Researchers from the Second Affiliated Hospital of Dalian Medical University have demonstrated that combining ruxolitinib with methylprednisolone as first-line therapy for acute graft-versus-host disease (aGVHD) significantly improves early treatment response compared to standard steroid monotherapy. The retrospective real-world study, published in Frontiers in Immunology, analyzed 133 patients who developed aGVHD following allogeneic hematopoietic stem cell transplantation between August 2014 and June 2023.
Enhanced Early Response Rates
The study's primary endpoint revealed striking differences in overall response rates (ORR) between treatment groups. While day 3 response rates were comparable between groups (59% vs 58%), the ruxolitinib/steroid combination demonstrated superior efficacy by day 7, achieving an 86% response rate compared to 68% with steroids alone (OR=2.78, 95% CI: 1.18-6.53, p=0.019). This advantage persisted at day 14, with 92% versus 79% response rates respectively (OR=2.77, 95% CI: 0.98-7.87, p=0.05).
The combination group received ruxolitinib at 10-15 mg daily alongside methylprednisolone at 0.5-2 mg/kg/day, with dosing determined by aGVHD severity. Patients with mild disease (grades I-II) received 0.5 mg/kg methylprednisolone, while those with severe gastrointestinal involvement or hyperacute GVHD received 2 mg/kg.
Long-term Survival Outcomes
Despite similar 3-year overall survival rates between groups (70.5% vs 67.6%), the analysis revealed that achieving early response was crucial for long-term outcomes. Patients who achieved ORR at day 7 demonstrated significantly better overall survival (HR=0.45, 95% CI: 0.23-0.88, p=0.02), with even stronger associations observed for day 14 responders (HR=0.37, 95% CI: 0.17-0.78, p=0.009).
Multivariate analysis identified day 14 ORR (HR=0.37, 95% CI: 0.16-0.88, p=0.02), aGVHD grade, and hematopoietic cell transplant-comorbidity index as independent predictors of overall survival. The median follow-up duration was 47 months for the combination group and 90 months for the steroid-only group.
Subgroup Analysis Benefits
In patients receiving peripheral blood stem cell transplantation, the ruxolitinib/steroid combination showed particularly pronounced benefits. Three-year overall survival was 64.3% versus 27.3% (p=0.046), with progression-free survival of 57.1% versus 27.3% (p=0.05) and superior 2-year failure-free survival (21% vs 9%, p=0.05).
Safety Profile and Adverse Events
The safety analysis revealed manageable toxicity profiles, with no patients discontinuing ruxolitinib due to side effects. The most frequently observed adverse events in the combination group included neutropenia (32.5% vs 12%, p=0.008), cytomegalovirus infection (34.9% vs 18%, p=0.036), and renal toxicity (20.4% vs 6%, p=0.024). These complications were effectively managed with granulocyte colony-stimulating factor and antiviral agents.
Clinical Implications
The study builds upon recent phase III trial data from Chinese researchers showing similar benefits of ruxolitinib-steroid combinations. The JAK1/2 inhibitor ruxolitinib works through multiple mechanisms, including reduced neutrophil migration, decreased T-cell priming via MHC-II downregulation, and limited cytokine release during aGVHD pathogenesis.
"The ruxolitinib/steroid combination cohort could indirectly influence OS, PFS, and FFS by improving the early ORR on days 7 and 14," the researchers noted, emphasizing the importance of rapid disease control in aGVHD management.
Study Limitations and Future Directions
The researchers acknowledged several limitations inherent to retrospective real-world studies, including non-randomized treatment assignment and potential selection bias. Additionally, the combination group had a higher proportion of grade II aGVHD patients compared to the steroid-only group.
The findings support the growing evidence for ruxolitinib as first-line therapy for aGVHD, particularly given the limitations of prolonged steroid therapy, which can cause serious adverse effects including hyperglycemia, osteoporosis, cardiovascular complications, and increased infection risk. Approximately 50% of patients fail to respond to standard steroid treatment, highlighting the need for more effective first-line approaches.
This real-world evidence complements controlled trial data and provides valuable insights into the practical implementation of ruxolitinib-steroid combinations for newly diagnosed aGVHD patients, potentially establishing a new standard of care for this challenging post-transplant complication.
