Belumosudil Versus Ruxolitinib for Steroid-Refractory or Breakthrough Hepatic cGVHD

Inclusion criteria

• Age ≥ 12 years at time of signing informed consent.
• Received allogeneic hematopoietic stem cell transplantation.
• 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.
• ECOG performance status ≤ 2.
• Able to take oral medication.
• Life expectancy ≥ 6 months.
• Adequate organ function: ANC ≥ 1.0×10⁹/L, platelets ≥ 50×10⁹/L, creatinine clearance ≥ 30 mL/min.
• 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.
• Willing and able to provide written informed consent and comply with study requirements.
• 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.).
• 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

• 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.
• Uncontrolled active acute GVHD (≥ grade 2).
• Active viral hepatitis or HIV infection.
• 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.
• Severe cardiovascular or cerebrovascular disease, including but not limited to: NYHA class ≥3, uncontrolled hypertension, severe arrhythmia, or myocardial infarction/stroke within 6 months.
• 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.
• 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.
• Significant neurological or psychiatric history (including epilepsy or dementia) that makes the subject unsuitable for participation.
• Relapsed primary malignancy or PTLD.
• 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.
• ECG abnormality: QTcF >450 ms (male) or >470 ms (female) at screening.
• Known alcohol or drug dependence.
• Pregnant or breastfeeding women.
• Allergy to study drug or its excipients.
• Any other condition that may affect patient safety or compliance, per investigator judgment.
• 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.
• Cohort 2: Patients with prior exposure to both ruxolitinib and belumosudil.