Background
Phase 3, double-blind, placebo-controlled trial. 309 patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF. Randomized 1:1. The pivotal US-based trial for ruxolitinib (JAK1/2 inhibitor) in myelofibrosis.
Interventions and follow up
Arm A: Ruxolitinib orally twice daily (dose based on platelet count; 15–20 mg BID; n=155)
Arm B: Placebo orally twice daily (n=154)
Primary endpoint: Proportion with spleen volume reduction ≥35% at 24 weeks (by MRI)
mFollow up: 24 weeks (primary); extended follow-up for OS
Arm B: Placebo orally twice daily (n=154)
Primary endpoint: Proportion with spleen volume reduction ≥35% at 24 weeks (by MRI)
mFollow up: 24 weeks (primary); extended follow-up for OS
Results
SVR ≥35% at 24 weeks (SVR35): 41.9% vs 0.7%, P<.001
Response durability ≥48 weeks: 67% of responders maintained response
TSS ≥50% improvement at 24 weeks (TSS50): 45.9% vs 5.3%, P<.001
Deaths at data cutoff: 13 (ruxolitinib) vs 24 (placebo), HR 0.50 (95% CI 0.25–0.98), P=.04
Response durability ≥48 weeks: 67% of responders maintained response
TSS ≥50% improvement at 24 weeks (TSS50): 45.9% vs 5.3%, P<.001
Deaths at data cutoff: 13 (ruxolitinib) vs 24 (placebo), HR 0.50 (95% CI 0.25–0.98), P=.04
Adverse events
Hematologic: anemia and thrombocytopenia were the most common AEs; each led to discontinuation in only 1 patient
Discontinuation/transformation: discontinuation 11.0% vs 10.6%; 2 patients transformed to AML, both in the ruxolitinib group
Nonhematologic: predominantly grade 1–2
Discontinuation/transformation: discontinuation 11.0% vs 10.6%; 2 patients transformed to AML, both in the ruxolitinib group
Nonhematologic: predominantly grade 1–2
Conclusions
Ruxolitinib produced highly significant spleen volume reduction and symptom improvement in intermediate-2/high-risk myelofibrosis, with a preliminary signal of improved overall survival (HR 0.50) versus placebo. This trial established ruxolitinib as the first FDA-approved therapy for myelofibrosis and defined the therapeutic paradigm for this disease.
Key Limitations
OS analysis at the primary timepoint was preliminary; only 37 deaths occurred. The placebo arm permitted crossover after 24 weeks, diluting long-term OS comparisons. Dose selection by platelet count is clinically complex. The trial was not stratified by driver mutation (JAK2 vs CALR vs MPL), which may affect response heterogeneity. Patients with very low platelet counts (<50×10⁹/L) were excluded. Extended (5-year) follow-up later confirmed an OS benefit.
Clinical Context
COMFORT-I led to FDA approval of ruxolitinib in November 2011 for intermediate- or high-risk myelofibrosis, the first approved treatment for this disease. Ruxolitinib remains the backbone of MF therapy. Subsequent agents (pacritinib for low-platelet MF; momelotinib for anemia-predominant MF; fedratinib as second-line; navitoclax combinations) address ruxolitinib's limitations. ESMO and ELN guidance support JAK inhibitor therapy as standard of care for symptomatic intermediate/high-risk MF.