Belumosudil Is Efficacious for the Management of Heavily Pretreated and Prolonged Chronic Graft-Versus-Host Disease: A Retrospective Multi-Center Real-World Study By the Israel Association for Bone Marrow Transplantation and Cellular Therapy
Authors: Varon Ben , Ram Ron , Shimoni Avichai , Avni Batia , Grisariu Sigal , Stavi Vered , Bar-On Yael , Yeshurun Moshe , Elhasid Ronit , Gefen Aharon , Yanir Asaf , Amit Odelia , Yehudai-Ofir Dana , Henig Israel , Zuckerman Tsila 
Published: December 2024

Introduction : Chronic graft-versus-host disease (cGvHD) remains one of the most important complications of allogeneic stem cell transplantation (ASCT) and is a leading cause of morbidity, late non-relapse mortality, and impaired quality of life. Recent advances in understanding the cGVHD mechanisms have led to the development of the Rho-associated coiled-coil containing protein kinase 2 (ROCK-2) selective inhibitor, belumosudil. The pivotal ROCKstar trial demonstrated the efficacy and acceptable safety profile of belumosudil in cGVHD patients, which led to its FDA approval for the use after &gt;2 prior lines of therapy (LOT). The current study aimed to investigate the efficacy and safety of belumosudil in patients with cGVHD in real-world settings across all transplant centers in Israel.

Methods : Data on patients treated with belumosudil for cGVHD at 6 adult and 3 pediatric transplant centers via compassionate use programs were collected and analyzed. These data included patient demographics, underlying disease requiring ASCT, transplant details, cGVHD details, and outcomes of belumosudil treatment.

Results : Forty-five patients were included in the final analysis: 42 were treated according to FDA indications, and 3 pediatric patients (ages 4, 4, and 6 years) were treated outside the FDA labeled indication. The median age was 46 (range, 4-75) years; 44.4% were females. GVHD prophylaxis included a calcineurin inhibitor and methotrexate in 66.7%, post-transplant cyclophosphamide in 13.3% and others in 20% of patients. Acute GVHD occurred in 48.9% of patients. The majority of patients (84.4%) had severe cGVHD with a median of 4 involved organ systems (range, 1-7) and received a median of 4 prior LOT (range, 2-6). Notably, 86.7% had prior ruxolitinib exposure, and 13.3% concurrently received belumosudil and ruxolitinib. Patients had been treated for cGVHD for a median of 2.3 (range, .08 - 19.1) years prior to belumosudil commencement. The median duration of belumosudil therapy was 7.8 (range: 1.2 - 28.8) months, with 73.3% of patients still on treatment. The median time to best response was 100 days (range: 32 - 328). Response rates were as follows: complete response (CR) 6.7%, partial response (PR) 48.9%, stable disease (SD) 40%, and progressive disease (PD) 4.4%, with an overall response rate (ORR) of 55.6%. Responses for skin cGVHD were: CR - 11.1%, PR - 50%, SD - 38.9%; for lung cGVHD: PR - 44.4%, SD - 48.1%, PD - 7.4%. The median reduction of the glucocorticoid dose was from 0.29 mg/kg/d of prednisone at the beginning of treatment to 0.02 mg/kg/d at the last follow-up or belumosudil cessation. The most common adverse events (AEs) were pulmonary infections (17.8%) and the primary reason for belumosudil discontinuation was cGHVD worsening. Only one patient stopped belumosudil due to AEs. While on treatment, 26.1% of patients had cGVHD progression. Six patients (13.3%) died, three from cGVHD worsening, two from pulmonary infections, and one from relapsed leukemia. At a median follow-up of 8 months (range 1.3-32), the GVHD relapse-free survival (RFS) was 72% (95% CI 59%-85%) and the estimated 12-month GVHD RFS was 66% (95% CI 46%-86%). Overall survival (OS) at 8 months was 92% (95% CI 81%-100%) and the estimated 12-month OS was 75% (95% CI 62%-88%).

Conclusions : The findings of this real-world study, while comparable to those observed in the ROCKstar trial, are encouraging, considering the heavily pretreated patient population with prolonged and severe cGVHD. No new safety signals emerged. Future studies are warranted to optimize patient selection and timing for treatment initiation.