What is the role of belumosudil (Rezurock) in treating steroid‑refractory chronic graft‑versus‑host disease after failure of at least two prior systemic therapies?

Belumosudil for Steroid-Refractory Chronic Graft-Versus-Host Disease

Belumosudil (Rezurock) is FDA-approved and should be used at 200 mg orally once daily for adult and pediatric patients ≥12 years with chronic GVHD after failure of at least two prior lines of systemic therapy. 1

FDA-Approved Indication and Dosing

• Belumosudil is specifically indicated for chronic GVHD patients who have failed ≥2 prior systemic therapies, taken orally once daily with food until disease progression requiring new systemic therapy 1
• The standard dose is 200 mg once daily, with tablets swallowed whole (not cut, crushed, or chewed) at approximately the same time each day 1
• Dose modifications to 200 mg twice daily are required when coadministered with strong CYP3A inducers or proton pump inhibitors 1

Mechanism and Clinical Rationale

• Belumosudil is a selective ROCK2 (rho-associated coiled-coil-containing protein kinase-2) inhibitor that downregulates IL-21 and IL-17 secretion while upregulating regulatory T cells to attenuate inflammatory responses 2
• The drug exerts antifibrotic effects by inhibiting the Rho-ROCK-MRTF pathway, downregulating pro-fibrotic genes and TGF-β signaling, and reducing M2-like macrophages 2

Clinical Efficacy Data

Response Rates and Durability:

• The pooled analysis of phase 2 studies (KD025-208 and ROCKstar) with median follow-up of 31.4 months demonstrated a best overall response rate of 72% in the modified intent-to-treat population 3
• Median duration of response was 62.3 weeks (range 36.1-82.6 weeks), indicating sustained clinical benefit 3
• The original phase IIa study showed overall response rates of 65-69% across different dosing cohorts in patients with heavily pretreated disease (78% severe cGVHD, 50% with ≥4 organs involved, 73% refractory to last line of therapy) 4

Survival Outcomes:

• Median failure-free survival was 15.1 months with 1-year and 2-year FFS rates of 56% and 40%, respectively 3
• The 2-year overall survival rate was 82% in the phase IIa study 4
• Median time to next treatment was 22.1 months, with 47% of patients requiring new systemic therapy by 36 months 3

Comparative Effectiveness:

• Real-world data comparing belumosudil to best available therapy showed 6-month overall response rate of 38.7% versus 26.8% (44.2% improvement, p=0.031) 5
• One-year failure-free survival was 61.2% with belumosudil versus 47.8% with best available therapy (13.5% difference, p=0.032) 5

Steroid-Sparing Effects

• Belumosudil enables meaningful corticosteroid dose reductions, with 19% of patients able to completely discontinue corticosteroid treatment 4
• Responses were associated with quality-of-life improvements alongside corticosteroid tapering 4
• Real-world data confirmed gradual improvement in immune subsets at 1-year post-treatment, suggesting preserved immune function despite ongoing therapy 6

Safety Profile

Favorable Toxicity Profile:

• Belumosudil demonstrates low rates of cytopenia and no apparent increased risk of infection, including cytomegalovirus infection and reactivation 4
• Real-world experience showed drug-related grade ≥3 toxicities in only 27% of belumosudil courses versus 36% with best available therapy 5
• No unexpected adverse events were identified in long-term follow-up 3

Hepatotoxicity Monitoring:

• Monitor total bilirubin, AST, and ALT at least monthly during treatment 1
• Hold belumosudil for Grade 3 AST/ALT (5-20× ULN) or Grade 2 bilirubin (1.5-3× ULN) until recovery to Grade 0-1, then resume at recommended dose 1
• Permanently discontinue for Grade 4 AST/ALT (>20× ULN) or Grade ≥3 bilirubin (>3× ULN) 1

Hepatic Impairment Considerations:

• Avoid use in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment without liver GVHD 1
• No dose adjustment needed for mild hepatic impairment 1

Organ-Specific Efficacy

• Belumosudil shows particular promise in ocular cGVHD, with case reports demonstrating significant improvement in corneal damage, meibomian gland inflammation, corneal leukoplakia, and neovascularization 2
• Responses were observed across multiple organ systems in patients with multiorgan involvement 4

Combination Therapy

• Real-world data on belumosudil combined with ruxolitinib (n=14) showed 6-month and 12-month overall response rates of 64% and 57%, respectively, with acceptable safety profile 6
• This combination may represent a viable option for patients requiring dual targeted therapy, though this is not FDA-approved 6

Clinical Context and Guidelines

Current Guideline Positioning:

• The NCCN (2020) guidelines note that ibrutinib was the only FDA-approved second-line therapy for steroid-refractory chronic GVHD at that time, with no preferred specific agent for second-line therapy 7
• Clinical trial enrollment is strongly encouraged for all patients with steroid-refractory cGVHD given the high mortality and lack of established standard therapy 7
• Note: Belumosudil received FDA approval in 2021 after these NCCN guidelines were published, representing an important new option in the treatment landscape 1, 4

Critical Implementation Points

When to Use Belumosudil:

• Reserve for patients who have definitively failed at least two prior systemic therapies for chronic GVHD 1
• Consider earlier in treatment sequence for patients with severe multiorgan involvement given the 72% response rate and favorable safety profile 3
• Particularly consider for patients with ocular manifestations or those requiring steroid dose reduction 2, 4

Treatment Duration:

• Continue until progression of chronic GVHD requiring new systemic therapy 1
• Deeper responses may develop with ongoing therapy beyond initial assessment timepoints 6
• Do not discontinue prematurely based on initial response assessment alone, as median duration of response exceeds 1 year 3

Common Pitfalls to Avoid:

• Do not use belumosudil as first- or second-line therapy; it is specifically indicated after ≥2 prior systemic therapies 1
• Do not crush or split tablets; must be swallowed whole with food 1
• Do not forget to increase dose to 200 mg twice daily when coadministering with strong CYP3A inducers or proton pump inhibitors 1
• Do not initiate in patients with moderate-to-severe hepatic impairment without liver GVHD 1

Embryo-Fetal Toxicity Warning

• Belumosudil can cause fetal harm based on animal studies showing embryo-fetal mortality and malformations at maternal exposures below those at recommended human doses 1
• Advise pregnant women of potential fetal risk and counsel patients of reproductive potential regarding contraception 1