INTRODUCTION The German Hodgkin Study Group (GHSG) HD21 trial for adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) was designed to reduce treatment-related morbidity (TRMB) and improve efficacy by comparing the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to the standard eBEACOPP protocol. Here, we report the final efficacy and safety including long-term progression-free survival (PFS), overall survival (OS), and late toxicity outcomes.

METHODS This open-label, international, randomized phase III trial included adults aged 18-60 with newly diagnosed AS-cHL, randomized 1:1 to treatment with 4–6 cycles of eBEACOPP or BrECADD, guided by positron emission tomography after two cycles (PET2). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Co-primary objectives were reduction of TRMB and superiority of PFS with BrECADD vs. eBEACOPP, both of which were met previously. The final analysis focused on long-term PFS, overall survival (OS), and second primary malignancies (SPMs). Kaplan-Meier estimates and Cox regression were used for time-to-event analysis in the intention-to-treat (ITT) population. Additionally, we describe prognostic factors for PET2 response among baseline characteristics including metabolic tumor volume (MTV) and the prognostic value of international prognostic score (IPS) variables and MTV at baseline for PFS, respectively, in the BrECADD arm. Univariate logistic regressions were used to identify associations with interim PET response (p<=.001), which were then compared using multivariate analyses.

RESULTS A total of 1,500 patients were enrolled between July 2016 and August 2020 across 233 sites in nine countries. Baseline demographics and disease characteristics were well balanced between arms. After 2 cycles of BrECADD, 235/664 patients (35%) with centrally reviewed PET2 were classified as PET-positive. ECOG > 0 (Odds Ratio [OR] 1.62, 95% CI 1.03-2.55) and higher MTV (OR 1.14 per 100 mL, 95% CI 1.06-1.22) at baseline were associated with positive PET after 2x BrECADD in multivariate analysis. Median follow-up for this final analysis was 60 months and seven new PFS-events occurred after the previous analysis at 48 months: Five in the eBEACOPP arm and two in the BrECADD arm. Confirming earlier analysis, the hazard ratio (HR) for PFS was 0.64 (95% CI 0.44–0.93) favoring BrECADD. The absolute 5-year PFS for BrECADD was 93.6% (95% CI 91.7–95.5) vs. 90.6% (95% CI 88.4-92.8) with eBEACOPP, with a particularly pronounced 5y PFS benefit in PET2-negative patients of 96.2% vs. 92.4% (HR 0.46, 95% CI 0.25–0.83;). Among the IPS variables, male sex (HR 2.68, CI 95% 1.37-5.27) and hemoglobin < 10.5 g/dL (HR 2.41, 95% CI 1.25-4.68) were associated with higher risk for PFS events in multivariate cox regression, whereas MTV at baseline in univariate cox regression was not (HR 0.95 per 100 mL, 95% CI 0.81-1.11). Salvage therapies were similar across treatment arms: most patients with progression or relapse received autologous stem cell transplantation (52/61 (82%) after eBEACOPP vs 29/38 (76%) after BrECADD). With four (two in each treatment group) new death events since the previous analysis, OS remained at 98% in both arms. The cumulative incidence of SPMs at 60 months was 2.1% after eBEACOPP and 2.8% after BrECADD, with differing patterns: more secondary MDS/AML occurred in the eBEACOPP arm (six vs. one), while more secondary NHL cases were observed in the BrECADD arm (two vs. eight). No new sMDS/AML events occurred beyond the primary analysis.

CONCLUSION With 5 years follow-up, this analysis confirms the unprecedented primary cure-rate and long-term safety profile of BrECADD. While higher baseline lymphoma burden associates with incomplete remission at PET2, the risk for treatment failure seems mitigated through response-adaptation. Taken together, our results establish individualized BrECADD as a standard treatment option for adult patients with newly diagnosed AS-cHL.

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2025
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