Background

Immune checkpoint inhibitors (ICI) have become central to treating relapsed or refractory classical Hodgkin lymphoma (R/R CHL), but their real-world safety and effectiveness remain unclear. Most data come from selective trial populations, with limited insight into risks such as venous thromboembolism (VTE), ICU admission, and healthcare burden. This study evaluates survival, thrombotic events, and healthcare utilization across five ICI-based treatment strategies in patients with R/R HL.

Methods A retrospective, real-world cohort study using the TriNetX Network, a global electronic health record database. Adults with R/R CHL who received systemic therapy were identified and assigned to one of five propensity score–matched comparisons: (1) brentuximab vedotin (BV) plus nivolumab vs BV alone, (2) nivolumab alone vs BV, (3) Ifosfamide, carboplatin and etoposide (ICE) plus nivolumab vs ICE alone, (4) ICE plus pembrolizumab vs ICE alone, and (5) ICE plus nivolumab vs ICE plus pembrolizumab. Matching was performed separately for each cohort pair based on baseline demographics (age, sex, race/ethnicity), comorbidities (including cardiovascular disease and history of VTE), and laboratory values (hemoglobin, platelet count, lymphocyte count, creatinine, albumin, and erythrocyte sedimentation rate)

The primary outcomes included overall survival, hospitalizations, ICU admissions, venous and arterial thromboembolic events, stroke, and acute coronary events. Outcomes were evaluated over a five-year follow-up period. Kaplan-Meier curves, log-rank tests, and multivariable models were used to compare outcomes across cohorts, with statistical significance defined as p<0.05.

Results After 1:1 propensity score matching, five cohort comparisons were concluded: BV + nivolumab vs BV alone (n = 150 per arm), nivolumab vs BV (n = 146 per arm), ICE + nivolumab vs ICE (n = 98 per arm), ICE + pembrolizumab vs ICE (n = 52 per arm), and BV + nivolumab vs ICE-based regimens (n = 92 per arm). Post-matching baseline characteristics were well balanced across all groups. The median age ranged from 38 to 42 years across cohorts, and the proportion of male patients ranged between 47% to 60%. Most patients were White (73–79%), followed by Black (9–15%) and Hispanic (5–6%). The median follow-up duration after matching ranged from 10.3 to 11.5 months.

In comparison with BV alone, immune checkpoint inhibitor (ICI) use was associated with significantly improved survival. BV + nivolumab resulted in a higher 1-year survival rate compared to BV alone (94.6% vs 83.7%; hazard ratio [HR] 0.40, 95% CI 0.21–0.78; p = 0.007). Nivolumab monotherapy led to higher 1 year survival (93.5% vs 83.5%; HR 0.42, 95% CI 0.21–0.85; p = 0.01), suggesting that even ICI monotherapy may be more effective than targeted antibody therapy alone in the salvage setting.

Among chemotherapy-based regimens, the addition of ICIs also demonstrated significant survival benefits. ICE + nivolumab showed improved 1-year survival compared to ICE alone (87.2% vs 76.6%; HR 0.43, 95% CI 0.21–0.89; p = 0.02), and ICE + pembrolizumab had the strongest effect (91.8% vs 76.5%; HR 0.34, 95% CI 0.13–0.88; p = 0.02). A non-significant trend toward increased venous thromboembolism (VTE) was noted in the ICE + nivolumab group (10.2% vs 5.1%; p = 0.20). No other comparisons showed statistically significant differences in short-term adverse outcomes, including hospitalization, ICU admission, stroke, or acute coronary syndrome.

In the final comparison, BV + nivolumab demonstrated superior 1-year survival relative to all ICE-based regimens combined (94.3% vs 81.1%; HR 0.36, 95% CI 0.17–0.74; p = 0.007). Safety profiles remained similar between the two groups: hospitalization (13.0% vs 12.0%; p = 0.8), ICU admission (1.1% vs 2.2%; p = 0.4), VTE (6.5% vs 7.6%; p = 0.7), stroke (1.1% vs 2.2%; p = 0.4), and ACS (1.1% vs 0.0%; p = 0.3) showed no statistically significant differences.Conclusion ICI, whether alone or in combination with BV or ICE, improved 1-year survival in patients with R/R CHL.BV + nivolumab showed the most favorable balance of efficacy and safety across all comparison groups. ICI monotherapy also outperformed targeted therapy alone, highlighting its potential as a less toxic salvage option. Toxicity outcomes, including VTE and ICU admission, were low and comparable across treatment arms. These findings support broader real-world adoption of ICI-based regimens and warrant prospective validation.

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2025
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