Romidepsin Plus Liposomal Doxorubicin Is Safe and Effective in Patients with Relapsed or Refractory T-Cell Lymphoma: Results of a Phase I Dose-Escalation Study

Khoan Vu,Frank Mccormick,Lawrence K Kaplan,Matthew J Wieduwilt,Pamela Heeter,Chen-Yen Yang,Jonathan E Brammer,Basem M William,Pierluigi Porcu,Chi-Heng Wu,Charalambos Andreadis,Wade Berry,Erika Cavallone,Aaron Zhan,Laura Pincus,Weiyun Z Ai

doi:10.1158/1078-0432.ccr-19-2152

Abstract

The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL. Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days. Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response. Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.

Highlights

Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma that principally involves the skin and, in advanced stages, the lymph nodes, peripheral blood, and visceral organs
Romidepsin plus liposomal doxorubicin (LD) demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory cutaneous T-cell lymphoma (CTCL). This combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL
We found that romidepsin was synergistic with doxorubicin in growth inhibition and apoptosis induction in both cutaneous T-cell lymphoma (CTCL) cell lines and patient-derived primary CTCL cells

Summary

Introduction

Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma that principally involves the skin and, in advanced stages, the lymph nodes, peripheral blood, and visceral organs. While patients with early-stage disease generally have a good prognosis, patients with relapsed or advanced stage (IIB to IVB) mycosis fungoides or Sezary syndrome, have a median overall survival (OS) of 4–5 years, a result that has not improved in over four decades [2,3,4]. These patients frequently require systemic therapy; complete response (CR) rates are low, and response dura-. J.E. Brammer and W.Z. Ai contributed to this article

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