Background
Phase III, open-label RCT (COG AHOD1331). 600 patients aged 2–21 years with newly diagnosed high-risk classical Hodgkin lymphoma (stage IIB with bulky mediastinal disease or ≥3 nodal sites, IIIB, IVA, or IVB). Treatment stratified by early response (rapid early responder [RER] vs. slow early responder [SER]) after 2 cycles; RT administered to SERs and consolidative RT to RERs at involved sites with incomplete response.
Interventions and follow up
Arm A: BV-AVE-PC — brentuximab vedotin 1.8 mg/kg day 1 + standard ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) × 2 lead-in cycles, then AVE-PC (without BV for cycles 3+); RT for SERs (n=300)
Arm B: Standard ABVE-PC chemotherapy ± RT for SERs (n=300)
Primary endpoint: Event-free survival (EFS)
Median follow up: ~3 years
Arm B: Standard ABVE-PC chemotherapy ± RT for SERs (n=300)
Primary endpoint: Event-free survival (EFS)
Median follow up: ~3 years
Results
3-yr EFS (BV-AVE-PC vs. ABVE-PC): 92.1% (95% CI 88.4–94.7) vs. 82.5% (95% CI 77.4–86.5), HR 0.41 (95% CI 0.25–0.67), P<.001
3-yr OS: 98.8% vs. 98.0% — no significant difference
EFS benefit in RERs: 94.6% vs. 85.3% (HR 0.36, P=.002)
EFS benefit in SERs: 87.7% vs. 77.1% (HR 0.46, P=.03)
3-yr OS: 98.8% vs. 98.0% — no significant difference
EFS benefit in RERs: 94.6% vs. 85.3% (HR 0.36, P=.002)
EFS benefit in SERs: 87.7% vs. 77.1% (HR 0.46, P=.03)
Adverse events
BV-AVE-PC: peripheral neuropathy any grade 37% (grade ≥3: 5%), febrile neutropenia 57%, grade ≥3 infections 23%
ABVE-PC: febrile neutropenia 52%, grade ≥3 infections 20%
Other: pulmonary toxicity (bleomycin) 5% both arms; secondary malignancies 2 (BV) vs. 1 (standard); no significant difference in treatment-related mortality
ABVE-PC: febrile neutropenia 52%, grade ≥3 infections 20%
Other: pulmonary toxicity (bleomycin) 5% both arms; secondary malignancies 2 (BV) vs. 1 (standard); no significant difference in treatment-related mortality
Conclusions
Addition of brentuximab vedotin to standard ABVE-PC significantly improved 3-year EFS (92.1% vs. 82.5%, HR 0.41) in pediatric high-risk Hodgkin lymphoma, the first major improvement in pediatric HL outcomes in over a decade. FDA approved BV for high-risk pediatric HL on November 10, 2022.
Key Limitations
EFS used as primary endpoint without a corresponding OS benefit — salvage effectiveness may explain OS equivalence but does not make EFS equivalence acceptable given retreatment toxicity. Peripheral neuropathy (37% any grade) is meaningful in a pediatric/AYA population; long-term QoL impact needs follow-up. The regimen uses BV lead-in only rather than continuous BV — optimal pediatric dosing is unestablished. No direct comparison with N+AVD or BrECADD in this age group. Long-term secondary malignancy and reproductive outcomes require extended follow-up.
Clinical Context
AHOD1331 established BV-AVE-PC as a standard for pediatric high-risk cHL (FDA approved November 2022), replacing standard ABVE-PC, and showed for the first time that an anti-CD30 ADC can improve outcomes in pediatric HL. Ongoing COG trials are exploring PD-1 inhibitor integration (nivolumab + AVD) following S1826 in adults; because S1826 enrolled patients ≥12 years, N+AVD can be extrapolated to adolescents.
References