HD21
HD21 for Advanced Stages Treatment Optimization Trial in the First-line Treatment of Advanced Stage Hodgkin Lymphoma; Comparison of 6 Cycles of Escalated BEACOPP With 6 Cycles of BrECADD
Phase 3N = 1,500NCT02661503
- Population
- Adults aged 60 years or younger with newly diagnosed advanced-stage classic Hodgkin lymphoma (Ann Arbor stage III or IV, or stage II with B symptoms and large mediastinal mass and/or extranodal lesions); median age 31 years.
- Design
- Randomised, multicentre, parallel, open-label phase 3 trial at 233 sites in nine countries: 4 or 6 cycles (21-day intervals) of BrECADD or escalated BEACOPP, guided by PET after two cycles. Hierarchical co-primary objectives: lower treatment-related morbidity, then non-inferior progression-free survival with an absolute margin of 6 percentage points; superiority of PFS tested if non-inferiority was shown. Intention-to-treat analysis; 1500 patients enrolled and 1482 analysed.
- Primary endpoint
- TRMB, PFS
- Arms
- BrECADD (experimental, n = 749): Brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone, 4 or 6 cycles guided by PET after two cycles
- eBEACOPP (control, n = 751): Escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone, 4 or 6 cycles guided by PET after two cycles
- People
- Borchmann P
Δ TRMB−17 pointsPFSHR 0.66 (95% CI 0.45–0.97)Δ 48-month PFS+3.4 pointsΔ 48-month OS+0.4 pointsGonadal function recoveryHR 1.69 (95% CI 1.34–2.14)Δ 48-month Gonadal function recovery+22 points
Show the numbers
| Endpoint | Analysis | BrECADD | eBEACOPP | Effect |
|---|---|---|---|---|
| TRMBPatients with at least one chemotherapy cycle documented (738 BrECADD, 732 eBEACOPP)Rate of predefined treatment-related toxicities during primary treatment and up to 30 days after the last dose: grade 4 anaemia, thrombocytopenia or infection, and grade 3 or 4 non-haematological organ toxicity in predefined organ classes (cardiac; gastrointestinal excluding vomiting, nausea and mucositis; hepatobiliary; nervous system excluding neuropathy; renal and urinary; respiratory, thoracic and mediastinal). Definition from the EMA assessment report. | primaryBorchmann 2024 | 42% | 59% | P<0.0001312 of 738 patients with BrECADD and 430 of 732 with eBEACOPP; relative risk 0.72 (95% CI 0.65 to 0.80). |
| PFSITT (1482 patients) | primarymedian follow-up 48 monthsBorchmann 2024 | 94.3% at 4 y (92.6–96.1%) | 90.9% at 4 y (88.7–93.1%) | HR 0.66 (95% CI 0.45–0.97)P=0.035Superiority test of PFS, done after non-inferiority was established against an absolute margin of 6 percentage points. |
| OSITT (1482 patients) | primarymedian follow-up 48 monthsBorchmann 2024 | 98.6% at 4 y (97.7–99.5%) | 98.2% at 4 y (97.2–99.3%) | — |
| Gonadal function recoveryWomen younger than 40 years without baseline gonadal dysfunction (patients of childbearing potential cohort); FSH measurements available | exploratorymedian follow-up 49.6 monthsFerdinandus 2025 | 95.3% at 4 y (92.0–98.8%) | 73.3% at 4 y (66.9–80.4%) | HR 1.69 (95% CI 1.34–2.14)Unplanned secondary analysis of fertility outcomes. Hazard ratio above 1 favours BrECADD. 4-year cumulative recovery based on follicle-stimulating hormone concentrations. |
| Gonadal function recoveryMen younger than 50 years without baseline gonadal dysfunction (patients of childbearing potential cohort); FSH measurements available | exploratorymedian follow-up 49.6 monthsFerdinandus 2025 | 85.6% at 4 y (80.8–90.8%) | 39.7% at 4 y (33.6–46.9%) | HR 3.28 (95% CI 2.51–4.30)Unplanned secondary analysis of fertility outcomes. Hazard ratio above 1 favours BrECADD. |
| Parenthood incidenceMen in the pregnancy and parenthood analysis (includes patients with baseline gonadal dysfunction) | exploratoryFerdinandus 2025 | 9.3% at 5 y (6.0–14.5%) | 3.3% at 5 y (1.7–6.5%) | P=0.0145-year incidence of parenthood after therapy; unplanned analysis. |
| Parenthood incidenceWomen in the pregnancy and parenthood analysis (includes patients with baseline gonadal dysfunction) | exploratoryFerdinandus 2025 | 19.3% at 5 y (13.7–27.3%) | 17.1% at 5 y (11.9–24.6%) | P=0.535-year incidence of parenthood after therapy; the difference was not statistically significant; unplanned analysis. |
| Endpoint | Analysis | BrECADD | eBEACOPP | Effect |
|---|---|---|---|---|
| TRMBPatients with at least one chemotherapy cycle documented (738 BrECADD, 732 eBEACOPP)Rate of predefined treatment-related toxicities during primary treatment and up to 30 days after the last dose: grade 4 anaemia, thrombocytopenia or infection, and grade 3 or 4 non-haematological organ toxicity in predefined organ classes (cardiac; gastrointestinal excluding vomiting, nausea and mucositis; hepatobiliary; nervous system excluding neuropathy; renal and urinary; respiratory, thoracic and mediastinal). Definition from the EMA assessment report. | primaryBorchmann 2024 | 42% | 59% | P<0.0001312 of 738 patients with BrECADD and 430 of 732 with eBEACOPP; relative risk 0.72 (95% CI 0.65 to 0.80). |
| PFSITT (1482 patients) | primarymedian follow-up 48 monthsBorchmann 2024 | 94.3% at 4 y (92.6–96.1%) | 90.9% at 4 y (88.7–93.1%) | HR 0.66 (95% CI 0.45–0.97)P=0.035Superiority test of PFS, done after non-inferiority was established against an absolute margin of 6 percentage points. |
| OSITT (1482 patients) | primarymedian follow-up 48 monthsBorchmann 2024 | 98.6% at 4 y (97.7–99.5%) | 98.2% at 4 y (97.2–99.3%) | — |
| Gonadal function recoveryWomen younger than 40 years without baseline gonadal dysfunction (patients of childbearing potential cohort); FSH measurements available | exploratorymedian follow-up 49.6 monthsFerdinandus 2025 | 95.3% at 4 y (92.0–98.8%) | 73.3% at 4 y (66.9–80.4%) | HR 1.69 (95% CI 1.34–2.14)Unplanned secondary analysis of fertility outcomes. Hazard ratio above 1 favours BrECADD. 4-year cumulative recovery based on follicle-stimulating hormone concentrations. |
| Gonadal function recoveryMen younger than 50 years without baseline gonadal dysfunction (patients of childbearing potential cohort); FSH measurements available | exploratorymedian follow-up 49.6 monthsFerdinandus 2025 | 85.6% at 4 y (80.8–90.8%) | 39.7% at 4 y (33.6–46.9%) | HR 3.28 (95% CI 2.51–4.30)Unplanned secondary analysis of fertility outcomes. Hazard ratio above 1 favours BrECADD. |
| Parenthood incidenceMen in the pregnancy and parenthood analysis (includes patients with baseline gonadal dysfunction) | exploratoryFerdinandus 2025 | 9.3% at 5 y (6.0–14.5%) | 3.3% at 5 y (1.7–6.5%) | P=0.0145-year incidence of parenthood after therapy; unplanned analysis. |
| Parenthood incidenceWomen in the pregnancy and parenthood analysis (includes patients with baseline gonadal dysfunction) | exploratoryFerdinandus 2025 | 19.3% at 5 y (13.7–27.3%) | 17.1% at 5 y (11.9–24.6%) | P=0.535-year incidence of parenthood after therapy; the difference was not statistically significant; unplanned analysis. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.66 | 0.45–0.97 |
| Gonadal function recovery | 1.69 | 1.34–2.14 |
| Gonadal function recovery | 3.28 | 2.51–4.3 |
Appears in
Sources
Borchmann P, Ferdinandus J, Schneider G, Moccia A, Greil R, Hertzberg M, et al. Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial. Lancet. 2024;404(10450):341-352.
Ferdinandus J, Schneider G, Moccia A, Greil R, Hertzberg M, Schaub V, et al. Fertility in patients with advanced-stage classic Hodgkin lymphoma treated with BrECADD versus eBEACOPP: a secondary analysis of the multicentre, randomised, parallel, open-label, phase 3 HD21 trial. Lancet Oncol. 2025;26(8):1081-1090.