Transforming Frontline Therapy in Hodgkin Lymphoma: Advancing Personalized Strategies for Optimal Outcomes

I do want to frame the landscape a little bit with this introductory slide 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.

[00:01:38]

Early Interim PET Negativity Predicts Favorable Outcomes

With that consideration, I will take you through a little bit about how Hodgkin lymphoma therapy has evolved in my mind over the last decade or 15 years. Major publication that really changed the way we thought about Hodgkin lymphoma for a long period of time is this study that looked at PET scanning and showed that no matter what the risk was for patients, if the PET scan was negative after 2 cycles, you can see on the top patients did very well, if the PET scan was positive after 2 cycles, patients did less well. This led to the paradigm of response adaptation.

[00:02:23]

S0816: PET-Adapted Approach to HL

Here is an example of a response adapted study. This was a single arm study but used response adaptation where all patients were treated with ABVD. If they were PET positive, they were escalated. If they were PET negative, they continued with ABVD. The goal was to try to lift that lower curve that I showed you up to closer to the higher curve, but spare the whole patient population from the toxicities of an escalated regimen.

[00:02:55]

S0816: 5-Yr PFS and PFS by PET2 Designation

If you look at 5 years of follow-up, this study did not have such great results. This is not that different from what you would see with ABVD alone. The reason for that is that the patients who were escalated actually did fairly well. But the patients who were not escalated did not do as well as we had expected. In other words, the initial curves of PET positivity vs PET negativity were probably overoptimistic compared to what we saw in this clinical trial.

[00:03:30]

RATHL: Response-Adapted Therapy for Advanced-Stage Hodgkin Lymphoma (Escalate or De-escalate)

That was reproduced in this RATHL trial that was a randomized trial, but also gave all patients 2 cycles of ABVD. PET negative patients were randomized to ask whether you could take out bleomycin, and PET positive patients were not randomized and got a flavor of escalation.

[00:03:50]

RATHL: Long-term Follow-up PFS of ABVD vs AVD

They really observed the same thing. Whether you had ABVD or AVD, if you were PET negative, you had the same outcome. But you can see that the outcome was not so great. In fact, it is very similar to the trial that I showed you, the 0816 trial. Ultimately, this means that 25% of patients are still going to relapse, even if they are PET negative at the end of 2 cycles of therapy.

[00:04:20]

ECHELON-1: Brentuximab Vedotin + AVD vs ABVD in Newly Diagnosed Stage III/IV Hodgkin Lymphoma

That really led us to conclude that this 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.

[00:05:00]

ECHELON-1 : Long-term Follow-up PFS, OS, and Other Outcomes

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.

[00:05:30]

ECHELON-1: Febrile Neutropenia and Neuropathy

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. You can see that 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.

[00:06:11]

Checkpoint Inhibition in Hodgkin Lymphoma

That leads us to the other new class of drugs. You had a little flavor of this in the polling questions, 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. When given as a single agent in a variety of settings, including patients who have had brentuximab and autologous stem cell transplant in the past, you can see that almost everybody has tumor shrinkage with nivolumab. You would see the same thing with pembrolizumab. In fact, the majority of these patients have an official response.

[00:07:00]

Why Is HL so Sensitive to PD1 inhibition?

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.

[00:07:51]

Mechanism of PD1-Based Therapy in HL: Survival Factors in Microenvironment

It is a bit more complicated than that. Just a very brief reminder that Hodgkin lymphoma also has a very complex microenvironment. When you give PD1 blockade, you are not only getting rid of the Reed-Sternberg cells, but you are also changing the microenvironment. It is likely that that change in the microenvironment also leads to some of the responses that we see.

[00:08:17]

Peripheral Immune Signature in cHL and Response to Checkpoint Blockade

The other important message that I wanted to give is that there is clear rationale as to why these drugs would work better up front than in the relapsed setting. Here is a data set that demonstrates that patients with newly diagnosed classical Hodgkin lymphoma have reduced T-cell receptor repertoire. In other words, their immune systems are disordered just by having Hodgkin lymphoma. That is much worse if you look at the relapse setting, which is that blue curve.

[00:08:48]

Peripheral Immune Signature in cHL and Response to Checkpoint Blockade

Now, this correlates to response to checkpoint blockade. In fact, if you give checkpoint blockade to patients with significantly disordered T-cell repertoires, the response is less. There is a clear rationale based on these data that it would make sense to give checkpoint blockade up front.

[00:09:11]

Rationale for Early Immune Checkpoint Blockade

It goes beyond just the T-cell. 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, and I think that sets up what Alex is going to say.

Practical Considerations for the Community HCP in the Application of Frontline Treatment of Hodgkin Lymphoma

[00:09:45]

Dr Herrera: We will focus in the next section on practical considerations in applying new changes to the frontline treatment of Hodgkin lymphoma.

[00:09:55]

Standard Management of Advanced-Stage cHL (2018-2023)

Dr Friedberg gave a fantastic introduction, getting us to this point. In 2018, this was how the treatment of advanced stage Hodgkin lymphoma looked. 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.

[00:10:54]

Incorporating PD-1 Blockade Into First-line cHL Therapy Is Well-Tolerated and Highly Effective

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 here there is 5 different studies, as you can see, 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. You can see some of the studies actually went out to 2, 3, even 5 years.

[00:11:55]

S1826: Nivo-AVD vs BV-AVD for Frontline cHL

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. As Dr Friedberg mentioned, 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.

[00:13:17]

S1826: Baseline Characteristics

Here are the baseline characteristics of the patients whom we enrolled. As you can see, 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. As you can see, we did have some. 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.

[00:14:03]

S1826: AEs in ≥10% of Patients

These are the most frequent toxicities that we observed in both arms in the trial. It is maybe a little hard to see from this figure. But some of the bars I guess go a little further to the right on the brentuximab side. But the toxicities were, as you would expect, gastrointestinal toxicities, hematologic toxicities, typical of a combination chemotherapy regimen.

[00:14:25]

S1826: N-AVD Better Tolerated Than BV-AVD

But I think this high-level overview that OS presented on this slide speaks to the tolerability differences between the 2 regimens. 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. As you can see, there were not really high rates of immune related toxicities in the nivolumab arm, which was reassuring to see. Pretty similar rates actually compared to the BV arm, which was interesting.

[00:15:33]

S1826: Treatment Discontinuation and Deaths

You can see in this slide that 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 that Dr Kelly will talk about in her portion of the talk.

[00:16:13]

S1826: N-AVD Prolongs PFS vs BV-AVD

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 rituximab arm.

[00:16:38]

S1826: PFS Benefit With N-AVD Consistent Across Patient Subgroups

Importantly, the progression free survival benefit that we observed with nivolumab-AVD was consistent across all the subgroups of patients enrolled to the trial. You can see here in this forest plot younger patients, older patients, patients with low IPS score, patients with high IPS score, stage III, stage IVB symptoms or not. All the subgroups really appear to benefit pretty clearly from nivolumab-AVD compared to brentuximab AVD.

[00:17:02]

S1826: Overall Survival

This is the overall survival that we saw on S1826, just at 2 years of follow-up. These data really were not mature, and we need to follow the patients longer. But I will note that there were twice the number of deaths in the BV arm even at this early time point.

[00:17:19]

HD21: Reducing Toxicity of eBEACOPP

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, like Dr Friedberg was mentioning. This was still using this idea of PET adaptation. 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.

[00:18:03]

HD21: Transforming BEACOPP

The primary endpoint was progression free survival. This table no need to look at it in excruciating detail, but basically the high points here on 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.

[00:18:42]

HD21: Gonadal Dysfunction as Determined by FSH

I do not have slides to talk about all the different reasons why, 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.

[00:19:12]

HD21: BrECADD Improves PFS vs eBEACOPP

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.

[00:19:29]

Practical Limitations: BrECADD vs N-AVD

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. You can see 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.

[00:20:05]

Changing the Standard of Care for Advanced-Stage cHL: Conclusions

Just to summarize this section, 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, like Dr Friedberg mentioned. Importantly, it is a key step towards harmonizing pediatric and adult therapy, and Dr Kelly will discuss that. 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.

[00:21:32]

Current Management of Advanced-Stage cHL

This is now, I would say, what the treatment of advanced stage Hodgkin lymphoma certainly looks like in North America and let us say in the West where patients with advanced stage disease. The most effective options and best tolerated options are nivo-AVD and BrECADD with the other regimens that we have historically used really more useful in certain circumstances.

[00:21:52]

Let’s Revisit a Question

We are going to move on back to that polling question that we had.

We are going to revisit this patient with advanced stage Hodgkin lymphoma, had a history of inflammatory bowel disease and strong concerns about preserving fertility.

[00:22:08]

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 my question F would be our pediatric regimen, the BV-ABD PC, 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 Herrera: We will say we engineered the question to generate a discussion with some missing options.

Dr Friedberg: Since you want discussion, I will turn it back. You 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 rituximab-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.

[00:25:35]

I think we will move on to the next section. Getting the blinking red lights. But I think we covered nicely a lot of the parts of the discussion here.

Special Considerations for Older Patients with Hodgkin Lymphoma

Dr Friedberg: So I will just add one last comment. 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.

[00:26:48]

Patient Case: 69-Yr-Old Man With Newly Diagnosed HL

Dr Friedberg: Not to touch anything up here. Thank you. This is a typical older patient. This is 69-year-old man who has advanced Hodgkin lymphoma with a good performance status. But some comorbidities including mild COPD, reasonable ejection fraction, no contraindication to anthracycline. He expresses a preference to avoid regimens with long-term toxicity risk and is open to novel therapies. I will stop and just say that, as you will see from some data, in this patient population, the number 1 priority has to be to try to cure the patient of Hodgkin lymphoma. I would worry less about long-term toxicities. First of all, he is 70, and the long term could be defined as 20 or 30 years. But also as you will see the rate of cure is lower.

[00:27:45]

OSOS of Advanced-Stage Hodgkin Lymphoma by Age

This is just SEER data, and these are not Kaplan-Meier curves. But we derived this from the most recent SEER update. If you look by age, you can see that there are dramatic differences in outcome of advanced stage Hodgkin lymphoma. Clearly, patients who are older than age 65 or even older than age 75, that does not look like a Hodgkin lymphoma outcome. This is absolutely consistent with our clinical experience. This is not something funny with the data. The small group of patients who are older than age 60 or 65, who present with Hodgkin lymphoma have largely been excluded from the improvements.

[00:36:31]

ECHELON-1: Inferior Outcomes in Older Patients (≥60 Yr)

Dr Friedberg: Here is an example in the ECHELON-1 trial. Keep in mind, these are the fittest of the older patients because they enrolled on this randomized Phase III trial and passed all the eligibility characteristics. The modified PFS was lower than what you would expect and there were 9 deaths on study in this group of patients, much higher than you saw in the other patient population.

[00:29:01]

Sequential BV-AVD-BV in Older Patients With HL

We have tried to modify dosing of chemotherapy, and this is a regimen that was in popularity for a period of time rather than give the BV and AVD together to try to split it up to minimize toxicity for older patients. The outcomes here were favorable in the group of patients who got through the entire regimen. But look at the bottom of the slide. There were 42 patients who started, and only 28 patients were able to finish the entire regimen. As good as the outcome was, you lose a lot of patients along the way because of toxicity other problems. If you try to give this regimen, it is really long. You are adding BV on top of 6 cycles of AVD, and it goes on for a very long period of time in an older patient.

[00:29:56]

LYSA: PVAB (Prednisone, Vinblastine, Doxorubicin, Bendamustine)

This is a more recent regimen that was published looking at bendamustine, which has high activity, usually of transient nature, in Hodgkin lymphoma along with vinblastine and doxorubicin. The outcome here was somewhat disappointing, and certainly looks very different from those curves that Alex showed you in the previous talk. One of the challenges is all of these trials are relatively small, and it is very difficult to understand who these patients really are because in most of the trials, there have been no measure of frailty, no measures of comorbidity that have been formal. I mean, there is a very big difference between a healthy 61-year-old and an almost 80-year-old who has a number of comorbidities and would be considered unfit or frail. I think the theme of what I am going to be saying is that that characterization of older patients is going to be an important step in making treatment decisions.

[00:31:00]

Phase II Study of Nivo-AVD for Older Patients

Nivo-AVD has been studied in older patients. There are 2 data sets really. This was a paper that came out earlier this year in JCO, a series from Memorial Sloan Kettering, patients over the age of 60 with advanced stage Hodgkin lymphoma. That is like the perfect study for this discussion. They did do some geriatric assessments as part of this, and they did a nice characterization of the patients. You can see that the outcome, although not as good as what we saw in the broad population, still looks very good with 78% PFS or so.

[00:31:52]

S1826: Nivo-AVD vs BV-AVD for Older Patients

These are the data from the randomized trial that Alex presented. Looking at the group of patients who were over age 60, it was about 100 patients total. You can see PFS on the left and overall survival on the right. A couple of messages here. Really, the brentuximab with AVD is too toxic for older patients. You can see if anything, there were a number of deaths that occurred in that arm. Those were toxic deaths. I would say that it is not premature to make the conclusion that brentuximab-AVD is too toxic for this patient population. Certainly, the data with nivolumab-AVD are quite promising and look quite similar to what Memorial published in their series. If these data hold up, I think that will be a very appealing regimen for the fit patient who is older.

[00:32:37]

SGN35-015: BV Combinations in Older Patients With HL

Now, there are a number of these patients who are not candidates for anthracycline based therapy, maybe not candidates for chemotherapy alone. Once patients are in their 70s or above age 75, I think Nivo-AVD may be a very tough regimen for a lot of those patients. This was a series of small cohorts that I was part of that looked at single agents and doublets building upon BV. We treated a group of patients with BV alone, BV with dacarbazine, BV with bendamustine, and BV with nivolumab. The BV and bendamustine arm had to close because of toxicity concerns. BV plus DTIC looked better than BV alone, and BV with nivolumab did look promising.

[00:33:30]

SGN35-015: PFS of BV + DTIC in Older Patients With HL

This was BV and DTIC. There are a couple of things to say about this. Clearly not as good as a chemotherapy combination, but a subset of patients did have durable responses, which is important if you are 80 years old and you cannot get chemotherapy. This is a very active regimen for Hodgkin lymphoma. This did make it in NCCN guidelines for a period of time. The median age of patients here were 72 and patients enrolled were up to age 88. Just to give you a flavor that this is a very different patient population from the patients in their young 60s that were on 1826.

[00:34:09]

SACCRU: PFS of BV + Nivo in Older Patients With HL

Another study of BV Nivo had a rather disappointing result. There are some issues with this study. They only gave a relatively short duration of the nivolumab and they also had a fairly strict criteria for what they were going to declare as being a successful study.

[00:34:31]

SGN35-015: PFS of BV + Nivo in Older Patients With HL

In our study that looked at this combination, the outcome was somewhat better. Again, what was exciting to me, this median follow-up is 50 months. This is a very long follow-up. You can see that some of these patients were probably cured of Hodgkin lymphoma with this combination. If you have a patient who cannot get chemotherapy and you think they can tolerate BV, I would certainly think about this combination. Just to show you that again, median age of 72, 48% of the patients took more than 13 seconds to complete the up and go test. I did pretty well getting out of that chair. That is a long time. These were very frail patients. I think I turn it back to you.

[00:35:19]

Let’s Revisit a Question

Let me make a conclusion statement. I think for the fit patient who is older, I gave you a series of chemotherapy options. 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.

[00:36:10]

Dr Herrera: Fantastic. Thank you so much, Dr Friedberg, for taking us through that.

Patient Case: 69-Yr-Old Man With Newly Diagnosed HL

We will revisit the polling question. This is the 69-year-old man with newly diagnosed Hodgkin lymphoma we were discussing earlier in the evening. Stage IIIB disease, ECOG performance status of 1, mild COPD, ejection fraction of 60%, and expresses a desire to avoid long-term toxicity and interested in novel therapies. We will say interested instead of open to.

[00:36:42]

Posttest 3: Which frontline treatment option would you choose for this patient?

All right. Again, everybody selected brentuximab plus nivolumab or Nivo-AVD. Maybe some more folks thinking about the non anthracycline containing options, since the patient expressed a desire to avoid long-term toxicity and was interested in novel agents. Jonathan, what do you think about in this patient? COPD.

Dr Friedberg: I think there are data available for both of these options. That said, I think that the Nivo-AVD regimen is probably the best chance for cure. Salvage ability in this scenario is probably limited. If you think a patient can tolerate combination chemotherapy, I think your first attempt would be to give Nivo-AVD. But it is hard to tell on paper. Sixty-9-year-olds like this can look very different when you see them. We all see that in clinic and sometimes with our relatives. I would think that over time we are going to learn that frailty assessments may play a really important role. If there were a lot of other comorbidities and the patient did not have support at home, I do think the BV-nivo option is, for some patients like this, not unreasonable.

[00:38:02]

Panel Discussion

Dr Herrera: Absolutely. I think, again, just staying consistent with the message that in the older patients, if they are fit for chemotherapy, the nivo right now appears to be the most the most appealing option. Just thinking about other possible discussion points. 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. There is just one thing I wanted to mention before we move on to the next section. 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. I think we do have some data. Dr Friedberg did not talk about it, but single agent checkpoint blockade. So far, the data that we have is not so promising in these older patients. That is probably a combination of perhaps tolerability in terms of immune related toxicities and things like that. But I will say something that we want to study is similar to the BV doublets, is using PD1 blockade together with a single chemotherapy to be able to benefit from some of that chemo sensitization and at least try to replicate what we saw with the BV doublets.

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 because of the results that we saw earlier, 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.

Special Considerations for Pediatric and AYA Patients with Hodgkin Lymphoma

[00:42:16]

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: Okay. Thank you. I appreciate the opportunity to present the pediatric oncology perspective. I am going to just show a case, a patient I took care of.

[00:42:47]

Real-world Case: Pediatric Patient With High-risk HL

We will come back to this at the end. But this is a 17-year-old that presented with a 2 month history of right neck swelling, drenching night sweats over the past 2 weeks, chest x ray did not show a bulky mediastinal mass. PET CT, though, showed multiple involved nodes both above and below the diaphragm. A pulmonary nodule uptake within the spleen that you can readily see there, as well as focal lesions in the bone in both the axial and appendicular skeleton.

[00:43:17]

Risk Groups

I do want to set the stage. 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. You can see for the advanced stage groups that while some things are the same, there are a lot of differences in what is considered to be advanced stage.

[00:44:21]

EuroNET-PHL-C1: Response-Adapted Omission of RT and Comparison of Consolidation CT in Pediatric Patients

What I am going to do tonight is just summarize some results of recent clinical trials, Phase III clinical trials for the pediatric population for advanced stage, or what we call high risk. The first one is from the European group, the EuroNET-PHL. This is the result of their C1 trial. This does not include any of the novel or new targeted agents. This is using conventional chemotherapy with response adapted radiotherapy. The trial was a randomized international titration Phase III study enrolling patients up to 18. Their goal was to maintain a 5-year event-free survival of 90%. The advanced stage fell into either the intermediate or the high-risk groups. They started with 2 cycles of OEPA under 1, an early response assessment, and then got additional chemotherapy comparing the standard COPP with a newer regimen that replaced the procarbazine for dacarbazine is an attempt to help preserve fertility. For this advanced stage group the radiation decision was based on that early response evaluation, but was a pretty strict definition in that the radiation was given to patients if their PET was positive, and positive was defined as a double score of 3, 4 and 5, which is a bit different. We in the US have used 4 or 5, but additionally they needed to have at least a PR to avoid radiation, which was defined by volume changes.

[00:46:02]

EuroNet-PHL-C1: TG2 and TG3 EFS

Trial results have been published and they did meet that bar. They maintained that 90% 5 year event-free survival, and they were able to avoid radiation in a good number of patients. Historically in the European studies, everybody in the advanced stage group got radiotherapy. Now, overall 60% of patients received radiotherapy, 40% did not. But still especially in that higher risk group 65% of patients were still receiving radiotherapy.

[00:46:39]

AHOD1331: Brentuximab Vedotin + AVE-PC in Pediatric High-Risk cHL

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. This is the results of 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 that you just heard about 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. Patients receive 5 cycles, and then radiation was based on if patients had a bulky mediastinal mass at presentation, or if they had slow responding sites of disease after 2 cycles of therapy.

[00:47:55]

AHOD1331: Study EFS (Primary Endpoint)

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%. As shown, on the bottom left panel, you can see there was a much earlier plateauing of events with the brentuximab containing ARM. Benefit was observed in most subgroups, but not all. I think most notably, there was no improvement in patients with stage IVB disease, especially if they had bone marrow involvement, which was disappointing since that is the group that we were really hoping to make a change. Radiation was still pretty considerable, but compared to previous trials that had been done by the Children's Oncology Group and by the Europeans, as I just showed, we are anywhere from like 65 to 100% of patients receive radiation. Here the radiation was a little over 50%, and it was mostly due to the presence of the bulky mediastinal masses. The rate of radiation for slow responding sites was only about 18%, and it was the same across both arms.

[00:49:08]

AHOD1331: Study EFS by Early Response

I think the other important take home point from this study, Dr Friedberg showed how trials did not really overcome show that we could overcome that predictive nature of the PET scan. This trial was one of the first that showed that with giving a more effective therapy, you could overcome that prognostic importance of a positive interim PET. You can see in the standard regimen, there was still a marked inferiority of the patients that were slow responders where with brentuximab the outcomes were the same.

[00:49:49]

AHOD1331: Clinically Significant AEs

The other important point about this regimen is that it still is intensive. Fortunately, younger patients tend to tolerate the therapies pretty well, but you can see there were about almost a third of patients experience febrile neutropenia, sepsis rates, fortunately, were low. They were in about the 2 and a half to 4% range. There was considerable GI toxicity. We saw peripheral neuropathy but interestingly, it was no different between the 2 arms unlike other trials. We believe it had to do with the dose modification criteria that were built into the trial. 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.

[00:50:52]

S1826: N-AVD for Pediatric Patients

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. You saw some of the data presented before. But specifically in this adolescent cohort 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. The decision to use radiation was a little bit different for because radiation had been such a big part of pediatric regimens that we actually said for patients enrolling through the children's oncology group that they had to if they met the criteria for radiation at the end of chemotherapy, they did need to get the radiation. Even despite that, you could see 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.

[00:52:28]

S1826: AEs With N-AVD for Pediatric Patients

The other important point is the tolerability of the regimen I showed before. We talked earlier about the neutropenia was higher with the Nivo-AVD, but the use of growth factor was much lower with that group. The febrile neutropenia rate I showed you with our pediatric regimens, it is 30% here. Here it was only 3%. That is a huge difference. The rates of peripheral neuropathy are also much lower with the Nivo-AVD. I think what was also very important about this trial is it represents the largest group of pediatric patients receiving checkpoint inhibitors in frontline therapy of any disease. We went into this with a little bit of trepidation, not knowing if there would be a different toxicity signal. But as you can see here, it was very well tolerated. We did not see any serious immune related adverse events. There was some thyroid dysfunction, as would be expected. But it still is an area where we still need more data. We need more observation. But at least with the first 120 patients that were treated with this, it is very encouraging that it was well tolerated as it was.

[00:53:49]

Actively Recruiting for AHOD2131: BV-Nivo vs SoC

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.

[00:55:03]

Individualizing and Optimizing Immunotherapy Strategies for Frontline Tx in Pediatric Patients With cHL

Just to really sum up, I think it still is important. I said at the beginning, we are at a crossroads. We know we are really just beginning to move our therapy in a different direction in treating our younger patients with Hodgkin lymphoma. But we do have to maintain the perspective. These patients do tolerate treatments differently. We also have to think about their long term. These patients, we are hoping that they are going to live another 60, 70, 80 years from their diagnosis. We have to be mindful about some of the unknown late effects with some of these newer approaches.

[00:55:44]

Current Management of Advanced-Stage Pediatric cHL

This figure summarizes where we are at right now in pediatric Hodgkin lymphoma management for patients with advanced stage disease. This is from the pediatric Hodgkin lymphoma NCCN guidelines. We have now 3 approaches that are based on solid associated with good results and are based on results of Phase III trials. The Nivo-AVD times 6. They had 1331 as well as the European C1 approach. There are a couple of other regimens that can be considered in special circumstances.

[00:56:23]

Determining Therapy for Pediatric Patients With High-Risk/Advanced-Stage cHL

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, 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. Additionally, even though the rates are very low for secondary cancers with the BV-AVE-PC, we anticipate it should be lower, especially with the omission of the radiotherapy, but also without any exposure to etoposide. 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.

Another factor is that the BV-AVE-PC has a slightly lower cumulative anthracycline dose. However, on the Nivo-AVD, I do want to point out that 80% of the pediatric patients receive dexrazoxane, which should be cardioprotective, although recently, there is been data showing perhaps an elevated risk of breast cancer with higher cumulative exposure to anthracycline. That is still something that is a bit unknown. As I mentioned before, the more dose intensive regimen is given over a shorter time period. It is 15 weeks vs the 24 weeks. For some of these younger patients that are looking to get back onto their lives again, that that might be attractive.

[00:59:57]

Follow-up After Completion of Treatment and Monitoring for Late Effects

I do also want to highlight the importance of continued monitoring after completion of therapy. What is listed here are the guidelines from NCCN. I think, especially with these novel agents, there is such a need to continue to monitor and track so that we have more comfort in using this over the long term.

[01:00:22]

Real-world Case: Pediatric Patient with High-risk HL

If we go back again to this patient, this is a patient with stage IVB disease, no bulky mediastinal involvement. In terms of treatment options, I think at the time this patient presented, he was treated with BV-AVE-PC and did not need radiotherapy. He did not have the bulky mediastinal disease, and he did have a negative PET scan after 2 cycles, is a long-term survivor. But I think if he were to come into my office today, especially with the stage IVB involvement, then uh Nivo-AVD would have been my treatment of choice in this setting.

[01:01:04]

Panel Discussion

Dr Herrera: I think we are pretty much at time for this section. I think we have actually talked a lot about a lot of these discussion points. I just wanted to ask Kara, as patients are presenting to you, I think you went you gave a really beautiful discussion of how to think about the long-term risks and how to balance them. But I think in the end, if you had a patient that was a patient with stage IV disease, I am curious, maybe a patient with stage IIIA or IIIB, where do you fall on the spectrum there?

Dr Kelly: I think the important point too, with pediatric patients, is that we really want to avoid relapse because the treatment burden is from relapse therapy. I always prefer to use a more effective therapy and to avoid that relapse setting. It is very important to keep that in mind, whether it is a pediatric patient or whether it is a 19-year-old or a 20-year-old. We know that high dose chemo transplant carries considerable risk and so if we can avoid that with the best therapy up front, that is going to have the biggest impact.

Dr Herrera: Absolutely. I think I really want to make sure we are giving the patients the best chance of being cured upfront. Patients want to be cured of their disease.

[01:02:34]

On The Horizon: Novel Agents and Combination Therapy 

Okay. I will be brief. We are low on time, but I just wanted to look ahead a little bit to the future directions, and where we are moving in Hodgkin lymphoma.

cHL Subtypes by Noninvasive ctDNA Genomic Profiling

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 Dr Friedberg presented 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.

[01:04:12]

cHL ctDNA Level Associated With Relapse Risk

This study just shows that it is a little busy but on the left you can see that this waterfall plot and basically on the top you can see there is these blue and orange bars. The orange bars on the top are patients that had a positive PET scan. But you can see that there were many patients who actually were ctDNA negative even though they had this positive PET scan and ultimately, again, a complicated picture, but they did not have that waterfall line going down the waterfall plot was a PFS event. They were PET positive, ctDNA negative, and they never relapsed. I think we have started to understand that ctDNA can identify a lot of patients who have false positive PET scans and actually have had an excellent response to therapy and are not going to relapse. On the right, you can see looking at interim circulating tumor DNA as a prognostic tool. I think you can see that patients who have undetectable circulating tumor DNA, the blue curves, do quite well, whereas patients who are ctDNA negative are the blue curves. They do quite well. Patients who were ctDNA positive are the orange curves, and they do not do quite as well. Maybe this is a tool we could use like we had used PET scans before.

[01:05:34]

Biologic Subtypes of cHL by Patient, Genomic and TME Features

Not only can you assess residual disease, you can characterize tumor biology. Now we have these novel agents, and you have checkpoint blockade, which may work particularly well in patients with a particular type of disease biology. For example, EBV. Hodgkin lymphoma is often associated with EBV and EBV can actually upregulate PD1 ligand expression in Hodgkin lymphoma. Again, patients who are EBV positive or have a virally driven Hodgkin lymphoma, we may really want to use PD1 blockade.

[01:06:02]

PFS by Biologic Subtype and MRD

This is just combining all of that, so combining this idea of assessing disease biology and residual disease with circulating tumor DNA. You can see really nicely that these blood tests for circulating tumor DNA can nicely both tell you about biology, but also assess residual disease and show that in certain biologic subtypes, patients who are ctDNA positive had pretty poor outcomes.

[01:06:30]

Novel Frontline Combination Therapies in cHL

Okay. Perhaps we can individualize therapy and personalize therapy by incorporating circulating tumor DNA. Maybe de-escalate or escalate therapy, depending on the results. What else are we doing in Hodgkin lymphoma? We are incorporating brentuximab and nivolumab combined. We have talked a lot about either BV or nivolumab in the frontline setting. But we have used both together in the frontline setting, and actually this middle study is actually a randomized Phase II study. One of the study arms actually is the experimental arm of the randomized study that Dr Kelly was talking about. Patients got 2 cycles of patients with early-stage Hodgkin lymphoma, got 2 cycles of ABVD, and then went on to get brentuximab and nivolumab. There were no relapses in the 4 year. I think 42 patients who were treated with that regimen. Again, just suggesting that it is a potentially promising approach to use both drugs for early-stage disease.

[01:07:33]

Novel Agents and Combination Therapy in R/R HL

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? You probably are familiar with CAR T-cells and the change, the advances, really incredible advances that we have made in non-Hodgkin lymphomas. CAR T-cells for Hodgkin lymphoma have not really made that same impact. We have seen responses, but the durability of those responses really has been concerning so far. There are NK engaging therapies. As Dr Friedberg mentioned, 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.

[01:09:45]

Trials Currently Recruiting in cHL

Finally, a couple of other novel agents being studied, SGN35C. This is a novel anti cd30 directed antibody drug conjugate. A newer version of brentuximab but we have changed the payload. Instead of the microtubule inhibitor, it is a camptothecin payload. In fact, in solid tumors, there is a lot of ADCs that use camptothecin payloads. Actually, so far, the data has not been presented. They are being presented this summer but I will just say that we have seen quite nice responses in many patients. So far, it has been well-tolerated. This PMRT5 inhibitor is also being studied. Of course, another plug for AHOD1331. This ongoing study in early-stage Hodgkin lymphoma that Dr Kelly mentioned.

[01:10:31]