Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T‐cell lymphoma

• Published in: British journal of haematology 2010-01, Vol.148 (2), p.256-267
• Main Authors: Bates, Susan E., Zhan, Zhirong, 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.
• Format: Article
• Language: English
• Subjects: Acetylation; Antibiotics, Antineoplastic - therapeutic use; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biopsy; Depsipeptides - therapeutic use; fetal haemoglobin; Fetal Hemoglobin - analysis; Hematologic and hematopoietic diseases; histone deacetylase inhibitor; Histone Deacetylase Inhibitors - therapeutic use; Histones - metabolism; Humans; Immunoblotting; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes, Mononuclear - metabolism; Lymphoma, T-Cell - drug therapy; Lymphoma, T-Cell - metabolism; Lymphoma, T-Cell, Peripheral - drug therapy; Lymphoma, T-Cell, Peripheral - metabolism; Medical sciences; p‐glycoprotein; Reverse Transcriptase Polymerase Chain Reaction; romidepsin; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; T‐cell lymphoma
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2009.07954.x

Summary 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.