Background
Phase III, open-label RCT (GHSG HD18). 2,101 patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (stage IIB with mediastinal bulk or extranodal involvement, III, or IV). All patients received 2 cycles of BEACOPPesc followed by PET (iPET2). iPET2-negative patients (~65%) were randomized to 4 vs. 8 total cycles of BEACOPPesc; iPET2-positive patients were randomized to continue BEACOPPesc with or without rituximab.
Interventions and follow up
Arm A: 4 total cycles BEACOPPesc (2 prior + 2 additional) — for iPET2-negative patients (de-escalation arm)
Arm B: 8 total cycles BEACOPPesc (standard) — for iPET2-negative patients
Primary endpoint: PFS; noninferiority of 4 vs. 8 cycles in iPET2-negative patients
Median follow up: 5 years (Borchmann Lancet 2017); extended follow-up (Kreissl Lancet Haematol 2021)
Arm B: 8 total cycles BEACOPPesc (standard) — for iPET2-negative patients
Primary endpoint: PFS; noninferiority of 4 vs. 8 cycles in iPET2-negative patients
Median follow up: 5 years (Borchmann Lancet 2017); extended follow-up (Kreissl Lancet Haematol 2021)
Results
5-yr PFS (4 cycles vs. 8 cycles, iPET2-negative): 92.3% vs. 91.9% — noninferior
5-yr OS (4 cycles vs. 8 cycles): 97.3% vs. 96.0% — improved with 4 cycles (fewer treatment-related deaths)
iPET2-positive patients (rituximab addition): no significant PFS benefit; rituximab arm dropped
5-yr OS (4 cycles vs. 8 cycles): 97.3% vs. 96.0% — improved with 4 cycles (fewer treatment-related deaths)
iPET2-positive patients (rituximab addition): no significant PFS benefit; rituximab arm dropped
Adverse events
Hematologic (per cycle, BEACOPPesc): grade ≥3 leukopenia ~70%, thrombocytopenia ~35%
Infectious: grade ≥3 infections ~15% per cycle
Cumulative (4 vs. 8 cycles): significantly less hematologic toxicity and fewer hospitalizations with 4 cycles; reduced secondary MDS/AML (6 vs. 16 cases, P=.03); infertility risk from alkylating agents present in both arms but lower with 4 cycles
Infectious: grade ≥3 infections ~15% per cycle
Cumulative (4 vs. 8 cycles): significantly less hematologic toxicity and fewer hospitalizations with 4 cycles; reduced secondary MDS/AML (6 vs. 16 cases, P=.03); infertility risk from alkylating agents present in both arms but lower with 4 cycles
Conclusions
Four cycles of BEACOPPesc was noninferior to eight cycles for PFS in iPET2-negative advanced-stage cHL and associated with improved OS due to fewer treatment-related deaths, establishing 4-cycle PET-adapted BEACOPPesc as the new GHSG standard for iPET-negative patients. Rituximab addition provided no benefit in iPET-positive patients.
Key Limitations
HD18 establishes the minimum effective dose of BEACOPPesc for iPET-negative patients, but does not address whether BEACOPPesc itself is optimal compared to emerging novel-agent combinations (BV+AVD, N+AVD). The rituximab-negative result for iPET-positive patients was unexpected but consistent with the absence of CD20 expression amplification by BEACOPPesc. OS benefit from 4 vs. 8 cycles is driven by treatment-related deaths, highlighting the intrinsic toxicity of BEACOPPesc at any dose. Long-term secondary malignancy and fertility data require extended follow-up.
Clinical Context
HD18 defined the PET-adapted BEACOPPesc approach in advanced cHL: 4 cycles for iPET2-negative patients (the majority) and continued BEACOPPesc (without rituximab) for iPET2-positive patients. Combined with HD21 results (BrECADD superior PFS and TRM vs. eBEACOPP in 2024), BrECADD has now largely supplanted 8-cycle BEACOPPesc as the preferred intensive regimen in Europe. In the US, BEACOPPesc-based approaches remain less commonly used, with N+AVD (S1826) dominating current practice.