In the phase III German Hodgkin Study Group (GHSG) HD21 study, the novel BrECADD regimen comprised of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone demonstrated superior progression-free survival (PFS) outcomes versus eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in patients with advanced-stage classical Hodgkin lymphoma and had a promising benefit-risk profile.
Introduction of eBEACOPP (HD9) improved progression-free survival (PFS) and subsequently overall survival (OS) by reduction of primarily progressive disease or early relapse. However, despite the fact that the benefit of this approach is most relevant for patients at higher risk for treatment failure, the risk of acute and late or persisting toxicities is increased for all patients. The high efficacy of the eBEACOPP regimen allowed to reduce treatment intensity to the individual patient’s need by early interim PET-guidance from 8 to only 4 cycles for most patients. In the HD21 study, researchers aimed to further improve this PET2-guided individualised approach by modifying the eBEACOPP regimen with brentuximab vedotin, a CD30-targeting antibody-drug-conjugate.
HD21 is an international, open-label, randomised phase III trial of BrECADD versus eBEACOPP in adult patients < 60 years with previously untreated advanced stage classical Hodgkin Lymphoma. Patients were randomly assigned 1:1 to receive either 2 cycles of BrECADD or 2 cycles of eBEACOPP before undergoing interim PET/CT staging (PET2) to determine if they had a complete metabolic response. Patients who were PET2-negative received 2 more cycles of the prescribed regimen, while those who were PET2-positive received 4 more cycles. The co-primary endpoints were: (I) to demonstrate superior tolerability defined by treatment-related morbidity (TRMB) with BrECADD and (II) to demonstrate non-inferior efficacy of 4-6 BrECADD compared with 4-6 eBEACOPP determined by PFS.
The intention-to-treat (ITT) population for the efficacy analysis consistent of 1.482 patients, of which 742 were randomised to BrECADD and 740 to eBEACOPP. Baseline patient characteristics were well balanced between study arms. Median age of the patients was 31 years and 44% of patients were female. PET2 was negative in 64% of patients in each treatment arm and these patients were scheduled for four treatment cycles. There was a significant reduction of acute and severe TRMB across all subgroups favouring the BrECADD group, compared to the eBEACOPP group (42% vs. 59%; relative risk [95%CI]: 0.72 [0.65-0.79], p< 0.0001). The clinical relevance of this reduction is reflected in the reduction of transfusion frequency for red blood cells (24% vs. 52%) and platelets (17% vs. 34%). Grade 2 or 3 peripheral neuropathy occurred in 7% of patients in the BrECADD group compared to 16% of patients in the BEACOPP group. There was a resolution of TRMB within one year in more than 99% of patients treated with BrECADD. The better tolerance of the BrECADD regimen led to a reduced dose reduction over the different treatment cycles. As such, during the 4th treatment cycle, 77.8% of patients received the full dose of the BrECADD combination compared to 58.5% with the BEACOPP combination.
After a median follow-up of 48 months, the 4-year PFS estimate was 90.9% with BEACOPP versus 94.3% with BrECADD (HR[95%CI]: 0.66[0.45-0.97], p= 0.035). The PFS benefit of BrECADD is observed across relevant subgroups. The 4-year OS rates were 98.2% with BEACOPP and 98.6% with BrECADD.
BrECADD is significantly better tolerated than eBEACOPP, with a recovery of TRMB after 12 months in more than 99% of patients. Because of the better tolerability, there is an improved feasibility, with up to 25% higher rate of full dose treatment. Finally, the efficacy of BrECADD was found to be superior to eBEACOPP, reaching an unprecedented PFS of 94.3% with mature follow-up of 4-years. Therefore, authors recommend individualised PET2-guided BrECADD as a standard treatment option for advanced stage classical Hodgkin Lymphoma.
Reference
Borchmann P, et al. The randomized study GHSG HD21 shows superior tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma. Presented at EHA 2024; Abstract S225.
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