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

Abstract

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.

MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor

“…Quantitative PCR analysis for a selection of MAPK downregulated genes was confirmed in another subset of patients and contrasted with ABCB1 ( Figure 5B), which we previously found upregulated in peripheral blood samples taken from patients treated with romidepsin. 14 These results demonstrate that romidepsin alters expression of genes controlled by the MAPK pathway, a finding consistent with a role for perturbation of this pathway in romidepsin effect.…”

“…30 Although Pgp confers transporter-mediated resistance to romidepsin, this was not observed in the clinical samples studied. 14 We thus focused on nonPgp resistance mechanisms, evaluating HuT78 CTCL sublines independently selected in romidepsin in the presence of verapamil or valspodar to prevent the emergence of Pgp-mediated resistance. 17 We probed potential resistance mechanisms in the romidepsin-resistant lines by using a high-throughput TaqMan-based quantitative RT-PCR assay, 31 finding increased INSR expression as well as increased IR protein and phospho-MEK expression.…”

“…12 Although epigenetic effects of romidepsin, including upregulation of MDR-1/Pgp were observed in normal and malignant peripheral blood mononuclear cells (PBMCs) of patients treated with romidepsin, no evidence for Pgp-mediated resistance emerged in clinical samples obtained from patients with CTCL or PTCL at the time of disease progression. 13,14 Other, non-Pgp mechanisms of resistance have been suggested, such as activation of the mitogen-activated protein kinase (MAPK) pathway. Lung cancer cells transfected with constitutively active MAPK kinase (MEK) acquired romidepsin resistance, 15 and cell lines harboring activated MEK were more sensitive to combined treatment with romidepsin and an MEK inhibitor than to romidepsin alone.…”

Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma

“…12,28 Although the half-life is relatively short at 3 hours, exploratory pharmacodynamic studies demonstrated increased histone acetylation in PBMCs extending from 4 to 48 hours. 29 These studies, which included both patients from the CTCL cohort and 18 of the 47 patients with PTCL reported here, *Two patients were excluded from response assessment: one patient discovered to be ineligible for enrollment after receiving the first dose and one patient whose T-cell lymphoma was reclassified as DLBCL. BLOOD, 2 JUNE 2011 ⅐ VOLUME 117, NUMBER 22 For personal use only.…”

Peripheral T cell lymphoma: clinical utility of romidepsin

“…24 Romidepsin is also likely to be a substrate of the organic transporter, OATP1B3, an influx transporter encoded by SLCO1B3, because other cyclic peptides have been shown to interact with the same transporter. 25,26 However, the role of single nucleotide polymorphisms in CYP3A4/5, ABCB1, and SLCO1B3 in the individual variability of romidepsin disposition has not been quantitatively assessed. Population pharmacokinetic analysis was performed in 98 patients enrolled in a Phase II multicenter clinical trial of romidepsin in patients with CTCL and PTCL and dosed at 14 mg/m 2 or 18 mg/ m 2 on day 1 during their first treatment cycle.…”