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Kreissl, Stefanie; Goergen, Helen; Buehnen, Ina; Kobe, Carsten; Moccia, Alden; Greil, Richard; Eichenauer, Dennis A.; Zijlstr, Josee M.; Markova, Jana; Meissner, Julia; Feuring-Buske, Michaela; Soekler, Martin; Beck, Hans Joachim; Willenbacher, Wolfgang; Ludwig, Wol-Dieter; Pabst, Thomas; Topp, Max S.; Hitz, Felicitas; Bentz, Martin; Keller, Ulrich Bernd; Kuehnhardt, Dagmar; Ostermann, Helmut; Hertenstein, Bernd; Ulitzky, Wafter A.; Maschmeyer, Georg; Vieler, Tons; Eich, Hans; Baues, Christian; Stein, Harald; Fuchs, Michael; Diehl, Volker; Dietlein, Markus; Engert, Andreas and Borchmann, Peter (2021): PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial. In: Lancet Haematology, Vol. 8, No. 6, E398-E409

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Background The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. Methods HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m(2) intravenous cyclophosphamide [day 1], 35 mg/m(2) intravenous doxorubicin [day 1], 200 mg/m(2) intravenous etoposide [day 1-3], 100 mg/m (2) oral procarbazine [day 1-7], 40 mg/m(2) oral prednisone [day 1-14], 1.4 mg/m(2) intravenous vincristine [day 8], and 10 mg/m(2) intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET- 2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP;ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m(2) intravenous rituximab;ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011;an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP;ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET- 2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. Findings Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89.9% (95% CI 85.7 to 94.1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87.7% (83.1 to 92.4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0.40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90.1% (95% CI 87.2 to 92.9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91.2% (95% CI 88.4 to 93.9) in 446 patients who received eight or six cycles of eBEACOPP and 93.0% (90.6 to 95.4) in 474 patients who received four cycles of eBEACOPP (difference 1.9% [95% CI -1.8 to 5.5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90.9% (95% CI 86.8 to 95.1) in 202 patients assigned to receive six cycles of eBEACOPP and 91.0% (86.6 to 95.5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0.1% [-5.9 to 6.2]). Interpretation Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

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