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- Title
Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma.
- Authors
Bates, Susan E.; Zhirong Zhan; Steadman, Kenneth; Obrzut, Tomasz; Luchenko, Victoria; Frye, Robin; Robey, Robert W.; Turner, Maria; Gardner, Erin R.; Figg, William D.; Steinberg, Seth M.; Ling, Alex; Fojo, Tito; To, Kin Wah; Piekarz, Richard L.
- 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 Cmax and area under the curve (AUC)last (ρ = 0·37, P = 0·03 and ρ = 0·36, P = 0·03 respectively) and inversely associated with clearance (ρ = −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.
- Subjects
UNITED States; T cells; LYMPHOMAS; HISTONES; ACETYLATION; NATIONAL Institutes of Health (U.S.)
- Publication
British Journal of Haematology, 2010, Vol 148, Issue 2, p256
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/j.1365-2141.2009.07954.x