Effectiveness and Safety of Belumosudil in Heavily-Treated Severe Chronic Graft-Versus-Host Disease (cGVHD) after Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT): A Real-World Observational Study
Authors: Wang Zhi , You Jianhua , Chen Wenting , Xing Tingting , Hu Jiong 
Published: December 2024

Background: Chronic GVHD is the leading cause of morbidity, late non-relapse mortality (NRM), and impaired quality of life in allo-HSCT recipients. The ROCKstar study has established the efficacy of belumosudil, an oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, in treating steroid-refractory cGVHD. In this retrospective study, we evaluated the effectiveness and safety of belumosudil for the treatment of severe cGVHD in a real-world setting.
Method: We retrospectively collected data on severe cGVHD patients who received belumosudil at Hainan Hospital of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from May 2023 to February 2024. Demographics, treatment pattern, treatment response and adverse events (AEs) were extracted from the medical records. The outcomes of study included overall response rate (ORR), time to response (TTR), failure-free survival (FFS), the change in Lee Symptom Scale (LSS) scores from baseline and safety.
Results: Among 20 enrolled patients who received allo-HSCT, the majority (75.0%, n=15) was male and the median age was 34.5 (range, 12-67) years, including 3 pediatric cases. Nearly half (45.0%, n=9) of patients had acute GVHD history. The median number of cGVHD involved organs was 7 (range, 2-8) and 90.0% (n=18) had at least 4 organs involved. In which, the most commonly involved organs were eyes (100.0%, n=20), lungs (95.0%, n=19) and mouth (95.0%, n=19). Most patients (90.0%, n=18) had cGVHD refractory to their last LOT and the median number of LOTs was 4, with 16 patients (80.0%) received ≥3 prior LOTs and 15 (75.0%) patients received ruxolitinib. The median time from cGVHD diagnosis to belumosudil treatment was 9.0 months (range, 4.0-62.0). All patients received 200mg belumosudil daily, and concomitant treatment included ruxolitinib in 15 patients (75.0%) and steroids in 14 patients (70.0%) when initiating belumosudil. The dose of ruxolitinib when initiating belumosudil was 5mg twice daily.
With a median follow-up of 5.0 months (range, 1.4-9.8), the ORR was 90.0% (95% confidence interval [CI], 68.3-98.8), all achieving partial response, with a median TTR of 1.6 months (range, 0.6-8.4). The response rates varied by organ: 70.6% in the skin, 75.0% in the eyes, 36.8% in the mouth, 100.0% in the liver, 47.4% in the lungs, 50.0% in the joints/fascia, 66.7% in the gastrointestinal tract, and 47.1% in the esophagus. At 3 months after the treatment, 16 patients (80.0%) showed clinically significant improvement (≥7 points) in LSS score, with an average decrease of 12.35±7.67 points. Three treatment failure events were reported, comprising one malignancy recurrence (5 weeks after belumosudil administration), one NRM and one progression of cGVHD, all occurred within 3 months. The median FFS was not reached with a 3-month FFS rate of 79.6% (95% CI, 61.4-100.0). Of the 14 patients who received concomitant steroids, 6 (42.9%) had a reduction in steroid dose, with a median reduction percentage of 50%.
Among 15 patients previously received ruxolitinib, the ORR was 86.7% (95% CI, 59.5-98.3), with a median TTR of 1.9 months (range, 0.9-8.4). The response rates in different organs ranged from 28.6% (in the mouth) to 100.0% (in the liver). Clinically significant improvement in LSS score was reported in 73.3% (n=11) of patients at month 3.
During the treatment, 15 patients (75.0%) reported at least one AE. The most common AEs were elevated alanine or aspartate aminotransferase (n=4, 20.0%); influenza (n=4, 20.0%); coronavirus infection (n=3, 15.0%); pneumonia (n=3, 15.0%); and diarrhea (n=2, 10.0%). Two patients (10.0%) reported ≥ grade 3 AEs, including one case of pneumonia and one case of influenza. One patient with history of pneumonia deteriorated and died of pneumonia after the initiation of belumosudil.
Conclusion: In this real-world study, belumosudil showed rapid, meaningful response with acceptable tolerability in a group of patients with heavily pretreated severe cGVHD with multi-organ involved. The observed effectiveness and safety were comparable with those from clinical trials, which supported belumosudil as an effective treatment option for refractory cGVHD. Notably, in patients with poor response to ruxolitinib, the addition of belumosudil provided remarkable response, highlighting the feasibility of this promising treatment strategy, which need further investigation.