Adding etanercept to ruxolitinib for severe steroid-refractory acute GVHD

Prospective Multicenter Randomized Study of Ruxolitinib Plus Etanercept vs Ruxolitinib Alone for Corticosteroid-Refractory Severe Acute GVHD After Allogeneic HSCT

This trial will test whether adding the TNF blocker etanercept to ruxolitinib helps people with severe acute GVHD that did not respond to steroids.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 122 (estimated)
• Ages: 12 Years to 70 Years
• Sex: All
• Sponsor: First Affiliated Hospital of Zhejiang University (Academic / other)
• Drugs / interventions: ruxolitinib
• Locations: 1 site (Hangzhou, Zhejiang)
• Trial ID: NCT07184853 on ClinicalTrials.gov

What this trial studies

This is a prospective, multicenter, randomized, open-label trial comparing ruxolitinib plus etanercept versus ruxolitinib alone in patients with grade III–IV steroid‑refractory acute graft‑versus‑host disease after allogeneic HSCT. Participants are randomized 1:1 with stratification by baseline disease severity, and treatment response is measured at a prespecified primary assessment time point. The trial enrolls adolescents and adults who have evidence of neutrophil and platelet engraftment and ECOG 0–2. Where feasible, centralized or blinded review procedures are used to support outcome adjudication.

Who should consider this trial

Good fit: Adolescents and adults aged 12–70 who have grade III–IV steroid‑refractory acute GVHD after allogeneic HSCT and documented neutrophil and platelet engraftment are the ideal candidates.

Not a fit: Patients with milder (grade I–II) aGVHD, uncontrolled active infections, or contraindications to JAK or TNF‑α inhibitors are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could raise response rates and reduce early mortality in patients with severe steroid‑refractory aGVHD, especially for gastrointestinal or hepatic involvement.

How similar studies have performed: Ruxolitinib is already approved for steroid‑refractory aGVHD and prior single‑arm multicenter reports of ruxolitinib plus etanercept showed encouraging activity, but randomized evidence is not yet available.

Eligibility criteria

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.

Where this trial is running

Hangzhou, Zhejiang

• The First Affiliated Hospital of Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (Recruiting)

Study contacts

• Study coordinator: Hengwei Wu, MD

Conditions Graft vs Host Disease; Ruxolitinib; Etanercept; JAK1/2 inhibitor; TNF-α inhibitor; Corticosteroid-refractory GVHD; Severe aGVHD; Allo-HSCT complications