Chronic graft-vs-host disease (cGVHD) is a late complication of allogenic hematopoietic stem cell transplantation (HSCT) involving tissue inflammation and fibrosis. Up to 70% of patients receiving an allogenic HSCT will go on to develop cGVHD.1 The condition is not only debilitating but can also lead to permanent organ dysfunction and mortality. Patients often try multiple medications to control complications of the disease, including steroids and immunosuppressants. More than two-thirds progress beyond 2 lines of systemic therapy, highlighting the need for further treatment options.2 Belumosudil is a kinase inhibitor used to treat adults and children 12 years and older with cGVHD after the failure of at least 2 prior lines of systemic therapy.
The ROCKstar study (NCT03640481) demonstrated significant efficacy across all affected organs, including lung, eyes, skin, and liver, in patients after the failure of at least 2 prior lines of systemic therapy. Investigators in the phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg once daily and 200 mg twice daily in patients who had received 2 to 5 prior therapies. The primary end point was best overall response rate (ORR) as defined by the 2014 National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Gfraft-versus-Host Disease. The best ORR (95% CI) in patients receiving belumosudil 200 mg once daily and those receiving 200 mg twice daily was 74% (62%-84%) and 77% (65%-87%), respectively. An ORR of 30% was considered clinically meaningful in the study population characterized as being refractory to other treatments. Investigators observed steroid reductions and discontinuations in 64% and 20% of patients, respectively, and calcineurin inhibitor reductions and discontinuations in 42% and 17% of patients, respectively. Further, they observed 63% of responses within 4 to 8 weeks, with 94% of responses observed by week 24. Failure-free survival was clinically significant, demonstrating a rate of 73% at 6 months and 57% at 12 months.
The safety and tolerability data come from 2 open-label clinical trials. Adverse events were similar among cGVHD patients receiving steroids and immunosuppressants. The most common adverse reactions included infection (53%), asthenia (46%), nausea (42%), diarrhea (35%), dyspnea (33%), cough (30%), lymphocytopenia (29%), decreased serum phosphate (28%), edema (27%), hemorrhage (23%), abdominal pain (22%), musculoskeletal pain (22%), hypertension (21%), increased gamma glutamyl transferase (21%), and headache (21%). Adverse events leading to dose discontinuation occurred in 18% of patients and those leading to dose interruptions occurred in 29%. Total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels should be monitored monthly.
Belumosudil is a therapy aimed at restoring immune homeostasis by targeting inflammatory and fibrotic processes associated with cGVHD. It is an inhibitor of rho-associated, coiled-coil–containing protein kinase (ROCK) and predominantly inhibits ROCK2 over ROCK1. Belumosudil decreases activation of STAT3, causing the downregulation of Th17 and T follicular helper cells, which leads to the downregulation of pro-inflammatory cytokines. Inhibition of ROCK2 also increases phosphorylation of STAT5, causing the upregulation of regulatory T cells to reduce inflammation. Belumosudil downregulates fibrosis by preventing the polymerization of globular actin to fibrous actin by ROCK2.
The recommended dose of belumosudil for patients with cGVHD is 200 mg once daily until unacceptable toxicity or progression of disease requiring new systemic therapy.3 Patients should be instructed to take belumosudil with a meal at approximately the same time every day. The tablets must be swallowed whole with water. As belumosudil has not been studied in patients with preexisting severe renal and hepatic impairment, both risks and benefits should be considered before starting therapy in this population. Modifying the dosage is recommended with hepatotoxicity or other adverse reactions during treatment. When coadministering belumosudil with strong CYP3A inducers or proton pump inhibitors, increase the dosage to 200 mg twice daily.