Combined Belumosudil-Ruxolitinib Therapy for the Treatment of Steroid-Refractory Chronic Graft-Versus-Host Disease (cGVHD) Was Associated with Robust Treatment Response and Was Well-Tolerated

cGVHD is a frequent complication of allogeneic hematopoietic cell transplant (allo-HCT) and the main cause of late non-relapse mortality (NRM). Most patients become refractory to upfront therapy with systemic corticosteroids. Several drugs have been recently approved for the treatment steroid-refractory (SR) and -dependent (SD) cGVHD including ruxolitinib (JAK1/2 inhibitor) and belumosudil (ROCK-2 inhibitor), which are typically used sequentially. We hypothesize that treatment combination using drugs with distinct mechanism of action is safe and efficacious in advanced cGVHD. Thus, we evaluated patients treated with combined belumosudil-ruxolitinb (bel-rux) dual therapy at a single transplant center. Our retrospective review identified 14 patients with SR/SD cGVHD treated with combined bel-rux therapy from 09/2021 to 10/2023. Treatment response was assessed at 6 and 12 months. Treatment failure was defined as stable or progression of symptoms, or treatment switch due to no response/benefit, or requirement for a higher dose of corticosteroids. The median age was 47 (range 38 to 57), and patients had a similar gender distribution. The majority had a PBSC graft (n= 9, 71%), followed by cord blood (n= 5, 29%). All patients received a calcineurin inhibitor-based GVHD prophylaxis (Table). Most had moderate and severe cGVHD with multiorgan involvement. Thirteen (93%) patients on ruxolitinib at a dose of 5-10 mg twice a day had belumosudil added to their GVHD treatment, whereas 1 patient on single drug belumosudil had ruxolitinib added after 6 months of treatment. With a median follow-up of 14 months, the 6-month overall response rate (ORR) was 71% (n=10, CR 2, PR 8), 29% (n= 4) had stable disease, and none had GVHD progression (Fig. 1). Notably, treatment responses were observed across all affected organs (Fig. 2). At 12-months, of the 10 evaluable patients, the ORR was 70% (n=7, CR 1, PR 6). Two patients had stable and 1 had progression of their cGVHD. One patient developed pulmonary alveolar proteinosis (PAP) that promptly recovered after treatment discontinuation as well as persistent norovirus that resolved with oral immunoglobulin treatment. No other grade ≥3 toxicities were observed, and no deaths occurred during the time of bel-rux treatment. This first report of dual bel-rux therapy for the treatment of advanced cGVHD demonstrated a robust treatment response and was overall well tolerated. Our findings suggest that treatment combination with drugs that have a distinct mechanism of action is feasible and possibly synergistic. Nonetheless, a large prospective study is needed to determine the role of drug combination in cGVHD.