Background
Phase 3, multicenter, open-label RCT (REACH3). 329 patients aged ≥12 years with steroid-refractory (SR) or steroid-dependent chronic graft-versus-host disease (cGvHD) across 94 centers worldwide. SR-cGvHD defined as progression on ≥1 mg/kg/day prednisone, no improvement after ≥8 weeks, or inability to taper below 0.5 mg/kg. Prior REACH2 established ruxolitinib in SR-aGvHD; REACH3 addressed the unmet need in chronic GvHD.
Interventions and follow up
Arm A: Ruxolitinib 10 mg orally twice daily (+ stable baseline immunosuppression)
Arm B: Best available therapy (BAT) — investigator's choice from 10 prespecified options including ECP, MMF, everolimus, ibrutinib, imatinib, rituximab, and others
Primary endpoint: Overall response rate (ORR = CR + PR) at cycle 7 (week 24)
Median follow up: 57.3 weeks
Arm B: Best available therapy (BAT) — investigator's choice from 10 prespecified options including ECP, MMF, everolimus, ibrutinib, imatinib, rituximab, and others
Primary endpoint: Overall response rate (ORR = CR + PR) at cycle 7 (week 24)
Median follow up: 57.3 weeks
Results
ORR at cycle 7: 49.7% vs 25.6%, OR 2.99 (95% CI 1.86–4.80), P<.001
CR rate: 6.7% vs 3.0%
Failure-free survival at 24 weeks: 63.0% vs 38.4%, HR 0.55 (95% CI 0.41–0.73), P<.001
Duration of response: not reached (ruxolitinib) vs 6.24 months (BAT)
Crossover: 60% of BAT arm crossed over to ruxolitinib at progression
CR rate: 6.7% vs 3.0%
Failure-free survival at 24 weeks: 63.0% vs 38.4%, HR 0.55 (95% CI 0.41–0.73), P<.001
Duration of response: not reached (ruxolitinib) vs 6.24 months (BAT)
Crossover: 60% of BAT arm crossed over to ruxolitinib at progression
Adverse events
Grade ≥3 AEs: 57.8% (ruxolitinib) vs 57.6% (BAT) — similar
Infections grade ≥3: 29.7% vs 22.7%; CMV reactivation 8.5% vs 4.9%
Cytopenias grade ≥3: thrombocytopenia 15.2% vs 13.6%; anemia 13.3% vs 14.4%; most toxicities manageable without dose interruption
Infections grade ≥3: 29.7% vs 22.7%; CMV reactivation 8.5% vs 4.9%
Cytopenias grade ≥3: thrombocytopenia 15.2% vs 13.6%; anemia 13.3% vs 14.4%; most toxicities manageable without dose interruption
Conclusions
Ruxolitinib significantly improved ORR and failure-free survival in steroid-refractory/dependent cGvHD compared with best available therapy, establishing it as a new standard second-line treatment for this condition.
Key Limitations
Design: open-label; subjective cGvHD response assessments introduce potential bias
Comparator: heterogeneous BAT of agents with variable activity, not a true single-agent standard
Interpretation: 60% BAT-to-ruxolitinib crossover complicates OS; prior-ibrutinib patients excluded, limiting generalizability for BTKi-pretreated patients
Comparator: heterogeneous BAT of agents with variable activity, not a true single-agent standard
Interpretation: 60% BAT-to-ruxolitinib crossover complicates OS; prior-ibrutinib patients excluded, limiting generalizability for BTKi-pretreated patients
Clinical Context
Ruxolitinib (Jakafi) was FDA approved September 2021 for SR-cGvHD in patients ≥12 years based on REACH3 and is now the preferred second-line agent. Ibrutinib (approved 2017) and belumosudil (ROCK2 inhibitor, ROCKstar trial) are alternatives, giving clinicians three approved options to choose among based on toxicity profile and prior therapy. ESMO and BMT CTN guidance incorporate ruxolitinib as a first choice after steroid failure.