title: Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial.
abstract: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results.
  
  
  
  Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment.
  
  
  
  Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%).
  
  
  
  The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF.
  
  
  
  ClinicalTrials.gov, NCT00952289.
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 418, Houston, TX, 77030, USA. sverstov@mdanderson.org.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Mayo Clinic Cancer Center, 13400 E. Shea Blvd, Scottsdale, AZ, 85259, USA.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.affiliation: Stanford Cancer Institute, 875 Blake Wilbur Drive, Room 2324, Stanford, CA, 94305, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.affiliation: Princess Margaret Cancer Center, University of Toronto, 610 University Avenue, Suite 5-217, Toronto, M5G 2M9, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Washington University School of Medicine, 660S Euclid Ave., St. Louis, MO, 63110, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: Frankston Hospital and Department of Clinical Haematology, Monash University, 2 Hastings Rd, Frankston, VIC, 3199, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Catalano
authors.affiliation: University of Utah Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.|Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Michael W N
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: Saint Agnes Cancer Institute, 900S Caton Ave., Baltimore, MD, 21229, USA.
authors.forename: Carole B
authors.initials: CB
authors.lastname: Miller
authors.affiliation: Weill Cornell Medical Center, 525 East 68th St., Payson Pavilion 3, New York, NY, 10021, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Silver
authors.affiliation: University of Michigan, 1500 E Medical Center Dr., Ann Arbor, MI, 48109, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Emory University School of Medicine, 1365 C Clifton Rd. Suite 1152, Atlanta, GA, 30322, USA.
authors.forename: Elliott F
authors.initials: EF
authors.lastname: Winton
authors.affiliation: Birmingham Hematology and Oncology, 1024 First St North, Birmingham, AL, 35204, USA.
authors.forename: Jimmie H
authors.initials: JH
authors.lastname: Harvey
authors.affiliation: Duke University Health System, DUMC 3912, Durham, NC, 27710, USA.
authors.forename: Murat O
authors.initials: MO
authors.lastname: Arcasoy
authors.affiliation: Abramson Cancer Center at the University of Pennsylvania, 3400 Civic Center Blvd., PCAM 2 West Pavilion, Philadelphia, PA, 19104, USA.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Hexner
authors.affiliation: Texas Oncology and US Oncology Research, 4411 Medical Dr., San Antonio, TX, 78229, USA.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Lyons
authors.affiliation: Cedars-Sinai, 10833 Le Conte Ave., 42-121 CHS, Los Angeles, CA, 90024, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Paquette
authors.affiliation: Columbia University Medical Center, Milstein Hospital Building, 6N-435, 177 Fort Washington Ave., New York, NY, 10032, USA.
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.affiliation: Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE, 19803, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Jones
authors.affiliation: Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE, 19803, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Kornacki
authors.affiliation: Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE, 19803, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 418, Houston, TX, 77030, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004311:Double-Blind Method; D005221:Fatigue / Q000139:chemically induced; D005500:Follow-Up Studies; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles; D011014:Pneumonia / Q000139:chemically induced; D055728:Primary Myelofibrosis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D018570:Risk Assessment; D018805:Sepsis / Q000139:chemically induced; D013163:Splenomegaly / Q000188:drug therapy; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053612:Janus Kinases
keywords: JAK; Janus kinase; Myelofibrosis