Belumosudil for chronic graft-versus-host disease in children under 12: A retrospective analysis of effectiveness and safety

Abstract Background: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. Conventional treatments are often inadequate, especially in addressing fibrosis feature of cGVHD, leading to irreversible organ damage. Belumosudil, a selective ROCK2 inhibitor, targets both the inflammatory and fibrotic pathways of cGVHD. While approved for patients aged 12 and older, its efficacy and safety in younger children are not well-established. This study aims to report its real-world data in pediatric populations. Methods: We retrospectively analyzed the clinical data of 34 pediatric patients aged 12 years and youngerwith steroid-refractory cGVHD treated with belumosudil at Dongguan taixin hospital between January 2024 to May 2025. We evaluated the overall response rate (ORR) and organ-specific responses at 12 weeks, safety, and the impact of treatment timing on outcomes, with a focus on fibrotic manifestations in the skin, joints, liver, and lungs. Results: 1.Baseline Characteristics: Thirty-four patients (median age 8.5 years, range 3-12; male:female 2.78:1) were included. The primary diseases were mainly non-malignant, including severe β-thalassemia (88.24%) and aplastic anemia (8.82%). Most patients (73.5%) received haploidentical transplants. Median time from allo-HSCT to cGVHD diagnosis was 10 months (range 6-24). Patients presented with median 3 involved organs (range 2-5).Cutaneous involvement (73.5%) predominated, featuring lichenoid changes and alopecia, followed by pulmonary (38.2% with bronchiolitis obliterans syndrome), ocular manifestations (26.5%), and hepatic (23.5%). 50% of patients have multi-organ involvement (≥2 organs). All patients had failed prior glucocorticoid+CNI therapy, with 19 (55.88%) receiving ≥2 prior lines. 2.Efficacy Outcomes:1）Overall Response: 77% (17/22) at 12 weeks, 85% (17/20) at 6 months;2）Organ-specific Responses: Skin/nails: 75% (12/16) at 12 weeks, 83% (15/18) at 6 months;Pulmonary: 60% (9/15) at 12 weeks, 80% (12/15) at 6 months;Ocular: 40% (6/15) at 12 weeks, 60% (9/15) at 6 months;Hepatic: 33% (5/15) at 12 weeks, 50% (7/14) at 6 months. 3.Key Predictors of Response: Early intervention (≤3 months post-cGVHD): 92% ORR vs 50% in delayed group (p=0.03);Pulmonary subgroup: 100% ORR with early treatment vs 20% delay (p=0.002);Mild cGVHD: 94% ORR vs 43% in severe cases (p0.001). 4.Treatment Challenges: Delayed responses observed in hepatic (median 6 months) and articular manifestations.Treatment failure in 4 cases: advanced pulmonary fibrosis (n=2, 1 fatal), delayed intervention (12 months, n=1), severe hepatotoxicity (AST200 U/L, n=1). Conclusion: Belumosudil demonstrates robust anti-fibrotic activity in pediatric cGVHD, achieving high response rates in skin, joints, and pulmonary tissues. Early initiation within 3 months of cGVHD onset is critical for optimal outcomes, particularly in visceral organs. The favorable safety profile supports its consideration as a preferred second-line therapy in this vulnerable population.