title: Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial.
abstract: Previous data established that plitidepsin, a cyclic depsipeptide, exerted activity in a mouse model of myelofibrosis (MF). New preclinical experiments reported herein found that low nanomolar plitidepsin concentrations potently inhibited the proliferation of JAK2V617F-mutated cell lines and reduced colony formation by CD34+ cells of individuals with MF, at least in part through modulation of p27 levels. Cells of MF patients had significantly reduced p27 content, that were modestly increased upon plitidepsin exposure. On these premise, an exploratory phase II trial evaluated plitidepsin 5 mg/m(2) 3-h intravenous infusion administered on days 1 and 15 every 4 weeks (q4wk). Response rate (RR) according to the International Working Group for Myelofibrosis Research and Treatment consensus criteria was 9.1% (95% CI, 0.2-41.3%) in 11 evaluable patients during the first trial stage. The single responder achieved a red cell transfusion independence and stable disease was reported in nine additional patients (81.8%). Eight patients underwent a short-lasting improvement of splenomegaly. In conclusion, plitidepsin 5 mg/m(2) 3-h infusion q4wk was well tolerated but had a modest activity in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia MF. Therefore, this trial was prematurely terminated and we concluded that further clinical trials with plitidepsin as single agent in MF are not warranted.
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pardanani
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Careggi, Firenze, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Careggi, Firenze, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bogani
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Careggi, Firenze, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Bartalucci
authors.affiliation: PharmaMar, Clinical R&D Department, Colmenar Viejo, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Rodríguez
authors.affiliation: PharmaMar, Clinical R&D Department, Colmenar Viejo, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Extremera
authors.affiliation: PharmaMar, Clinical R&D Department, Colmenar Viejo, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Pérez
authors.affiliation: PharmaMar, Clinical R&D Department, Colmenar Viejo, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Alfaro
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Careggi, Firenze, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Vannucchi
mesh_terms: D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic; D011087:Polycythemia Vera / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013163:Splenomegaly / Q000188:drug therapy / Q000473:pathology; D013920:Thrombocythemia, Essential / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D047630:Depsipeptides; D010456:Peptides, Cyclic; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C098980:plitidepsin