Highlights
- BrECADD regimen provides significantly higher rates of gonadal function recovery than eBEACOPP in both men and women with advanced-stage classic Hodgkin lymphoma.
- Parenthood rates post-treatment are significantly higher in men treated with BrECADD; women show a numerical but non-significant benefit.
- BrECADD maintains high efficacy and acute tolerability, with reduced treatment-related morbidity compared to eBEACOPP.
- These findings support BrECADD as the preferred first-line therapy for patients with fertility concerns.
Clinical Background and Disease Burden
Classic Hodgkin lymphoma (cHL) affects predominantly young adults, many of whom have not completed family planning at diagnosis. Advanced-stage cHL requires intensive chemotherapy, but standard regimens such as eBEACOPP, while effective, are highly gonadotoxic, leading to substantial risks of permanent infertility. The preservation of reproductive potential is a major unmet need in this population, with profound implications for quality of life and long-term survivorship. BrECADD, a novel regimen incorporating brentuximab vedotin and a modified chemotherapy backbone, has demonstrated promising efficacy and improved tolerability in primary analyses, prompting further investigation of its impact on fertility.
Research Methodology
The HD21 trial was a multicentre, randomised, parallel, open-label, phase 3 study conducted at 233 sites in nine countries, enrolling patients aged 18 to 60 years with newly diagnosed, advanced-stage cHL and an ECOG performance status of 0-2. Patients were randomised 1:1 to receive 4–6 cycles of either BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) or eBEACOPP (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), with treatment intensity guided by interim PET response.
The primary outcomes of the trial—progression-free survival and treatment-related morbidity—have been reported previously. This secondary, unplanned analysis focused on fertility outcomes. Key endpoints included:
– Gonadal function recovery, assessed via follicle-stimulating hormone (FSH) levels
– Anti-Müllerian hormone (AMH) levels in women and inhibin B in men
– Frequency of pregnancies and parenthood incidence post-therapy
The fertility analysis involved the cohort of patients of childbearing potential (POCBP): women <40 years and men <50 years without baseline gonadal dysfunction. Pregnancy and parenthood analyses also included patients with pre-existing gonadal dysfunction.
Key Findings
Between July 2016 and August 2020, 1183 POCBP were enrolled (592 eBEACOPP, 591 BrECADD; 692 men, 491 women). Median follow-up was 49.6 months. FSH measurements were available for 767 patients.
Gonadal function recovery at 4 years was markedly higher with BrECADD:
– Women: 95.3% (95% CI 92.0–98.8) with BrECADD vs 73.3% (66.9–80.4) with eBEACOPP; HR 1.69 (95% CI 1.34–2.14)
– Men: 85.6% (80.8–90.8) vs 39.7% (33.6–46.9); HR 3.28 (2.51–4.30)
AMH and inhibin B concentrations, surrogate markers of ovarian and testicular reserve respectively, were consistently higher post-treatment in the BrECADD group compared to eBEACOPP.
Regarding reproductive outcomes:
– 92 pregnancies were reported among female patients, and 36 among partners of male patients.
– 108 childbirths occurred in 99 patients (59 BrECADD, 40 eBEACOPP).
– Five-year parenthood incidence after therapy was significantly higher in men treated with BrECADD (9.3% [95% CI 6.0–14.5]) versus eBEACOPP (3.3% [1.7–6.5]; p=0.014), but not significantly different in women (19.3% [13.7–27.3] vs 17.1% [11.9–24.6]; p=0.53).
These results are particularly notable given that BrECADD retained or improved efficacy: 4-year progression-free survival was 94.3% (95% CI 92.6–96.1) for BrECADD and 90.9% (88.7–93.1) for eBEACOPP; overall survival was nearly identical (>98% for both regimens). Importantly, treatment-related morbidity was significantly lower with BrECADD.
Mechanistic Insights and Biological Plausibility
The superior fertility outcomes with BrECADD are biologically plausible given the regimen’s omission of procarbazine, a highly gonadotoxic alkylating agent present in eBEACOPP. Brentuximab vedotin, an antibody-drug conjugate targeting CD30, and the substitution of dacarbazine for procarbazine, likely contribute to reduced cumulative gonadal toxicity, particularly in men. The preservation of ovarian function may also be attributable to the avoidance of procarbazine and the overall reduction in alkylator burden.
Expert Commentary
Leading guidelines and lymphoma experts have emphasized the critical importance of fertility preservation in young patients with cHL. These results align with the evolving therapeutic landscape, where efficacy must be balanced against long-term quality of life. As stated by Borchmann and Behringer (Lancet Oncol. 2025), “BrECADD’s favorable fertility profile, coupled with improved tolerability and sustained disease control, marks a paradigm shift for first-line treatment of advanced-stage cHL in patients with reproductive aspirations.”
Controversies and Limitations
This was an unplanned secondary analysis, and while the large sample size and comprehensive follow-up strengthen the findings, residual confounding cannot be excluded. Fertility endpoints such as pregnancies and parenthood are influenced by diverse sociocultural and personal factors beyond gonadal function. The study was conducted primarily in European and Australasian populations, and generalizability to broader global cohorts may require confirmation. Notably, pregnancy and parenthood rates were not significantly different in women, possibly reflecting multifactorial influences on female fertility post-therapy.
Conclusion
The HD21 trial’s fertility analysis establishes BrECADD as the preferred first-line regimen for advanced-stage classic Hodgkin lymphoma among patients desiring fertility preservation. BrECADD offers significantly better gonadal function recovery and higher parenthood rates in men, without compromising disease control or increasing morbidity. These results should inform clinical practice, patient counseling, and future guideline development, emphasizing individualized treatment selection that integrates survivorship goals.
References
1. Ferdinandus J, Schneider G, Moccia A, 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 Aug;26(8):1081-1090. doi: 10.1016/S1470-2045(25)00262-1.
2. Borchmann P, Ferdinandus J, Schneider G, 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 Jul 27;404(10450):341-352. doi: 10.1016/S0140-6736(24)01315-1.
