RecruitingNot ApplicableNCT07184853

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

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

Sponsor

First Affiliated Hospital of Zhejiang University

Enrollment

122 participants

Start Date

Sep 25, 2025

Study Type

INTERVENTIONAL

Conditions

Graft vs Host Disease

Summary

This is a prospective, multicenter, randomized controlled trial designed to evaluate whether the combination of ruxolitinib and etanercept provides superior efficacy compared with ruxolitinib monotherapy in patients with severe corticosteroid-refractory acute graft-versus-host disease (SR-aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Acute graft-versus-host disease (aGVHD) is one of the most common and life-threatening complications following allo-HSCT. Although corticosteroids remain the standard first-line treatment, many patients do not respond adequately. For patients with severe steroid-refractory aGVHD, the prognosis is extremely poor, with high short-term mortality and very low long-term survival. Ruxolitinib, a JAK1/2 inhibitor, has been approved for the treatment of SR-aGVHD, but response rates remain suboptimal, particularly in patients with gastrointestinal involvement. Etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, has shown activity in GVHD by targeting inflammatory pathways. Previous observational studies from our center suggested that combining ruxolitinib with etanercept may improve response rates, especially in gastrointestinal and hepatic GVHD, without significantly increasing relapse risk. In this trial, approximately 122 patients with grade III-IV SR-aGVHD will be randomized 1:1 to receive either ruxolitinib alone or ruxolitinib plus etanercept. The primary endpoint is the overall response rate (ORR) at day 28. Secondary endpoints include durable response, best overall response, failure-free survival, overall survival, cumulative incidence of relapse, non-relapse mortality, incidence of chronic GVHD, and safety outcomes. This study seeks to provide new clinical evidence for an optimized treatment strategy for patients with severe SR-aGVHD, aiming to improve outcomes in this high-risk population.

Eligibility

Min Age: 12 YearsMax Age: 70 Years

Inclusion Criteria13

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 Criteria18

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.

Interested in this trial?

Get notified about updates and connect with the research team.

Interventions

DRUGRuxolitinib (JAKAVI®)

Ruxolitinib will be administered orally at a dose of 10 mg twice daily (approximately every 12 hours), with or without food. Dose modifications are allowed according to protocol-defined safety and efficacy criteria. Ruxolitinib may be continued for up to 24 weeks, with tapering guided by patient response and GVHD status.

DRUGEtanercept (Enbrel)

Etanercept will be administered as a subcutaneous injection at a dose of 25 mg twice weekly for 4 weeks (total 8 doses). For patients with partial response at day 28, treatment may be extended once weekly for an additional 2-4 weeks at the investigator's discretion.