A Review of Approved Therapies for SR cGvHD

Opinion
Video

A panelist discusses how four FDA-approved agents treat steroid-refractory cGVHD, including ibrutinib (65% response rate), belumosidil (74% response rate), ruxolitinib (50% vs 25% in phase 3 trial), and exotilimab (74% response rate with durable responses lasting 17.2 months median failure-free survival).

First-Line Treatments and Early Approvals for Chronic GVHD

For steroid-refractory or steroid-dependent chronic GVHD patients, ibrutinib was the first FDA-approved drug based on a phase 2 study using 420mg daily doses. This multicenter trial enrolled approximately 45 patients with moderate to severe chronic GVHD involving oral mucosa and skin, achieving overall response rates of around 65%. Ibrutinib represented a breakthrough as the first approved agent for chronic GVHD that had failed to respond to frontline steroid therapy.

The second approved therapy was belumacept (belimacidil), evaluated in the ROCKSTAR study at 200mg twice daily and 200mg once daily dosing schedules. Both dosing regimens demonstrated impressive overall response rates of approximately 74% in the 60-patient trial, leading the FDA to approve the 200mg once-daily dose for patients with moderate to severe chronic GVHD who had failed two prior lines of treatment. Belumacept was particularly effective for visceral organs like the GI tract and esophagus, though skin response rates were around 30%.

Belumacept's mechanism of action involves inhibiting the ROC2 pathway, which is critical for activating alloreactive T cells responsible for GVHD manifestations. Additionally, it reduces fibrotic manifestations by inhibiting the MRTF transcription factor that drives fibrogenic peptide secretion. This dual mechanism addressing both inflammatory and fibrotic aspects of chronic GVHD made belumacept particularly valuable for managing complex presentations of the disease in heavily pretreated patient populations.

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