Belumosudil Versus Ruxolitinib for Steroid-Refractory or Breakthrough Hepatic cGVHD

Belumosudil Versus Ruxolitinib for Steroid-Refractory or Breakthrough Hepatic cGVHD: A Prospective, Multicenter Study With Randomization in Treatment-Naïve Patients and Switch in Pretreated Patients

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.

Inclusion Criteria:

1. Age ≥ 12 years at time of signing informed consent.
2. Received allogeneic hematopoietic stem cell transplantation.
3. Meets 2014 NIH consensus criteria for hepatic cGVHD (≥1 of: total bilirubin > 2×ULN, ALP > 2×ULN, ALT > 2×ULN, or liver biopsy-proven cGVHD-related injury), after excluding other causes.
4. ECOG performance status ≤ 2.
5. Able to take oral medication.
6. Life expectancy ≥ 6 months.
7. Adequate organ function: ANC ≥ 1.0×10⁹/L, platelets ≥ 50×10⁹/L, creatinine clearance ≥ 30 mL/min.
8. Female patients of childbearing potential have negative pregnancy test and agree to effective contraception during study and for 6 months after last dose; male patients agree to same.
9. Willing and able to provide written informed consent and comply with study requirements.
10. Cohort 1 (Steroid-refractory): Progressive disease on stable steroids (1 mg/kg/day) within 1-2 weeks prior to screening, or persistent cGVHD without improvement after ≥4 weeks of prednisone (or equivalent) > 0.5 mg/kg/day. (Prior aGVHD JAK inhibitor use allowed if stopped ≥8 weeks.).
11. Cohort 2 (Breakthrough hepatic cGVHD): Patients on stable (≥2 weeks) ruxolitinib or belumosudil monotherapy for non-hepatic cGVHD for ≥4 weeks, who develop new-onset hepatic cGVHD or experience no response or progression on current therapy for hepatic cGVHD, not attributable to other etiologies (e.g., viral hepatitis, drug-induced liver injury, biliary obstruction, iron overload, alcoholic liver disease), with no prior exposure to the alternative study agent.

Exclusion Criteria:

1. Receiving newly initiated systemic cGVHD therapy other than corticosteroids and calcineurin inhibitors (CNIs); corticosteroids and CNIs must be on a stable regimen for ≥2 weeks prior to screening.
2. Uncontrolled active acute GVHD (≥ grade 2).
3. Active viral hepatitis or HIV infection.
4. Liver function abnormalities due to other causes, including but not limited to drug-induced liver injury, autoimmune hepatitis, alcoholic liver disease, biliary obstruction, VOD/SOS, iron overload, Gilbert's syndrome, or hemolysis.
5. Severe cardiovascular or cerebrovascular disease, including but not limited to: NYHA class ≥3, uncontrolled hypertension, severe arrhythmia, or myocardial infarction/stroke within 6 months.
6. Respiratory failure requiring mechanical ventilation, resting pulse oxygen saturation <90%, or severe/uncontrolled pulmonary cGVHD or other respiratory disease that may significantly affect patient safety or study assessment, per investigator judgment.
7. Inability to take oral medication, severe gastrointestinal dysfunction (NCI CTCAE v5.0 ≥ grade 3), severe GI cGVHD requiring parenteral nutrition, daily diarrhea >1 L, or any other condition significantly affecting GI absorption.
8. Significant neurological or psychiatric history (including epilepsy or dementia) that makes the subject unsuitable for participation.
9. Relapsed primary malignancy or PTLD.
10. History of other malignancies, except cured and fully resected basal or squamous cell skin carcinoma, surgically cured cervical carcinoma in situ, resected ductal carcinoma in situ of the breast, prostate cancer (Gleason <6 with stable PSA >12 months), or other malignancies with no evidence of recurrence after curative treatment.
11. ECG abnormality: QTcF >450 ms (male) or >470 ms (female) at screening.
12. Known alcohol or drug dependence.
13. Pregnant or breastfeeding women.
14. Allergy to study drug or its excipients.
15. Any other condition that may affect patient safety or compliance, per investigator judgment.
16. Cohort 1: Prior cGVHD treatment with JAK inhibitors (e.g., ruxolitinib) or ROCK2 inhibitors (e.g., belumosudil); receipt of other investigational therapy within 30 days prior to randomization, or <5 half-lives since last investigational product.
17. Cohort 2: Patients with prior exposure to both ruxolitinib and belumosudil.