Seminal studies of allogeneic bone marrow engraftment in leukemia patients were reported by Dr. Thomas in 1957. Approximately 25% of the first 200 patients succumbed to GVHD; none survived. Despite poor outcomes, Dr. Thomas persevered and led a team of talented clinician-scientists who used a canine model to advance GVHD prevention and therapy. Early GVHD prophylaxis in dogs and mice initially centered upon strategies that were globally immune suppressive. From preclinical mouse acute GVHD (aGVHD) studies, tacrolimus and sirolimus both of which are broadly immune suppressive, expanded our GVHD prophylaxis armamentarium. Targeted therapy blocking the CD28/CTLA4 costimulatory pathway, CTLA4-Ig ameliorated murine aGVHD. In ex vivo studies, blockade of T cell costimulation induced tolerance of donor T cells against host alloantigens that intriguingly proved to be dependent upon CD4+/CD25+ regulatory T cells (Tregs), a small population of suppressor cells. An unexpected outcome was proof that the infusion of donor Tregs reduced aGVHD in mice and later in patients.

Until recently, no GVHD drugs were approved. From 2017-21, four GVHD drugs were FDA approved. Following a phase II study, CTLA4-Ig, in combination with a calcineurin inhibitor and methotrexate, became the first FDA approved aGVHD regimen. Preclinical murine studies with phase 1b/2, open-label, multicenter data advanced ibrutinib, a Bruton’s tyrosine kinase inhibitor, as the first FDA approved cGVHD therapy. Belumosudil, a selective ROCK2 inhibitor, decreased murine pathogenic Th17 cells and fibrosis, while increasing Tregs. In conjunction with a phase 2, randomized multicenter registration trial for cGVHD treatment, belumosudil progressed to obtaining FDA approval. Ruxolitinib, a JAK1/2 inhibitor, reduced both acute and chronic murine GVHD. Multicenter, randomized, open-label phase 3 trials for steroid-refractory aGVHD or cGVHD showed clinical improvement. Ruxolitinib developed into the first aGVHD and third cGVHD FDA approved drug for treating steroid-refractory disease. This lecture will review the past, present and ongoing current efforts to enhance acute and chronic GVHD outcomes.