Abstract Background: Chronic GvHD (cGvHD) is the most significant risk factor for late morbidity and mortality after allogeneic stem cell transplantation (alloSCT). There are no standard treatment options beyond first-line corticosteroids and second-line ruxolitinib. The selective ROCK-2 inhibitor belumosudil, a novel FDA-, but not yet EMA-approved agent, has shown efficacy in phase-2 trials and has recently been made available to German and Austrian patients within a managed-access program (MAP). In this study, we analyzed the clinical benefits of belumosudil within the MAP program in the German Austrian cohort. Methods: This retrospective, multicenter study was performed within the German cooperative transplant group (KTS) and included 113 patients who received belumosudil in the MAP provided by Sanofi-Aventis. Fifteen German and one Austrian transplant center contributed data to this analysis. Patients could enter the MAP after at least two and a maximum of five prior lines of treatment (LOT) for chronic GvHD, which had to include ruxolitinib if not intolerant. Organ scoring and response assessment were performed according to the NIH-consensus criteria before start, and at month 1, 3, 6 and 12 thereafter. Events defining failure-free survival (FFS) are relapse, death or start of a new immunosuppressive agent. Adverse events are reported according to the CTCAE criteria (version 5.0). The last-follow-up was on July 31th 2025. Statistical analyses were performed with GraphPad Prism5 and SPSS 28.0. Results: In total, 113 patients (60% male) with a median age of 62 years (range, 20 – 77) were included into the analysis. Underlying diseases were acute myeloid leukemia (50%), myeloproliferative neoplasm (17%), myelodysplastic syndrome (15%), acute lymphoblastic leukemia (8%), lymphoma (6%) and other (4%). Initial cGvHD presentation was quiescent onset in 23%, progressive onset in 13%, and de novo onset in 63% of patients. The cohort had undergone a median of 3 prior LOT (range, 2 – 13). Ninety-three percent of patients were refractory to the previous treatment line. Patients had a history of ruxolitinib and ibrutinib pre-treatment in 93% and 12%, respectively. At belumosudil initiation, 81% of patients presented with severe cGvHD with a median of 3 NIH-defined organ manifestations (range, 1 – 7). Belumosudil (200mg qd and 200mg bd in 67% and 33% of patients) was started at a median of 47 months after alloSCT (range, 8 – 274) with a median treatment duration of 196 days (range, 14 to 856). The best objective response at one and three months was partial remission or better in 41 and 52 patients (36%, one complete remission, and 46%, one complete remission, one mixed response), respectively. Responses were observed across all organ systems. Stable disease was noted in 64 and 36 patients at one and three months (57 and 32%), respectively. At six months, 41 of 67 patients evaluable showed partial remission or better (61%, three complete remissions, one mixed response) and 17 patients were in stable disease (25%). Belumosudil treatment was discontinued in 21 patients (19%) and a new immunosuppressive medication was commenced in 15 patients (13%) over the complete observation time. Forty-four percent of patients were treated with steroids at belumosudil start. Steroid dose reduction was achieved in 17 of these patients (34%). FFS was 89,6%, 84% and 68,4% at three, six and 12 months. One-year overall survival was 91,5%. Treatment-emergent adverse reactions CTCAE grade III-IV were mostly infectious complications and occurred in 23 patients (20%). These adverse reactions included upper respiratory infections/ pneumonia (n=15), urinary tract infection (n=2), pneumococcal meningitis (n=1), mycobacterial infection (n=1), gastrointestinal infection (n=1), ARDS/ sepsis (n=1), herpes zoster (n=1) and EBV-reactivation (n=1). Non-infectious adverse events were diarrheal (n=1), non-melanoma skin cancer (n=1), epileptic seizure (n=1), apoplex (n=1), hypertensive crisis (n=1), mucous membrane hyperplasia (n=1) and one case of Grade IV pancytopenia without alternative cause resolving after belumosudil discontinuation. Conclusions: This retrospective analysis of a large real-world cohort demonstrates efficacy and safety of belumosudil in refractory chronic GvHD patients. Dynamics of organ response are currently under investigation. Further prospective trials are needed to determine the duration of response and the impact on GvHD-related mortality.
Holtick et al. (Mon,) studied this question.