In this podcast, experts discuss the latest frontline treatment options for advanced Hodgkin lymphoma and approaches to personalizing treatment for the general patient population, older patients, and pediatric patients.
In this episode, Jonathan W. Friedberg, MD; Alex F. Herrera, MD; and Kara Kelly, MD, discuss the latest frontline treatment options for advanced Hodgkin lymphoma (HL) and approaches to personalizing treatment for the general patient population, older patients, and pediatric patients. This podcast was adapted from a live presentation held in May 2025.
Presenters:
Jonathan W. Friedberg, MD
Director, Wilmot Cancer Institute
Samuel Durand Professor of Medicine and Oncology
University of Rochester
Rochester, New York
Alex F. Herrera, MD
Chief, Division of Lymphoma
Professor, Department of Hematology and Hematopoietic Cell Transplantation
Medical Director of the City of Hope Clinical Trials Office
Associate Medical Director of the Briskin Center for Clinical Research
City of Hope Medical Center
Duarte, California
Kara M. Kelly, MD
Waldemar J. Kaminski Endowed Chair of Pediatrics
Roswell Park Comprehensive Cancer Center
Division Chief and Professor of Pediatrics
University at Buffalo Jacobs School of Medicine and Biomedical Sciences
Buffalo, New York
Content based on an online CME program supported by an independent educational grant from Bristol Myers Squibb.
Link to CME: Claim Credit
https://bit.ly/3TQ0M45
Link to full program:
https://bit.ly/4eV8AuW
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Hello and welcome to the Clinical Care Options Oncology podcast. I’m your host, Amber Williams. Today’s episode features expert discussion of the latest frontline treatment options for advanced Hodgkin lymphoma and approaches to personalizing treatment for the general patient population, older patients, and pediatric patients. We’re joined today by Dr Jonathan Friedberg, from the University of Rochester, Dr Alex Herrera, from the City of Hope Medical Center, and Dr Kara Kelly, from the Roswell Park Comprehensive Cancer Center.
This episode is part of a larger educational program titled, “Transforming Frontline Therapy in Hodgkin Lymphoma: Advancing Personalized Strategies for Optimal Outcomes.” For more information on our expert faculty, along with a link to the larger education program and to claim credit, please visit the show notes for this episode.
Now let’s get started and hear what the experts have to say.
Dr Friedberg: I do want to frame the landscape a little bit and emphasize some of the challenges of trying to make treatment decisions in Hodgkin lymphoma. We have to think about that as we go through the evening, particularly with this focus on children, and adolescent, and young adult patients. The clinical trial data that we have generally as short-term follow-up, you get response rates, you get some progression free survival signals, usually a 2 or 3 years. Long-term follow-up for a clinical trial might be a 5-year follow-up. But we know in this disease, as a paradigm for other diseases and cancer, that there are late toxicities that occur.
For example, when aggressive radiation therapy used to be used for Hodgkin lymphoma, although initial responses were fantastic, the morbidity and at times mortality of these late toxicities was substantial, including breast cancers, cardiac disease. Some of these do not emerge until 20 or 30 years later. But if you are treating a patient who is 18 or 20 years old, that means they are still only 40 or 50 years of age. When we are making decisions, we not only have to make decisions about what is going to be important today and what is going to cure them, but what is going to happen in the future. The challenge is, of course, that the clinical trials do not have this. We need cancer registries and special survivorship cohorts to study this. This has been a real challenge.
The 0816 trial and RATHL trial with ABVD led us to conclude that response adaptation was not going to substantially change the natural history of Hodgkin lymphoma. Fortunately, we had new agents that we could study. The first new agent that came along was brentuximab vedotin that had a very high response rate in the relapse setting and as a single agent, even in patients who had relapsed after autologous stem cell transplant. When it was combined with bleomycin, it was overly toxic. But when taking bleomycin out and substituting with brentuximab, there were initial results that looked promising.
That led to the ECHELON trial that showed in long-term follow-up, both the progression free survival benefit and an overall survival benefit to the incorporation of brentuximab. It was felt that it was going to be very hard to show an overall survival benefit in this scenario. The fact that you saw it obviously created enthusiasm, and this became a new standard of care in many practice situations, particularly in the United States.
This is not without toxicity, though, and the big toxicities that we see are an increased risk of febrile neutropenia. All patients on this regimen need to get growth factor, and neuropathy is a major toxicity with Brentuximab. Over time this neuropathy improves significantly and resolves. But a percentage of patients are left with neuropathy even 4 to 5 years later. This neuropathy can be fairly disabling. Again, if you are dealing with young patients, this could mean major changes in their employment or what they would want to do.
That leads us to the other new class of drugs and that is the checkpoint inhibitors, which obviously have very high activity in many of the solid tumors. The concept of these checkpoint inhibitors are they really take the brakes off of the T cells and allow the T cells to come in and cause anti-tumor immunity.
Why is Hodgkin lymphoma so sensitive to PD1 inhibition? A board's question that is often asked is what is the number one tumor that responds to PD1 blockade. It is Hodgkin lymphoma. It is not melanoma, it is not lung cancer. The reason for that was found somewhat serendipitously, this was not that we knew this and then decided to test PD1 blockade, but it was in the reverse. The Reed-Sternberg cells, which have been hard to characterize because they are so infrequent in biopsies, have copy number alterations of 9p24 locus. This is where PD1 and PD-L1 are encoded, and that results based on a variety of these changes in the highest single agent response rates.
It turns out that the mechanism of checkpoint blockade in Hodgkin lymphoma also probably involves innate effector cells. This innate immunity changes similarly are such that by giving the checkpoint blockade up front, it makes more sense. Taken together, this provides a strong rationale to incorporate checkpoint inhibition early in the treatment of Hodgkin lymphoma
Dr Herrera: So, in 2018, As it had been for decades, we used ABVD or BEACOPP to treat newly diagnosed advanced stage disease, but we had gained this new option of brentuximab vedotin combined with AVD. Because of the toxicities that Dr Friedberg mentioned, with increased febrile neutropenia, and increased sepsis, increased neuropathy, it was still a decision. Even though, at least in 2018, there had been a progression free survival benefit, there was still decision-making to be had about which regimen to use. The overall survival benefit that came more recently in the last couple of years, I think, really spelled the end of ABVD for advanced stage disease.
But as Dr Friedberg mentioned, there was a really strong rationale to start studying PD1 blockade in the frontline setting. This disease, Hodgkin lymphoma, was uniquely vulnerable to PD1 blockade. Studies incorporating PD1 blockade into the frontline treatment of Hodgkin lymphoma, either combined with or sequentially prior to AVD chemotherapy, demonstrated really promising tolerability and efficacy in the frontline setting. These studies using either nivolumab or pembrolizumab, either in combination with or sequentially with AVD chemotherapy. All have progression free survival benefits greater than 90%, which is really the best we had seen to date with an ABVD backbone type of therapy.
Based on this idea that there were still many patients who received brentuximab vedotin AVD who were relapsing, there was increased toxicity that was observed in terms of neuropathy, and sepsis, and febrile neutropenia and this really strong rationale to use PD1 blockade in the frontline setting. We designed the randomized Phase III SWOG S1826 trial. Important to mention, this was a collaboration between the adult North American cooperative groups and the pediatric cooperative group, the Children's Oncology Group. We actually enrolled patients as young as 12 on the study and there was no upper age limit because we were not using BEACOPP. Patients who could tolerate anthracycline containing chemotherapy could receive either of these regimens. Patients with stage III or IV Hodgkin lymphoma were randomized in a one-to-one fashion to receive either nivolumab combined with AVD or brentuximab combined with AVD. Patients on the brentuximab arm were required to receive G-CSF. patients in the nivolumab arm, where it was optional to use G-CSF, and patients were stratified based on age, the IPS score, and the intent to use radiation at the end of therapy, and it was allowed for treating investigators to administer end of treatment radiation to residual FDG avid lesions. The primary endpoint of the study was progression free survival, and we enrolled nearly 1000 patients on the study.
We enrolled about a quarter of the patients that were under the age of 18, about 10% of the patients were over the age of 60, a quarter of the patients were either Hispanic or Black, about 2 thirds of the patients had stage IV disease, about a third of the patients had high IPS scores, and patients with HIV were allowed to enroll onto the study, actually. Overall, I think one thing to say about S1826 is that it was really a broadly representative study of the patients that we treat in North America and also included high-risk patients. Actually, more than some of the other studies that had been conducted in the last decade or so in advanced stage Hodgkin lymphoma.
The toxicities were, as you would expect, gastrointestinal toxicities, hematologic toxicities, typical of a combination chemotherapy regimen.
One thing that we did see was more neutropenia with Nivo-AVD. But that was not entirely surprising because it was required to get growth factor on the brentuximab arm. What is important is that we did not see any increase in infections or fibrinogen as a consequence of that increase in neutropenia. This is basically going back to the days of ABVD, where all patients really are neutropenic, and it is not necessary to give growth factor. A lot more bone pain in the brentuximab arm because of that growth factor use. There was quite a bit more neuropathy in the brentuximab arm and higher grade neuropathy, almost 3 times the amount of grade 2 or higher peripheral neuropathy. There was more thyroid dysfunction in the nivolumab arm. Any of you that are familiar with these checkpoint inhibitors know that that is pretty common. There was more liver function test abnormalities in the rituximab arm. There were not really high rates of immune related toxicities in the nivolumab arm, which was reassuring to see.
There really were pretty major tolerability differences and patients being able to get a full course of therapy. In the brentuximab arm, 12% of patients had to discontinue therapy completely compared to less than 8% in the nivolumab arm, and 22% of patients discontinued brentuximab at any time, compared to 9% in the nivolumab arm, 27% of patients actually had dose reduction of Brentuximab vedotin. Importantly, there were very few patients who received radiation less than 1% of patients, which is quite a big paradigm shift.
Most importantly, S1826, demonstrated that nivolumab-AVD prolonged progression free survival compared to brentuximab vedotin AVD in patients with stage III or IV Hodgkin lymphoma. At 2 years of follow-up, the hazard ratio of 0.45 and the 2 year progression free survival with Nivo-AVD was 92%, compared to 83% in the brentuximab arm.
In parallel, while we were conducting S1826 in North America, in Europe, HD21 was an ongoing study, randomized, again, Phase III study. This was a non-inferiority study looking at trying to improve on this BEACOPP backbone and incorporate brentuximab into BEACOPP while removing some of the chemotherapies that were causing a lot of the toxicity that we associate with BEACOPP. It was a PET adapted study, Patients who were PET negative got 4 total cycles of therapy, and patients who were PET positive on their interim scan had 6 total cycles of therapy.
The changes from BEACOPP to BrECADD were omission of bleomycin, some minor changes in the doses of etoposide and doxorubicin, vincristine was omitted, brentuximab vedotin was added, and then most importantly, I think in my mind is that we removed procarbazine, which is associated with gonadal toxicity and second cancers and substituted in dacarbazine. There was also some changes in the steroids, actually less steroids. The steroids were given for a shorter duration of time.
But BrECADD was much better tolerated than BEACOPP. Importantly, there appeared to be less impact on gonadal function. This is just measurements of FSH levels in men and women a year after therapy, and the FSH levels returned back to baseline in the BrECADD patients, this brentuximab based BrECADD regimen, whereas they remained elevated in patients who received BEACOPP.
Not only was BrECADD noninferior, in fact, it was actually superior to BEACOPP. The 4 year progression free survival was 94% with BrECADD, compared to around 91% with escalated BEACOPP.
Now, just to place the regimens a little bit into context, there are some differences in hematologic toxicity and infections between BrECADD and what we observed with nivolumab-AVD on S1826. There is quite a bit more grade 3 hematologic toxicity. Almost a quarter of patients required a red blood cell transfusion, 17% of patients required a platelet transfusion with BrECADD, and 28% of patients who received BrECADD had febrile neutropenia, typically requiring admission to the hospital. All of those rates were quite different with nivolumab-AVD. Just important to note some pretty significant supportive care differences between the regimens and toxicity differences. Fourteen percent of patients require radiation in the BrECADD study, as opposed to less than 1% that we observed with nivo-AVD in S-1826.
Just to summarize, these new modifications of these historic backbones, ABVD and escalated BEACOPP really have moved the needle and advanced, brought a new paradigm of nova agent based frontline therapy for advanced stage Hodgkin lymphoma. Nivolumab-AVD improved progression free survival compared to brentuximab AVD in advanced stage Hodgkin lymphoma. It was better tolerated than brentuximab vedotin AVD. There were a few immune related adverse events observed, which was reassuring. Very few patients received consolidative radiotherapy, and that may reduce late effects in this typically younger population. Importantly, it is a key step towards harmonizing pediatric and adult therapy. BrECADD improved progression free survival compared to BEACOPP, similar to what we observed in S1826, and BrECADD was also better tolerated than escalated BEACOPP with less impact on gonadal function. Overall, these newer regimens were both more effective and better tolerated.
We will start off with a real-world case. This 30-year-old woman with newly diagnosed at stage IV Hodgkin lymphoma has a high intermediate IPS score. She is a violinist, and she is concerned about preserving her fertility. Dr Friedberg, what are your considerations when seeing this patient in your clinic?
Dr Friedberg: I think this is a fairly typical patient. IPS score of 4 is a relatively high risk. Working as a violinist, I think is a question that neuropathy may be a particularly devastating toxicity for this individual. With these new agents, the knowledge on long-term fertility is limited, and we should emphasize that. There are hints that fertility is going to be preserved. I think we are comfortable with the AVD backbone that those chemotherapy regimens do not, in and of themselves, cause major infertility. But in somebody who is concerned about preserving fertility, I would certainly send them to have a discussion about options prior to starting treatment. Clearly, I think nivolumab-AVD is the option that, with short follow-up, has the most likely chance that she is going to be cured. But the fertility preservation would be recommended in the sense that we do not really know with nivolumab-AVD combination in long-term follow-up what the impact on fertility would be.
Dr Herrera: Thanks, Dr Friedberg. Modify the question a little bit. This is maybe an 18-year-old, and maybe, the 18-year-old is not a violinist.
Dr Friedberg: Aspiring violinist.
Dr Herrera: Aspiring violinist, a freshman in college. That is right. How does the discussion change a little bit?
Dr Kelly: I think it would be quite similar, especially in the younger patients, an 18-year-old fertility is going to be a major consideration. Nivo-AVD would be a preferred option. I think the one thing, and I will touch on it a bit in my presentation, is that some of the pediatric regimens are more dose intensive and are given over a shorter period of time. For an 18-year-old who may be starting college, that is still a trade-off because nivo-AVD does take 24 weeks to deliver. I think again, discussing with the patients, understanding what their priorities are is critical for choosing which regimen.
Dr Herrera: Yes. That is an excellent point. Differences in the duration of these regimens is certainly worth keeping in mind.
How do you both approach management of a newly diagnosed Hodgkin lymphoma patient who has autoimmune disease? Let us say they have active disease that requires, let us say, a TNF alpha inhibitor in the case of inflammatory bowel disease.
Dr Friedberg: I think it is a challenging question. We should emphasize that these patients were not included in the 1826 clinical trial. They were excluded given concerns over autoimmune exacerbation with the checkpoint blockade. Clearly, we know from other scenarios that there is the risk of that. That risk may be higher in these Hodgkin lymphoma patients because they are younger. I think the younger immune systems may be more likely to increase. My approach to this particular case would probably be choice E, which would be BV-AVD. I have a lot more experience giving BV-AVD. Obviously, we were doing that for years before the nivolumab data. That Is likely what I would choose over BrECADD. The BrECADD results are probably better, and I think that is also a very reasonable answer. I think both of those would be preferred over ABVD.
Dr Herrera: Absolutely. That makes perfect sense. Anything to add, Dr Kelly?
Dr Kelly: I think BV-ABD PC would be our pediatric regimen which was studied in the younger population and was associated with the high event-free survival rate. That would be a consideration for a patient like this.
Dr Friedberg: have probably the most experience of any of us with the checkpoint inhibitors. What is your sense as far as the risk of autoimmune exacerbations?
Dr Herrera: You know, personally, I actually I agree with both of you. I would tend to avoid using nivolumab in a patient with active inflammatory bowel disease, as in this case. I think a lot of the folks who we have polled probably have a lot of experience with these drugs to treating solid tumors, and I think it is perhaps a different scenario than what we might be thinking about in a patient with metastatic solid tumor. Here we have BrECADD or ABVD or associated with cure rates of upwards of 85 to 95%. I think given how effective the regimens are, and certainly, we know that there is a higher rate of immune related adverse events in patients with autoimmune diseases, I would tend to want to use a non checkpoint containing regimen just to make sure we are getting through the therapy, we are not complicating things, we do not have to interrupt and delay and things like that due to hepatotoxicity or gastrointestinal toxicity exacerbating her inflammatory bowel disease. I agree with both of you. I think BrECADD vs BV-AVD personally I have used a lot of brentuximab-AVD and these types of patients with lupus and other autoimmune diseases. Often the autoimmune disease gets better for a little while after they have gotten chemotherapy.
Dr Friedberg: I think it is going to be very important for us to continue to follow the patients on 1826 and understand the intermediate toxicities and long-term toxicities. I think we all participated in that trial. We led the trial. At this point, we are not aware of any major signals of problems. That is not only coming from our trial, but other studies of the checkpoint inhibitors that Alex mentioned that had longer follow-up. But given the youth of this patient population, I think it is going to be important for us to continue to pay attention to that.
Dr Herrera: Absolutely. Really, really critical. We will advance the clock a few decades now and as you all probably know, there is a late peak of incidence of Hodgkin lymphoma in older patients in their late 60s, 70s, early 80s. Dr Friedberg is going to talk about considerations for older patients with Hodgkin lymphoma.
Dr Friedberg: I think for the fit patient who is older. You should appreciate that any BEACOPP regimen is really contraindicated. It has not been studied in patients over the age 60 because when it was, it was too toxic. You are thinking of an AVD type of backbone, and given the poor outcomes that we have seen in contemporary studies adding BV to AVD, I think Nivo-AVD is very appealing. The real question is what to do with the unfit and the frail patients. Unfit patients may be able to get Nivo-AVD. We need to study that. But certainly some of the unfit patients and frail patients, I think there are some either single or doubled options that need further exploration.
Dr Herrera: How do you assess frailty and fitness? Are we doing get up and go walking tests in clinic?
Dr Friedberg: I come from an institution that has an expertise and interest in geriatric oncology. We have not formally moved a lot of that into our lymphoma population. Most of their data is in solid tumors. There are a number of tools that have been published and explored that include patients with various types of lymphoma. The most robust one is in diffuse large B-cell lymphoma that was developed in Italy, and this tool is relatively straightforward. You can do it in clinic in 5 to 10 minutes and does, at least for diffuse large B-cell lymphoma, categorize patients into fit, unfit, and frail. I do think that we need to be able to do that when we do trials in this patient population. For example, understand can an unfit patient get Nivo-AVD? Where is the cutoff where we would say that the patient should not get combination chemotherapy. In that small remaining group, what is the best option? Maybe BV-nivo is too toxic as well. Maybe you have to do them in sequence. I think this is an unmet need to study this. I will speak from the US cooperative group standpoint that we have had interest in studying this, but right now, it is very difficult to design a trial because the number of patients that, we think, are going to be eligible for this trial is relatively low, given the positive outcomes of the Nivo-AVD. I think we want to get a little more experience with that before we think about a study that maybe uses an integral biomarker of some fitness tool.
Dr Herrera: That is perfect. I agree, it is really important. We are trying to do this more and more in our clinics, too, to try to do a little better than just the eye test. One thing that I do not typically do in these patients, unless there is a reason why I cannot give them brentuximab, if I have an unfit older patient with Hodgkin lymphoma, I do not typically give them PD1 alone as the first thing.
Dr Friedberg: I will add one last thing. Just have to get one more point. One tool that is a very effective treatment for Hodgkin lymphoma is radiation therapy. The risk of late toxicities in many of these older patients is negligible. They are going to be too old for those risks to occur. I think that although I rarely use radiation therapy in advanced stage Hodgkin lymphoma, a scenario where it may be part of treatment and I have a lower threshold to give it would be for the older unfit patient and even sometimes achieving a PR with shrinking a lymph node that is causing symptoms can buy you a lot of time relative to their age.
Dr Herrera: Absolutely. I always hear in my head what you and other folks have said, that radiation is probably one of the single most effective therapies we have for Hodgkin lymphoma. Not to forget that. Next we will have Dr Kelly give a talk focused on pediatric and AYA patients with Hodgkin lymphoma.
Dr Kelly: We are really at a crossroads in managing Hodgkin lymphoma in the pediatric age group. Historically, we treated things quite differently. That really evolved due to the earlier recognition of many of the late side effects that occur from radiation, as well as high cumulative doses of chemotherapy. Because of that, our patients are younger. They have many decades of life ahead of them. We develop different regimens that try to balance some of the risks associated with that. As part of those regimens, we also used quite different risk stratification compared to what is used in the adult groups. Unfortunately, too, which limits comparability across regimens, is that even across the different pediatric Hodgkin lymphoma clinical trials, there was quite a lot of variability in what is considered to be advanced stage.
In North America, fortunately, we have had a bit earlier access to some of the new agents, and the first agent that we evaluated is the brentuximab vedotin with the Children's Oncology Group trial, AHOD1331. That compared the standard children's oncology group regimen for patients with both intermediate and high risk disease, which is the 6 drug AVE-PC, an adaptation of ABVD, including some etoposide and cyclophosphamide. The new regimen replaced the bleomycin with brentuximab and omitted one of the doses of vincristine. In this study, again, the risk stratification is a little bit different than the advanced stage studies on the adult side. This trial enrolled patients with stage IIB and bulk, IIIB and all stage IV. It was ages 2 to 21 years of age.
This study, the brentuximab arm, was very successful. We saw an almost 10% improvement in event-free survival, with the brentuximab arm being up to 92.1%. Radiation was still pretty considerable, but compared to previous trials that had been done by the Children's Oncology Group and by the Europeans, radiation was a little over 50%, and it was mostly due to the presence of the bulky mediastinal masses.
The other important point about this regimen is that it still is intensive. Overall, it was manageable, but it still is quite toxic and really does represent an opportunity for us to try to improve upon this with less toxic therapies, as well as identify ways to further decrease the use of radiotherapy.
We were fortunate to come together with our adult colleagues in the National Cancer Institute's National Comprehensive Network, and we worked together to design the S1826 trial and included patients 12 and up. Here I am presenting the results of the adolescent cohort. This is patients age 12 to 17 years. There were 240 in that age group. Pretty sizable number of patients. I think the important take homes here is it was highly effective. With Nivo-AVD, 2 year PFS of 95%, 12% improvement over BV-AVD, and really I think most exciting thing was how few patients received radiotherapy. Only one in the nivo arm, 2 in the BV-AVD arm received radiation, which is just an absolutely huge advancement for this pediatric Hodgkin management.
Here, I summed up what my thought process is when I am seeing patients and trying to decide between the 2 regimens that are mostly used in North America. The advantages of the Nivo-AVD approach include the ability to limit the use of radiotherapy, especially in a patient with a bulky mediastinal mass, where in the AHOD1331 approach BV-AVE-PC, radiation was used in all patients. We do not really have any data about whether we can omit that. I also for patients with stage IVB involvement, especially if there is bone marrow involvement, that group did not show a benefit with the 1331 approach.
Some of the acute toxicity concerns, there is less peripheral neuropathy with Nivo-AVD, you can avoid use of bone pain from growth factor use, and there is a marked reduction in febrile neutropenia. From a long-term toxicity, we anticipate that there is probably less effect on fertility with the Nivo-AVD since the AHOD1331 regimen still includes 6g/m² of cyclophosphamide. From an ease of administration, the Nivo-AVD is given once every 2 weeks. It is much easier to tolerate. Patients where I might consider BV-AVE-PC, our patients that have comorbidities, that may impact treatment choice.
We talked a lot about the autoimmune disease that applies to this younger population as well. Unfortunately, because we only enrolled patients 12 and up, we do not have any data yet on nivo-AVD in the much younger population. Roughly about a third of patients that present in a pediatric oncology practice are going to be under age 12, and so we do not have any data there. It is a little harder to know whether the safety of that approach in these younger patients. I think there still are. Of course, we do not have the long-term data of the checkpoint inhibitors. There are some efforts that are underway, including a new initiative by the Childhood Cancer Survivor study to specifically enroll patients on that study who have received checkpoint inhibitors.
Dr Herrera: I just wanted to look ahead a little bit to the future directions, and where we are moving in Hodgkin lymphoma.
Talk about some of the new drugs that are being developed and maybe some of the new approaches. We have poked around this idea, a little bit of starting to think about how to personalize therapy more and risk adapt patients. Historically, we have used PET scans, but we saw that really PET scans are an imperfect tool. In fact, with checkpoint blockade, PET scans are particularly imperfect, really, when we use PD1 blockade in Hodgkin lymphoma, and we are trying to assess disease with PET scans, there is a lot of non-specific FDG uptake that we see. What are some other tools or other ways that we could think about assessing response and potentially risk adapting patients? Circulating tumor DNA many of you may be familiar with. It is certainly starting to have some uptake in many, in the solid tumor setting. We have started to use it more in lymphoma. Circulating tumor DNA is a highly sensitive and specific way of assessing for residual disease. We have several different studies now showing that we can assess the mutation profile of patients with Hodgkin lymphoma and with excellent sensitivity and specificity. Now start to assess for residual disease.
Now that we are using checkpoint blockade in the frontline setting, we are curing more patients. Unfortunately, we are not curing all of the patients. Patients are still going to potentially need salvage therapies down the road and other novel agents. What are we doing about that? There are NK engaging therapies. Innate immune cells and responses might be important in Hodgkin lymphoma and in the microenvironment, and K engager therapies have been found to be promising so far. Dual checkpoint blockade. I think in melanoma, for example, there is a lot of LAG3 and combined LAG3 and PD1 inhibition that is approved actually and is used. We studied that in Hodgkin lymphoma and saw that patients who had been resistant to prior checkpoint blockade actually responded to anti-LAG3 and anti-PD1 blockade. Also, we have shown that with epigenetic modifiers like HDAC inhibitors or hypomethylating agents combined with PD1 blockade can actually help recapture responses to PD1 blockade and patients who are progressing on therapy. Patients progress on PD1 blockade. You add the epigenetic modifying agent that have various immunologic effects tickle the immune system, and we have seen responses in those patients even after they have progressed on PD1 blockade. Here at ASCO, we have seen the presentation of 2 studies as oral presentations. One was combining chemotherapy and typical salvage chemotherapy with ice, and that was a randomized study comparing to just ice chemotherapy alone, showing that the response rates and the progression free survival was much better in patients who received PD1 blockade combined with salvage chemotherapy. Not surprising really. This has become a standard already. But this was nice to see a randomized study to validate that, and then a multicenter study showing that these NK engaging therapies, combined with the infusion of NK cells, indeed could produce responses in a multicenter setting.
Dr Kelly: I just want to do a quick plug for a study that we do have open. Now, this is for early-stage Hodgkin lymphoma and building on the successful collaboration with the adult cooperative groups. This early-stage study is being led by the Children's Oncology Group but was jointly developed together. This study is enrolling patients ages 5 to 60 years of age, and it is evaluating whether more of an immune therapy approach for consolidation therapy as a means of being able to limit exposure to conventional chemotherapy agents and radiation therapy. The standard of care is using a EORTC H10 type of approach, whereas the experimental arm after 2 cycles of ABVD, the investigational arm is 4 cycles of BV-nivo and radiation is only reserved for the slow responding patients, which we anticipate will be about 15%. Study right now is open at over 300 centers in North America, and just would encourage you to participate if you are part of the NCTN.
Thank you, Dr Friedberg, Dr Herrera, and Dr Kelly, and many thanks to you, our listeners, for joining us. As a reminder, to view the full program “Transforming Frontline Therapy in Hodgkin Lymphoma: Advancing Personalized Strategies for Optimal Outcomes,” and to claim credit, please click the link in the show notes. And be sure to check back regularly for more episodes on important CCO Oncology topics!