Overview
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.
Description
Steroid-refractory severe acute graft-versus-host disease (SR-aGVHD) remains a leading cause of early morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Although ruxolitinib (JAK1/2 inhibition) improves outcomes versus best available therapy, non-response and limited durability-particularly with gastrointestinal involvement-underscore the need for rational combination strategies. Tumor necrosis factor-α (TNF-α) is a proximal driver of allo-inflammation; biomarker analyses suggesting elevated TNFR1 among non-responders to JAK inhibition support TNF-α pathway engagement as a potential mechanism of resistance. Prior single-arm, multicenter experience with ruxolitinib plus etanercept has shown encouraging activity in severe disease, including gastrointestinal and hepatic involvement, without an apparent increase in relapse risk, providing the rationale for this randomized evaluation.
This prospective, multicenter, randomized, open-label study tests whether adding etanercept to ruxolitinib improves clinical response at the prespecified primary assessment time point in patients with corticosteroid-refractory severe aGVHD after allogeneic transplantation. Participants are randomized 1:1 to combination therapy or ruxolitinib alone, with stratification by baseline disease severity to balance key prognostic factors across arms. The open-label design reflects practical differences in administration; where feasible, centralized or blinded review procedures are implemented to mitigate assessment bias.
Study treatment follows protocol-defined principles for initiation, modification, and discontinuation that align with current practice, including management algorithms for cytopenias, organ dysfunction, and relevant drug interactions. Systemic corticosteroids at enrollment are required for the SR definition; tapering after response is guided by predefined algorithms. Concomitant supportive care, infection prophylaxis, and transfusion support are provided according to institutional standards. Rescue therapy or treatment withdrawal is permitted under prespecified lack-of-benefit or safety criteria.
The primary objective is to determine superiority of combination therapy over ruxolitinib alone on clinical response at the primary time point. Key secondary objectives address response durability, transplant-related outcomes, corticosteroid exposure, and safety/tolerability; exploratory analyses include infection burden and biomarker assessments to characterize pharmacodynamic effects and response heterogeneity. Outcome definitions and time frames are specified in the Outcome Measures section; eligibility criteria are provided in the Eligibility section.
Safety is actively monitored throughout treatment and follow-up, with predefined surveillance for infections (including viral reactivation), cytopenias, and organ-specific toxicities. An independent safety review process periodically evaluates unblinded data per charter. The trial is sized to detect a clinically meaningful difference under conservative assumptions and includes longitudinal follow-up to capture durability, survival, and late safety signals, thereby informing whether dual pathway modulation (JAK and TNF-α) can improve outcomes in this high-risk population without unacceptable toxicity.
Eligibility
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.