Nivolumab with AVD in advanced Hodgkin lymphoma

A 19-year-old student comes to the health unit with intense itching, night sweats and a hardened lymph node in the neck that has not gone away for two months. Excisional biopsy confirms classic Hodgkin lymphoma, nodular sclerosis subtype. Staging PET-CT shows disease on both sides of the diaphragm and lesions in the spleen: stage IV. At the consultation, he wants to know two things: whether he will be able to go back to college and whether he will be able to have children. The team discusses which regimen to offer. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is first-line treatment of advanced classic Hodgkin lymphoma after the SWOG S1826 study, which compared nivolumab with AVD against brentuximab vedotin with AVD. The question Dr. Alexei proposed for the series is this: how do you choose the regimen that cures with less late damage in a patient who has decades ahead of him? The text does not replace your country's guideline or your service's protocol. The role of interim PET in guiding treatment is in the post on interim PET in Hodgkin lymphoma; here the focus is choosing the regimen. If you play the case of the day on NEXO, you already know that deciding well includes thinking about what comes after discharge.

Key points

• Classic Hodgkin lymphoma is highly curable, and the challenge is to cure with less late toxicity.
• In S1826, nivolumab with AVD improved progression-free survival compared with brentuximab with AVD in stages III and IV.
• The nivolumab regimen was better tolerated, with less neuropathy and fewer interruptions.
• The gain appeared in adolescents, in adults and in patients aged 60 or older.
• Almost no patient needed radiotherapy in S1826.
• Thyroid dysfunction is the most typical immune effect and calls for periodic tests.

Why this is a reasoning scenario

Hodgkin lymphoma has a bimodal age distribution and is often diagnosed in people aged 20 to 30. Schimmoeller and colleagues recall that, with ABVD and radiotherapy, 5-year survival approaches 95 out of every 100 patients (Schimmoeller and colleagues, 2023). In children and adolescents, De Re and colleagues report 5-year survival above 95 out of every 100 with current therapies (De Re and colleagues, 2022).

When cure is the rule, clinical reasoning shifts focus. The question is no longer only which regimen cures more, and it now includes which regimen cures with less damage. A young person cured at 19 will live with the consequences of treatment for 50 or 60 years: in the heart, in the lungs, in fertility, in the risk of a second cancer. The first-line choice is, at the same time, a decision about the relapse you want to avoid and about the toxicity you accept.

The field's shift over the last decades shows this logic. In pediatric oncology, De Re and colleagues describe 20 years of studies that gradually abandoned adult regimens, reduced radiotherapy fields and began using early PET response to limit radiotherapy in those who respond well and intensify treatment in those who respond poorly (De Re and colleagues, 2022). The arrival of immunotherapy in the first line is the most recent step on that path.

What makes this error easy to make

The very high cure numbers give the impression that any regimen will do. But the differences between regimens show up precisely at the margins: the relapse that requires a transplant, the neuropathy that stops a young person from playing an instrument, the mediastinal radiotherapy that raises the risk of breast cancer in a young woman. Another common error is choosing the regimen out of service habit, without reviewing what has changed in recent years.

The price of cure with the old regimens

ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) was the standard for decades. Schimmoeller and colleagues recall its long-term effects: doxorubicin dose-dependent cardiotoxicity, bleomycin pulmonary toxicity, risk of infertility and treatment-induced cancers decades later (Schimmoeller and colleagues, 2023).

Pulmonary toxicity was measured prospectively by Jona and colleagues in 84 patients at a Hungarian center. Lung scintigraphy detected the damage more sensitively than carbon monoxide diffusion, and intravenous bleomycin reduced pulmonary clearance; involved-field mediastinal radiotherapy, in current forms, had less pulmonary toxicity than bleomycin (Jona and colleagues, 2021).

The arrival of brentuximab

Brentuximab vedotin is an anti-CD30 antibody conjugated with chemotherapy. Barefah summarizes that the ECHELON-1 study established BV-AVD as superior to ABVD in advanced disease, with better progression-free survival and overall survival (Barefah, 2026). The S1826 paper itself recalls the other side: BV requires more growth factor support, is more toxic than ABVD in adults, and 53 in every 100 pediatric patients still received radiotherapy with BV-based regimens (Herrera and colleagues, 2024).

What S1826 tested

S1826 was a phase 3 study conducted by the American SWOG group with other cooperative groups. It randomized patients aged 12 or older with untreated stage III or IV classic Hodgkin lymphoma to nivolumab with AVD (N-AVD) or brentuximab vedotin with AVD (BV-AVD). There were 994 patients included, of whom 970 were eligible (Herrera and colleagues, 2024). About a quarter were aged 12 to 17 (Castellino and colleagues, 2026).

Study doses

Both regimens were given intravenously on days 1 and 15 of 28-day cycles, for 6 cycles (Herrera and colleagues, 2024):

• nivolumab 240 mg in adults, or 3 mg/kg in those under 18, capped at 240 mg;
• brentuximab vedotin 1.2 mg/kg in the comparator arm, with weight capped at 100 kg;
• doxorubicin 25 mg/m²;
• vinblastine 6 mg/m²;
• dacarbazine 375 mg/m².

Granulocyte colony-stimulating factor was mandatory with BV-AVD and optional, at the investigator's discretion, with N-AVD. Dexrazoxane was allowed to reduce the cardiac risk of doxorubicin. Radiotherapy was only allowed for pre-defined metabolically active residual lesions. Always check the package insert and your service's protocol.

What S1826 showed

At the second planned interim analysis, with a median follow-up of 12.1 months, N-AVD had already crossed the efficacy boundary, with a hazard ratio for progression or death of 0.48. With a median follow-up of 2.1 years, 2-year progression-free survival was 92 in every 100 with N-AVD versus 83 with BV-AVD (Herrera and colleagues, 2024). Only 7 patients received radiotherapy across both arms. Immune events were infrequent, and BV led to more treatment discontinuations.

Bock and colleagues summarize the update with 3.1 years of follow-up: 3-year progression-free survival was 91 in every 100 with N-AVD versus 82 with BV-AVD, and the nivolumab regimen was incorporated into American guidelines as a standard first-line option (Bock and colleagues, 2026). Barefah describes N-AVD as the emerging preferred standard for most fit patients with advanced disease, in an area of practice still evolving (Barefah, 2026).

Group	Patients	N-AVD	BV-AVD
All, 2 years	970 eligible	92 in every 100 without progression	83 in every 100 without progression
Adolescents aged 12 to 17, 3 years	240	93 in every 100 without progression	82 in every 100 without progression
Aged 60 or older, 2 years	99 eligible	89 in every 100 without progression	64 in every 100 without progression
EBV positive, 3 years	Subgroup with known EBV	91 in every 100 without progression	70 in every 100 without progression
Non-nodular sclerosis histology, 3 years	102	86 in every 100 without progression	63 in every 100 without progression

Subgroups with worse prognosis

Epstein-Barr virus-associated Hodgkin lymphoma and the different nodular sclerosis subtypes usually have a worse course. In the prespecified analysis of S1826, N-AVD improved 3-year progression-free survival in EBV-positive patients, 91 versus 70 per 100, and in the non-nodular sclerosis subtypes, 86 versus 63 (Ahmed et al., 2026). Non-nodular sclerosis histology remained an independent factor for a worse course, but N-AVD kept an advantage within this risk group.

Adolescents and older adults

The two age extremes were analyzed separately, and both are clinically important.

Adolescents

Among the 240 patients aged 12 to 17 years, 3-year progression-free survival was 93 per 100 with N-AVD versus 82 with BV-AVD, with a hazard ratio of 0.37 (Castellino et al., 2026). Only 1 patient in the N-AVD arm and 2 in the BV-AVD arm received radiotherapy to a residual site. Febrile neutropenia and sepsis were infrequent in both groups. Thyroid dysfunction appeared in 7 per 100 with N-AVD, and grade 2 or higher sensory neuropathy was more frequent with BV-AVD, 14 versus 7 per 100.

This matters because pediatric oncology spent 20 years trying to reduce radiotherapy. In the European EuroNet-PHL-C1 study, with 2,102 children and adolescents recruited, 40 per 100 patients with intermediate or advanced stage disease had an adequate response and no longer received radiotherapy (Mauz-Körholz et al., 2022). In S1826, radiotherapy nearly disappeared.

The same European study compared two consolidations. Replacing procarbazine with dacarbazine in the COPDAC regimen may be slightly less effective, but it is much less toxic to the gonads in boys and girls (Mauz-Körholz et al., 2022). The authors conclude that omitting radiotherapy in those who respond well tends to reduce late effects such as second cancers. This is the background that explains why the S1826 result in adolescents drew so much attention.

Patients aged 60 years or older

Older patients with Hodgkin lymphoma have lower survival than younger ones. Among 99 eligible patients aged 60 years or older, 2-year progression-free survival was 89 per 100 with N-AVD versus 64 with BV-AVD, and 2-year overall survival was 96 versus 85 (Rutherford et al., 2025). All 6 cycles were given without dose reduction in 69 per 100 with N-AVD and in 26 with BV-AVD. Non-relapse mortality was 16 per 100 with BV-AVD and 6 with N-AVD. The authors conclude that N-AVD is a new standard for older patients able to receive anthracycline.

Before the first cycle

Choosing the regimen is only part of the first consultation. What is done before the first cycle protects the patient during and after treatment. S1826 allowed dexrazoxane to protect the heart and set clear rules for support with colony-stimulating factor (Herrera et al., 2024). With nivolumab, baseline tests that allow a later immune event to be recognized gain importance, such as thyroid function and liver enzymes (Guerrero, 2026).

• Adequate biopsy with review by a hematopathologist.
• Staging PET-CT.
• Baseline thyroid function and liver enzymes.
• Cardiac assessment before doxorubicin.
• Conversation about fertility preservation.
• Contact plan for fever and new symptoms.

Why relapse still matters

De Re et al. recall that most relapses of classic Hodgkin lymphoma occur in the first 3 years and that relapses after 5 years are rare (De Re et al., 2022). The same authors state that the outcome of patients with relapsed or refractory disease is still unsatisfactory. This explains why a gain of 9 to 10 points in 2- or 3-year progression-free survival is so valuable: each relapse avoided spares the patient a salvage treatment with high-dose chemotherapy and transplant.

The main S1826 article justifies the study with the same argument: even with the advances, more than half of pediatric patients were still receiving consolidation radiotherapy, and relapse remained a challenge; PD-1 blockade had already shown efficacy in Hodgkin lymphoma, including in preliminary studies in untreated patients (Herrera et al., 2024).

Toxicity: what to watch for

Nivolumab is an immune checkpoint inhibitor, and its adverse effects differ from those of chemotherapy. Guerrero, in a review aimed at advanced practice professionals, reports that pneumonitis, gastritis, rash and colitis had similar frequency in the two arms, while hypothyroidism and hyperthyroidism were more common with N-AVD, in 7 and 3 out of every 100, versus fewer than 1 and 0 with BV-AVD (Guerrero, 2026). Febrile neutropenia, pneumonitis, transaminase elevation and colitis were comparable.

Outside the trials

Experience outside clinical trials helps calibrate expectations. In a retrospective analysis of 327 adults treated at 20 American centers between 2023 and 2025, with a median age of 37 years and 24 out of every 100 aged 60 or older, Bock et al. report that nivolumab was the component most often discontinued, in 11 out of every 100 patients, always due to a suspected or confirmed immune event, and that the entire treatment was discontinued due to toxicity in 4 out of every 100 (Bock et al., 2026). The most common grade 3 or higher events, other than hematologic ones, were infection in 10, immune events in 9 and liver toxicity in 3 out of every 100. Febrile neutropenia occurred in 10 out of every 100, and neutropenia of any grade in 71 out of every 100.

• Order thyroid function tests at baseline and during treatment.
• Monitor transaminases.
• Ask about cough, shortness of breath, diarrhea and skin spots.
• Tell the patient about fever during neutropenia.
• Ask about tingling in the hands and feet.

Cost

Cost weighs on the decision in public systems. A Chinese cost-effectiveness analysis based on S1826 concluded that, from the perspective of the Chinese payer, N-AVD was dominant over BV-AVD, with more quality-adjusted life years and a lower total cost (Li et al., 2026). These results depend on local prices and cannot be transposed directly to another country.

Radiotherapy, fertility and life afterwards

For the student in the scene, cure is only part of the question. He wants to go back to college and he wants to have children.

Radiotherapy

Mediastinal radiotherapy in young people increases the risk of heart disease and second cancers years later. S1826 showed that, with N-AVD, almost no patient needed radiotherapy, which is a concrete advantage for those with decades ahead of them (Herrera et al., 2024).

Fertility

Schimmoeller et al. recall that many young patients need to undergo fertility preservation before treatment (Schimmoeller et al., 2023). In women, Ciccarone et al. observed with ABVD a drop in anti-Müllerian hormone, in ovarian follicles and in endometrial thickness at 6 months, with recovery close to baseline values at 12 months; more intensive regimens may be more harmful (Ciccarone et al., 2023). The conversation about preservation should happen before the first cycle, for both men and women.

Work and quality of life

Magyari et al. studied Hodgkin lymphoma survivors at a large Hungarian center and found less psychological distress in those who were working or studying. Late effects of treatment, age 30 or older at diagnosis and lower education were associated with inactivity (Magyari et al., 2017). The authors recall that most survivors are in early adulthood and that the goal is to return them to normal life after cure.

How to answer the student's two questions

About college, it is worth being honest: treatment lasts about 6 months, with sessions every 2 weeks, and there will be days of fatigue and low counts. Many patients manage to keep part of their activities, with adjustments, and the team's stated goal should be a return to normal life after the cure, as Magyari and colleagues argue (Magyari and colleagues, 2017). Agreeing with him on exam dates and the weeks of highest infection risk is part of the plan.

About children, the answer starts before the first cycle. For men, semen cryopreservation is simple and should be offered to everyone; in women, the process is more complex and depends on age and the time available (Ciccarone and colleagues, 2023). Regimens with fewer alkylating agents and without pelvic radiotherapy preserve fertility better, which is one more point in favor of avoiding treatments more intensive than necessary.

A third question usually comes later, sometimes from a family member: what if it comes back? The honest answer is that relapse is less likely with current regimens, that it usually happens in the first years and that there are still salvage options with a chance of cure. Knowing this helps the patient go through follow-up without living each exam as a sentence.

Other comparisons

Not all comparisons come from head-to-head studies. Kristo and colleagues used an adjusted indirect comparison to compare BV-AVD with PET-guided ABVD in advanced disease (Kristo and colleagues, 2026). In the comparison with the RATHL and SWOG S0816 studies, overall survival favored BV-AVD, with hazard ratios of 0.48 and 0.49. Indirect comparisons help raise hypotheses, but they have limits that a randomized study does not have. When a question arises about relapse after first-line treatment, the post on lymphoma relapse covers salvage.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the code in ICD-10. Advanced Hodgkin lymphoma is a good exercise because it forces you to think about two horizons at once: the cure now and life 30 years from now. The post on differential diagnosis shows how to organize the clues, and the post on clinical decision-making helps weigh benefits and harms. The lymphoma team's organization appears in lymphomas, from hematopathology to cell therapy.

Three exercises with cases

Change the age. Say what changes if the patient were 68 years old and had diabetes.

Change the thyroid. Say what you would do if TSH rose in the third cycle.

Change the final PET. Say what you would do faced with an active residual lesion in the mediastinum.

The post on diagnostic uncertainty helps in the conversation about long-term risks. The limits of the game's use are described on the NEXO economy page. If you research teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information in curation and in creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Is N-AVD the new standard?

For most eligible patients with stage III or IV disease, it is the emerging preferred standard, in a practice still evolving (Barefah, 2026).

How many cycles and at what interval?

In S1826, 6 cycles of 28 days, with doses on days 1 and 15 (Herrera and colleagues, 2024).

Does it work for adolescents?

Yes, the study included patients from 12 years old, with a similar gain (Castellino and colleagues, 2026).

And for those over 60?

In the subgroup aged 60 or older, N-AVD was more effective and less toxic (Rutherford and colleagues, 2025).

Which adverse effect requires the most attention?

Thyroid dysfunction, which appeared in about 7 of every 100 patients on N-AVD (Guerrero, 2026).

Final checklist

• I confirmed the diagnosis by excisional or adequate biopsy.
• I staged with PET-CT.
• I discussed fertility preservation before the first cycle.
• I ordered baseline thyroid, liver and cardiac function.
• I discussed N-AVD and the alternatives with the patient.
• I planned the use of colony-stimulating factor.
• I arranged monitoring for immune events.
• I scheduled PET at the end of treatment.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Ahmed S, Li H, Herrera AF, et al. Impact of EBV status and histology on patient outcomes with nivolumab-AVD vs BV-AVD in advanced classic Hodgkin lymphoma (S1826). Blood Adv. 2026. PMID 42526889.
2. Barefah AS. Advances in First-Line Treatment of Classical Hodgkin Lymphoma in the Era of Novel Agents. J Clin Med. 2026. PMID 42452536.
3. Bock AM, Hao P, Xu Y, et al. Nivolumab in combination with AVD as frontline treatment for patients with classic Hodgkin lymphoma: A real-world analysis from 20 US centers. Hemasphere. 2026. PMID 42038745.
4. Castellino SM, Li H, Herrera AF, et al. Three-Year Follow-Up of Nivolumab-AVD Versus Brentuximab Vedotin-AVD in Adolescents With Advanced-Stage Classic Hodgkin Lymphoma on S1826. J Clin Oncol. 2026. PMID 41512237.
5. Ciccarone M, Cavaceppi P, Tesei C, et al. Effects of ABVD chemotherapy on ovarian function: epidemiology, hormonal dosages and ultrasound morphologic analyses in 270 patients with Hodgkin's disease. Front Oncol. 2023. PMID 37152067.
6. De Re V, Repetto O, Mussolin L, et al. Promising drugs and treatment options for pediatric and adolescent patients with Hodgkin lymphoma. Front Cell Dev Biol. 2022. PMID 36506094.
7. Guerrero MD. Advances in Hodgkin Lymphoma Treatment: Clinical Considerations for Managing Toxicities in Nivolumab-AVD Therapy. J Adv Pract Oncol. 2026. PMID 42170498.
8. Herrera AF, LeBlanc M, Castellino SM, et al. Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma. N Engl J Med. 2024. PMID 39413375.
9. Jona A, Miltenyi Z, Pinczes L, et al. Pulmonary Toxicity of Hodgkin Lymphoma Treatment: A Prospective Single-Center Study. J Hematol. 2021. PMID 35059088.
10. Kristo F, Molinari A, Lan Z, et al. Matching-adjusted indirect treatment comparison of A+AVD vs PET-guided ABVD in newly diagnosed advanced Hodgkin lymphoma. Future Oncol. 2026. PMID 41524385.
11. Li B, Yang J, Li J, et al. Nivolumab-AVD versus Brentuximab Vedotin-AVD as First-Line Treatment for Advanced-Stage Classical Hodgkin Lymphoma: A Cost-Effectiveness Analysis. Clinicoecon Outcomes Res. 2026. PMID 42199529.
12. Magyari F, Kósa K, Berecz R, et al. Employment status and health related quality of life among Hodgkin-lymphoma survivors'- results based on data from a major treatment center in Hungary. Health Qual Life Outcomes. 2017. PMID 28927453.
13. Mauz-Körholz C, Landman-Parker J, Balwierz W, et al. Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. Lancet Oncol. 2022. PMID 34895479.
14. Rutherford SC, Li H, Herrera AF, et al. Nivolumab-AVD Versus Brentuximab Vedotin-AVD in Older Patients With Advanced-Stage Classic Hodgkin Lymphoma Enrolled on S1826. J Clin Oncol. 2025. PMID 40523203.
15. Schimmoeller CJ, Bastian C, Fleming J, et al. A Review of Hodgkin Lymphoma in the Era of Checkpoint Inhibitors. Cureus. 2023. PMID 37565112.