Rethinking Pediatric Hodgkin Lymphoma Care

Podcast Transcript

Dale Shepard, MD, PhD:  Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shephard, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program at Cleveland Clinic.

Today I'm happy to be joined by Dr. Ilia Buhtoiarov, a physician at the Division of Pediatric Hematology Oncology and Blood and Marrow Transplantation at Cleveland Clinic Children's and Dr. Rabi Hanna, Chair of the Division of Pediatric Hematology Oncology and Bone Marrow Transplantation at Cleveland Clinic. Dr. Hanna was previously a guest on this podcast to discuss gene therapy for patients with sickle cell disease, and that episode is still available for you to listen to. Today we're here to discuss rethinking care for pediatric patients with Hodgkin lymphoma. So welcome.

Ilia Buhtoiarov, MD: Thank you. Great honor to join you.

Dale Shepard, MD, PhD:  Welcome back, Rabi.

Rabi Hanna, MD: Thank you so much for having us, Dale.

Dale Shepard, MD, PhD:  Give us a little bit of an idea. Remind us what you do here at the clinic.

Rabi Hanna, MD: So it's really a privilege for me to work here with fantastic colleagues and team to serve patient kids and young adults who have blood diseases and cancer. And I serve as the Chair of the Division of Pediatric Hematology Oncology and also the Director of the Bone Marrow Transplant program.

Dale Shepard, MD, PhD:  Excellent. And then Ilia, what do you do here?

Ilia Buhtoiarov, MD: I am also very glad to join this conversation in my role of a staff physician for the last 10 years here at the Cleveland Clinic. I joined it as a lead of the leukemia lymphoma program in 2015, and we witnessed lots of great successes and treatment of patients with Hodgkin lymphoma in particular.

Dale Shepard, MD, PhD:  So, excellent. We are going to focus on Hodgkin lymphoma in children here today. Maybe as a backdrop, people from a lot of different backgrounds might be listening in. I guess first off, give us a little bit of an idea of the scope of Hodgkin lymphoma, about how many people develop Hodgkin lymphoma? And then maybe a little bit of an idea of how we've historically treated it.

Ilia Buhtoiarov, MD: Well, Hodgkin lymphoma is one of the commonest neoplasms in pediatric and adolescent patients. Around 1,300 of pediatric patients are being diagnosed yearly with that, and the treatment has been very well standardized, although there are very new clinical trials and advances that allow us to do better than we were doing before at a much lower cost with respect to the long-term side effects and the consequences that come with the treatment as the cost of that.

Dale Shepard, MD, PhD:  And so let's explore that a little bit. This balance between being aggressive to treat a tumor and not being too aggressive to lead to either acute or long-term side effects.

Ilia Buhtoiarov, MD: The pediatric oncologists who have been in practice for years seem to be comfortable to call Hodgkin lymphoma a salvageable tumor, meaning that we could possibly treat patients with as much therapy as they need without exceeding on side effects. And if the patients happen to have their disease recurrence, there is always a plan B, more toxic than the first-line therapy that would still retain the same success rate. Historically, Hodgkin lymphoma survival in pediatric and AYA patients has been around 80 to 85%. Again, about 15% of patients are destined to fight the recurrent condition, and we have a great array of methods right now to keep all of them alive.

Dale Shepard, MD, PhD:  Excellent. Kind of as your role overseeing the department, what sort of resources do you guys have available for that long-term managing survivorship in these patients and looking at that long-term toxicity?

Rabi Hanna, MD: Yeah, I'm glad that you asked that question. It's so important for us. It's the philosophy of our care here at the clinic and especially at our department. We want patient not only to survive, but rather to thrive. As Ilia mentioned, that Hodgkin lymphoma, it's actually affecting many of the adolescents or even young adult where they are just starting their life. And it's also, most of this lymphoma happens in the mediastinum and the chest, and that's very important because back in the '70s and the '80s, radiation therapy and the transplant was a hallmark for patient who were refractive or they relapsed. So unfortunately, as we are moving a decade later after we saved them from the lymphoma, we noticed that there is increased risk of secondary malignancy. Many young female in their 20s, 30s start to have a breast cancer or they have heart failure at very early in their life.

It's actually almost two-thirds of patients who were survival of a transplant post for relapse Hodgkin refractory had a burden of chronic disease. So that's why we developed survivorship program that is led by Dr. Seth Rotz who is trained in both medicine and in pediatrics, and he have a liaison with all the other services to be able to address many of these long-term side effect that impact on this patient, including also fertility. So it is to the surprise of many of our survival as they are 10 years later and they want to start their life, they get surprised that they are infertile and they cannot have their kids. So it's important to have access to a survivorship comprehensive program that can address many of the side effects. But what excites me today, it is really the ability to hopefully prevent this long-term side effect and be able to let the patient thrive and not even have to worry as much about the side effect.

Dale Shepard, MD, PhD:  And then that reduction is by decreased intensity of treatment and some of these newer approaches. So let's kind of jump into some of those newer approaches. So tell us a little bit about some, let's start thinking about some of these newer studies, newer approaches. So the CheckMate 744 trial, what is it and how does it change what we do?

Ilia Buhtoiarov, MD: Well, that was one of the hallmark clinical trials that looked at the opportunity to use the novel class of drugs called the checkpoint inhibitors for treatment of patients with the Hodgkin lymphoma. And the novel idea of using the limited amount of chemotherapy in combination with the checkpoint inhibitors to try to induce remission and of patients and then stratify them based on their response either into the category of the low risk relapse or the standard risk relapse to further treat them either with the transplant-based approach or trying to omit it and use the radiation in place. That unique study, unlike many others, included patients of a wide range of categories starting from age of five up to age 30, so truly the pediatric and adolescent and young adult patients. And they included patients of all different kinds, but in a very precise manner.

They took into consideration how patients presented at the very beginning, how they relapsed, how long it took for the patients to relapse and what treatment they receive before they relapsed. And based on all these four considerations, they had different approaches to patients. And as a result, now we're able to conclude that patients who could be called to have the low risk relapse as they undergo the treatment for the recurrent conditions can be retrieved or salvaged into the durable remission without the use of autologous stem cell transplantation with the limited amount of chemotherapy with the use of checkpoint inhibitors and some radiation therapy.

Dale Shepard, MD, PhD:  As you talk about the range of patients, very young up to young adults, within Hodgkin lymphoma, do we see differences in response to therapy, tolerance to therapy within this AYA group, much like you see with some of the leukemias?

Ilia Buhtoiarov, MD: That is quite accurate assessment. We do know that age is a factor, not as prominent as we know about it in patients with leukemia. But yes, those who seem to be older, they have somewhat inferior outcome. But also those older patients would have certain type of histology in the tumor that is a biological factor that explains their inferior survival.

Dale Shepard, MD, PhD:  Makes sense. We think about how we pick the right patients, right therapies, durations of therapies, what's the role of imaging and maybe some advanced imaging techniques to figure out things about duration of treatment, things like PET scans?

Rabi Hanna, MD: So in the second study that we highlighted in our review article in JAMA, we report on the European net study where they did include PET-CT, which is really an advanced modality to be able to detect any increased FDG activity. So they use that after two cycles. And the patient who were very strict in terms of response, one or two doable response, which is really very good after two cycles, was able to detect basically or risk stratify this patient and say, those are the patient who even only with the two cycles were able to achieve, let's call the deep remission of Hodgkin or good response.

Those patients may not need high dose chemotherapy and autologous transplant versus the patient who were still positive, they went on and they received bone transplant. And the study showed the outcome of that group that they have a very early good response were equal in terms of progression and early and event-free survival of around 89 to 90%. And the two group, the one who didn't receive bone marrow transplant versus the one who PET scan was still positive and they went on to receive high dose chemotherapy. So it was very good because it was almost 40 patients who saved them from the effect of high dose chemotherapy.

Dale Shepard, MD, PhD:  And of course, anytime you think about trials, does this sort of translate to the real world and has this been something that we've been able to adopt in clinical practice and has been shown to be effective?

Ilia Buhtoiarov, MD: The PET-CT has been in clinical practice for probably a good 10 years now with a lot of data to support again, the risk stratification based on the numbers the nuclear medicine provides us. It still stems around definitions of the rapid response and slow response, but this is what we nowadays use in our clinical practice compared to the time when we did not have universal and uniform access to the PET-CT when we were relying on anatomical measurements of the tumor and the size reduction of the first two cycles, which would be a difficult and cumbersome approach to some patients with complex masses in complex anatomical locations. So the PET-CT allows us to see the very early response before the tumor even began to predict the outcome and be able to lay out the treatment plan with limited toxicity of the same effectiveness.

Rabi Hanna, MD: So the PET-CT has been used as an image for the last 10 years in upfront Hodgkin lymphoma to help us with the risk stratification. But what this studies recently showed that the same methodology could be applied in the relapse settings to be able to detect within that sector biologically that they are good responders so we could save them from high dose chemotherapy.

Dale Shepard, MD, PhD:  Just as we're running through talking about minimizing therapy essentially in many cases or changing that sort of full front sort of attack on tumors, how do patients, families, even other providers think through that? So you have people who are young, they've got a bad disease, and then you're like, "Well, let's see how little treatment." So what's the response usually from patients and families?

Rabi Hanna, MD: I think it is really very important to shared medical decision between the oncologist and the family. It's good to have options nowadays, and it is important to look and consult the family about side effect and long-term, because honestly, many family when they come, they are scared of cancer. They just want to be treated and they don't want to have to deal with a relapse. So occasionally you'll see them want to do what it is really old and tried and just not have to worry about this, but it will take assurance. It will need counseling for them to tell them about the option and educate them about both what could be acute and long-term side effects so they can make the best decision.

And I would involve even the patient if it is adolescent and 13, 14, if it is female. If it is male, there could be actually different approaches with the same efficacy, but a different side effect profile when it comes to fertility, for example. So it's good we have multiple options. It make it a little bit confusing sometimes to family, but the key is take time and assurance because there is no urgency to treat this immediately. Most of the time we have the luxury of time here compared with other cancer that we could come up with the best comprehensive plan. That's usually my approach. Anything to add, Ilia?

Ilia Buhtoiarov, MD: I would just add that it is extremely important to partner with parents of younger children and advise them on long-term side effects if we, for whatever reason, decide to be aggressive with the treatment up front versus rely on the science advances and try something that brings promise, would be less toxic, and at a later age, would bring much shorter list of the long-term side effects and consequences from the treatment. Hodgkin lymphoma is known for the long-term side effects. As Rabi mentioned, that is a fertility issue that is a chronic fatigue. Patients who receive radiation, which is still the modality to use, they tend to develop secondary cancers. In 50% of cases it would be in the radiation field, patients develop cardiac toxicity, patients may develop some pulmonary fibrosis from the medications and combination of other factors. So all this need to be taken into consideration for younger patients as we project the great outcome, the full life of joyful events to make sure that we do not overdo and over-treat.

Dale Shepard, MD, PhD:  Makes sense. Ilia, in your review, you talked about a children's oncology group trial looking at sort of durability responses without transplant. Tell us a little bit about what that had shown.

Ilia Buhtoiarov, MD: Yes. So there was another clinical trial that essentially used the combination of two novel, at that time, agents, gemcitabine and rituximab, vedotin for patients who would be treated with that before the transplant. And the interim analysis of the responders demonstrated that some patients may not need the transplant. Not all of those patients did not receive transplant by their choice, some were not eligible for transplant, other decided not to proceed with that. But again, that was a study that showed that even two agents could induce durable remission in patients and save them from those high dose chemotherapy and stem cell transplant related complications.

Dale Shepard, MD, PhD:  Talked about radiation here and some of the complications. Where does radiation sit right now in terms of its role? Is there anything being done to sort of try to minimize that radiation exposure, either how it's given or things like that?

Rabi Hanna, MD: Yeah, no, it's very important question. And I think there has been great advances in the radiation from decreasing it to only the area that it is still showed active disease to even omitting the radiation for only the relapsed patient. But on the other side, other than the risk stratification to know who does need and where, there is even advances in the technology of radiation. So now we have a proton therapy that it is used for other type of cancer. This report does not, there is no studies that are talking about this proton, but this is one of the advances now that could be considered on a case by case with oncologists and the radiation oncologists, whether that could be potentially effective and it's shown to be safer modality than the other methodology of radiation.

That could be considered. If it is too close to the heart or other areas where you still need radiation because radiation, I want to emphasize it, is very, very effective modality to treat refractory Hodgkin. But the question then, is there anything to do to decrease the area of radiation so you could only do it for the refractory? And the second thing is there any safer modality like proton therapy for this patient?

Dale Shepard, MD, PhD:  Ilia, let's wrap up with some progress we're making in the area. VeloSano is something that we have here at the clinic and supports a lot of research. What are you studying in terms of Hodgkin lymphoma right now that's exciting?

Ilia Buhtoiarov, MD: Well, there was lots of excitement recently amongst the Hodgkin lymphoma enthusiasts about how to treat patients better. First, I would like to mention that there has been a great effort to harmonize the approaches between pediatric and adolescent and adult patients. It used to be quite different between adult patients and pediatrics years ago with the treatment approaches and prognosis and even the medications available. Now, the approaches seem to be more uniform and the novel clinical trials seem to encompass patients of all ages starting as early as five up until age of 90. So that is one of those things. Second, one of the greatest advances that we in the pediatric field became closer to our medical oncology colleagues on how to assign the risk stratification at the very beginning. In our field, it used to be the low risk, intermediate risk, and high risk and in medical oncology, it used to be early favorable, early unfavorable, and then the advanced state. Now it is called uniformly in this third definitions.

And also the access to de novo agents and checkpoint inhibitors, the Hodgkin lymphoma is known for its very rich inflammatory background in the tumor and the Hodgkin lymphoma or the Reed-Sternberg cells by themselves create that inflammatory environment. So using those novel agents with the side effects that do not overlap with toxicities known for chemotherapy is one of the greatest advantages that we could offer to our pediatric patients. What seemed to be still unknown is the role of what we call the minimal residual disease or minimal detectable disease, something that has already received quite nice development in some types of non-Hodgkin lymphoma and of course in acute leukemia. So what our group was doing, we had a trial sponsored by VeloSano to look at traces of DNA specific uniquely to the Reed-Sternberg cells of individual patients.

So each patient would have their own signature of the circulating DNA in the blood that would be released from the tumor. And our study successfully recruited 10 patients and the analysis is not complete. So we can clearly see that the decrease in the amount of circulating DNA in those patients who we see responding well on the PET scan correlate very nicely. So we are getting closer to the moment where instead of doing the PET scans or other scans, which also are about the radiation exposure burden, we may one day to do the blood test and say, "Look, with the greater sensitivity in a very unique way for individual patients can predict the same response and outcome."

And also, if we are able to establish this approach for individual patients, it would allow us to track that patient when they are in remission for any possible recurrence. Because again, the risk of or likelihood of disease recurrence in high-scale lymphoma patients is still close to about 10 to 15%. So those patients uniquely would benefit from the results of the clinical trial that we are having active in our division and hope to be able to present very soon at one of the major national meetings.

Dale Shepard, MD, PhD:  Wow. So you guys are doing good work. Lots of encouraging things coming up and appreciate you being with us to share your insights today.

Rabi Hanna, MD: Thank you so much for having us.

Ilia Buhtoiarov, MD: Thank you. Great honor to join you.

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