In a randomised, multicentre, open-label, phase III, HD21 study conducted among the adult patients with newly diagnosed, classical Hodgkin lymphoma (cHL), a new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) had superior efficacy regarding progression-free survival (PFS) and superior tolerability in terms of treatment-related mortality compared with escalated doses of etoposide, doxorubicin, cyclophosphamide, and standard doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP regimen).
The study was designed with the assumption that BrECADD would be as effective as eBEACOPP. However, after finding non-inferiority of BrECADD at an interim analysis, the superiority test revealed a significant PFS benefit of BrECADD versus eBEACOPP. With a 4-year PFS of 94.3%, the primary cure rate of BrECADD is unprecedented. With the individualised PET-guided after 2 cycles (PET-2-guided), shortened treatment, the BrECADD regimen shows a favourable risk–benefit profile for most patients and is recommend as a standard treatment option for adult patients with newly diagnosed, advanced-stage cHL according to Prof. Peter Borchmann of the Department I of Internal Medicine, University Hospital of Cologne in Cologne, Germany and colleagues from the German Hodgkin Study Group, the Swiss Group for Clinical Cancer Research, the Arbeitsgemeinschaft Medikamentöse Tumortherapie, the Nordic Lymphoma Group, and the Australasian Leukaemia and Lymphoma Group, who published the findings on 3 July 2024 in The Lancet.
Advanced-stage cHL mainly affects young adults with a median age at onset around 30 years. The optimal risk–benefit ratio of chemotherapy regimens has been the subject of controversial scientific debate, because higher chemotherapy intensity increases efficacy, but might be offset by aggravated toxicities. The German Hodgkin Study Group developed eBEACOPP to eradicate malignant clones upfront with excellent PFS rates. However, the treatment burden for patients is high and persisting organ dysfunction can substantially affect a patient's long-term health-related quality-of-life.
The authors wrote in the background that CD30 cell surface protein is constitutively expressed at high levels in cHL and therefore, it is an attractive therapeutic target. The antibody-drug conjugate brentuximab vedotin has shown a favourable risk–benefit ratio in relapsed or refractory cHL as a single agent. The study team developed the BrECADD regimen incorporating brentuximab vedotin with intent to replicate the high efficacy of eBEACOPP while reducing acute and late or persisting treatment-related toxicities, including gonadal dysfunction and infertility, peripheral neuropathy, or secondary neoplasia.
Based on phase II data, the study investigators hypothesised that BrECADD applied within an individualised treatment approach and PET-2-guides could improve the risk–benefit ratio compared with eBEACOPP for patients with newly diagnosed, advanced-stage cHL. This randomised, multicentre, parallel, open-label, phase III study was conducted in 233 sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage cHL (i.e., Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions).
Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of eBEACOPP or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show: (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by PFS with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of PFS was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle.
Between 22 July 2016 and 27 August 2020, a total of 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP; 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24–42); 56% were male and 44% were female. Most patients were White (91%).
Treatment-related morbidity was significantly lower with BrECADD than with eBEACOPP, 42% versus 59% (relative risk 0.72, 95% confidence interval [CI] 0.65–0.80; p < 0.0001). At a median follow-up of 48 months, BrECADD improved PFS with a hazard ratio of 0.66 (0.45–0.97; p = 0.035); 4-year PFS estimates were 94.3% (95% CI 92.6–96.1) for BrECADD and 90.9% (88.7–93.1) for eBEACOPP. 4-year overall survival rates were 98.6% (97.7–99.5) and 98.2% (97.2–99.3).
The investigators observed high rates of gonadal function recovery in female and male patients, as well as high numbers of childbirth with BrECADD, which is most likely linked to the omission of procarbazine. Use of dacarbazine instead of procarbazine might also have contributed to the low incidence of secondary myelodysplasia or acute myeloid leukaemia in the BrECADD group. However, the numbers are too small, and the observation period is too short to reach a definitive conclusion on second primary malignancies.
A recent analysis of a large cohort of patients with former HL revealed that cumulative doxorubicin exposure of more than 200 mg/m2 is independently associated with a 1.5-fold increased risk of developing breast cancer. Among contemporary strategies available for first-line treatment of advanced-stage cHL, only response adapted treatment with eBEACOPP or BrECADD allows anthracycline exposure below this threshold. Patients with PET-2-negative disease receive a cumulative dose of 160 mg/m2 doxorubicin with the BrECADD regimen. Moderate anthracycline exposure with PET-2-guided BrECADD might also reduce the risk of developing cardiomyopathy and congestive heart failure.
The tolerability of intensive chemotherapy for advanced-stage cHL is sex-dependent. Female patients tend to suffer more treatment-related toxicities than male patients when treated with the same doses of polychemotherapy. This increase in toxicity is associated with a better PFS. In this study, female patients showed greater benefit than male patients in terms of treatment-related morbidity and PFS, indicating a particularly favourable risk–benefit ratio of BrECADD for female patients.
The authors concluded that PET-2-guided BrECADD achieves high response rates, and most patients can be treated with four cycles. It is better tolerated and more effective in terms of PFS than eBEACOPP. The rates of PFS observed with BrECADD are the highest reported in a randomised controlled study in patients with newly diagnosed, advanced-stage cHL to date.
This study was supported by a research grant from Takeda Oncology.
Reference
Borchmann P, Ferdinandus J, Schneider G, et al. on behalf of the German Hodgkin Study Group, the Swiss Group for Clinical Cancer Research, the Arbeitsgemeinschaft Medikamentöse Tumortherapie, the Nordic Lymphoma Group, and the Australasian Leukaemia and Lymphoma Group. 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. The Lancet; Published online 3 July 2024. DOI: https://doi.org/10.1016/S0140-6736(24)01315-1