title: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.
abstract: BACKGROUND
  Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.
  
  
  METHODS
  In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.
  
  
  RESULTS
  The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.
  
  
  CONCLUSIONS
  Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).
authors.affiliation: Leukemia Department, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. sverstov@mdanderson.org
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Richard S
authors.initials: RS
authors.lastname: Levy
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: John V
authors.initials: JV
authors.lastname: Catalano
authors.forename: Michael
authors.initials: M
authors.lastname: Deininger
authors.forename: Carole
authors.initials: C
authors.lastname: Miller
authors.forename: Richard T
authors.initials: RT
authors.lastname: Silver
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Elliott F
authors.initials: EF
authors.lastname: Winton
authors.forename: Jimmie H
authors.initials: JH
authors.lastname: Harvey
authors.forename: Murat O
authors.initials: MO
authors.lastname: Arcasoy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hexner
authors.forename: Roger M
authors.initials: RM
authors.lastname: Lyons
authors.forename: Ronald
authors.initials: R
authors.lastname: Paquette
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
authors.forename: Susan
authors.initials: S
authors.lastname: Erickson-Viitanen
authors.forename: Iphigenia L
authors.initials: IL
authors.lastname: Koumenis
authors.forename: William
authors.initials: W
authors.lastname: Sun
authors.forename: Victor
authors.initials: V
authors.lastname: Sandor
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D057194:Intention to Treat Analysis; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D009929:Organ Size; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D011788:Quality of Life; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013163:Splenomegaly / Q000188:drug therapy*
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053613:Janus Kinase 1; D053614:Janus Kinase 2