title: A phase II study of panobinostat in patients with primary myelofibrosis (PMF) and post-polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF).
abstract: Myelofibrosis is a chronic and progressive myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating symptoms and leukemic transformation. Ruxolitinib, an oral JAK1/2 inhibitor, is highly effective in ameliorating systemic symptoms and reducing splenomegaly. Current clinical research is focused on the evaluation of agents based on pre-clinical rationale that can result in disease course modification. Panobinostat is a pan-histone deacetylase inhibitor that has demonstrated clinical activity as a single agent in early phase trials of myelofibrosis. We previously conducted a phase I trial of panobinostat monotherapy in patients with myelofibrosis and determined 25mg thrice weekly as the recommended phase II dose. We then completed an investigator initiated, Simon 2-stage, phase II trial of 22 myelofibrosis patients at our single institution. After 6 cycles of therapy, the overall response rate by IWG-MRT criteria was 36% (8/22; 95% CI: 16-56%). The median percent reduction in spleen volume was 34% (range, 1.6%-73%) in eight evaluable patients. The average reduction in JAK2V617F allele burden was 6.8% (Range; -4.0% to 20.2%) and one patient obtained a complete molecular response. Six patients remained on therapy in the extension phase for a median of 18 months (range, 7-44). Treatment discontinuation was frequent due to patient/physician perception of therapy ineffectiveness. The optimal dosing of panobinostat for the treatment of MF remains somewhat ill-defined but appears to be most effective and better tolerated when administered at lower doses over a prolonged duration of therapy.
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address: john.mascarenhas@mssm.edu.
authors.forename: John
authors.initials: J
authors.lastname: Mascarenhas
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Lonette
authors.initials: L
authors.lastname: Sandy
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: James
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Division of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Petersen
authors.affiliation: Division of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Newsom
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Division of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY, United States.
authors.forename: Tsivia
authors.initials: T
authors.lastname: Hochman
authors.affiliation: Division of Biostatistics, New York University School of Medicine, New York, NY, United States.
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.affiliation: Tisch Cancer Institute, Division of Hemato and Oncologylogy, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D000077767:Panobinostat; D011087:Polycythemia Vera / Q000188:drug therapy*; D055728:Primary Myelofibrosis / Q000188:drug therapy*; D013154:Spleen / Q000473:pathology; D013920:Thrombocythemia, Essential / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D053614:Janus Kinase 2
keywords: Epigenetics; Histone deacetylase inhibitor; Myelofibrosis; Panobinostat; Phase II