Alex Herrera, MD, Hematologist at City of Hope, talks about treating Hodgkin lymphoma.
Interview conducted by Ivanhoe Broadcast News in 2024.
What is Hodgkin lymphoma?
Herrera: Hodgkin lymphoma is a cancer of the immune system. It’s a cancer of a type of white blood cell called a lymphocyte. And what happens is once this type of lymphocyte, becomes cancerous, our immune system of patients, our person’s immune system tries to fight off the cancer. It ends up forming a tumor, but if you look at a mass of Hodgkin’s tumor, it’s only about 5 percent or so of a tumor that is the actual cancer cells. Most of it is our immune system trying to fight off the cancer, which is a pretty unique type of Hodgkin lymphoma.
Is there a certain age group or gender that this targets?
Herrera: The most common age group that Hodgkin lymphoma affects is folks in their teens into early 30s. But there’s what we call a bimodal distribution of the disease. It affects younger adults, teenagers, and young adults, but also older patients in their late 60s, 70s, early 80s.
Was it strange to get the call to see your patient Georgie Garabet, who seems a little bit younger than that?
Herrera: No, Hodgkin lymphoma can affect patients of people of any age. I only focus on Hodgkin lymphoma, so I’ve seen it all. But again, the typical age of presentation will be somebody in their late teens and through the early 30s or somebody older in their 60s,70s.
What’s the traditional treatment for this?
Herrera: For decades, the standard treatment for Hodgkin lymphoma has been combination chemotherapy, and in patients with early-stage Hodgkin lymphoma, patients will get radiation historically. For patients who have Stage 3 or 4 Hodgkin lymphoma, it’s just been a combination of chemotherapy drugs primarily. For years, we have been working on incorporating new treatments into the treatment of Hodgkin lymphoma. A standard over the last several years has been using a targeted drug called brentuximab vedotin which is an antibody that has chemotherapy attached to it, and so it’s a targeted delivery of chemotherapy directly to the tumor cells. That is combined with three chemotherapy drugs. AAVD or brentuximab vedotin combined with AVD. That’s been a standard treatment for Stage 3 or 4 Hodgkin lymphoma.
You are starting a new clinical trial. I mean, you are leading a new clinical trial. How does that differ?
Herrera: The clinical trial that we designed SWOG S1826, tried to incorporate one of our new Hodgkin lymphoma treatments called nivolumab. It’s an immune therapy. There’s no chemotherapy involved in nivolumab itself. It’s an antibody. What it does is part of the way Hodgkin lymphoma becomes a cancer is by basically tricking our immune system hiding from our immune system. Nivolumab targets the signal that allows it to do that and allows our immune system to see the cancer and fight it off. And so it’s an approved treatment and a very effective treatment for patients who have resistant Hodgkin lymphoma. Our clinical trial incorporated nivolumab combined with standard AVD chemotherapy to try to establish it as a new standard for Stage 3 or 4 Hodgkin lymphoma. What we did is we compared it to an old standard, older standard, which was brentuximab vedotin combined with AVD. This was a simple randomized Phase 3 trial. Patients were randomized in a one-to-one fashion, to either receive brentuximab vedotin, AVD, or the standard nivolumab combined with AVD. Hopefully, the new standard or the experimental treatment. Patients could receive radiation after their chemotherapy was completed, that is a standard, particularly amongst the youngest pediatric patients. And so, we enrolled 1,000 patients just under 1,000 patients to receive either of these treatments over about three years. We completed the trial a little over a year ago. Very quickly, sooner than we were expecting, we discovered that actually, the clinical trial had shown that nivolumab combined with AVD, was the superior treatment and appeared to produce a durable response in more patients compared with the older standard brentuximab vedotin with AVD.
What was the difference? Do you have percentages?
Herrera: The one-year progression-free survival, which was the metric that we used as the primary endpoint for the study was 94 percent. Patients treated with the nivolumab AVD and was 86 percent of patients treated with brentuximab vedotin and AVD, that it was actually- patients were twice as likely to have a relapse or disease progression if they were in the brentuximab vedotin.
Is the relapse usually within a year?
Herrera: It typically is. The most common time for a patient with Hodgkin lymphoma to have a relapse or, the disease progress is within a year of their treatment.
Does this put this into remission? Is it a cure or a remission?
Herrera: The intent of treatment for Hodgkin lymphoma, whether early or advanced stage, in this case, we were treating patients with Stage 3 or 4 disease is to cure the disease. More or less what we found, although, we still need to follow the patients for a longer period, since this was such an early readout of the trial, is that the combination of nivolumab, combined with AVD appeared to lead to a cure in more patients than patients treated with brentuximab vedotin and AVD.
How long have you been treating patients with Hodgkin lymphoma?
Alex Herrera: For over a decade.
Did you ever think you’d be saying that this is a cure?
Herrera: Hodgkin lymphoma is a disease that we’ve studied for years and it is one of the first cancers that we figured out how to cure. The incredible thing about the disease is that we are thankfully able to cure a majority of patients, and thankfully because this is a disease that affects people typically. To say that we would be able to improve the outcomes by as much as we did. So cut the proportion of patients that had a disease progression or relapse in half. I would not have- I would not have expected that it was a dramatic improvement in how many patients we were able to cure. What was also particularly exciting about this trial is that the experimental treatment of Hodgkin lymphoma combined with AVD was also better tolerated than the brentuximab vedotin AVD. We were able to cure more patients. It was better tolerated. And lastly, as I mentioned, younger patients in pediatric patients, they’ve often historically received radiation after the completion of their treatment. About 60 percent of patients, of our very youngest patients, would get radiation which can be associated with second cancers, and heart-cardiac and lung toxicities down the road. With this new treatment, less than one percent of the patients treated received radiation. We were able to cure my patients. It was better tolerated, and presumably, we’re going to reduce the risk of these late, toxicities or side effects these young patients with Hodgkin lymphoma are quite susceptible to. It was an incredible result and your question was whether I expected this or whether I could’ve imagined this, and it’s a really incredible advance for patients.
Is there any reason why you wouldn’t give this to a patient? Is there too much of a risk? Are there some patients that just wouldn’t tolerate it?
Herrera: It’s better tolerated, for the most part. Patients who have historically not received this kind of immunotherapy are patients with autoimmune diseases, for example, because of how it works, it can lead to worsening of autoimmune diseases. That’s a particular group of patients, we tend not to use this for. In fact, if we just this year at our ash meeting in 2023, we presented the subgroup of the older patients in the cohort, 60 years old or older, and they had dramatically better outcomes than with nivolumab AVD combined with AVD. It’s quite the opposite, actually, it’s much better tolerated in our very most vulnerable older patients. There really are few patients in whom I wouldn’t use this, but autoimmune diseases and lung fibrosis and things like that. Those are patients for whom we have not used these drugs.
Is this going for FDA approval?
Herrera: The plan is to use the results of this trial to submit to the FDA for nivolumab AVD to be a standard and approved option for patients with stage 3 or 4 Hodgkin’s lymphoma.
When do you think that would get in front of them?
Herrera: The hope is before the end of this year.
Is there anything next for the trial?
Herrera: There is. We are actually very soon going to be able to report longer follow-ups for the study. When we first presented the results this past summer at the ASCO annual meeting, we presented one year of follow-up results, so it was pretty early still, probably this spring, we’re going to be able to report two-year follow-up, which will be important. The goal of treating these patients is to cure them, so we want to make sure that those results are durable, and that we’re curing patients durably for the long term. That’s the first step that we will take. We will report as I mentioned, the older patients treated on the trial, as well as the very youngest patients treated on the trial, the pediatric cohort. Those are going to be analyses that we’re going to do. We’re looking at patient-reported outcomes important in this disease, not only to cure patients, but as I mentioned, this disease often affects young folks, and so really want to make sure that they are having improvements in their quality of life of this treatment. We’re also performing correlative studies to look at trying to understand what factors might predict for a patient to do better with this, with this treatment, or age factors or different factors in the tumor tissue that we’re going to test. We also collected blood from the patients, to be able to analyze a particular test that can help us identify the lymphoma, the lymphoma in the blood circulating tumor DNA. We’ll be looking at that and those studies are ongoing. We will be performing that testing over the course of this year. There’s going to be a whole series of different analyses that we’re going to do. The study is going to teach us a lot about patients with chgophoma and why this treatment ended up being so much more effective, but also how patient’s quality of life was with it.
When you first met Georgie, can you tell me a little bit about that? He was at stage 3.
Herrera: Georgie, he’s a lovely guy, and when we first met, he was terrified. But he was accepting of having this diagnosis, and he said, Listen, I want to do whatever it takes to get better from this. We talked about the clinical trial. We talked about the option to receive this newer treatment and all the promising studies of Nivolumab that had been conducted beforehand. He was excited.
For someone with stage 3 advanced Hodgkin’s lymphoma, is it a very curable disease or is there a lot of risk to it?
Herrera: It’s a curable disease, for sure. Historically, we’ve cured upwards of at least 75 percent of patients with stage 3 or 4 Hodgkin’s lymphoma. But the treatment is long. It’s six months of chemotherapy. It has a risk of long-term side effects and toxicities, and even short-term mortality, especially as patients get older, there’s more risk of lung toxicities and things like that, but the old drugs that we use like Lmcin. There’s risk. We are often able to cure the disease, but it’s finding better-tolerated treatments was a goal.
When you get someone like Georgie and he has two little kids under the age of three, that has to feel pretty important, knowing that this father’s going to be around to watch his little babies grow up.
Herrera: This job is humbling and people put their trust in us as physicians and cancer doctors as this disease affects young people. It is often folks who are either just starting off their professional careers or they’re in college, they’re just starting to open the door to life or they’re young parents. It’s a tough time, but I feel fortunate to be able to care for people like Georgie and connect with them and earn their trust and a huge part of what I do is research to find treatments that cure more patients. Having patients who are willing to participate in research, but trust each other and take forward this partnership is a really special opportunity.
Whatever happened with it becoming the standard of care, and standard of treatment?
Herrera: One important step for Nivolumab AVD to become a standard treatment is for it to be approved by the FDA. We’re working on that submission to be able to allow it to be used commercially for the treatment of states 3 or 4 Hodgkin’s lymphoma. But unquestionably based on these results, and again, more effective treatment, better-tolerated treatment, hopefully reducing long-term toxicities, it’s poised to become a standard of care for stage 3 or 4 Hodgkin’s lymphoma moving forward.
What makes this work? What does it do?
Herrera: Remember, nivolumab is combined with in this particular trial, we combined it with three of the standard chemotherapy drugs. The chemotherapy is, it’s chemotherapy. But the nivolumab as I mentioned, Hodgkin’s lymphoma becomes a cancer because actually there are genetic changes in the lymphoma cells that allow it to camouflage itself from our immune system to hide from our bodies. Nivolumab is an antibody that blocks the signal. We determined what the signal was that allows the Hodgkin lymphoma to hide from our body. Nivolumab blocks that signal, unmasks the cancer, takes off the camouflage, and lets our immune system recognize the cancer and fight it. It’s a very targeted therapy for Hodgkin’s lymphoma, as I mentioned, there are genetic changes in the lymphoma that allow it to depend on this way of hiding from our immune system. Nivolumab is an incredibly targeted therapy for Hodgkin’s lymphoma.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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