title: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis.
abstract: BACKGROUND
  Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis.
  
  
  METHODS
  We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography.
  
  
  RESULTS
  A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy.
  
  
  CONCLUSIONS
  Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).
authors.affiliation: Guy's and St. Thomas' National Health Service Foundation Trust, Guy's Hospital, London, United Kingdom. claire.harrison@gstt.nhs.uk
authors.forename: Claire
authors.initials: C
authors.lastname: Harrison
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Kiladjian
authors.forename: Haifa Kathrin
authors.initials: HK
authors.lastname: Al-Ali
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Roger
authors.initials: R
authors.lastname: Waltzman
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Stalbovskaya
authors.forename: Mari
authors.initials: M
authors.lastname: McQuitty
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Hunter
authors.forename: Richard
authors.initials: R
authors.lastname: Levy
authors.forename: Laurent
authors.initials: L
authors.lastname: Knoops
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Tiziano
authors.initials: T
authors.lastname: Barbui
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002423:Cause of Death; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; 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*; D016019:Survival Analysis
chemical_list: D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; D053613:Janus Kinase 1; D053614:Janus Kinase 2