{"entity":{"id":"paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","kind":"paper","name":"COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1110557"},{"label":"ClinicalTrials.gov NCT00952289","url":"https://clinicaltrials.gov/study/NCT00952289"}],"tags":[],"related":["paper-momentum-momelotinib-lancet-2023"],"cancers":["myeloproliferative-neoplasms"],"sections":[],"technologies":[],"targets":["jak2"],"drugs":["ruxolitinib","fedratinib","pacritinib","momelotinib"],"companies":["incyte","novartis"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-toxicity-qol","b-rare-cancers"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2012,"doi":"10.1056/NEJMoa1110557","authors":"Verstovsek S, Mesa RA, Gotlib J, et al.","paperType":"rct","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."],"whatItMeans":"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."],"changedPractice":true,"participants":309},"route":"/key-papers/paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012/","neighbours":{"paper":[{"id":"paper-momentum-momelotinib-lancet-2023","kind":"paper","name":"MOMENTUM: momelotinib versus danazol for myelofibrosis patients with anaemia after a prior JAK inhibitor","route":"/key-papers/paper-momentum-momelotinib-lancet-2023/"}],"cancer":[{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"},{"id":"primary-myelofibrosis","kind":"cancer","name":"Primary myelofibrosis","route":"/cancers/primary-myelofibrosis/"}],"target":[{"id":"jak2","kind":"target","name":"JAK2","route":"/targets/jak2/"}],"drug":[{"id":"fedratinib","kind":"drug","name":"Fedratinib","route":"/drugs/fedratinib/"},{"id":"momelotinib","kind":"drug","name":"Momelotinib","route":"/drugs/momelotinib/"},{"id":"pacritinib","kind":"drug","name":"Pacritinib","route":"/drugs/pacritinib/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"}],"company":[{"id":"incyte","kind":"company","name":"Incyte","route":"/companies/incyte/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-toxicity-qol","kind":"bottleneck","name":"Toxicity and quality of life are undervalued","route":"/bottlenecks/b-toxicity-qol/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"person":[{"id":"claire-harrison","kind":"person","name":"Claire Harrison","route":"/people/claire-harrison/"}],"trial":[{"id":"comfort-i","kind":"trial","name":"COMFORT-I","route":"/trials/comfort-i/"}]}}