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Advanced-stage (AS) classic Hodgkin lymphoma (cHL) has been historically treated with combination chemotherapy regimens such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP).1, 2 While these approaches have achieved high cure rates, they pose significant short- and long-term toxicities for a young patient population. Recently, immunotherapy with programmed death-1 (PD-1) blockade via nivolumab has been established as an effective strategy for relapsed/refractory cHL.3, 4 The S1826 study was a randomized Phase 3 trial comparing nivolumab in combination with AVD (NAVD) versus BV-AVD in 994 patients with previously untreated AS cHL, including approximately one quarter pediatric patients.5 S1826 demonstrated a 1-year investigator-assessed progression-free survival (PFS) of 94% for NAVD compared to 86% for BV-AVD.6 With a longer follow-up of 3.1 years, the 3-year PFS of NAVD was durable at 91% compared to 82% in the BV-AVD arm.5, 7 Immune-related adverse events (irAEs) were reported to be infrequent and consistent with the known safety profile of nivolumab. Based on these promising results, NAVD has been incorporated into US guidelines as a standard first-line treatment option for AS cHL.8 AEs and efficacy of NAVD as frontline therapy in cHL patients have not been reported outside of a clinical trial. Therefore, we conducted a multicenter retrospective study to evaluate the safety and efficacy of NAVD in newly diagnosed patients with AS cHL. This study included adult patients (≥18 years) with newly diagnosed, histologically confirmed, AS cHL treated with NAVD as standard-of-care frontline therapy between January 1, 2023, and October 1, 2025, at one of the 20 participating US sites (Figure S1). Characteristics of the 327 patients are shown in Table S1. Median age was 37 years (range 18–88), with 24% older patients ≥ 60 years of age. Most patients had stage IV disease (61%), nodular sclerosis subtype (84%), and extranodal involvement (62%). Among patients with complete data, 29% had an International Prognostic Score (IPS) of 4–7, 26% were EBV positive, and 8% had a history of an autoimmune (AI) disease. Treatment was ongoing in 11% of patients (n = 35). Granulocyte colony-stimulating factor (G-CSF) was given in 64% of patients (56% as primary prophylaxis). Treatment was interrupted (any length) in 26% (Table S2). AEs were the most common reason for treatment interruption (16%) with a median delay of 8 days. The most common AE leading to treatment interruption was infection/febrile neutropenia in 6%. Chemotherapy was reduced in 11%, most commonly for neuropathy due to vinblastine, which occurred in 5%. Any treatment was discontinued in 15% of patients. Nivolumab was the most frequently discontinued therapy in 11% of patients, all due to suspected or known irAEs. All therapy was discontinued in 4% due to toxicity. The median number of cycles completed was 6 (range 1–6), including patients who were still receiving treatment. Any grade AE and any Grade ≥3 AE (≥G3) were observed in 93% and 61% patients, respectively. Treatment-related AEs are summarized in Table 1. The most common non-hematologic ≥G3 AEs included infection (10%), irAEs (9%), and hepatotoxicity (3%). Febrile neutropenia occurred in 10% of patients, with 8% of patients hospitalized for febrile neutropenia. Febrile neutropenia and ≥G3 infections both occurred in 12% of older patients (≥60) compared to 8% and 10% among patients < 60 years of age. Neutropenia of any grade occurred in 71% (50% ≥G3), with comparable rates among older patients ≥ 60. Hospitalization for an AE occurred in 21%, which were mainly chemotherapy as opposed to irAE-related (Table 1). Hospitalization for an AE was more common for older patients (29%) compared to younger patients (19%), driven by admissions for chemotherapy-related AEs in older versus younger patients (17% vs. 8%), with similar admission rates for irAEs (7% vs. 5%). Among patients with complete irAE data (n = 324), any irAE occurred in 94 patients (29%) with any ≥G3 irAE in 29 patients (9%) and a total of 108 irAE events (n = 79 G1–G2, n = 29 ≥G3). The most common irAEs included hypothyroidism (10%, all G1/G2), hepatotoxicity (2% G1/G2, 4% ≥G3), inflammatory arthritis (4% G1/G2, 0.9% ≥G3), rash (3%, all G1/G2), and colitis (1% G1/G2, 1% ≥G3) (Table 1). Other notable ≥G3 irAEs included adrenal insufficiency (n = 2), acute kidney injury secondary to acute tubular necrosis and renal failure requiring hemodialysis (n = 1), myocarditis (n = 1), Type 1 diabetes (n = 1), pneumonitis (n = 1), and pancreatitis (n = 1). All irAEs are shown in Table S3. There was no difference in any irAE among older patients compared to younger patients (29% vs. 29%) with ≥G3 irAEs occurring in 12% and 9% of older (≥60) and younger (<60) patients, respectively. Rates of the most common irAEs did not differ by age other than a slightly higher frequency of any grade inflammatory arthritis in older patients (7% vs. 3%). Dose interruption for an irAE occurred in 15% of patients with a median interruption of 14 days (range 3–42). Among all patients, 16% required systemic steroids for a suspected or confirmed irAE at any time (56%, n = 53/94 among patients with an irAE). Oral and intravenous (IV) steroids were given in 11% and 5%, respectively. Among patients with a suspected or confirmed irAE (n = 94), oral or IV steroids were given in 37% (n = 35) and 17% (n = 16), respectively. Among all patients, 14% (n = 46) required long-term treatment for an irAE, defined as ongoing or prolonged treatment following initial management with steroids and after treatment completion/discontinuation. Most patients who required long-term treatment required levothyroxine for hypothyroidism (9% overall, 30% among patients with irAE, n = 28/94). Additional therapy required in patients experiencing irAEs included supplemental steroids in 3% (n = 11), other adjunctive immunosuppressive or immunomodulatory therapy in 2% (n = 7; certolizumab = 1, ustekinumab = 1, hydroxychloroquine/colchicine = 1, mycophenolate mofetil = 1, tofacitinib = 1, sulfasalazine = 1, and other/unknown = 1), and other management strategies for an irAE in 0.9% (n = 3; hemodialysis = 1, heart failure treatment = 1, and insulin = 1). Of patients with a history of prior AI disease (n = 25), 32% (n = 8) either had worsening of co-existing AI disease and/or developed a distinct systemic non-endocrine irAE unrelated to their prior/current AI disease (Table S4). Rates of any grade irAE and any ≥G3 irAE were not different excluding patients with a history of AI disease (any grade 28%, ≥G3 9%). Among all patients, 282 (86%) had an interim positron emission tomography/computed tomography (PET-CT) after 2–4 cycles. The overall response rate (ORR) and complete response rate (CRR) at interim PET-CT were 98% and 78%, respectively (Table S5). Interim PET-CT response was not associated with a difference in 1-year PFS (Table S5). The end of treatment (EOT) ORR and CRR were 94% and 86%, respectively (Table S5). Among patients who had progressive disease (PD) at EOT PET-CT (n = 11), eight had subsequent confirmation of residual disease by biopsy, and three were considered to have PD based on imaging alone. One patient with PD had a biopsy showing a new secondary malignancy and no definitive evidence of residual cHL. Seven of these 10 patients went on to receive second-line therapy, and one patient was lost to follow-up. The other two patients with PD at EOT have been observed without recurrence for 3 months. Among patients with partial response (PR), stable disease (SD), or a mixed response on EOT PET-CT (n = 29), only two patients with a PR later had PD requiring additional therapy. At a median follow-up of 12.5 months (range 0.5–32.4 months), the median PFS and overall survival (OS) were not reached. The 1-year PFS and OS estimates were 94.5% (95% CI: 91.5%−97.7%) and 99.7% (95% CI: 99.0%–100.0%), respectively (Figure 1). Among the 18 patients with progression/relapse, 11 were primary refractory (relapse within 3 months of EOT). Seventeen patients started second-line therapy (Table S7). Among all patients, there were two reported deaths. One patient deceased during Cycle 1 of NAVD with the cause of death being unknown and the other was due to progression of lymphoma following relapse and within 2 months of starting pembrolizumab + gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) as second-line therapy. Univariable and multivariable analyses were performed to identify whether baseline clinicopathological or disease characteristics were associated with CRR or PFS. The results are shown in Figures S2 and S3, and Table S6. In this large real-world cohort, patients treated with NAVD demonstrated response rates and 1-year survival outcomes comparable to those reported in the pivotal S1826 trial. AE rates were similar overall, with most events being low grade. However, our findings underscore the importance of upfront patient counseling and close monitoring for irAEs, given the potential for long-term toxicity from checkpoint inhibitors (CPI) in this young patient population and the notable incidence of ≥G3 irAEs observed in our study (9%). Efficacy parameters including CRR, PFS, and OS were similar to that observed in S1826, confirming that the national US cooperative group study enrolled a diverse and high-risk patient population reflective of the US patient population being treated outside of a clinical trial setting. Similar to S1826, our study included ~30% of patients with an IPS ≥ 4 and 61% with stage IV disease. Our patient cohort was older than S1826 (median age 37 compared to 27; 24% older than 60) and enrolled some patients who would not have qualified for the S1826 study including 8% of patients with a history of AI disease. We observed FDG uptake on interim and EOT scans in patients who have not had progression, which suggests that the positive PET-CT may be due to non-specific inflammatory uptake, a finding that was observed in other studies of nivolumab and CPI used for lymphoma and solid tumors.9-11 Several patients with EOT PR, PD, or mixed response had no evidence of residual disease on biopsy and/or have been safely observed with serial imaging without evidence of recurrence (with limitation of short follow-up). This finding emphasizes the importance of biopsy to confirm relapsed disease prior to initiating second-line therapy and the utility of employing the LYRIC criteria12 for indeterminate responses to CPI treatment. Toxicities in our standard-of-care cohort were similar to those of NAVD-treated patients enrolled onto S1826 and also consistent with previously reported AE rates for nivolumab and AVD. Overall, there was low treatment discontinuation and mortality compared to prior pivotal and real-world studies for AS cHL.13-15 We observed a higher use of G-CSF for both primary and secondary prophylaxis in our study, possibly in part due to the older age of our patient population compared to S1826. Despite this, rates of neutropenia were similar to S1826 but febrile neutropenia (10% vs. 6% S1826), any infection (25% vs. 10% S1826), and severe infections (≥G3, 10% vs. 4% S1826) were higher compared to S1826. This finding is partly due to the higher proportion of older patients in our cohort, yet even patients <60 had higher rates of febrile neutropenia (8% vs. 6%) and severe infections (10% vs. 4%) compared to S1826. Given the incidence of febrile neutropenia and severe infections, G-CSF administration may be beneficial to reduce the risk of these complications, especially in high-risk and older patients. We observed that any grade irAE occurred in 29% of patients, with 9% having a ≥G3 irAE, emphasizing the need for close monitoring for irAEs both during and after treatment. The overall incidence and rate of ≥G3 irAEs including pneumonitis, colitis, and adrenal insufficiency were similarly low (2% or less) in both S1826 and our study. Hepatotoxicity was the most common ≥G3 irAE in our study (4%) and S1826 (ALT/AST elevation 5%/2%). Since transaminitis can be both chemotherapy and immune-mediated, close monitoring of hepatic function is essential to prevent serious toxicity. Additionally, our study included patients with any history of systemic AI disease unlike S1826 which did not allow systemic therapy within the last two years. Of these patients, 32% (n = 8) developed a non-endocrine irAE half of which were considered ≥G3. Our results suggest that patients with a history of, or active, systemic AI disease may be better candidates for alternative treatment. Strengths of this study include a large multicenter cohort of patients and detailed irAE data, which are limited in S1826. Limitations include those inherent with a retrospective study design and possible selection bias as only patients treated with NAVD were included, not all cHL patients. In conclusion, despite differences between our cohort and the S1826 trial population, both included diverse patient demographics, including older patients and those with higher IPS, who are at increased risk of relapse. The comparable survival outcomes and favorable safety profile in our real-world cohort suggest that the results of S1826 are reflective of the broader US population with AS cHL and further support the use of NAVD as a standard frontline treatment option for this patient population. We acknowledge the support of the Huntsman Cancer Institute and Division of Hematology, including statistical analysis support. We acknowledge the statistical analysis by Elena Nazarenko. Allison M. Bock: Methodology; formal analysis; data curation; writing—original draft. Peirong Hao: Formal analysis; writing—review and editing. Yizhe Xu: Formal analysis; writing—review and editing. Efrat Luttwak: Data curation; writing—review and editing. Swetha Kambhampati Thiruvengadam: Data curation; writing—review and editing. Kanithra Sekaran: Data curation; writing—review and editing. Dahlia Sano: Data curation; writing—review and editing. John Vaughn: Data curation; writing—review and editing. John Sharp: Data curation; writing—review and editing. Ajay Major: Data curation; writing—review and editing. Vrutti Patel: Data curation; writing—review and editing. Gordon Smilnak: Data curation; writing—review and editing. Nicole Araujo: Data curation; writing—review and editing. Ritwick Mynam: Data curation; writing—review and editing. Daniel Reef: Data curation; writing—review and editing. Marisa Palmeri: Data curation; writing—review and editing. Drew Gerber: Data curation; writing—review and editing. Anuja Abhyankar: Data curation; writing—review and editing. Grace Baek: Data curation; writing—review and editing. Ayo Falade: Data curation; writing—review and editing. Madiha Iqbal: Data curation; writing—review and editing. Boyu Hu: Data curation; writing—review and editing. Praveen Ramakrishnan Geethakumari: Data curation; writing—review and editing. Urshila Durani: Data curation; writing—review and editing. Mengyang Di: Data curation; writing—review and editing. Alex Niu: Data curation; writing—review and editing. Hua–Jay J. Cherng: Data curation; writing—review and editing. Joanna M. Rhodes: Data curation; writing—review and editing. Natalie Grover: Data curation; writing—review and editing. Priyanka Pophali: Data curation; writing—review and editing. Tatyana Feldman: Data curation; writing—review and editing. Krithika Shanmugasundaram: Data curation; writing—review and editing. Jakub Svoboda: Data curation; writing—review and editing. Timothy Voorhees: Data curation; writing—review and editing. Catherine Diefenbach: Data curation; writing—review and editing. Yasmin Karimi: Data curation; writing—review and editing. Reem Karmali: Data curation; writing—review and editing. Alex F. Herrera: Data curation; writing—review and editing. Pallawi Torka: Data curation; writing—review and editing. Narendranath Epperla: Conceptualization; methodology; formal analysis; writing—review and editing. A.M.B.: research funding (to institution): Regeneron, Genmab, and AbbVie; consulting/advisory board participation: Genmab and Incyte; speaker's bureau: Genmab and AbbVie. E.L.: consulting/advisory: Pfizer and ADC Therapeutics. S.T.: research funding (to institution): Genentech, ADC Therapeutics, Genmab/AbbVie, and Ipsen; consultancy/advisory board: Kite, AbbVie, Ipsen, and Incyte. A.M.: research funding (to institution): GSK and Incyte; consulting/advisory board participation: Genentech, BMS, and Kite. D.R.: equity ownership in Regeneron Pharmaceuticals, Intellia Therapeutics, Beam Therapeutics, and Summit Therapeutics. G.B.: consulting/advisory board participation: AstraZeneca. M.I.: consultancy: US Sanofi, BMS, and ADC Therapeutics. B.H.: consultancy: BeOne, Genentech, and BMS; research funding (to institution): Genentech, Morphosys AG, Caribou Biosciences, Aritva Biotherapeutics, Newave, AstraZeneca, and Lyell Immunopharma. P.R.G.: consultancy/advisory board: Kite Pharma and Bristol Myers Squibb; advisory boards: ADC Therapeutics, IPSEN, Regeneron, Acrotech Biopharma, Sobi, and Ono Pharma. M.D.: consultancy (includes expert testimony): AbbVie, BeOne, Genentech, and Incyte; research funding: BeOne, Dren Bio, Lilly, Regeneron, Schrodinger, and AbbVie; honoraria: Merck. H.-J.J.C.: research funding (to institution): ADC Therapeutics and CStone Pharmaceuticals; consulting/advisory board participation: ADC Therapeutics. J.M.R.: consultancy/advisory board: Pfizer, AstraZeneca, Epizyme, Morphosys, Janssen, ADC Therapeutics, Merck, Eli Lilly, Genmab, AbbVie, Genentech, Pharmacyclics, BMS, Johnson & Johnson, BeOne, and Loxo Oncology; research funding: Acerta, Merck, Janssen, Eli Lilly, Pharmacyclics, Johnson & Johnson, BeOne, Loxo Oncology, ADC Therapeutics, Epizyme, Oncternal, AbbVie, and AstraZeneca. N.G.: research funding (to institution): Merck, Cabaletta, Regeneron, and Poseida; consulting/advisory board participation: BMS, Regeneron, Novartis, Incyte, and Genentech. P.P.: research funding to institution: SeaGen, Marker Therapeutics, and Fate Therapeutics; advisory Board: SeaGen, ADC Therapeutics, Genentech, AbbVie, and BMS. T.F.: research funding (to institution): AstraZeneca, Corvus, Genmab, Kymera, Merck, and Seagen; consulting: ADC Therapeutics, AstraZeneca, BMS, Genmab, Pfizer/Seagen, AbbVie, and Kite/Gilead; advisory board: Kite/Gilead, AbbVie, Genmab, Syneos Health, and Johnson & Johnson; honoraria: ADC Therapeutics, AstraZeneca, Ipsen Biopharmaceuticals, Inc, Genmab, Pfizer/Seagen, AbbVie, Kite/Gilead, BMS, Syneos Health, and Johnson & Johnson. K.S.: research funding: Sobi; consulting/advisory board participation: Bristol-Myers-Squibb, and ADC Therapeutics. J.S.: consultancy: Pfizer, Pharmacyclics, Incyte, Genmab, BMS, Atara, AstraZeneca, Adaptive, and ADC Therapeutics; research funding: Pfizer, Pharmacyclics, Merck, Incyte, BMS, AstraZeneca, Adaptive, and Kite. T.V.: research funding: Kite, Incyte/Morphosys, Genmab/AbbVie, and Recordati; advisory board: Genmab/AbbVie and ADC Therapeutics; consultancy: Novartis, Recordati, and Genmab. Y.K.: consultancy/advisory board: AstraZeneca, Genmab, Genentech, AbbVie, Merck, and ADC Therapeutics; research funding: Genentech, Lilly, Xenocor, Pfizer, Genmab, Kite, Merck, AstraZeneca, AbbVie, and BeOne. R.K.: advisory board/consulting: Genentech, Genmab, BMS, Kite/Gilead, AvenCell, Miltenyi, and AbbVie; speaker's bureau: AstraZeneca, BMS, and BeOne; institutional research funding: Merck, BMS, Kite/Gilead, and AbbVie. A.F.H.: consultancy/advisory board: Regeneron, Allogene Therapeutics, AstraZeneca, Caribou Biosciences, SeaGen, BMS, Pfizer, Adicet Bio, ADC Therapeutics, Karyopharm Therapeutics, Tubulis, Merck, Takeda, AbbVie, Genmab, and Genentech; research funding: Lilly, AstraZeneca, SeaGen, BMS, Merck, Kite, Genentech, and Gilead Sciences. P.T.: research funding (to institution): Genmab/AbbVie, Genentech, and Incyte; consulting/advisory board participation: Bristol Myers Squibb, Genentech, Genmab, Seagen, AbbVie, Lilly Oncology, and Pfizer. N.E.: research funding (to institution): Beigene, Lilly, Incyte, ADC Therapeutics, and Ipsen; consulting/advisory board participation: CRISPR Therapeutics, Genentech, and Ipsen. P.H., Y.X., K.S., D.S., J.V., J.S., V.P., G.S., N.A., R.M., M.P., D.G., A.A., U.D., A.N., A.F., M.I., J.M.R., and C.D.: none. The study protocol was approved by Institutional Review Board at all the participating sites. The study was performed in accordance with the Declaration of Helsinki. The authors declare no source of funding. The datasets generated and/or analyzed during the current study are not publicly available due to privacy concerns but are available from the corresponding author on reasonable request as permitted by the IRB. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.