A phase II study on the role of gemcitabine plus romidepsin (GEMRO regimen) in the treatment of relapsed/refractory peripheral T-cell lymphoma patients

Pellegrini et al. Journal of Hematology & Oncology A phase II study on the role of gemcitabine plus romidepsin (GEMRO regimen) in the treatment of relapsed/refractory peripheral T-cell lymphoma patients Cinzia Pellegrini 2 Anna Dodero 1 Annalisa Chiappella 0 Federico Monaco 3 Debora Degl'Innocenti 1 Flavia Salvi 3 Umberto Vitolo 0 Lisa Argnani 2 Paolo Corradini 1 Pier Luigi Zinzani 2 On behalf of the Italian Lymphoma Foundation (Fondazione Italiana Linfomi Onlus 0 Azienda Ospedaliera-Universitaria Città della Salute e della Scienza di Torino , Turin , Italy 1 Fondazione IRCCS Istituto Nazionale dei Tumori , Milan , Italy 2 Institute of Hematology “L. e A. Seràgnoli”, University of Bologna , Via Massarenti, 9-40138 Bologna , Italy 3 A.O. SS Antonio e Biagio e Cesare Arrigo , Alessandria , Italy Background: There is no consensus regarding optimal treatment for peripheral T-cell lymphomas (PTCL), especially in relapsed or refractory cases, which have very poor prognosis and a dismal outcome, with 5-year overall survival of 30 %. Methods: A multicenter prospective phase II trial was conducted to investigate the role of the combination of gemcitabine plus romidepsin (GEMRO regimen) in relapsed/refractory PTCL, looking for a potential synergistic effect of the two drugs. GEMRO regimen contemplates an induction with romidepsin plus gemcitabine for six 28-day cycles followed by maintenance with romidepsin for patients in at least partial remission. The primary endpoint was the overall response rate (ORR); secondary endpoints were survival, duration of response, and safety of the regimen. Results: The ORR was 30 % (6/20) with 15 % (3) complete response (CR) rate. Two-year overall survival was 50 % and progression-free survival 11.2 %. Grade ≥3 adverse events were represented by thrombocytopenia (60 %), neutropenia (50 %), and anemia (20 %). Two patients are still in CR with median response duration of 18 months. The majority of non-hematological toxicities were mild and transient. No treatment-related death occurred and no toxicity led to treatment interruption. Conclusions: GEMRO combination regimen shows efficacy data similar to those of single-agent romidepsin with additional hematologic toxicities. Synergy observed in preclinical phase did not turn into ability to improve clinical outcomes. Trial registration: The trial was registered under EudraCT 2012-001404-38; ClinicalTrials.gov number, NCT01822886. Peripheral T-cell lymphoma; Relapsed; Refractory; Gemcitabine; Romidepsin Background Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of lymphoid malignancies arising from mature T-cells which present with different phenotypes and clinical presentations [ 1, 2 ]. These aggressive lymphomas are uncommon, constituting 10–12 % of non-Hodgkin’s lymphomas (NHL) in Western countries [3] but are relatively common in Eastern Asian, constituting about 20 % of mature NHL [ 4 ]. There is no consensus regarding optimal treatment for PTCL, especially in relapsed or refractory cases, which have very poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been accepted as a salvage treatment for eligible patients, although the evidence is unclear [ 5 ]. Moreover, the overall prognosis remains dismal in patients unsuitable for ASCT. Thus, effective salvage chemotherapy prior to ASCT or optimal therapeutic approach for patients ineligible for ASCT should be investigated in order to improve the prognosis of PTCL patients. Despite the enormous advances in our understanding of aggressive lymphomas, it is clear that progress in PTCL management has lagged well behind other B-cell malignancies. Over the past 5 years, the US Food and Drug Administration (FDA) has approved four drugs for patients with relapsed/refractory PTCL, and, counting the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/lymphoma, five drugs have been approved worldwide [ 6–10 ]. These approvals have led to the initiation of no fewer than four randomized clinical studies, exploring the integration of these new agents into standard CHOP (cyclophosphamide–adriamycin–vincristine–prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL [ 11–14 ]. In addition, new waves of studies are exploring the potential benefits of novel drug combinations, an effort to build on the obvious singleagent successes. What has emerged most recently is the recognition that PTCL may be a disease characterized by epigenetic dysregulation: this could explain PTCL sensitivity to histone deacetylase (HDAC) inhibitors and open the door for even more creative combination approaches. Gemcitabine (2′,2′-difluorodeoxycytidine) is a pyrimidine anti-metabolite with clinical activity in aggressive lymphomas. The overall response rates (ORR) for gemcitabine as a single agent in relapsed/refractory PTCL are up to 50 % [ 15, 16 ], while the single-agen (...truncated)