Multicenter real-world experience of belumosudil treatment in heavily pretreated patients with steroid-refractory chronic graft-versus-host disease: Clinical outcomes and risk factor analysis for failure-free survival.

Abstract Introduction Belumosudil (BEL), a selective Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, has shown significant clinical activity to improve overall response rate (ORR) and failure-free survival (FFS) in patients (pts) with steroid-refractory chronic graft-versus-host disease (cGvHD) in the randomized phase 2 Rockstar study. Over the last 2 years, multiple real-world experience (RWE) studies repeatedly reported improved ORR, although the studies were limited by relatively small number of pts in each individual studies. The present study expanded the cohort to 216 pts through international, multicentre collaboration, and presents preliminary data on ORR, FFS and clinical significant adverse events (AEs) following BEL treatment. Patients and methods This retrospective study evaluated the efficacy of BEL treatment of 216 pts in Canada, Spain and Germany from March 2023 to July 2025. Baseline characteristics, prior cGvHD treatments history, and details of BEL treatment were captured retrospectively, along with ORR, complete response (CR) rates, clinical benefit (defined as CR or partial response plus stable disease with significant steroid dose reduction), and significant AEs. The primary endpoint was FFS, defined as the time from initiation of BEL to subsequent GVHD therapy due to inadequate response or toxicity, disease relapse, or death. Results Two hundred and sixteen pts with cGvHD who received BEL as third line therapy or beyond were included, of whom 191 were evaluated for their response to BEL. At the time of BEL starts, 165 (80.1%) out of 206 pts showed severe grade cGvHD; a median of 3 involved organs (range 1-7), and a median of 4 prior lines of therapy (range 2-14). The median interval from onset of cGvHD to BEL therapy was 46.1 months (range 0.4-303). One hundred and twenty-seven pts (58.8%) received BEL as a monotherapy, while 89 (41.2%) received a BEL combination: 61 with ruxolitinib (BEL-RUX) (28.2%), 15 with RUX and extracorporeal photopheresis (ECP) (6.9%), and 13 with ECP only (6.0%). The majority (n=187; 90.8%) initiated BEL at a dose of 200 mg daily and corticosteroids (CS) were used in 60.2% (n=130). With a median follow-up of 10.4 months (95% CI [8.7–11.9 months]) after BEL initiation, the ORR was 45.0% (n=86/191) at 3 months and 43% (n=41/96) at 6 months, while the CR rate was 4.2% (n=8/191) and 5% (n=5/96), respectively. A clinical benefit was found for 50.3% (n=97/193) and 49% (n=47/96) of patients at 3 and 6 months. The CS dose was significantly reduced over the course of BEL treatment from a baseline of 0.12 ± 0.02 mg/kg/day (mean ± S.E.), to 0.09 ± 0.01, 0.08 ± 0.01, and 0.04 ± 0.01 at 3, 6 and 12 months (p < 0.001, generalized linear model). The 6 and 12 months' FFS rates were 80.9% [74.5–85.8] and 66.8% [58.9–73.5] respectively. A total of 77 pts (35.6%) failed BEL therapy: switched to the next line therapy due to inadequate response (n=56, 25.9%) or intolerance to BEL (n=13; 6.0%), non-relapse mortality (n=5; 2.3%), or disease relapse (n=3; 1.4%). Among the 13 pts who discontinued BEL due to intolerance, none experienced grade 4 AEs; 5 experienced grade 3 AEs (AST/ALT elevation, bowel perforation, severe fatigue with daily living limitation, recurrent lung infections, and retinal detachment). The remaining 8 pts experienced grade 2 AEs, including nausea and decreased oral intake (n=2), bilirubin elevation and muscle cramps, muscle weakness of the limbs, limb edema, fatigue and muscle cramps, dyspepsia, and malaise. When comparing characteristics between the BEL monotherapy group (n=127) and the combined BEL-RUX group (n=61), patients in the BEL group had fewer cases of overlap syndrome (22% vs. 42%, p=0.009) and less frequent exposure to RUX treatment (58% vs. 93%, p<0.001), while most of the BEL-RUX group had previously failed RUX therapy. However, although the BEL-RUX group had a higher rate of prior RUX therapy failure with a higher rate of overlap syndrome, no significant difference in FFS was observed between the two groups: the 12-month FFS rate was similar (71.2% for BEL vs. 66.2% for BEL-RUX), after adjustment for overlap cGvHD and prior RUX exposure. Conclusion The present study confirms therapeutic efficacy with impressive FFS at 6 and 12 months and an excellent safety profile for heavily pretreated patients with SR-cGVHD. Combination therapy of BEL with RUX seems promising for patients with prior RUX therapy or those presenting with overlap syndrome.