COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis
Ruxolitinib shrank the enlarged spleen by more than a third in 42% of myelofibrosis patients versus under 1% on placebo, and halved symptom scores in nearly half.
COMFORT-I was a double-blind phase 3 trial that randomised 309 patients with intermediate-2 or high-risk myelofibrosis to the JAK1/JAK2 inhibitor ruxolitinib or placebo. The primary endpoint was the proportion with at least a 35% reduction in spleen volume at 24 weeks by imaging. This was 41.9% versus 0.7%, and a 50% or greater improvement in total symptom score was seen in 45.9% versus 5.3%. Anaemia and thrombocytopenia were the main toxicities. A parallel trial, COMFORT-II, showed similar spleen responses against best available therapy. Later analyses suggested a survival advantage for ruxolitinib despite crossover. It was the first drug approved for myelofibrosis and the first approved JAK inhibitor for a malignancy.
- 309 patients with intermediate-2 or high-risk myelofibrosis; ruxolitinib vs placebo, double-blind.
- Spleen volume reduction of at least 35% at week 24: 41.9% vs 0.7%.
- Symptom score improvement of at least 50%: 45.9% vs 5.3%.
- Grade 3-4 anaemia 45% and thrombocytopenia 13% with ruxolitinib; rarely led to discontinuation.
- Pooled COMFORT analyses later showed an overall survival advantage (hazard ratio about 0.7) despite extensive crossover.
COMFORT-I turned the 2005 discovery of the JAK2 V617F mutation into the first effective medicine for myelofibrosis, transforming symptom control for a disease with no prior standard. Ruxolitinib is still the reference first-line therapy, with fedratinib, pacritinib and momelotinib as alternatives for cytopenic patients. It does not eliminate the malignant clone or reverse fibrosis in most patients.
- Primary endpoint was spleen volume, a surrogate; survival gains were shown only in later, crossover-confounded analyses.
- Ruxolitinib worsens anaemia, limiting use in already-anaemic patients.
- Benefit is largely symptomatic; molecular responses are uncommon.
- Discontinuation is followed by rapid symptom rebound.
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