Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease

Abstract

Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT) and is associated with significant morbidity and mortality. For many years, there have been few effective treatment options for patients with GVHD. First-line systemic treatment remains corticosteroids, but up to 50% of patients will develop steroid-refractory GVHD and the prognosis for these patients is poor. Elucidation of the pathophysiological mechanisms of acute and chronic GVHD has laid a foundation for novel therapeutic approaches. Since 2017, there have now been 4 approvals by the US Food and Drug Administration (FDA) for GVHD. Ruxolitinib, an oral selective JAK1/2 inhibitor, received FDA approval for the treatment of steroid-refractory acute GVHD in 2019 and remains the only agent approved for acute GVHD. There are currently 3 FDA approvals for the treatment of chronic GVHD: (1) ibrutinib, a BTK inhibitor traditionally used for B-cell malignancies, was the first agent approved for chronic GVHD after failure of one or more lines of systemic therapy, (2) belumosudil, an oral selective inhibitor of ROCK2, for patients with chronic GVHD who received at least 2 prior lines of treatment, and (3) ruxolitinib for chronic GVHD after failure of one or two lines of systemic therapy. In this review, we highlight the clinical data which support these FDA approvals in acute and chronic GVHD with a focus on mechanism of actions, clinical efficacy, and toxicities associated with these agents.

Rapamycin Treatment Alleviates Chronic GVHD-Induced Lupus Nephritis in Mice by Recovering IL-2 Production and Regulatory T Cells While Inhibiting Effector T Cells Activation

“…Although efforts have been made to develop new anti-GVHD treatment methods, including blocking the costimulatory pathway, inducing the tolerance of donor cells, deviation of the recipient immune system towards the Th2 response, and interference with the function or expression of adhesion molecules, cytokines or T cells, cGVHD is still a serious problem. Therefore, it is necessary to better understand the induction and pathogenesis of cGVHD [ 27 , 28 , 29 , 30 , 31 ].…”

Safety of autologous freshly expanded mesenchymal stromal cells for the treatment of graft-versus-host disease

“…Ruxolitinib is the only agent currently approved by the FDA for the treatment of steroid-refractory acute GVHD, based on clinical trial data with CR ranging from 27% to 34% and OR ranging from 55% to 62% at day 28 ( 20 , 21 ). In chronic GVHD, three agents are now approved for the treatment of refractory disease, ibrutinib, belumosudil, and ruxolitinib, with best OR ranging from 67% to 76% and CR ranging from 5% to 21% ( 22 ). Steroids remain the pillar of upfront therapy for GVHD but often lead to significant morbidity including likely impairment in epithelial healing, which can further complicate the clinical picture of GI GVHD ( 23 ).…”

Mode of action, indications and recommendations on extracorporeal photopheresis (ECP)

“…Treatment with IL‐22 is also a possible option 40 . Other drugs recently approved by the FDA for the treatment of chronic GvHD are ruxolitinib, ibrutinib and belumosudil 41 …”

“…40 Other drugs recently approved by the FDA for the treatment of chronic GvHD are ruxolitinib, ibrutinib and belumosudil. 41 Extracorporeal photopheresis as second-line as well as adjuvant therapy in chronic GvHD with mucocutaneous involvement could achieve good results, particularly in the treatment of sclerotic skin changes a therapeutic response could be recorded. 2,35,42 The possibility of reducing the required steroid dose by more than 50% proved to be particularly advantageous in the treatment of this chronic disease.…”