BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

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 Australia

China Medical University Hospital Taichung Taiwan

CHRU de Lille Lille cedex Nord Pas de Calais France

Debreceni Egyetem Debrecen Hajdu Bihar Hungary

Department of Medical Oncology and University of British Columbia BC Cancer Vancouver Canada

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

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

Freeman Hospital Newcastle upon Tyne UK

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

IRCCS Azienda Ospedaliero Universitaria di Bologna Istituto di Ematologia 'Seràgnoli' Bologna Italy; Dipartimento di Medicina Specialistica Diagnostica e Sperimentale Università di Bologna Bologna Italy

John Theurer Cancer Center Hackensack Meridian Health School of Medicine Hackensack USA

MD Anderson Cancer Center University of Texas Houston USA

Memorial Sloan Kettering Cancer Center New York USA

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

National Cancer Center Hospital Tokyo Japan

Odense University Hospital Odense Denmark

Saitama Medical University International Medical Center Saitama Japan

Seagen Inc Bothell USA

Stanford Cancer Center Blood and Marrow Transplant Program Stanford USA

Sungkyunkwan University School of Medicine Samsung Medical Center Seoul Republic of Korea

Universitatsklinikum Essen Essen Nordrhein Westfalen Germany

Universitätsmedizin Göttingen Göttingen Germany

University of Virginia Cancer Center University of Virginia Charlottesville USA

University of Washington Medical Center Seattle USA

Washington University School of Medicine St Louis USA

Zobrazit více v 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;26:4124–4130. 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;111:5496–5504. PubMed

Chihara D, Fanale MA, Miranda RN, et al. The survival outcome of patients with relapsed/refractory peripheral T-cell lymphoma-not otherwise specified and angioimmunoblastic T-cell lymphoma. Br J Haematol. 2017;176:750–778. PubMed PMC

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;124:1570–1577. PubMed

Bellei M, Foss FM, Shustov AR, et al. The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-cell Project. Haematologica. 2018;103:1191–1197. PubMed PMC

Maurer MJ, Ellin F, Srour L, et al. International assessment of event-free survival at 24 months and subsequent survival in peripheral T-cell lymphoma. J Clin Oncol. 2017;35:4019–4026. PubMed PMC

Mak V, Hamm J, Chhanabhai M, et al. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J Clin Oncol. 2013;31:1970–1976. PubMed

Wulf GG, Altmann B, Ziepert M, et al. Alemtuzumab plus CHOP versus CHOP in elderly patients with peripheral T-cell lymphoma: the DSHNHL2006–1B/ACT-2 trial. Leukemia. 2021;35:143–155. PubMed

Kluin-Nelemans HC, van Marwijk Kooy M, Lugtenburg PJ, et al. Intensified alemtuzumab-CHOP therapy for peripheral T-cell lymphoma. Ann Oncol. 2011;22:1595–1600. PubMed

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;54:1373–1379. PubMed

Deng S, Lin S, Shen J, Zeng Y. Comparison of CHOP vs CHOPE for treatment of peripheral T-cell lymphoma: a meta-analysis. Onco Targets Ther. 2019;12:2335–2342. PubMed PMC

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;151:159–166. PubMed

Sabattini E, Pizzi M, Tabanelli V, et al. CD30 expression in peripheral T-cell lymphomas. Haematologica. 2013;98:e81–e82. PubMed PMC

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;131:2120–2124. PubMed PMC

Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393:229–240. PubMed PMC

Zain JM. Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification and management. Am J Hematol. 2019;94:929–946. PubMed

Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586. PubMed

Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004;104:634–641. PubMed

Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004;104:626–633. PubMed

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;116:3418–3425. PubMed

Bachy E, Camus V, Thieblemont C, et al. Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the Ro-CHOP phase III study (conducted by LYSA). J Clin Oncol. 2022;40(3):242–251. PubMed

Jagadeesh D, Horwitz SM, Bartlett NL, et al. Response to brentuximab vedotin by CD30 expression: results from five trials in PTCL, CTCL, and B-cell lymphomas. J Clin Oncol. 2019;37:7543.

Gardai SJ, Epp A, Law CL. Brentuximab vedotin-mediated immunogenic cell death. Cancer Res. 2015;75:2469.

Li F, Emmerton KK, Jonas M, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76:2710–2719. PubMed

Muller P, Martin K, Theurich S, et al. Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res. 2014;2:741–755. PubMed

Jagadeesh D, Horwitz S, Bartlett NL, et al. Response to brentuximab vedotin by CD30 expression: results from five trials in PTCL, CTCL, and B-cell lymphomas. Hematol Oncol. 2019;37:470–471.

Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123:3095–3100. PubMed PMC

Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390:555–566. PubMed

Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. Results of a phase II trial of brentuximab vedotin for CD30+ cutaneous t-cell lymphoma and lymphomatoid papulosis. J Clin Oncol. 2015;33:3759–3765. PubMed PMC

Bartlett NL, Smith MR, Siddiqi T, et al. Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leuk Lymphoma. 2017;58:1607–1616. PubMed

Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125:1394–1402. PubMed

Oflazoglu E, Stone IJ, Gordon KA, et al. Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. Blood. 2007;110: 4370–4372. PubMed

Jagadeesh D, Sims RB, Horwitz SM. Trial-in-progress: frontline brentuximab vedotin and CHP (A+CHP) in patients with peripheral T-cell lymphoma with less than 10% CD30 expression. Blood. 2020;136:30.

Bartlett NL, Chen R, Fanale MA, et al. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014;7:24. PubMed PMC

Ahmed S, Lisano J, Newhook T. A phase 2 study of retreatment with brentuximab vedotin in patients with cHL, sALCL or other CD30-expressing PTCL. Blood. 2019;134:4054.

Herrera AF, Zain J, Savage KJ, et al. Preliminary results from a phase 2 trial of brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone (CHEP-BV) followed by BV consolidation in patients with CD30-positive peripheral T-cell lymphomas. Blood. 2019;134:4023. PubMed

Herrera AF, Zain J, Savage KJ, et al. Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone (CHEP-BV) followed by BV consolidation in patients with CD30-expressing peripheral T-cell lymphomas. Blood. 2021;138:133.

Brentuximab vedotin plus chemotherapy for the treatment of front-line systemic anaplastic large cell lymphoma: subgroup analysis of the ECHELON-2 study at 5 years' follow-up

Role of stem cell transplant in CD30+ PTCL following frontline brentuximab vedotin plus CHP or CHOP in ECHELON-2

Chimeric Antigen Receptor Based Cellular Therapy for Treatment Of T-Cell Malignancies