Brentuximab vedotin (Bv)+AVD efficacy is influenced by interim PET, age, ECOG performance status and CIRS-g in previously untreated patients with stage IV classical Hodgkin lymphoma: An Italian real-life multicentric study

Abstract Introduction: In Italy, Brentuximab vedotin (Bv) with AVD (adriamycin, vinblastine, dacarbazine) received approval for the first-line treatment of stage IV classical Hodgkin lymphoma (cHL) in September 2021, with no upper age restriction. Considering the upcoming novel standards for the first-line therapy of advanced stage cHL and the issue of older patients, factors impacting the efficacy and toxicity of Bv+AVD outside clinical trials are of interest. Methods: A retrospective multicentric study involving 13 Italian centres aimed to analyze toxicity and efficacy of Bv+AVD in adult patients with stage IV cHL, treated outside clinical trials, compared to a control cohort of stage IV cHL patients treated with ABVD from 2018 to 2021. Progression-free survival (PFS) was defined as occurrence of progression, relapse or death for any cause. The Frailty score (Lia R et al. Haematologica; doi: 10.3324/haematol.2025.287509), based on age >=70 years, ECOG performance status (PS)>=2 and Cumulative Illness Rating Scale-Geriatric (CIRS-G)>=8, was applied to identify fit (0), unfit (1-2) or frail (3 points) patients. PET data were collected from revising clinical files. Results: By March 2025, 132 patients treated with Bv+AVD and 87 with ABVD were collected. Baseline characteristics were not significantly different. Median age was 37 years (range 17-83), 48% were female, 18% were >60 years old, 30% had bulky disease and 62% reported B-symptoms. Age was >70 years in 8% (n=18), ECOG performance status was 2-4 in 10% (n=21), CIRS-G was >4 in 6% (n=12) and >8 in 2% (n=4). Any grade (G) peripheral neuropathy (PN) was significantly higher in the Bv+AVD group compared to ABVD (48% vs 21%, p<0.001), with comparable G3-4 PN (16% vs 18%, p=0.9). Any G neutropenia was comparable in the Bv+AVD vs ABVD group (44% vs 55%, p=0.14), as well as G3-4 infections (5% vs 8%, p=0.2). Eighty% of Bv+AVD patients received primary prophylaxis with G-CSF vs 61% of ABVD group. Toxicity-treatment modifications (TTM) such as treatment schedule delays (32% vs 13%, p=0.001), dose adjustment (25% vs 6%, p=0.001) and dose number reduction (12% vs 2% p=0.009) were more frequent in the Bv+AVD group. No difference was observed in the complete response rate (Deauville score, DS 1-3) at interim PET/CT, performed in 212/219 patients (80% Bv+AVD vs 80% ABVD, p=0.9), neither at final PET/CT (Bv+AVD 87% vs ABVD 91%, p=0.4). Of note, 7/14 patients in the Bv+AVD group had excisional biopsy proven false positive final PET (DS4-5), of which 4 had autoimmune comorbidity and none relapsed at current follow-up. Treatment intensification was performed in 12% of ABVD patients and only in 5% of Bv+AVD (p=0.042). After a median follow-up of 25.6 months for the Bv+AVD and 53.5 months for the ABVD group, with the limits of a historical comparison and of the different follow-up, PFS rates for Bv+AVD vs ABVD were 84% vs 78% at 2 years and 84% vs 72% at 3 years. OS rates were comparable (3y-OS 94% vs 96%, p=0.49). Positive interim-PET was predictive of inferior outcome also within the Bv+AVD group with 3-y PFS of 53% vs 93% (p<0.0001) and 3-y OS of 79% vs 99% (p= 0.001). The advantage of Bv+AVD vs ABVD was significant only in young patients <60 years old (3y PFS 87% vs 74%, p=0.048) and in patients who did not receive TTM (3y PFS 91% vs 71%, p=0.018). Among Bv+AVD group, age>60 years (HR 2.83, CI 1.11-7.19, p=0.029), age>70 years (HR 4.47, CI 1.61-12.4, p=0.004), ECOG-PS >2 (HR 4.79, CI 1.88-12.2, p=0.001) and CIRS-G score (HR 1.21, CI 1.03-1.42, p=0.021) were associated with reduced PFS. According to the Frailty Score, among patients treated with Bv+AVD, unfit (17%, n=22) and frail patients (1%, n=1) showed an inferior PFS (HR 3.96, CI 1.59-9.87, p=0.003), compared to fit patients. Conclusions: In a real-life population of stage IV adult cHL, the Bv+AVD regimen efficacy on PFS is influenced by TTM, interim PET DS4-5 (that also impacted on OS), age, ECOG-PS and CIRS-G. The Frailty score appears useful to select who can benefit less from Bv-AVD and could represent a tool to better stratify patients in the era of novel standards for the first-line therapy of advanced stage cHL.