title: Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma.
abstract: Romidepsin has shown promise in the treatment of T-cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters C(max) and area under the curve (AUC)(last) (rho = 0.37, P = 0.03 and rho = 0.36, P = 0.03 respectively) and inversely associated with clearance (rho = -0.44; P = 0.03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0.026) as was the increase in fetal haemoglobin (P = 0.014); this latter association may be due to the longer on-study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) - the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity.
authors.affiliation: Medical Oncology Branch, National Institutes of Health, Bethesda, MD 20892, USA. sebates@helix.nih.gov
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Steadman
authors.forename: Tomasz
authors.initials: T
authors.lastname: Obrzut
authors.forename: Victoria
authors.initials: V
authors.lastname: Luchenko
authors.forename: Robin
authors.initials: R
authors.lastname: Frye
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Maria
authors.initials: M
authors.lastname: Turner
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Alex
authors.initials: A
authors.lastname: Ling
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
authors.forename: Kin Wah
authors.initials: KW
authors.lastname: To
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001706:Biopsy; D047630:Depsipeptides / Q000627:therapeutic use*; D005319:Fetal Hemoglobin / Q000032:analysis; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D005319:Fetal Hemoglobin; C087123:romidepsin