Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma.
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.
Bates
Susan E
SE
Medical Oncology Branch, National Institutes of Health, Bethesda, MD 20892, USA. sebates@helix.nih.gov
Zhan
Zhirong
Z
Steadman
Kenneth
K
Obrzut
Tomasz
T
Luchenko
Victoria
V
Frye
Robin
R
Robey
Robert W
RW
Turner
Maria
M
Gardner
Erin R
ER
Figg
William D
WD
Steinberg
Seth M
SM
Ling
Alex
A
Fojo
Tito
T
To
Kin Wah
KW
Piekarz
Richard L
RL
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
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