Romidepsin-CHOEP Plus Intensification with up-Front Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: Final Results of Phase Ib PTCL13 Study of the Fondazione Italiana Linfomi

Introduction.The recommended treatment for newly diagnosed nodal Peripheral T-cell lymphomas (PTCLs) patients eligible to high-dose therapy is cyclophosphamide-doxorubicin-vincristine plus etoposide (CHOEP) followed by autologous stem cell transplantation (auto-SCT) in chemo-sensitive disease. However, 25-30% of patients experienced primary refractoriness or early progression. Romidepsin (Ro), a histone deacetylase inhibitor, showed antitumor activity and a manageable toxicity profile in PTCLs. On these bases, we designed the FIL-PTCL13 phase Ib/II study (NCT02223208), aimed to define the maximum tolerated dose (MTD) of Ro in addition to CHOEP followed by consolidation with auto or allogeneic-SCT according to clinical response, and to evaluate the safety and the efficacy of this combination as first line in PTCLs. Patients and methods. Inclusion criteria were: untreated PTCL not otherwise specified, angioimmunoblastic, ALK negative anaplastic lymphoma at stage II-IV, aged 18-65. Treatment scheme was: an induction with 6 courses of CHOEP every 21 days combined with Ro at the allocated dose, at day 1 and 8 of each cycle (Ro-CHOEP). Patient in complete (CR) or partial response (PR) without an available donor, received one course of cisplatin, citarabine, desamethasone (DHAP) followed by stem cell harvest and proceeded to auto-SCT; patients in PR and with an available donor, were sent to upfront allogeneic-SCT. Romidepsin dose allocation for sequential cohorts of 3 patients at each dose was defined according to the Continual Reassessment Method (O'Quigley and Zohar, 2006). Dose-limiting toxicity (DLT) of Ro-CHOEP were: any grade ≥ 3 non-hematologic toxicity (according to the NCI Common Terminology Criteria for Adverse Events, version 4.0) or a delay >15 days of planned cycle date, observed during the first 2 cycles. The MTD of Ro was defined as the dose that achieved a DLT in 33% of patients. Four dose levels of Ro were tested, namely 8, 10, 12 and 14 mg/ms. Results. From September 2014 to July 2017, 21 patients were enrolled into the phase Ib part of the study. Clinical characteristics were: median age 57 years (IQR 53;61); bone marrow involvement in 6 (29%) patients; stage III-IV in 18 (86%); International Prognostic Index (IPI) risk ≥3 in 8 (38%). The first cohort of 3 patients was treated with Ro at 12 mg/ms, and no DLTs were observed; the subsequent 6 cohorts were treated with Ro at 14 mg/ms. Nine DLTs were reported in 7 patients: 3 events of grade (g)3 m