularly in severe cases. The use of corticosteroids as first-line therapy remains standard of care, despite limited efficacy in high-risk cases and associated toxicities. Ruxolitinib has emerged as the treatment of choice for patients who fail corticosteroids, but there remains a need for novel treatment strategies. In this review, we examine the evolving therapeutic landscape of aGVHD and summarize emerging approaches including small molecule inhibitors, biologics, and cellular- and microbiome-modulating therapies. We explore how improved understanding of aGVHD pathophysiology continues to inform new interventions while also addressing the operational and conceptual challenges that constrain clinical trial design and regulatory progress. Finally, we discuss new innovations in biomarker-driven strategies and adaptive clinical trial designs that may facilitate future therapeutic development and advance outcomes for patients with aGVHD.