Background: The incidence of classical Hodgkin lymphoma (cHL) in the elderly is increasing, outcomes among elderly patients with advanced-stage disease are historically poor, and prospective clinical trials dedicated to this vulnerable population are scarce. We hypothesized that the combination of the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) with a tolerable anthracycline-containing chemotherapy constitutes a feasible and effective first-line treatment.

Methods: The international GHSG-NLG intergroup phase II BVB trial (NCT02191930) evaluated six cycles of B-CAP, consisting of BV (1.8mg/kg on day 1), cyclophosphamide (750mg/m2 d1), doxorubicin (50mg/m2 d1) and prednisone (100mg/day 2-6) as first-line treatment for advanced-stage cHL patients ≥60 years considered eligible for polychemotherapy. Primary endpoint was objective response rate (ORR) determined by computed tomography (CT) after completion of B-CAP. B-CAP was to be considered effective in case of an ORR > 60%. Secondary endpoints included feasibility, toxicity, progression-free (PFS) and overall survival (OS).

Results: A total of 49 patients with a median age of 66 years (range: 60-84, IQR 64-70) were evaluable in the intention-to-treat population. The majority presented with ECOG performance status 1 (61%, range 1-3), stage IV cHL (65%), international prognostic score ≥4 (50%), and CIRS-G score 1-3 (51%, range 0-7).

The intended number of six cycles B-CAP were administered in 46/49 patients (94%). Three patients terminated treatment early due to toxicity, including one infection-related death (grade 5 [G5] sepsis) before response assessment who was excluded from efficacy evaluations. With primary G-CSF support documented in 98% of patients, the maximum dose level was maintained in 86% of patients, and the mean relative dose intensity was 93%. Most patients experienced hematological toxicities (any G: 92%, G3: 8%, G4: 53%); i.e. neutropenia (G3/4: 61%), anemia (G3/4: 18%) and thrombocytopenia (G3/4: 10%). Febrile neutropenia occurred in 27% and infections in 61% (G3: 29%, G4: 2%, G5: 2%) of patients, respectively. Neuropathy increased with accumulating B-CAP exposure, was mostly sensory and reported in 67% of patients (G2: 20%, ≥G3: 0). Dose-reduction or omission of BV occurred in 3 patients each. Persisting peripheral neuropathy was reported in 11/49 (22%) of patients at last available follow-up (G1: 9 patients, G2: 2 patients).

After 2 cycles B-CAP, 94% had an objective response including 34% with CR. The predefined primary endpoint was met with a CT-based ORR after end of treatment of 98% (95%CI: 90.5-100; CR: 44%), respectively. Positron emission tomography (PET) after the last cycle showed metabolic CR in 31/48 evaluable patients (65%). Ten patients (20%) received consolidative 30 Gy radiotherapy to PET+ residues. With a median follow-up of 35 months, 16 patients (33%) experienced tumor progression or relapse and 9 (18%) died, mostly from cHL (6 patients, 12%). 3-year PFS and OS are 64% (95%CI: 50-79) and 91% (95%CI: 82-99), with more favorable 3-year PFS observed in patients achieving a metabolic CR (82%) compared to patients with metabolic PR (33%; HR 6.7, 95%CI 2.3-19.7).

Conclusions: The B-CAP regimen is a feasible and effective treatment option for older patients with advanced-stage cHL, resulting in high response rates already after 2 cycles and favorable 3-year PFS in patients achieving a metabolic CR.

Disclosures

Bröckelmann:BMS: Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Need Inc.: Consultancy, Current holder of stock options in a privately-held company; Stemline: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Else-Kröner Fresenius Foundation: Other: Excellence Stipend; BeiGene: Honoraria, Research Funding. Böll:Amgen, Kite/Gilead, MSD, Miltenyi, Noscendo, Novartis, Pfizer, Celgene, Astellas, J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Molin:Roche: Honoraria. Leppä:Abbvie, BeiGene, Genmab, Gilead, Incyte, Novartis, Orion, Roche: Membership on an entity's Board of Directors or advisory committees. Hutchings:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Janssen/J&J: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Schnetzke:Abbvie, Novartis, Kite Gilead, BMS, Janssen, Sobi, Takeda, Beigene: Consultancy, Honoraria, Other: travel support . von Tresckow:AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis: Other: Travel and congress support ; Esteve (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), and Takeda (Inst): Research Funding; AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Roche and Takeda: Honoraria; Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Regeneron, Roche, Sobi and Takeda: Consultancy. Borchmann:Takeda Oncology, BMS, Roche, Amgen, Miltenyi Biotech, Gilead, MSD: Consultancy; Takeda Oncology, BMS, Roche, MSD, Celgene, Miltenyi Biotech, Gilead, Abbvie: Honoraria; Takeda Oncology, MSD, Incyte: Research Funding.

Off Label Disclosure:

Brentuximab vedotin in combination with CAP is not yet approved as first-line treatment for Hodgkin lymphoma.

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2024
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