Targeted Beacopp Variants in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma: Final Analysis of a Randomized Phase II Study
Authors: Borchmann Peter , Eichenauer Dennis A. , Pluetschow Annette , Haverkamp Heinz , Kreissl Stefanie , Fuchs Michael , Soekler Martin , Hellmuth Johannes C. , Meissner Julia , Mathas Stephan , Behringer Karolin , Dietlein Markus , Kobe Carsten , Diehl Volker , Engert Andreas 
Published: October 2019

Abstract
Rationale: The intensified BEACOPPescalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has substantially improved the survival of advanced stage Hodgkin Lymphoma (HL) patients. However, the efficacy of this regimen comes along with severe acute toxicities. Brentuximab vedotin (BV) is an anti-CD30 directed antibody-drug conjugate that has shown very promising single-agent activity and good tolerability in relapsed/refractory HL. We introduced BV into the BEACOPP regimen in order to improve its toxicity profile while maintaining its efficacy.
Methods: Two modified BEACOPP regimens were developed. In a more conservative variant (BrECAPP: BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone), vincristine was replaced by BV and bleomycin omitted. A more experimental variant (BrECADD: BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) was designed to reduce procarbazine induced gonadal toxicity. Both regimens are administered q21d for 6 cycles. This is a randomized phase II study with the combined primary endpoint being the PET-based complete response rate (CRR) after chemotherapy and the complete remission rate (CR/CRu rate) at final restaging including early follow-up for each of the regimens. Safety and feasibility are secondary trial objectives.
Results: From October 2012 to May 2014, 104 patients have been enrolled and are evaluable for this analysis (52 patients in each treatment arm). Median age is 29 years (range 18-60 years), 61% are male, and 83% have Ann-Arbor stage III or IV disease. Overall, risk factors were well balanced between the treatment arms and in line with the previous GHSG studies besides a higher number of patients presenting with large mediastinal mass (40% in each treatment arm). 102 patients qualify for the safety analysis (BrECADD n=52, BrECAPP n=50) with two patients not having commenced treatment in the latter group. All 52 patients with BrECADD received the planned number of cycles, 2/50 terminated BrECAPP after 2 and 3 cycles due to toxicity and revision of initial staging by expert panel, respectively. 70% and 60% with complete cycles of BrECADD and BrECAPP received the last treatment cycle at full dose level. The majority of patients did not have treatment delays.
101 patients qualify for the efficacy analysis (BrECADD n=52, BrECAPP n=49). CRR is 88% (95%-CI: 77% - 96%) for the BrECADD regimen and 86% (95%-CI: 73% - 94%) for BrECAPP with both groups achieving the required number of 42 patients with CRR demanded by the protocol. Regarding the co-primary endpoint CR/CRu, the corresponding rates were 88% for BrECADD (95%-CI: 77% - 96%), and 94% (95%-CI: 83% to 99%) for BrECAPP. Survival analyses for the BrECADD regimen revealed a progression free survival (PFS) of 94% (95%-CI: 87% - 100%) at 12 months, and 89% (95%-CI: 77% - 100%) at 18 months. Corresponding numbers for BrECAPP were 98% (95%-CI: 94% - 100%), and 93% (95%-CI: 83% - 100%). Overall survival (OS) after a median follow-up time of 18 months for BrECADD was 100%. In the BrECAPP group the median follow-up was 16 months and one patient died. This patient had never received the study treatment. However, this event led to a 1-year OS of 98% (95%-CI: 94% - 100%) in the BrECAPP group.
Hematological toxicity grade 3 or 4 occurred in 42/52 (88%) of BrECADD treated patients, and in 47/50 (96%) with BrECAPP. Main hematotoxicity was leukopenia resulting in 15% (BrECADD) and 8% (BrECAPP) grade 3 or 4 infections. Organ toxicity grade 3 or 4 occurred in 4% of BrECADD treated patients (all events grade 3), and in 17% in the BrECAPP group (5% grade 4). Severe neurotoxicity (i.e. grade 3 or 4) was not observed in the BrECADD group and in one patient (2%) in the BrECAPP group (grade 3 sensory neuropathy). Grade 1 or 2 sensory neuropathy occurred in 35% and 30%, respectively.
Conclusion: This is the largest study of BV in combination with chemotherapy in the first line treatment of HL reported so far. Both targeted BEACOPP variants are active and well feasible. Based on its superior organ toxicity profile, we have chosen the BrECADD regimen to challenge the GHSG standard of care escalated BEACOPP for advanced stage HL patients in an international, randomized phase III study.

Disclosures
Borchmann: Millennium: Research Funding. Engert:Milennium: Research Funding.