Treatment Related Morbidity in Patients with Classical Hodgkin Lymphoma: Results of the Ongoing, Randomized Phase III HD21 Trial By the German Hodgkin Study Group

INTRODUCTION Interim PET (PET2)-guided intensive upfront treatment of newly diagnosed advanced stage (AS) classical Hodgkin Lymphoma (cHL) patients with eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). CD30-targeted therapy with the antibody-drug conjugate brentuximab vedotin (BV) has proven high efficacy and favorable tolerability in cHL. For the German Hodgkin Study Group (GHSG) HD21 study we thus hypothesized that using BV to remodel the eBEACOPP regimen could further decrease TRMB while maintaining the high efficacy of PET2-guided eBEACOPP. Here, we report the final analysis of the TRMB endpoint from the HD21 study.

Methods This international open label randomized phase III trial included adult patients ≤ 60 years of age with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4-6 cycles of either standard eBEACOPP or experimental BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) treatment. PET2 was assessed by blinded panel review (PP-2).

Reduction of TRMB was the first part of the co-primary endpoint, whereas non-inferiority of efficacy as determined by progression-free survival was the second part. TRMB was determined using the Cochran-Mantel-Haenszel method. Stratification factors included sex, age, International Prognostic Score (IPS), and location of trial site. TRMB was defined as any CTCAE grade 3 or 4 organ toxicity or grade 4 hematological toxicity (defined as anemia, thrombocytopenia, infection) during study treatment. Categorical variables were compared using fisher´s exact test. Exploratory analyses were performed for further safety outcome parameters. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines.

Results Between July 2016 and August 2020, we enrolled 1,500 patients from 9 countries and more than 250 trial centers. The intention-to-treat (ITT) population comprised 1,470 patients. Baseline characteristics such as sex (56 % male), age (79% ≤45 years), IPS (54% 0-2), location (92% Europe), performance status (70% ECOG 0), B symptoms (68%), and Ann-Arbor stage III/IV (84%) were well balanced between the treatment arms. As recommended by PP-2, 59% of patients (n=861, eBEACOPP n=430, BrECADD n=431) received 4 cycles and 41% (n=609, eBEACOPP n=302, BrECADD n=307) received 6 cycles of therapy.

TRMB was analyzed in the ITT cohort comprising 732 patients in the eBEACOPP and 738 patients in the BrECADD group. Overall, TRMB was documented in 59% and 42 % of patients in the eBEACOPP and BrECADD groups, respectively (relative risk for eBEACOPP 1.41; 95% CI, 1.27 - 1.56, p<0.001, relative risk for BrECADD 0.72; 95% Confidence interval [CI], 0.65 - 0.79, p<0.001). The relative risk estimates remained stable among the stratification factors (sex, age, IPS, location). In the eBEACOPP group 52% of patients had hematological TRMB events compared to 31% in the BrECADD group (p<0.001). The significant difference for hematological TRMB was reflected in the reduction in red cell and platelet transfusions. At least one red cell transfusion was given in 22% of patients in the eBEACOPP group and in 8% in the BrECADD group, and at least one platelet transfusion in 13% and 6%, respectively. Leukopenia grade 4 was observed in 94% and 87%, respectively. TRMB organ toxicity was documented in 17% of patients in the eBEACOPP group and 19% in the BrECADD group (p = 0.455). Peripheral sensory neuropathy all grades was documented in 49% and 38% in the eBEACOPP and BrECADD group, respectively, which was mainly grade 1 (33% and 31%), whereas grade 2 occurred in 14% and 6%, and grade 3 in 2% and 1%, respectively. Peripheral motor neuropathy all grades was documented in 4% in both treatment groups, which was grade 1 in 3%, and grade 2 in 1% in each group, respectively.

CONCLUSION This analysis of the GHSG HD21 for patients with newly diagnosed AS-cHL shows a significant and clinically relevant reduction in treatment-related morbidities with BrECADD as compared to eBEACOPP.

Borchmann:Miltenyi Biotec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novarts: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Greil:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding; Hoffmann - La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Research Funding. Hertzberg:Beigene: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Keil:Novartis: Honoraria; Incyte: Honoraria; Janssen: Honoraria; BMS: Honoraria; Gilead: Honoraria; Abbvie: Honoraria, Research Funding; Roche: Honoraria; Takeda: Honoraria, Research Funding; Astra Zeneca: Honoraria. Haenel:Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; JAZZ: Consultancy, Honoraria. Novak:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Ideogen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; H & O Communication: Honoraria. Viardot:Kite Gilead: Consultancy, Honoraria, Other: Support for meeting attendance; Novartis: Consultancy, Honoraria, Other: Support for meeting attendance; BMS: Consultancy, Honoraria, Other: Support for meeting attendance; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Other: Support for meeting attendance; Janssen-Cilag: Honoraria, Other: Support for meeting attendance; Astra Zeneca: Honoraria, Other: Support for meeting attendance; Incyte: Consultancy, Other: Support for meeting attendance. Molin:MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; BMS: Honoraria. Hallek:Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Roche, Janssen: Honoraria, Research Funding; Abbvie, AstraZeneca: Consultancy, Honoraria, Research Funding.

BV in combination with ECADD in cHL