Ask AI
Back Back
Frontline Tx Advanced Hodgkin Lymphoma
Expert Perspectives on Frontline Therapy for Advanced Hodgkin Lymphoma

Released: July 29, 2025

Jonathan W. Friedberg
Jonathan W. Friedberg, MD
Alex F. Herrera
Alex F. Herrera, MD
Kara M. Kelly
Kara M. Kelly, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Nivolumab-AVD is an effective new frontline therapy in advanced Hodgkin lymphoma that prolongs progression-free survival vs BV-AVD.
  • Patient-specific presentation, such as the presence of active autoimmune conditions and patient fitness, help guide frontline treatment decisions.

The recent evolution of frontline therapy in advanced Hodgkin lymphoma (HL) requires healthcare professionals to personalize treatment for each patient’s life circumstances and goals. This commentary summarizes insights from a recent symposium with Jonathan W. Friedberg, MD; Alex F. Herrera, MD; and Kara M. Kelly, MD, covering important considerations in the use of newer agents like nivolumab and brentuximab vedotin (BV) and navigating complex treatment decisions to optimize outcomes and patient experience.

Case 1: 28-Year-Old Violinist With Stage IV HL
Let’s consider the case of a 28-year-old woman newly diagnosed with stage IV HL with an International Prognostic Score (IPS) of 4. She works as a professional violinist and is concerned about preserving her fertility.

Jonathan W. Friedberg, MD: This is a fairly typical patient with relatively high-risk disease due to the IPS score of 4. Because she works as a violinist, neuropathy may be a particularly devastating toxicity for her. For that reason, I would recommend nivolumab (nivo) plus doxorubicin, vinblastine, and dacarbazine (AVD), which has the highest likelihood of curing her HL without the neurotoxicity associated with BV. The phase III S1826 trial found that nivo-AVD prolonged progression-free survival (PFS) vs BV-AVD with a 2-year PFS of 92% vs 83%. However, the data on long-term fertility are limited for novel agents like nivolumab. In the S1826 trial of nivo-AVD in the frontline setting for advanced HL, long-term fertility is being evaluated as part of the patient-reported outcomes. In the meantime, the AVD chemotherapy backbone itself does not seem to pose a significant risk to fertility, given the data for BV-AVD and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). I would advise this patient to meet with a fertility specialist prior to starting treatment.

How would you approach the management of this patient if she had an autoimmune disease such as inflammatory bowel disease?
Jonathan W. Friedberg, MD: Patients with autoimmune disease were excluded from the S1826 clinical trial that evaluated nivo-AVD due to concerns of autoimmune exacerbation with nivolumab. The risk of autoimmune exacerbation may be higher in patients with HL because they are an overall younger population and younger immune systems may be more likely to be aggravated. Therefore, depending upon the severity of the autoimmune disease, my approach to this case would be to consider alternative treatment with BV-AVD or possibly brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD).

Alex F. Herrera, MD: I agree, and I would tend to avoid using nivolumab in a patient with active autoimmune disease. Given the higher rate of immune-related adverse events in patients with autoimmune diseases, I would use a regimen without an immune checkpoint inhibitor to ensure treatment does not have to be interrupted due to hepatotoxicity or gastrointestinal toxicity exacerbating her inflammatory bowel disease. I personally would choose to treat this patient, and most patients who have autoimmune diseases, with a BV-based regimen like BrECADD or BV-AVD. Of interest, one thing that I have noticed at least anecdotally is that the autoimmune disease often temporarily improves after chemotherapy.

What are the practical challenges of implementing nivo-AVD?
Alex F. Herrera, MD: Although not common, some patients experience immune-related adverse events with the nivo-AVD regimen. If a patient has had a favorable response to treatment and immune-related toxicity occurs later on in the course of therapy, I would discontinue the nivolumab and finish the remaining cycles of AVD.

If a patient has an immune-related toxicity during the first cycle or early in the second cycle and you are unable to resume the PD-1 blockade, I would recommend switching the nivolumab for BV. We know that BV-AVD is an effective regimen that improves survival compared to ABVD and this switch was a strategy used for some patients in the S1826 trial.

Kara M. Kelly, MD: The data from the S1826 study are very encouraging regarding the discontinuation of nivolumab, although this occurred in only 9% of patients. In the pediatric cohort, all patients who discontinued nivolumab still had very good outcomes with no relapses.

Jonathan W. Friedberg, MD: This is an important point. We do not know how many cycles of nivolumab are necessary to achieve a durable response. In the S1826 trial, nivolumab was administered with each treatment cycle, which was a somewhat arbitrary decision. But nivolumab was well tolerated and achieved an excellent outcome. However, because it is an antibody with a long half-life, we could speculate that less nivolumab might achieve similar response rates.

Case 2: 69-Year-Old Man With Stage IIIB HL
Let’s consider another case of a 69-year-old man who is newly diagnosed with stage IIIB HL. He has an ECOG performance status of 1, mild chronic obstructive pulmonary disease (COPD), and an ejection fraction of 60%. He has no contraindications to immunotherapy, although due to his age, he is at increased risk for bleomycin-induced pulmonary toxicity and COPD. He expresses a preference to avoid regimens with high long-term toxicity risk and is open to novel therapies.

Jonathan W. Friedberg, MD: Nivo-AVD would be my preferred treatment option for a fit older patient who can tolerate combination chemotherapy. However, fitness can vary widely amongst patients like this. I believe over time we will see that formal frailty assessments may play an important role in choosing therapy. For a similar but unfit patient with many additional comorbidities and who may not have support at home, I think BV-nivo would be a reasonable treatment option.

How do you assess frailty and fitness in older patients? 
Jonathan W. Friedberg, MD: My institution has an expertise and interest in geriatric oncology, although we have not formally begun evaluating fitness in patients with lymphoma. There are robust tools being explored in older patients with diffuse large B-cell lymphoma that can be completed in 5-10 minutes and effectively categorize patients into groups of fit, unfit, or frail. I think this kind of evaluation would be valuable to apply to clinical trials of older patients with HL to understand the optimal treatment for each fitness classification. Although the US Cooperative Group has an interest in studying this, right now it is very difficult to design such a trial because the number of eligible patients would be relatively low, given the positive outcomes with nivo-AVD.

Case 3: 17-Year-Old With High-Risk, Stage IVB HL
Finally, let’s consider the case of a 17-year-old male who presents with a 2-month history of right neck swelling and has had drenching night sweats over the past 2 weeks. A chest x-ray did not show a bulky mediastinal mass, but a PET/CT scan showed multiple involved nodes both above and below the diaphragm. The scan also showed a pulmonary nodule, uptake within the spleen, and focal lesions in the bone in both the axial and appendicular skeleton.

Kara M. Kelly, MD: This was a patient of mine with stage IVB disease and no bulky mediastinal involvement. At the time this patient presented, he was treated with BV-AVE-PC and did not need radiotherapy. He had a negative PET scan after 2 cycles and is now a long-term survivor. However, if he were to come into my office today, nivo-AVD would be my treatment of choice.

How would you approach a pediatric patient with stage IIIA or IIIB HL?
Kara M. Kelly, MD: In pediatric patients, the treatment burden is usually from disease relapse, so I always prefer to use a more effective therapy to avoid that relapse setting. It is important to keep this in mind whether it is a pediatric patient or even a 20-year-old. In addition, avoiding high-dose chemotherapy and stem cell transplant—which carries considerable risk for these patients—in favor of alternative front-line therapies will significantly benefit long-term patient outcomes.

However, I was recently asked about the optimal treatment of a 5-year-old with stage IIIA bulky disease. This is a scenario that highlights some of the gaps in the data for novel agents due to the design of the clinical trials which were restricted to the most at-risk patient populations. For instance, the AHOD1331 trial of BV-AVE-PC only included patients with IIIB disease, not IIIA. The S1826 trial of nivo-AVD included patients with stage IIIA disease, but enrollment was restricted to patients aged 12 years or older because this group had inferior outcomes and we were cautious of exposing younger patients to checkpoint inhibitors in the frontline setting.

For patients like this, I do not necessarily have a clear evidence-based answer. Choice of treatment in these cases should be based on a conversation with the parents about regimens with the most relevant data. These would be conventional chemotherapy with ABVE-PC and response-adapted radiotherapy. However, I admit that not using a more targeted agent, like nivo-AVD or BV-AVE-PC, feels like we may not be giving the best care.

Alex F. Herrera, MD: We have studied nivo-AVD in progressively younger patient populations and so far, have not seen any unexpected toxicities. Although there have been some immune-related toxicities, as expected, we have not observed a safety signal that would preclude us from thinking it could be used in even younger patients. However, for a 5-year-old patient with stage IIIA HL, I may use a more traditional approach because it seems safer and is still quite effective. Unfortunately, we sometimes treat patients in data-free zones.

Jonathan W. Friedberg, MD: I think we are uniquely positioned in oncology in that we have historically been curing the majority of patients with HL. We have also been extremely conservative at adopting new therapies within populations that have not been robustly studied. It is a challenge to choose the most optimal treatment while also minimizing harm when dealing with such a curable disease.

Your Thoughts
How do you incorporate patient priorities into your frontline treatment decisions for advanced HL? Have you encountered challenges managing adverse events in the era of immunotherapy for advanced HL? Join the conversation and share your experience with personalized frontline strategies.

Continue

Poll

1.

How often do you recommend nivo-AVD as the preferred regimen for your patients with newly diagnosed advanced HL?

Submit