title: Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia.
abstract: The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition.
authors.affiliation: The Johns Hopkins Oncology Center, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA. Steven.Gore@jhu.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Weng
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Suoping
authors.initials: S
authors.lastname: Zhai
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: George
authors.initials: G
authors.lastname: Dover
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Constance
authors.initials: C
authors.lastname: Griffin
authors.forename: Louise B
authors.initials: LB
authors.lastname: Grochow
authors.forename: Anita
authors.initials: A
authors.lastname: Hawkins
authors.forename: Kathleen
authors.initials: K
authors.lastname: Burks
authors.forename: Yelena
authors.initials: Y
authors.lastname: Zabelena
authors.forename: Carole B
authors.initials: CB
authors.lastname: Miller
mesh_terms: D000208:Acute Disease; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D005319:Fetal Hemoglobin / Q000187:drug effects / Q000378:metabolism; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009325:Nausea / Q000139:chemically induced; D010654:Phenylbutyrates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D010654:Phenylbutyrates; D005319:Fetal Hemoglobin