Background Elderly patients (≥60 years) with classical Hodgkin lymphoma (cHL) experience disproportionately poor outcomes, with historical 5-year overall survival (OS) rates of 50% globally due to treatment-related toxicity, comorbidities, and disease biology. In China, this population faces additional challenges including delayed diagnoses and limited access to novel therapies-brentuximab vedotin (BV) and PD-1 inhibitors were only approved in 2020 and 2019, respectively. Real-world data on treatment evolution and survival impacts in elderly Chinese cHL patients, particularly those with high comorbidity burdens (CIRS-G ≥10 prevalence >30% in prior studies), remain critically scarce. This 15-year multicenter analysis aims to define the survival benefit of novel agents and identify key prognostic factors in this vulnerable cohort.

Methods We conducted a retrospective study of 493 consecutive newly diagnosed cHL patients ≥60 years treated at 13 tertiary centers across China (2008-2023). Inclusion required pathological confirmation and ≥6-month follow-up. Collected variables: 1) Baseline characteristics: age, Ann Arbor stage, B-symptoms, ECOG PS; 2) Geriatric metrics: CIRS-G comorbidity index (severe: ≥10), Activities of Daily Living (ADL) scale (impairment: score <6); 3) Treatment details: frontline/salvage regimens (chemotherapy/radiotherapy/novel agents), BV/PD-1 utilization timelines; 4) Response and toxicity: PET-CT parameters (Deauville, total metabolic tumor volume [TMTV] available in 336 patients [68%]), grade 3-5 adverse events (CTCAE v5.0); 5) Molecular profiling: 475-gene next-generation sequencing panel in 158 patients (32%). Survival endpoints (OS/PFS) were compared between novel-agent-containing (BV±PD-1±chemo) and chemo-only groups using Kaplan-Meier/log-rank tests. Multivariable Cox regression identified OS predictors adjusting for age, stage, CIRS-G, and ADL. Biomarker correlations used logistic regression.

Results The cohort (median age 72 years, 58% male) exhibited high-risk features: 64% stage III/IV, 48% with ≥3 comorbidities (CIRS-G≥10: 31%), and 22% ADL impairment. Treatment patterns shifted dramatically post-2020: BV utilization increased from 0 (pre-2020) to 21% (2020-2023), while PD-1 inhibitor use rose from 1% to 27% (P<0.001). Frontline regimens included ABVD (43%), AVD (20%), BV-AVD (8%), and PD-1±chemo (7%). Landmark survival analysis demonstrated transformative benefits with novel agents: 3-year OS was 78% (95%CI 72-84) for novel-agent recipients (n=142) versus 53% (95%CI 47-59) for chemo-only patients (n=351) (HR=0.45, P<0.001); 3-year PFS was 65% (59-71) vs 38% (32-44) (HR=0.49, P<0.001). This OS advantage persisted in high-risk subgroups: age >75 years (HR=0.52, P=0.008) and CIRS-G≥10 (HR=0.57, P=0.01). Overall cohort median OS was 58 months (5-year OS 46%), with multivariable analysis confirming independent OS predictors: age >75 years (HR=2.1, P=0.001), ADL impairment (HR=2.8, P<0.001), and ≥3 comorbidities (HR=1.9, P=0.01). Grade ≥3 toxicity was lower with novel agents (38% vs 52% for chemo-only, P=0.03), though BV-related neuropathy was more frequent (18% vs 6%, P<0.001). Exploratory biomarker analysis revealed high TMTV (>80 cm³) predicted inferior PFS (HR=1.8, P=0.02), and TP53 mutations (21%) associated with primary refractoriness (OR=3.1, P=0.004).

Conclusion This largest real-world study of elderly Chinese cHL establishes that BV and PD-1 inhibitors confer unprecedented survival improvements (25% absolute 3-year OS gain), fundamentally altering treatment paradigms for this high-risk population. The survival benefit extends to traditionally excluded subgroups (>75 years, high comorbidity burden), supporting frontline integration of novel agents in fit patients. Geriatric assessments (ADL/CIRS-G) outperform conventional staging in predicting mortality risk, underscoring their essential role in treatment stratification. While toxicity profiles differ from chemotherapy, novel regimens demonstrate overall better tolerability. Emerging biomarkers (TMTV, TP53) offer pathways for personalized therapy-a critical need given the 46% 5-year OS rate with conventional approaches. Prospective trials optimizing novel-agent combinations guided by geriatric and molecular metrics are urgently warranted.

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2025
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