The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Despite the use of prophylactic immunosuppression including calcineurin inhibitors, antimetabolites, antithymocyte globulin, or posttransplant cyclophosphamide, patients still develop severe aGVHD. In particular, patients with glucocorticoid-refractory GVHD (SR-GVHD) have a dismal prognosis with a low 1-year post-allo-HCT survival rate. Most classical drugs used to prevent or treat aGVHD target 1 specific pathway such as calcineurin inhibitors or mammalian target of rapamycin inhibitors, or they interfere with fast-dividing activated cells (eg, methotrexate, mycophenolate, and cyclophosphamide). In contrast to these drugs, inhibition-of-signaling molecules, used by multiple immune cells and critical for signal transduction of multiple proinflammatory cytokines, could be more efficacious at blocking GVHD. Ruxolitinib blocks Janus kinases 1 and 2, which are required to mediate the downstream signaling of multiple cytokine receptors. Recently, a multicenter phase 3 clinical trial showed that ruxolitinib led to significant improvements in efficacy outcomes compared to best available therapy, which will lead to a paradigm shift in the treatment of SR-GVHD.