title: A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea.
abstract: BACKGROUND
  Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial.
  
  
  METHODS
  Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to <45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms.
  
  
  RESULTS
  Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit <45% without phlebotomy was achieved in 97% of patients by week 24.Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification.
  
  
  CONCLUSIONS
  Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rosen
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gattoni
authors.forename: Lisa
authors.initials: L
authors.lastname: Pieri
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Elena
authors.forename: Shui
authors.initials: S
authors.lastname: He
authors.forename: Nancy
authors.initials: N
authors.lastname: Contel
authors.forename: Bijoyesh
authors.initials: B
authors.lastname: Mookerjee
authors.forename: Victor
authors.initials: V
authors.lastname: Sandor
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Tiziano
authors.initials: T
authors.lastname: Barbui
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D000075202:Contraindications; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006098:Granulocytes / Q000473:pathology; D006400:Hematocrit; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011087:Polycythemia Vera / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D055815:Young Adult
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D006918:Hydroxyurea