Brentuximab Vedotin, Cyclophosphamide, Doxorubicin and Prednisone (B-CAP) First-Line Treatment of Advanced-Stage Hodgkin Lymphoma: Final Results of the GHSG-NLG Phase II Bvb Trial

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.