title: Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes.
abstract: OBJECTIVE
  Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML).
  
  
  METHODS
  Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m(2) i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done.
  
  
  RESULTS
  Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypophosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed.
  
  
  CONCLUSIONS
  Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. klimekv@mskcc.org
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Klimek
authors.forename: Sophia
authors.initials: S
authors.lastname: Fircanis
authors.forename: Peter
authors.initials: P
authors.lastname: Maslak
authors.forename: Ilhem
authors.initials: I
authors.lastname: Guernah
authors.forename: Michael
authors.initials: M
authors.lastname: Baum
authors.forename: Nian
authors.initials: N
authors.lastname: Wu
authors.forename: Katherine
authors.initials: K
authors.lastname: Panageas
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D001141:Aromatase / Q000235:genetics; D047630:Depsipeptides / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001141:Aromatase; D047630:Depsipeptides; D018719:Erb-b2 Receptor Tyrosine Kinases; C087123:romidepsin; C508053:ERBB2 protein, human