BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

4th Department of Internal Medicine Haematology Charles University Hospital and Faculty of Medicine Hradec Králové Czech Republic

Azienda Ospedaliera Spedali Civili di Brescia Brescia Italy

Calvary Mater Newcastle Hospital Waratah NSW Australia

China Medical University Hospital Taichung Taiwan

Columbia University Medical Center New York NY USA

Division of Cancer Sciences Faculty of Biology Medicine and Health University of Manchester National Institutes of Health and Research Biomedical Research Centre Manchester Academic Health Sciences Centre Christie Hospital National Health Service Foundation Trust Manchester UK

Division of Hematology and Oncology Department of Medicine Northwestern University Feinberg School of Medicine Chicago IL USA

Freeman Hospital Newcastle upon Tyne UK

Hackensack University Medical Center Hackensack NJ USA

Institut Catala D'oncologia L'Hospitalet de Llobregat Barcelona Spain

Institute of Hematology Seràgnoli University of Bologna Bologna Italy

MD Anderson Cancer Center University of Texas Houston TX USA

MD Anderson Cancer Center University of Texas Houston TX USA; Seattle Genetics Inc Bothell WA USA

Memorial Sloan Kettering Cancer Center New York NY USA

Millennium Pharmaceuticals Inc Cambridge MA USA a wholly owned subsidiary of Takeda Pharmaceutical Company

National Cancer Center Hospital Tokyo Japan

Odense University Hospital Odense Denmark

Saitama Medical University International Medical Center Saitama Japan

Samsung Medical Center Seoul South Korea

Seattle Genetics Inc Bothell WA USA

Stanford Cancer Center Blood and Marrow Transplant Program Stanford CA USA

Universitatsklinikum Essen Essen Nordrhein Westfalen Germany

Universitätsmedizin Göttingen Göttingen Germany

University of British Columbia and the Department of Medical Oncology British Columbia Cancer Centre for Lymphoid Cancer Vancouver BC Canada

University of Debrecen Faculty of Medicine Department of Hematology Debrecen Hungary

University of Lille Centre Hospitalier Universitaire de Lille Groupe de Recherche sur les formes Injectables et les Technologies Associées Lille France

University of Washington Medical Center Seattle WA USA

Washington University School of Medicine St Louis MI USA

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Lancet. 2019 Jan 19;393(10168):201-202. doi: 10.1016/S0140-6736(18)33127-1. PubMed

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Lancet. 2019 Jan 19;393(10168):228. doi: 10.1016/S0140-6736(18)33123-4. PubMed

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Ann Oncol. 2022 Mar;33(3):239-241. doi: 10.1016/j.annonc.2021.12.011. PubMed

Zobrazit více v PubMed

Tang T, Tay K, Quek R, et al. Peripheral T-cell lymphoma: review and updates of current management strategies. Advances in hematology 2010; 2010: 624040. PubMed PMC

Horwitz SM, Zelenetz AD, Gordon LI, et al. NCCN Guidelines® insights: Non-Hodgkin's lymphomas, version 3.2016 featured updates to the NCCN guidelines. JNCCN Journal of the National Comprehensive Cancer Network 2016; 14(9): 1067–79. PubMed

d'Amore F, Gaulard P, Trumper L, et al. Peripheral T-cell lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 Suppl 5: v108–15. PubMed

Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004; 15(10): 1467–75. PubMed

Simon A, Peoch M, Casassus P, et al. Upfront VIP-reinforced-ABVD (VIP-rABVD) is not superior to CHOP/21 in newly diagnosed peripheral T cell lymphoma. Results of the randomized phase III trial GOELAMS-LTP95. Br J Haematol 2010; 151(2): 159–66. PubMed

Vose J, Armitage J, Weisenburger D, International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26(25): 4124–30. PubMed

Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008; 111(12): 5496–504. PubMed

Reimer P, Rudiger T, Geissinger E, et al. Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. J Clin Oncol 2009; 27(1): 106–13. PubMed

d'Amore F, Relander T, Lauritzsen GF, et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol 2012; 30(25): 3093–9. PubMed

Weisenburger DD, Savage KJ, Harris NL, et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood 2011; 117(12): 3402–8. PubMed

Jantunen E, Boumendil A, Finel H, et al. Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: a retrospective study by the EBMT. Blood 2013; 121(13): 2529–32. PubMed

Perrone G, Corradini P. Autologous stem cell transplantation for T-cell lymphomas. Seminars in hematology 2014; 51(1): 59–66. PubMed

Bossard C, Dobay MP, Parrens M, et al. Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels. Blood 2014; 124(19): 2983–6. PubMed

Sabattini E, Pizzi M, Tabanelli V, et al. CD30 expression in peripheral T-cell lymphomas. Haematologica 2013; 98(8): e81–2. PubMed PMC

Pro B, Advani RH, Brice P, et al. Five-year survival data from a pivotal Phase 2 study of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood 2016; 128(22): Abstract 4144.

Fanale MA, Horwitz SM, Forero-Torres A, et al. Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. Blood 2018; 131(19): 2120–4. PubMed PMC

Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed.: IARC; 2008.

Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25(5): 579–86. PubMed

Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Controlled clinical trials 1996; 17(4): 343–6. PubMed

Ellin F, Landstrom J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood 2014; 124(10): 1570–7. PubMed

Federico M, Bellei M, Marcheselli L, et al. Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network. Br J Haematol 2018; 181(6): 760–9. PubMed PMC

Kluin-Nelemans HC, van Marwijk Kooy M, Lugtenburg PJ, et al. Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. Ann Oncol 2011; 22(7): 1595–600. PubMed

Advani RH, Ansell SM, Lechowicz MJ, et al. A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. Br J Haematol 2016; 172(4): 535–44. PubMed PMC

Foss FM, Sjak-Shie N, Goy A, et al. A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study. Leuk Lymphoma 2013; 54(7): 1373–9. PubMed

Dupuis J, Morschhauser F, Ghesquieres H, et al. Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. The Lancet Haematology 2015; 2(4): e160–5. PubMed

Mahadevan D, Unger JM, Spier CM, et al. Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma: Southwest Oncology Group Study S0350. Cancer 2013; 119(2): 371–9. PubMed PMC

Gleeson M, Peckitt C, To YM, et al. CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial. The Lancet Haematology 2018; 5(5): e190–200. PubMed PMC

Schmitz N, Trumper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010; 116(18): 3418–25. PubMed

Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood 2014; 123(20): 3095–100. PubMed PMC

Pro B, Advani R, Brice P, et al. Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood 2017; 130(25): 2709–17. PubMed PMC

Carson KR, Horwitz SM, Pinter-Brown LC, et al. A prospective cohort study of patients with peripheral T-cell lymphoma in the United States. Cancer 2017; 123(7): 1174–83. PubMed PMC

D'Amore F, Relander T, Lauritzen GF, et al. Dose-dense induction followed by autologous stem cell transplant (ASCT) leads to sustained remissions in a large fraction of patients with previously untreated peripheral T-cell lymphomas (PTCLs) - overall and subtype-specific results of a phase II study from the nordic lymphoma group. Haematologica 2009; 94(Suppl 2): 437. PubMed

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Zobrazit více v PubMed

ClinicalTrials.gov
NCT01777152