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134 Adding Romidepsin to CHOEP in First Line Treatment of Peripheral T-Cell Lymphomas Does Not Improve the Response Rate: Final Analysis of Phase II PTCL13 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: T/NK Cell Lymphoma Frontline Clinical Trials
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Lymphomas, Non-Biological, Clinical Research, Chemotherapy, Clinically Relevant, T Cell Lymphoma, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies
Saturday, December 11, 2021: 12:15 PM

Annalisa Chiappella, MD1, Cristiana Carniti2*, Alessandro Re3*, Claudia Castellino4*, Andrea Evangelista5*, Valentina Tabanelli6*, Rosanna Ciancia7*, Lorella Orsucci8*, Antonello Pinto9*, Sara Veronica Usai10*, Annalisa Arcari11*, Fiorella Ilariucci12*, Francesca Gaia Rossi13*, Fabio Benedetti14*, Leonardo Flenghi15*, Chiara Ghiggi16*, Anna Lia Molinari17*, Vittorio Stefoni18,19*, Stefano Volpetti20*, Vittorio Ruggero Zilioli21*, Filippo Ballerini22*, Riccardo Bruna23*, Federica Cavallo, MD, PhD24,25*, Gerardo Musuraca26*, Caterina Patti27*, Francesca Re28*, Monica Tani, MD29*, Marzia Varettoni30*, Manuela Zanni31*, Anna Dodero1*, Stefano A Pileri6, Giovannino Ciccone5* and Paolo Corradini, MD1,32,33

1Division of Hematology and Stem Cell Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
2Laboratory of Hematology, Division of Hematology and Stem Cell Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
3Hematology Division, ASST Spedali Civili di Brescia, Brescia, ID, Italy
4Division of Hematology, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
5Unit of Clinical Epidemiology, Azienda Ospedaliera e Universitaria Città della Salute e della Scienza and CPO Piemonte, Torino, Italy
6Hematopathology Division, IEO Istituto Europeo di Oncologia IRCCS, Milano, Italy
7Onco-hematology and Stem Cell Transplantation and Cellular Therapies, Centro di Riferimento Oncologico (CRO) IRCCS, Aviano, Italy
8Division of Hematology, Azienda Ospedaliera e Universitaria Città della Salute e della Scienza, Torino, Italy
9Hematology-Oncology & Stem Cell Transplantation Unit, Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale, Napoli, Italy
10Hematology, Ospedale Oncologico Armando Businco, Cagliari, Italy
11Hematology Unit, Ospedale Guglielmo da Saliceto, Piacenza, Italy
12Hematology, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
13Division of Hematology, Fondazione IRCCS Cà Granda, OM Policlinico, Milano, Italy
14Hematology and Stem Cell Transplantation, Azienda Ospedaliera Universitaria di Verona, Verona, Italy
15Hematology, Azienda Ospedaliera di Perugia, Perugia, Italy
16Hematology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
17Hematology Unit, Ospedale degli Infermi, Rimini, Italy
18Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
19Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
20Clinic of Hematology, Presidio Ospedaliero Universitario "Santa Maria della Misericordia” di Udine, ASUFC, Udine, Italy
21Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, IT-MI, Italy
22Clinic of Hematology, IRCCS Ospedale Policlinico San Martino Università di Genova, Genova, Italy
23Division of Hematology, Ospedale Maggiore Della Carità, Novara, Italy
24Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Torino, Italy
25Hematology, Azienda Ospedaliera e Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
26Division of Hematology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
27Division of Onco-Hematology, Azienda Villa Sofia Cervello, Palermo, Italy
28Hematology and CTMO, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy
29Hematology Unit, Ospedale Santa Maria delle Croci, Ravenna, Italy
30Division of Hematology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
31Division of Hematology, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
32Chair of Hematology, University of Milano Istituto Nazionale Tumori, Milano, Italy
33On behalf of Fondazione Italiani Linfomi, FIL, Italy, Italy

Introduction: Peripheral T-cell lymphomas (PTCL) have a 40-50% cure rate when treated with cyclophosphamide-doxorubicin-etoposide-vincristine-prednisone (CHOEP) and hematopoietic stem cell transplantation (HSCT). Romidepsin, a histone deacetylase inhibitor, showed promising activity in relapsed or refractory PTCLs.

Methods: On these premises, we designed a phase I/II trial (PTCL13 NCT02223208) to evaluate whether the addition of romidepsin to CHOEP improves the outcome of newly diagnosed PTCLs. In the phase Ib part of the study, we defined 14 mg/ms as the maximum tolerated dose of romidepsin when administered in combination with CHOEP (Ro-CHOEP). Thus, in the phase II part of the study we evaluated the efficacy of Ro-CHOEP followed by HSCT in young patients. The primary objective of the study was to demonstrate a 15% increase in 18-months progression-free survival (PFS) for the combination Ro-CHOEP plus HSCT (from 55% to 70%, planned sample size=110), compared to the previous Italian trial (Corradini P et al, Leukemia 2014). Patients aged 18-65 years with stage II-IV PTCL-NOS, angioimmunoblastic/T follicular helper (AITL/THF) and ALK negative anaplastic large cell lymphoma, were eligible. Treatment plan consisted of 6 courses of Ro-CHOEP every 21 days (14 mg/ms Ro day 1 and 8), followed by cisplatin-cytarabine-dexamethasone (DHAP) with stem cell harvest and HSCT. Patients in complete response (CR) after induction proceeded to autoHSCT, while those in partial response (PR), with an available HLA-matched donor, proceeded to alloHSCT upfront.

Results: From September 2017 to October 2020, 86 patients were enrolled into the phase II part of the study; median age was 55 years (IQR 49;60); 78 (91%) had stage III-IV and 31 (36%) IPI score >2. Pathological materials were collected at the time of diagnosis, and centrally reviewed by expert hemo-pathologists; subgroups were: 33 PTCL-NOS, 21 ALK negative, 31 AITL/THF, and one case not classified due to inadequate material. According to the statistical plan, an interim analysis was performed on the first 75 patients. At a median follow-up of 26 months, the 18-months PFS was 48% (95% CI: 0.36-0.58) and the OS was 75% (95% CI: 0.64-0.83). The 18-months PFS for PTCL-NOS versus ALK negative vs AITL/THF was 37% (95% CI: 0.20-0.54) vs. 51% (95% CI: 0.28-0.70) vs. 58% (95% CI: 0.36-0.74), p 0.118; the 18-months OS for PTCL-NOS vs. ALK negative vs. AITL/THF was 72% (95% CI: 0.51-0.85) vs. 76% (95% CI: 0.51-0.89) vs. 81% (95% CI: 0.60-0.92), p 0.957. All 86 patients completed the induction phase and were evaluable for response after 6 Ro-CHOEP: the overall response rate (ORR) was 71% (61 patients), with 62% (53 patients) CR. Four patients with ongoing treatment are not evaluable for response at the end of therapy, at the time of the analysis. Only 39 of 82 patients (48%) underwent HSCT and 43 did not: 28 due to progressive disease, 8 for poor mobilization, 7 for adverse events (1 sepsis, 2 cardiological events, 4 others). Among the 82 patients evaluable for response at the end of treatment, the final ORR after HSCT was 40% (33 patients), with 39% CR (32 patents). The most frequent toxicities during Ro-CHOEP treatment were hematological, with grade 3-4 neutropenia and thrombocytopenia in 33% and 34% of all the 459 cycles, respectively; severe febrile neutropenia was reported in only 4% of Ro-CHOEP courses. Severe non-hematological toxicities were observed in 35 (41%) of patients: cardiological in 5 patients (6%), gastrointestinal in 9 (10%), infections in 10 (12%), others in 11 (13%). Twenty-four deaths were recorded: 22 due to lymphoma progression, 1 due to transplant related mortality for a septic shock after alloSCT, 1 due to secondary malignancy.

Conclusions: In the PTCL13 phase I part of the study we demonstrated the feasibility of the combination Ro 14 mg/ms plus CHOEP followed by high-dose chemotherapy and HSCT; in the phase 2 part of the study, the primary objective was not achieved, with a 18-months PFS of 48%. Based on these results, the enrollment of the trial was stopped due to inefficacy of the experimental combination. The benefit of adding romidepsin to chemotherapy was not observed neither in PTCL-NOS nor in AITL/THF. In conclusion, the addition of romidepsin to CHOEP did not ameliorate prognosis in newly diagnosis PTCLs eligible to HSCT.

Disclosures: Chiappella: Takeda: Other: lecture fee, advisory board; Roche: Other: lecture fee, advisory board; Clinigen: Other: lecture fee, advisory board; Novartis: Other: lecture fee; Gilead Sciences: Other: lecture fee, advisory board; Astrazeneca: Other: lecture fee; Incyte: Other: lecture fee; Janssen-Cilag: Other: lecture fee, advisory board; Celgene Bristol Myers Squibb: Other: lecture fee, advisory board. Flenghi: Roche: Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses. Zilioli: Gentilli: Consultancy, Speakers Bureau; Takeda: Consultancy, Other, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Italfarmaco: Consultancy. Cavallo: Servier: Speakers Bureau; Gilead: Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees. Musuraca: roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Varettoni: janssen: Membership on an entity's Board of Directors or advisory committees; beigene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees. Corradini: Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy.

OffLabel Disclosure: Romidepsin is not registered in first line treatment. Romidepsin was provided free for the clinical trial.

*signifies non-member of ASH