ROCK 2 inhibition with belumosudil for the treatment of chronic graft-versus-host disease: a narrative review.

Abstract

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). The global incidence of cGVHD remains high, despite prophylactic regimens for patients undergoing HSCT. Systemic corticosteroids are the standard first-line treatment for cGVHD, but most treated individuals will require second-line or further treatment because of suboptimal disease control or toxicity from long-term corticosteroid use. No standard treatment algorithm exists for steroid-refractory cGVHD, with similar response rates and poor outcomes across different pharmacologic regimens. The pathogenesis of cGVHD is driven by an imbalance in effector T helper 17/T follicular helper cells and regulatory T-cells that leads to an inability to reverse a proinflammatory environment and the loss of immune tolerance, which causes irreversible fibrosis in target organs. Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) signaling plays key roles in regulating T-cell-mediated immune responses, promoting the differentiation of fibroblasts into myofibroblasts, and stimulating transforming growth factor β-induced fibrosis. Belumosudil, an oral selective ROCK2 inhibitor, targets the ROCK2 pathway, thus correcting disrupted immune homeostasis, downregulating proinflammatory cytokines, and reversing fibrosis in cGVHD. Clinical trials demonstrated rapid and sustained overall response with belumosudil, and a favorable adverse effects profile with a low risk of infection and cytopenia in pretreated and multiorgan involved cGVHD patients, resulting in its approval for use in cGVHD. This narrative review provides an overview of the pathophysiology of cGVHD and the limitations of current treatment, and describes the pharmacologic activity, clinical studies, and real-world data supporting belumosudil use in patients with cGVHD.