Introduction Belumosudil (BEL), a selective Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, has shown clinical efficacy in the management of chronic graft-versus-host disease (cGvHD), particularly in reversing fibrosis. Patient-reported outcomes (PROs) are increasingly recognized as valuable tools for assessing treatment response in cGvHD, such as the modified Lee Symptom Score (mLSS) serving as a practical tool for evaluating symptom burden. The current study aims to assess the clinical activity of BEL based on the symptom burden longitudinally measured by the mLSS in cGvHD patients treated with BEL after multiple prior therapy failures.

Patients and methods This retrospective, multicentre study evaluated clinical outcomes and longitudinal improvement in mLSS following BEL therapy in patients with cGVHD who had failed multiple lines of therapy. We included 87 patientswho started BEL therapy between March 2023 and June 2024 and had the mLSS assessed as a standard of care.

The 7-domain mLSS (skin, eye/mouth, breathing, eating/digestion, muscle/joints, energy, mental/emotional health) was assessed at baseline, 3, 6, and 12 months after the initiation of BEL. The sum of these domains was calculated to derive the total mLSS. A fibrotic sum score (FSS) was invented, calculated by summing the scores for limited joint movement, difficulty swallowing solids and liquids, and thickened skin, representing cGvHD manifestation of fibrosis. Clinically meaningful improvement (CMI) was defined as a reduction of ≥7 points in mLSS, ≥2 points in the FSS, and ≥ 1 point in each domain.

Longitudinal changes in overall mLSS, FSS, and the sum of mLSS in each domain were analyzed using repeated measures with a general linear model (GLM), as well as the proportion of patients showing clinically meaningful improvement (CMI).

Results A total of 87 patients with cGVHD were treated with BEL and had mLSS data available. At the time of starting BEL, 68% (n=59) patients had severe grade cGvHD, with a median of 3 (1-7) affected organs, and had received a median of 4 (2-10) prior lines of therapy. Most patients (82%, n=69/84) started BEL at 200 mg daily. With a median follow-up duration of 15.8 months among survivors (range 1–27) after BEL, the 6- and 12-month FFS rates were 82.3% (95% CI [71.9–89.2]) and 72.2% [60.0–81.3], respectively.

The mLSS scores showed gradual decline pattern over time: 25.9 ± 1.6 (mean±SE; n=87), 19.0±1.8 (n=59), 16.7±2.3 (n=34), and 16.9±2.7 (n=20) at baseline, 3, 6, and 12 months (p<0.001 by repeated measures using GLM). Compared to the baseline, the mLSS was reduced by 4.4 ± 0.9, 6.1 ± 1.5, and 8.3 ± 2.2 at 3, 6, and 12 months, respectively. The proportion of patients who achieved a CMI-mLSS at 3, 6, and 12 months was 46% (n=27/59), 53% (n=18/34), and 65% (n=13/20); when analyzed for the best improvement, 62% (n=37/60) of the patients showed a CMI-mLSS. When comparing both the continuous mLSS and the proportion of CMI-mLSS to overall response rate and clinical benefit, the only difference was found in patients with a CMI-mLSS at 6 months (76%, n=13/17), who had a higher clinical benefit rate compared to those without a CMI-mLSS (33%, n=5/15; p=0.031).

Similarly, the mean FSS scores were 4.2±0.4 (n=48), 2.4±0.5 (n=25), 2.4±0.7 (n=14), and 2.3±0.9 (n=8) at baseline, 3, 6, and 12 months, suggesting a significant reduction of fibrotic component of cGvHD over time with BEL therapy (p<0.001 by GLM). The proportion of patients who achieved a CMI-FSS at 3, 6, and 12 months was 20% (n=5/25), 43% (n=6/14), and 62% (n=5/8). When analyzed for the best improvement within 12 months of BEL treatment, 31% (n=8/26) showed a CMI-FSS.

Except for the eating/digestion domain (15%), a minimum of 30% of patients demonstrated a CMI in each domain; the highest CMI was reported in muscle/joints (58%), followed by eye/mouth (54%), skin (50%), breathing (42%), energy (38%), and mental/emotional health (31%).

Conclusion Our study reports a significant improvement in symptom burden with BEL therapy, as measured by the mLSS, over time. While it is challenging to observe objective response in fibrotic component of cGvHD only by NIH consensus criteria, the mLSS is a feasible and practical tool for capturing early clinical improvement, esp. fibrotic component, following BEL treatment, This highlights the importance of longitudinal monitoring of the mLSS and the urgent need for a reliable tool to assess symptom burden improvement with novel cGVHD therapies.

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2025
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