Dose-Adjusted EPOCH Chemotherapy for Untreated Peripheral T-Cell Lymphomas: Multicenter Phase II Trial of West-Jhog PTCL0707
Authors: Maeda Yoshinobu , Nishimori Hisakazu , Hiramatsu Yasushi , Yoshida Isao , Uno Masatoshi , Masaki Yasufumi , Sunami Kazutaka , Masunari Taro , Nawa Yuichiro , Gomyo Hiroshi , Yamane Hiromichi , Takahashi Tsutomu , Yano Tomofumi , Takimoto Hidetaka , Matsuo Keitaro , Yoshino Tadashi , Tanimoto Mitsune 
Published: October 2019

Abstract
Introduction: Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases that represent around 10-15% of non-Hodgkin's lymphoma (NHL) in adults. The most common subtypes are the nodal T cell lymphomas, not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) and ALK-negative ALCL. There is no standard therapy for PTCLs, however, cyclophosphamide, prednisone, vincristine, hydroxyl doxorubicin (CHOP) is the most commonly used, resulting poor overall survival. The addition of etoposide to CHOP-based regimens improved CR in PTCL patients in some studies. Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab regimen were reported excellent outcome in primary mediastinal B-cell lymphoma, as well as germinal center B-cell diffuse large B-cell lymphoma and Burkitt lymphoma. In this study, we undertook a multicenter phase II, prospective study to evaluate whether dose-adjusted EPOCH may improve outcomes in patients with the nodal PTCLs.
Patients and Methods: Forty two consecutive patients with untreated nodal PTCLs were prospectively included in the protocol from August 2007 to October 2011. Eligibility requirements included disease stages II to IV lymphomas, age of 15 to 79 years old and performance status (ECOG) 0 to 2. Patients were also required to have adequate organ function. The dose-adjusted EPOCH starting dose level consisted of doxorubicin 10 mg/m2, etoposide 50 mg/m2 and vincristine 0.4 mg/m2 as a continuous infusion on days 1 to 4; cyclophosphamide; 750 mg/m2 on day 5; and prednisone 60 mg/m2 on days 1 to 5. If patients were older than 70, the starting dose were reduced 20%. Subsequent cycles were dose adjusted every cycle based on the neutrophil nadir on etoposide, doxorubicin and cyclophosphamide. The cycles were repeated every 3 weeks, and patients received at least two cycles beyond CR for a minimum of six and a maximum of eight cycles.
Results: Histological diagnosis was reviewed by a panel of expert haematopathologists and 41 patients with untreated PTCL were included in the analysis of toxicity and response; one patient was diagnosed NK/T cell lymphoma. PTCL-NOS was the predominant histologic finding (n = 22; 53.7%), and followed by AITL (n = 16; 39.0%), ALK-positive ALCL (n = 2; 4.9%), ALK-negative ALCL (n = 1; 2.4%). Median age was 64 years (range, 32 to 79 years) and more than half patients were older than 60. The majority of the patients were in stage III and IV and according to International Prognostic Index criteria, 51.2% were at high-intermediate or high risk. Among all of 41 patients assessed, 61.0% had a CR (95% confidential interval; CI, 44.5-75.9 %) and 17.0 % had a PR (95% CI, 32.1-71.5 %) to dose-adjusted EPOCH treatment. 1 year/ 2 years progression-free survival (PFS) and overall survival (OS) was 60.9%/ 53.0% and 97.6%/ 75.3%, respectively. In multivariate analyses, there were no factors as significant prognostic factors in both PFS and OS. The most common grade ≥ 3 adverse events were neutropenia (74.5%), anemia (40.8%), and thrombocytopenia (22.0%). Febrile neutropenia and Grade 3 infections occurred in 9.0 % and 14.7% of patients. Gastrointestinal, liver or renal toxicity was mild and there were no cardiac complications or treatment related deaths.
Conclusion: Our results indicates that dose-adjusted EPOCH therapy had a high response rate and may provide an improvement in PFS and OS in patients with the nodal PTCLs with tolerable toxicities.

Disclosures
Maeda: Mundipharma KK: Research Funding. Yoshida:kyowa-kirin: Honoraria, Research Funding; mundipharma: Consultancy; chugai-pharm: Honoraria, Research Funding; celgene: Honoraria. Masaki:Takeda: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding. Sunami:Takeda: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding.