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 mucositis and one event of g3 maculopapular rash, g3 fatigue, g3 fever, g3 respiratory failure, g3 typhlitis and g4 neutropenic fever. The observed toxicity was 35.2% (95%CI: 17.1%-56.5%) and prompted to define 14 mg/ms the recommended dose of Ro in addition to CHOEP. No unexpected toxicities and no toxic deaths were reported. The most frequent toxicities reported during Ro-CHOEP were g3-4 neutropenia in 38% and thrombocytopenia in 45% of all the performed 117 courses. Severe extra-hematological toxicities by patients were: g3 arrhythmia in one (5%), g3 gastrointestinal in 3 (14%) and g3-4 infections in 5 (24%). The addition of Ro during induction did not impact the harvest, with a median of 4.3 × 10⁶ (IQR 3.4-5.71) peripheral blood CD34-positive cells/Kilogram collected. At least 90% of the planned dose of doxorubicine, cyclophosphamide, etoposide and vincristine were administered in: 87%, 86%, 83% and 89% of Ro-CHOEP, respectively. Median interval time between Ro-CHOEP was 21 days (range 19-36). At the end of induction 12/21 (57%) patients obtained CR and underwent auto-SCT, one patient (5%) in PR received auto-SCT due to lack of identical donor; 8 (38%) did not perform SCT due to lymphoma progression in 7 and to toxicity in one. At a median follow-up of 26 months, 12-months Progression Free Survival was 52% (95%CI: 29-71) and 12-months Overall Survival was 76% (95%CI: 52-89). Biomarkers and biological analysis are ongoing. The enrollment of the phase II part of the study is still open. Conclusions.The phase Ib FIL-PTCL13 part of the study defined Romidepsin 14 mg/ms on day 1 and day 8 as the MTD, when administered in combination to CHOEP as induction prior consolidation with up-front SCT, in untreated young PTCLs patients. The addition of Ro to chemotherapy did not impact the feasibility of CHOEP, without unexpected toxicities. The efficacy of this scheme is under investigation in the phase II part of the study.