Belumosudil Versus Ruxolitinib for Steroid-Refractory or Breakthrough Hepatic cGVHD

Summary

This prospective, randomized, open-label, multicenter trial aims to compare second-line treatment strategies for hepatic cGVHD after allo-HSCT. Ruxolitinib and belumosudil are both effective for cGVHD, but no head-to-head comparison specifically in hepatic cGVHD has been reported. Two cohorts are enrolled: Cohort 1 comprises patients with steroid-refractory hepatic cGVHD without prior ruxolitinib or belumosudil exposure, randomized to receive either agent. Cohort 2 includes patients who develop new-onset hepatic cGVHD after ≥4 weeks of therapy with ruxolitinib or belumosudil for other-organ cGVHD (stable for ≥2 weeks), or patients with non-response/progression on either agent for hepatic cGVHD; these patients will be switched to the opposite drug. Key questions include: • In steroid-refractory hepatic cGVHD, does 24-week hepatic overall response rate differ between belumosudil and ruxolitinib? • What is the hepatic response rate after drug switching in Cohort 2? • How do the two agents compare in safety and tolerability for hepatic cGVHD? • What are their impacts on corticosteroid tapering, failure-free survival, and long-term outcomes? Participants will: • Receive assigned treatment per cohort and randomization • Undergo regular efficacy/safety monitoring, including hepatic cGVHD scoring, liver function tests, and adverse event recording • Provide peripheral blood samples at baseline and multiple on-treatment time points for exploratory biomarker analysis • Complete 24-week primary efficacy assessment with follow-up until progression or discontinuation Primary endpoint is 24-week hepatic overall response rate (CR+PR, per 2014 NIH cGVHD criteria). Secondary endpoints include duration of response, failure-free survival, corticosteroid tapering rate, safety (AE/SAE incidence), liver function improvement, and patient-reported outcomes. This head-to-head comparison will provide high-level evidence for selecting second-line and beyond therapies for hepatic cGVHD.

Timeline

Start

2026-10-01

Primary completion

2030-04-01

Completion

2030-12-31

Publications

• Background Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015 Mar;21(3):389-401.e1. doi: 10.1016/j.bbmt.2014.12.001. Epub 2014 Dec 18.
• Background Hall K, Lazaryan A, van der Laan M, Lee C, Logan AC, Gruber S, Kabadi S, Khan I, Nicholls C, Rota L, Nikai E, Ponomareva E, Koumas A, Waller EK. Efficacy and safety of belumosudil as compared with best available therapy for the treatment of cGVHD in the United States. Blood Adv. 2026 Feb 10;10(3):682-693. doi: 10.1182/bloodadvances.2025015832.
• Background Lee SJ, Pavletic S, Blazar BR, Yao Y, Ji R, Marshall K, Cutler C; KD025-208 and ROCKstar Study Investigators. Belumosudil for Chronic Graft-Versus-Host Disease: Analysis of Long-Term Results from the KD025-208 and ROCKstar Studies. Transplant Cell Ther. 2025 Jul;31(7):434.e1-434.e10. doi: 10.1016/j.jtct.2025.04.020. Epub 2025 May 1.
• Background Ibrahimova A, Bidgoli A, Ashraf A, Krogman A, Klink G, Teusink-Cross A, Schoettler ML, Davies SM, Khandelwal P. Real world experience using belumosudil for treatment of chronic graft versus host disease in children and young adults. Bone Marrow Transplant. 2026 Apr;61(4):487-489. doi: 10.1038/s41409-025-02795-9. Epub 2026 Jan 21. No abstract available.
• Background Nalkurthi C, Schroder WA, Melino M, Irvine KM, Nyuydzefe M, Chen W, Liu J, Teng MWL, Hill GR, Bertolino P, Blazar BR, Miller GC, Clouston AD, Zanin-Zhorov A, MacDonald KPA. ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis. JHEP Rep. 2021 Oct 6;4(1):100386. doi: 10.1016/j.jhepr.2021.100386. eCollection 2022 Jan.
• Background Modi B, Ngo D, Chen J, Yang D, Shan H, Sandhu K, Rashid N, Amanam I, Otoukesh S, Nakamura R, Ali H, Salhotra A. Belumosudil for the treatment of chronic graft-versus-host disease: a single center real-world experience. Bone Marrow Transplant. 2025 Apr;60(4):555-557. doi: 10.1038/s41409-024-02498-7. Epub 2025 Feb 4. No abstract available.
• Background Michonneau D, Malard F, Le Grand S, Magro L, D'Aveni M, Tudesq JJ, Villate A, Meunier M, Maillard N, Castilla-Llorente C, Marcais A, Cabrera Q, Huynh A, Menard AL, Forcade E, Labussiere-Wallet H, Raus N, Loschi M. Efficacy and safety of belumosudil for treatment of cGVHD: multicenter retrospective analysis of the French cohort of the compassionate use program, on behalf of the French Society of Bone Marrow Transplantation and Cellular Therapy. Bone Marrow Transplant. 2025 Jun;60(6):779-786. doi: 10.1038/s41409-025-02554-w. Epub 2025 Apr 1.
• Background Jagasia M, Lazaryan A, Bachier CR, Salhotra A, Weisdorf DJ, Zoghi B, Essell J, Green L, Schueller O, Patel J, Zanin-Zhorov A, Weiss JM, Yang Z, Eiznhamer D, Aggarwal SK, Blazar BR, Lee SJ. ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease. J Clin Oncol. 2021 Jun 10;39(17):1888-1898. doi: 10.1200/JCO.20.02754. Epub 2021 Apr 20.
• Background Inamoto Y, Kato K, Kawakita T, Onishi Y, Matsuoka KI, Shiratori S, Ikegame K, Hiramoto N, Toyosaki M, Katayama Y, Murayama S, Sasagawa Y, Maeda Y, Hatake K, Teshima T. An open-label study of belumosudil, a selective ROCK2 inhibitor, as second or subsequent line of therapy for steroid-dependent/steroid-resistant chronic GVHD. Am J Hematol. 2024 Oct;99(10):1917-1926. doi: 10.1002/ajh.27424. Epub 2024 Jun 27.
• Background Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta R, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin J, Im A, Langston A, Liesveld J, Juckett M, Logan A, Schachter L, Alavi A, Howard D, Waksal HW, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green L, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic S. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021 Dec 2;138(22):2278-2289. doi: 10.1182/blood.2021012021.
• Background Zeiser R, Russo D, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hamad N, Burock K, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F. Ruxolitinib in Patients With Corticosteroid-Refractory or Corticosteroid-Dependent Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of the Phase III REACH3 Study. J Clin Oncol. 2025 Aug 10;43(23):2566-2571. doi: 10.1200/JCO-24-02477. Epub 2025 Jun 25.
• Background Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F; REACH3 Investigators. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021 Jul 15;385(3):228-238. doi: 10.1056/NEJMoa2033122.
• Background Zeiser R, Lee SJ. Three US Food and Drug Administration-approved therapies for chronic GVHD. Blood. 2022 Mar 17;139(11):1642-1645. doi: 10.1182/blood.2021014448.
• Background Hematopoietic Stem Cell Application Group, Chinese Society of Hematology, Chinese Medical Association. [Chinese expert consensus on the diagnosis and treatment of chronic graft-versus-host disease (2024)]. Zhonghua Xue Ye Xue Za Zhi. 2024 Aug 14;45(8):713-726. doi: 10.3760/cma.j.cn121090-20240611-00217. Chinese.

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