PET-guided treatment with BrECADD vs. BEACOPP for advanced stage Hodgkin Lymphoma: Results from the Phase III GHSG HD21 trial

Introduction: ¹⁸F-FDG PET/CT scans are used to guide the number of treatment cycles and the use of radiotherapy in patients with advanced-stage Hodgkin lymphoma. Here, we analyzed data of the HD21 trial of the German Hodgkin Study Group (GHSG), spanning 1,500 patients across 9 countries and 233 trial sites. We compared PET/CT results in patients treated with a new combination of immuno- and chemotherapy vs. those receiving chemotherapy alone. The experimental arm received the BrECADD combination regimen of immunotherapy (Brentuximab vedotin) and chemotherapy (etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone). The standard of care (SOC) arm was treated with eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procar­bazine, prednisone).

Methods: This international open-label phase III trial recruited adult advanced-stage Hodgkin lymphoma patients aged ≤ 60 between 2016 and 2020. Patients were randomly assigned to 4-6 cycles of BrECADD (n=751) or eBEACOPP (n=749). An ¹⁸F-FDG PET/CT was performed after 2 cycles of BrECADD or eBEACOPP (PET2) and at the end of treatment, each assessed by blinded panel review. PET response was rated according to the Deauville score (1-3: negative; 4-5: positive). Progression-free survival (PFS) was compared at an interim analysis between BrECADD (n=742) and eBEACOPP arms (n=740) in the intend-to-treat (ITT) cohort. Treatment-related morbidity (TRMB) was compared between BrECADD (n=738) and BEACOPP patients (n=732). The trial was registered (NCT02661503) and conducted according to guidelines of good clinical practice.

Results: We found similar PET2-negativity rates in BrECADD regime (n=432; 58.2%) and eBEACOPP group (n=435; 58.8%). Comparing local vs. central review of PET2 in BrECADD regime the PET interpretation was concordant in 525 patients (69.9%), discordant in 149 patients (19.8%), and 77 patients were without central review (10.3%). The data in the eBEACOPP regime were 543 pts. (72.5%), 124 pts. (16.6%), and 82 pts. (10.9%). PET2-negative patients had 3-year PFS rates of 97.1% with BrECADD (95%-CI 95.5-98.7%) vs. 93.6% with eBEACOPP (95%-CI 91.3-95.9%). PET2-positive patients exhibited 3-year PFS of 93.5% after BrECADD (95% CI 90.6-96.5%) vs. 90.6% after eBEACOPP (95% CI 87.1-94.1%). Overall, 96% of patients received the number of treatment cycles as recommended by blinded central review of PET2 scans. The risk ratio of a TRMB event was 0.72 (95% CI 0.65-0.79) in the BrECADD group vs. eBEACOPP group. Consolidation radiotherapy was recommended by blinded review of PET after BrECADD in 125 patients (16.6%) and eBEACOPP in 127 patients (17%). 13.8% (BrECADD) and 15.1% (eBEACOPP) actually received radiotherapy. Comparing local vs. central review of end of treatment PET in BrECADD regime the PET interpretation was concordant in 599 patients (79.8%), discordant in 118 patients (15.7%), and 34 patients were without central review (4.5%). The corresponding numbers in the eBEACOPP regime were 595 pts. (79.4%), 120 pts. (16.0%), and 34 pts. (4.5%).

Conclusions: The PET2-guided stratification of treatment intensity is feasible. The BrECADD regimen with individualized PET2-guided treatment duration resulted in the longest 3-year progression-free survival (PFS) reported to date for advanced-stage Hodgkin lymphoma. PET2-negative patients had a very high 3-year PFS of 97.1% with 4 cycles, PET2-positive patients had a high 3-year PFS of 93.5% with 6 cycles BrECADD, suggesting that PET2 guidance allows the reduction to 4 cycles for the majority of patients with optimal treatment outcomes.