Background
Phase III, open-label RCT (GHSG HD21). 1,500 adults aged ≤60 years with newly diagnosed advanced-stage classical Hodgkin lymphoma (stage IIB with mediastinal bulk or extranodal involvement, III, or IV). PET-guided treatment: after 2 cycles, iPET2-negative patients completed 4 total cycles; iPET2-positive patients completed 6 total cycles.
Interventions and follow up
Arm A: BrECADD — brentuximab vedotin 1.8 mg/kg day 1 + etoposide 150 mg/m² days 1–3 + cyclophosphamide 750 mg/m² day 1 + doxorubicin 25 mg/m² day 1 + dacarbazine 375 mg/m² days 1–2 + dexamethasone 40 mg days 1–4, q3w × 4 cycles (iPET2-negative) or 6 cycles (iPET2-positive) (n=749)
Arm B: eBEACOPP — standard escalated BEACOPP × 4–8 cycles, PET-adapted to 6 cycles if iPET2-negative (n=751)
Primary endpoint: Co-primary: treatment-related morbidity (TRM) score (superiority) and PFS (noninferiority)
Median follow up: ~4 years
Arm B: eBEACOPP — standard escalated BEACOPP × 4–8 cycles, PET-adapted to 6 cycles if iPET2-negative (n=751)
Primary endpoint: Co-primary: treatment-related morbidity (TRM) score (superiority) and PFS (noninferiority)
Median follow up: ~4 years
Results
4-yr PFS (BrECADD vs. eBEACOPP): 94.3% vs. 90.9%, HR 0.66 (95% CI 0.45–0.97), P=.035 — BrECADD superior
TRM score (BrECADD vs. eBEACOPP): 42% vs. 59%, RR 0.72 (95% CI 0.65–0.80), P<.001 — BrECADD significantly less toxic
4-yr OS: ~98% both arms — no significant difference
TRM score (BrECADD vs. eBEACOPP): 42% vs. 59%, RR 0.72 (95% CI 0.65–0.80), P<.001 — BrECADD significantly less toxic
4-yr OS: ~98% both arms — no significant difference
Adverse events
eBEACOPP: grade ≥3 leukopenia 69%, grade ≥3 infections 17%, secondary MDS/AML 1.3%
BrECADD: grade ≥3 peripheral neuropathy 18% (brentuximab), grade ≥3 leukopenia 46% (lower than eBEACOPP), secondary MDS/AML 0.4%
Other: febrile neutropenia rates and alopecia less severe with BrECADD; infertility risk lower with BrECADD (no alkylating agent) vs. eBEACOPP (cyclophosphamide)
BrECADD: grade ≥3 peripheral neuropathy 18% (brentuximab), grade ≥3 leukopenia 46% (lower than eBEACOPP), secondary MDS/AML 0.4%
Other: febrile neutropenia rates and alopecia less severe with BrECADD; infertility risk lower with BrECADD (no alkylating agent) vs. eBEACOPP (cyclophosphamide)
Conclusions
BrECADD achieved significantly superior 4-year PFS (94.3% vs. 90.9%) and substantially lower treatment-related morbidity compared to eBEACOPP in advanced-stage cHL, simultaneously improving both efficacy and tolerability. BrECADD is now the preferred intensive regimen for advanced-stage cHL in Europe.
Key Limitations
TRM score as co-primary endpoint is a composite measure that may not capture all toxicities uniformly. The superior PFS was not accompanied by a significant OS difference — OS equivalence may reflect effective salvage rather than true PFS-to-OS translation. BrECADD includes brentuximab vedotin (anti-CD30 ADC), adding peripheral neuropathy as a novel toxicity. Long-term reproductive outcomes and secondary malignancy rates require extended follow-up. No direct comparison with N+AVD (S1826) or BV+AVD (ECHELON-1) has been conducted, making cross-regimen comparisons indirect.
Clinical Context
HD21 has rapidly replaced eBEACOPP as the preferred intensive regimen in Europe (ESMO 2024, GHSG guidelines), offering better PFS with less toxicity. BrECADD is particularly favorable for patients concerned about fertility or long-term morbidity, as it avoids the alkylating agents (cyclophosphamide, procarbazine) in BEACOPP. In the US, N+AVD (S1826) is now preferred for most advanced-stage cHL based on superior PFS, while BrECADD is a guideline-listed alternative especially relevant for European patients receiving intensive therapy.
References