title: Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis.
abstract: JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.
authors: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors: A
authors: A
authors: Pardanani
authors: R R
authors: RR
authors: Laborde
authors: T L
authors: TL
authors: Lasho
authors: C
authors: C
authors: Finke
authors: K
authors: K
authors: Begna
authors: A
authors: A
authors: Al-Kali
authors: W J
authors: WJ
authors: Hogan
authors: M R
authors: MR
authors: Litzow
authors: A
authors: A
authors: Leontovich
authors: M
authors: M
authors: Kowalski
authors: A
authors: A
authors: Tefferi
mesh_terms: D000368:Aged; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000188:drug therapy*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D053613:Janus Kinase 1; D053614:Janus Kinase 2