Ruxolitinib Plus Etanercept vs Ruxolitinib for Steroid-Refractory Severe Acute GVHD

Inclusion Criteria: Received allogeneic hematopoietic stem cell transplantation (allo-HSCT) from any donor source (matched sibling, matched unrelated, or haploidentical), using bone marrow, peripheral blood stem cells, or cord blood; conditioning regimen may be myeloablative, reduced-intensity, or non-myeloablative. Age between 12 and 70 years. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. Clinical diagnosis of grade III-IV acute graft-versus-host disease (aGVHD) according to MAGIC criteria. Evidence of neutrophil and platelet engraftment prior to study treatment (absolute neutrophil count \>1,000/mm³ and platelet count ≥20,000/mm³ within 48 hours before study entry; growth factor support and transfusion permitted). Diagnosis of steroid-refractory aGVHD, defined as one of the following: Disease progression after 3-5 days of methylprednisolone 2 mg/kg/day (or equivalent). No improvement after 7 days of methylprednisolone 2 mg/kg/day (or equivalent). Progression from grade II to grade III-IV aGVHD after 3-5 days of methylprednisolone 1 mg/kg/day (or equivalent). Able to take oral medication. Expected survival \>8 weeks. Women of childbearing potential must have a negative serum β-HCG test prior to enrollment; both male and female participants of reproductive potential must agree to use effective contraception during the study and for 3 months after study completion. Voluntary written informed consent provided and ability to comply with study procedures. Exclusion Criteria: Prior systemic treatment for aGVHD other than corticosteroids with or without calcineurin inhibitors (CNI); prophylactic use of MTX, MMF, or CD25 monoclonal antibody is permitted. Clinical features consistent with de novo chronic GVHD or overlap syndrome (per Jagasia 2015). Uncontrolled active infection, including severe bacterial, fungal, viral, or parasitic infection. Patients on appropriate treatment without evidence of progression may be eligible. Evidence of active tuberculosis. Known HIV infection. Relapse of primary malignancy or post-transplant lymphoproliferative disorder. Severe respiratory disease, including mechanical ventilation or resting oxygen saturation \<90%. Renal dysfunction: serum creatinine \>2.0 mg/dL, requirement for dialysis, or creatinine clearance \<30 mL/min (Cockcroft-Gault). Active hepatitis B infection (HBsAg positive with HBV DNA ≥1×10³ IU/mL) or active hepatitis C infection (HCV antibody positive with detectable HCV RNA above normal). Clinically significant or uncontrolled cardiac disease, including recent myocardial infarction, uncontrolled hypertension, NYHA class III/IV heart failure, unstable angina, or clinically significant arrhythmia (e.g., sustained ventricular tachycardia, second- or third-degree AV block). Cholestatic disease or unresolved hepatic veno-occlusive disease not attributed to aGVHD. History of progressive multifocal leukoencephalopathy (PML). Prior exposure to JAK inhibitors after allo-HSCT. Participation in another investigational drug trial within 30 days or within 5 half-lives of the investigational drug (whichever is longer). Prior history of grade ≥3 non-hematologic adverse events attributable to ruxolitinib or etanercept. Any condition judged by the investigator to place the patient at undue risk or interfere with study participation. Known hypersensitivity or intolerance to systemic immunosuppressive agents. Pregnant or breastfeeding women.