# COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis

Source: https://onco.cc/key-papers/paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012/  
OnCo record `paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2012
- DOI: 10.1056/NEJMoa1110557
- Authors: Verstovsek S, Mesa RA, Gotlib J, et al.
- Findings: 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.
- What it means: 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.
- Caveats: 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.

## Sources

- Full text (DOI): https://doi.org/10.1056/NEJMoa1110557
- ClinicalTrials.gov NCT00952289: https://clinicaltrials.gov/study/NCT00952289

## Connected records

- key papers: [MOMENTUM: momelotinib versus danazol for myelofibrosis patients with anaemia after a prior JAK inhibitor](https://onco.cc/key-papers/paper-momentum-momelotinib-lancet-2023/)
- cancers: [Myeloproliferative neoplasms (PV, ET, myelofibrosis)](https://onco.cc/cancers/myeloproliferative-neoplasms/), [Primary myelofibrosis](https://onco.cc/cancers/primary-myelofibrosis/)
- targets: [JAK2](https://onco.cc/targets/jak2/)
- drugs: [Fedratinib](https://onco.cc/drugs/fedratinib/), [Momelotinib](https://onco.cc/drugs/momelotinib/), [Pacritinib](https://onco.cc/drugs/pacritinib/), [Ruxolitinib](https://onco.cc/drugs/ruxolitinib/)
- companies: [Incyte](https://onco.cc/companies/incyte/), [Novartis](https://onco.cc/companies/novartis/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- people: [Claire Harrison](https://onco.cc/people/claire-harrison/)
- trials: [COMFORT-I](https://onco.cc/trials/comfort-i/)

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