Experimental JAK inhibitors: the current, present, and future in graft-versus-host disease management?

Graft-versus-host disease (GVHD) remains the primary barrier to successful allogeneic hematopoietic cell transplantation, contributing significantly to non-relapse mortality. With approximately 50% of patients developing GVHD despite prophylaxis, there is an urgent need for effective alternatives. Janus kinase (JAK) inhibitors have emerged as a promising class of targeted immunomodulators to address this clinical challenge.

This review examines the mechanistic rationale for JAK inhibition in GVHD and summarizes key preclinical and clinical data. We evaluate the efficacy and safety of selective and nonselective agents, including ruxolitinib, baricitinib, itacitinib, pacritinib, and rovadicitinib. Furthermore, the review analyzes recent advancements in peri-transplant prophylaxis, biomarker-driven strategies, and the comparative landscape of FDA-approved therapies for acute and chronic GVHD.

The future of GVHD management is shifting from broad immunosuppression toward precision medicine. We anticipate a transition from the current 'steroid-first' paradigm to risk-stratified algorithms utilizing biomarker profiling and novel combination strategies. While ruxolitinib is the current cornerstone, the development of highly selective inhibitors and the resolution of financial access barriers will be crucial for establishing JAK inhibitors as the frontline standard of care over the next decade.