Real-World Efficacy of Belumosudil in Treating Fibrotic Symptom Burden in Chronic Gvhd: Modified Lee Symptom Score Assessment after Multiple Treatment Failures
Authors: Desai Nihar , Law Arjun , Lemieux Christopher , Vachon Keven , Jamani Kareem , Elemary Mohamed , Viswabandya Auro , Kumar Rajat , Mattsson Jonas , Kim Dennis Dong Hwan 
Published: December 2024

Background:
Belumosudil (BEL), a selective Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, has demonstrated clinical efficacy in managing chronic graft-versus-host disease (cGvHD), particularly its fibrotic component. The modified Lee Symptom Score (mLSS) is a practical tool for evaluating symptom burden. While real-world clinical studies indicate improved responses overall, the effect of BEL in reversing fibrosis is unclear. BEL has been available in Canada since March 2023 under a compassionate use program. Herein, we present our preliminary data on serial changes in mLSS, clinical response rates, and failure-free survival (FFS) following BEL treatment.
Methods and patients:
This retrospective study evaluated the efficacy of BEL in 37 patients enrolled in the compassionate program from 4 Canadian centers (Toronto, Quebec City, Saskatoon, and Calgary) from March 2023 - July 2024. Baseline characteristics, prior treatments received, and details of BEL treatment were captured in addition to overall response rates (ORRs), mLSS, treatment outcomes, and adverse events.
The 7-day mLSS was serially captured as the standard of care in the clinic in 28 patients at baseline, 3, 6, 9, and 12 months. The summary score and sum of 7 domains (i.e. skin, eye/mouth, breathing, eating/digestion, muscle/joints, energy, and mental/emotional) as well as the fibrotic sum score (FSS; defined as the sum of the score for limited joint movement, difficulty swallowing solids and liquids, and thickened skin) were calculated at each time point and compared with the score from baseline using a repeated measure based on general linear model (GLM). Repeated measure analysis using a GLM assessed serial changes mLSS at 4-time points, examining within-subjects and between-subjects effects, respectively.
Clinically meaningful improvement in overall mLSS was defined as a reduction of mLSS ≥ 7 points, while for a domain a reduction of the sum by ≥2 was clinically meaningful. For the fibrotic component of cGvHD, a reduction of the FSS by ≥2 was considered clinically meaningful. Failure-free Survival (FFS) was defined as the time from starting BEL to the addition of new GVHD therapy, relapse, or death.
Results:
Thirty-seven patients were treated with BEL, and 27 were evaluated for response with a minimum follow-up of 3 months. At the time of starting BEL, 25 (67.5%) patients had severe grade cGvHD, with a median of 4 (1-4) affected organs, and had received a median of 5 (2-10) prior lines of therapy. The median duration from cGvHD onset to BEL was 41 months (9-150). Corticosteroids were the most common concurrent treatment with BEL (n=20, 56%), and 13 (36%) patients were treated with a combination of BEL and ruxolitinib.
With a median follow-up of 10.1 months (2-17) after BEL, the ORR at 3 and 6 months was 55.0% (n=15/27) and 69% (n=11/16). The corticosteroid dose was reduced from baseline in 9 (45%) patients. The 6-month FFS was 71.9%. Five patients discontinued treatment (n=2 for intolerance to BEL; n=2, GvHD progression requiring additional treatment; n=1, mortality due to pre-existing infection).
The mLSS score showed a statistically significant reduction over time (p=0.04 by repeated measure by GLM): 28.7 ± 2.4 (mean ± S.E.), 22.9 ± 2.9, and 20.9 ± 4.2 at baseline, 3, and 6 months. When compared to baseline, the mLSS was reduced by 6.6 ± 1.3, 7.8 ± 1.8, 11.4 ± 5.0, and 15.8±4.5 at 3, 6, 9, and 12 months. The proportions of patients showing clinically meaningful improvement of the mLSS (≥7 points) at 3, 6, 9, and 12 months were 59%, 75%, 60% and 100%. Over 30% of patients showed clinically meaningful improvement (≥2 points) in skin, eyes/mouth, breathing, and joint/muscle domains.
In terms of the FSS, it showed a statistically significant reduction over time (p=0.002 by repeated measure by GLM): 4.3±0.6 (mean ± S.E.), 3.5±0.6, 4.1±0.8 and 3.2±1.1 at baseline, 3, 6 and 9 months. In comparison to the FSS from baseline, the FSS was reduced by 1.4±0.5, 1.6±0.8, 3.8±0.6 and 3.2±0.6 at 3, 6, 9 and 12 months.
Conclusion:
The current study replicated a similar ORR of 69% compared to the previously reported best ORR in the ROCKstar study (74%). Also, our study showed a significant improvement in symptom burden based on the mLSS and the FSS over time. This highlights the importance of longitudinal monitoring of the mLSS as a follow-up tool, particularly for the fibrotic/sclerotic nature of cGvHD.