Real-world clinical outcomes with novel agent combination therapies for the frontline treatment of pediatric and adult advanced-stage Hodgkin lymphoma

Abstract Introduction: Brentuximab vedotin (BV) and nivolumab (N) have resulted in significant progress in the treatment of advanced-stage Hodgkin lymphoma (AS-HL). The SWOG 1826 trial demonstrated a progression-free survival (PFS) and safety benefit with frontline N-AVD (doxorubicin, vinblastine, and dacarbazine) compared to BV-AVD; however, real-world data are limited. This study evaluates the efficacy, toxicity and feasibility of these regimens outside of the clinical trial setting. Methods: This multicenter retrospective study evaluates pediatric (age 12-17) and adult patients (pts)(age ≥18 years(yrs)) treated with BV-AVD or N-AVD in the real-world setting for AS-HL. Fifteen institutions contributed data, and Lugano criteria were utilized to assess response. Adverse events (AEs) graded according to CTCAE 5.0 criteria. Survival outcomes evaluated relative to treatment start date. Results: Between 9/2011 - 2/2025, 556 pts received BV-AVD (433 pts - 78%) or N-AVD (123 pts – 22%). Median age 32 yrs (range, 12-90), 41.7% (n=232) of pts were female, 5.4% (n=26) ECOG ≥2, 6.8% (n=38) were pediatric, and 16.5% (n=92) were older adults (age >60 yrs). Baseline characteristics, including age, sex, ECOG, stage, comorbidities, laboratories and disease characteristics (B symptoms, bulky disease, extranodal disease, stage) were comparable between N-AVD and BV-AVD (all p>0.05). Evaluating treatment delivery, 8% (n=34) of BV-AVD pts and 6% (n=7) of N-AVD pts were unable to complete the intended 6 cycles of therapy (p=0.56). Growth factor support was administered in 92.1% (n=386) receiving BV-AVD compared to 49.6% (n=60; primary prophylaxis: 32 pts, asymptomatic neutropenia: 17, neutropenic fever/infection: 5, other/unknown: 6) receiving N-AVD (p<0.0001). N-AVD was associated with higher rates of neutropenia (any grade (gr): 77.9% vs 48.9%, p<0.0001; gr ≥3: 57.4% vs 37.8%, p=0.0002) and any gr infections (34.2% vs 19.8%, p=0.001) compared to BV-AVD; however, gr≥3 infections (11.7% vs 8.6%, p=0.29) or febrile neutropenia (14.9% vs 13.8%, p=0.77) did not differ between N-AVD to BV-AVD. Dose delays were not significantly different (BV-AVD: 27.6% vs N-AVD: 26.4%, p=0.91), but dose reductions/omissions were more common in BV-AVD group (37.8% vs 13.3%, p<0.0001) compared to N-AVD. In pts treated with N-AVD, immune-related AEs of any gr occurred in 24.2% (n=29), with gr≥3 events in 8.3% (n=10). With BV-AVD, a higher incidence of cardiovascular toxicities (thrombosis, cardiac structural or arrythmia events - any gr: 13.6% vs 2.9%, p=0.01; gr≥3: 9.1% vs 0%, p=0.005) and neuropathy (any gr: 58.9% vs 21.5%, p<0.0001; gr≥3 11.6% vs 0%, p<0.0001) were found compared to N-AVD. Response rates were similar between BV-AVD and N-AVD: overall response rate 92% vs 97% (p=0.20), complete response rate 86% vs 90% (p=0.35). Progressive disease at end-of-therapy: 7.0% (BV-AVD) vs 2.6% (N-AVD). One-yr PFS in pts treated with N-AVD and BV-AVD was 91% (95% CI, 84-98%) and 88% (95% CI, 85-91%), respectively. No death events were observed in N-AVD group (1-yr OS: 100%), 24 deaths in BV-AVD group [1-yr OS: 98% (95% CI, 96-99)] secondary to: infection/sepsis - 10 pts, secondary malignancy - 3, HL - 2, cardiogenic shock - 1, unknown - 8. At current data cutoff, follow-up for N-AVD pts was short (median: 9.8 months vs 30.0 months) compared to BV-AVD, limiting direct survival comparisons. To balance follow-up, additional analyses were conducted on pts treated between 2022-2025 (n=339). No differences in PFS/OS were observed in pediatric pts or older adults (p>0.05); however, improved PFS was seen with N-AVD (1-yr PFS: 96 vs 87% p=0.04) compared to BV-AVD in adult patients (n=253; 18-60 yrs). Conclusions: This large real-world multicenter study demonstrates that response rates and 1-yr survival outcomes with N-AVD and BV-AVD are similar to the published SWOG 1826 trial (N-AVD vs BV-AVD: 1-yr PFS: 94% vs 86%, Herrera et al. 2024). Increased cardiovascular AEs, dose reductions/omissions and neuropathy with BV-AVD indicate better tolerability with N-AVD; however, the higher rate of febrile neutropenia and infections in comparison to SWOG 1826 in N-AVD pts suggests that growth factor prophylaxis may be beneficial in select high-risk subgroups. Longer-term follow-up data will be available at time of presentation, but even with short follow-up, pts (age 18-60) demonstrated a significant PFS benefit with N-AVD, supporting the change to N-AVD as the standard for AS-HL.