title: Open-label study of oral CEP-701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2-V617F mutation.
abstract: JAK2-V617F is central to the pathogenesis of myeloproliferative neoplasms. We examined whether lestaurtinib decreased JAK2-V617F allele burden and evaluated its clinical benefits and tolerability in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET). This phase 2, open-label, multicentre study was designed to detect ≥15% reduction in JAK2-V617F allele burden in 15% of patients. Eligible patients received lestaurtinib 80 mg twice daily for 18 weeks and could participate in a 1-year extension phase of treatment. Of 39 enrolled patients, 27 (69%) had PV; 12 (31%) had ET. While the pre-specified responder rate of 15% was not met, lestaurtinib modestly reduced JAK2-V617F allele burden and reduced spleen size in a subset of patients. Of 37 patients in the full efficacy analysis, 5 (14%) responded clinically. Every patient had ≥1 adverse event, most commonly gastrointestinal (95%). Fifteen patients (38%) experienced serious adverse events; 23 (59%) withdrew due to adverse events. This is the first reported study of JAK2-inhibitor treatment in patients with PV/ET and highlights both the need for further studies to assess the role of JAK2 inhibition in treatment of PV/ET and the use of JAK2-V617F as a biomarker for response. This trial was registered at www.clinicaltrials.gov as NCT00586651.
authors.affiliation: University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hexner
authors.forename: Gail
authors.initials: G
authors.lastname: Roboz
authors.forename: Ron
authors.initials: R
authors.lastname: Hoffman
authors.forename: Selina
authors.initials: S
authors.lastname: Luger
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Regina
authors.initials: R
authors.lastname: Clementi
authors.forename: Debra
authors.initials: D
authors.lastname: Bensen-Kennedy
authors.forename: Alison
authors.initials: A
authors.lastname: Moliterno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002227:Carbazoles / Q000627:therapeutic use*; D005260:Female; D005663:Furans; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D002227:Carbazoles; D005663:Furans; D047428:Protein Kinase Inhibitors; C119379:lestaurtinib; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: CEP-701; JAK2-V617F mutation; essential thrombocythaemia; lestaurtinib; polycythaemia vera