Dr. Kathryn Lurain shares about the advancements in HIV-associated DLBCL treatment, covering research, challenges, and future directions. 

She highlights the stigma and misconceptions in healthcare that contribute to the exclusion of HIV-positive individuals from trials, despite the ability to manage HIV as a chronic condition. Dr. Lurain emphasizes the need for inclusive clinical trials and suggests exploring specific therapies that target the unique aspects of HIV-related lymphomas, such as immunosuppression and viral infections like EBV and KSHV.

Additionally, Dr. Lurain describes a study she is working on that combines pomalidomide, an oral drug used in multiple myeloma, with the EPOCH chemotherapy regimen for treating HIV-associated lymphomas. The study aims to exploit pomalidomide’s ability to target cancer cells directly and mitigate the negative effects of viruses associated with lymphoma development in HIV-positive patients. She emphasizes the importance of including HIV-positive individuals in future trials to improve their treatment outcomes.

Kat: Welcome to today's episode of Health Tree Podcast for DLBCL, a show that connects patients with lymphoma researchers. I'm your host, Kat Richardson. Thank you to our episode sponsors, Regeneron and Bristol Myers Squibb, for their support of this Health Tree Podcast show. Before we get started with today's show, I'd like to mention three upcoming events that we will be hosting. September 18th, we will have a live webinar about tumor lysis syndrome in DLBCL with Dr. Asrani. On October 22nd, Dina Smith will join Health Tree to talk about stress management for caretakers. And finally, on October 29th, Dr. Iqbal will join us to talk about stem cell transplants. To register for this event and submit questions, visit healthtree .org forward slash DLBCL forward slash community forward slash events.

Our guest speaker for today's episode is Dr. Kathryn Lurain.

Dr. Lurain is an associate research physician in the HIV AIDS malignancy branch at the National Cancer Institute at the National Institutes of Health. She is an expert in the treatment of a variety of HIV -associated cancers, including those caused by Kaposi's sarcoma herpesvirus.

Her clinical research is focused on the development of new immunotherapy -based treatments for HIV -associated lymphomas and other virus -associated cancers. Dr. Lurain is an advocate for people living with HIV and their inclusion in clinical trials. She is trained in the clinical care of sexual and gender minorities. Okay, thank you, Dr. Lurain, for being here.

Kate Lurain: Thanks very much, Kat. I'm delighted to speak with you and your listeners today.

Kat: So my first question is, what is your role at the National Institute of Health? Do you participate mostly in research or do you see patients? Can you explain that for us?

Kate Lurain: I am the clinical director of the HIV AIDS Fluency Branch at the National Cancer Institute. So I do primarily clinical research. So I take care of patients and I get to do science. So I design and run clinical trials, taking care of patients, thinking about potential new treatments, working with our laboratory colleagues within our branch to see what they're doing in the lab, to see if it would work in our patients, and taking what we learn in our patients and bringing it back to the lab as well.

Kat: Thank you so much for that. And we'll start by talking about HIV -associated lymphomas. Can you give us a general background on HIV -associated DLBCL?

Kate Lurain: HIV itself, it increases the risk for a variety of different types of cancers and lymphoma is one of the major ones, diffuse large B -cell lymphoma in particular. And among people living with HIV in United States, lymphomas are the most common cause of cancer and diffuse large B -cell lymphoma is the most common subtype of lymphoma among people with HIV, similar to the general population of patients without HIV. And the reason why people with HIV are at higher risk for lymphoma than the general population is because HIV affects our immune system's ability to fight cancer. So our immune system is not just important for fighting viruses, bacteria, and other types of infections, it's also important for controlling cancer.

So HIV, decreases the number of a type of cell we have in our body called T cells, one type of T cell, the CD4 T cell. And when that happens, patients with HIV are at higher risk for infections, but also for certain types of cancers like lymphoma. HIV also has effects on the B cells. So the B cells that patients have, they have the normal number, but they don't function appropriately. And this occurs in people who are on good treatment for their HIV, which is called antiretroviral therapy. So being on antiretroviral therapy and having well -controlled HIV drastically decreases that risk for lymphoma, but it's still there. So even in people who have well -controlled HIV, they still have a higher risk for diffuse large B -cell lymphoma than the general population.

And not only do people with HIV get more lymphoma, but they also get more aggressive lymphoma. So they tend to have higher stage or more advanced stage disease when the lymphoma presents. They also tend to have involvement of the organs outside the lymph nodes, so involving the bone marrow or involving the brain or the fluid around the brain or other internal organs. They also tend to have sort of negative prognostic markers in the tumors themselves, so things that make the tumors behave more aggressively inside the tumors, things that people might have heard called mic translocation or rearrangements. Those are more frequent in people with HIV. And also, people with HIV have lymphomas that are inside their tumor, they're infected with one of two different types of viruses commonly. So the first

And they're both types of herpes viruses. People may have heard of herpes viruses. They can cause cold sores around your mouth. But there's eight different types of herpes viruses that can infect people. And two of them, one called Epstein virus or EBV, which is also the cause of mono, the disease we can get when we're in college. That virus, EBV, can sit around and people all of us, but when we have HIV, it decreases our immune system and that virus can sort of get out of control and cause problems in our B cells, which can lead to lymphoma. The other herpes virus that can cause lymphoma in people with HIV is called Kaposi sarcoma herpes virus. That's also sometimes called human herpes virus 8, and that causes a different type of lymphoma. It causes a type of large cell lymphoma and also another rare type of lymphoma called primary effusion lymphoma. But diffuse large B -cell lymphoma in people with HIV most of the time is associated with EBV. And usually EBV positive lymphomas tend to have a worse prognosis compared to lymphomas without EBV. So not only do people with HIV get more lymphoma, they have lymphoma that has a worse prognosis compared to the general population.

But we know that for many subtypes of lymphoma, when people with HIV get the same exact treatment as people who don't have HIV, and if you sort of say they have the same, if you take aggressive lymphoma and someone with HIV and a really aggressive lymphoma and someone without HIV, you give them the same treatment, they tend to have the same outcome. So they do have just about the same survival.

And that's if people with HIV get good HIV care and get good antiretroviral therapy to control their HIV and get good aggressive therapy, that's the standard that would be given to someone who doesn't have HIV.

Kat: Thank you for that explanation. So usually it's HIV and another virus together that are with the DLBCL. Is that what you're saying?

Kate Lurain: Yeah, that's the most common scenario. there's different, so DLBCL is not just one type of tumor. We can sort of break it down into two groups with what we know currently, sort of by what type of B cell is causing the DLBCL. So there's one called germinal center like DLBCL or GCBDLBCL.

And that lymphoma, about 30 % of those lymphomas in people with HIV also have EBV inside the tumor. And then the activated B cell, the other type of cell that can lead to diffuse large B cell lymphoma, it's closer to 90 % of those lymphomas are caused by EBV. So it's not HIV itself that causes the lymphoma.

HIV causes immune problems, immune suppression, immune dysregulation that sort of allows these viruses, EBV and case HIV, to cause the lymphoma.

Kat: Thank you so much for clarifying that. So today we'll be talking about a study titled, palmylitamide and dose -digested EPOC plus or minus rotexamab for HIV -associated lymphomas. What flaws or challenges currently exist in treating this population that would justify the need for this study? So basically, why does this study need to be done?

Kate Lurain: Well, unfortunately, people with HIV have been excluded from most of the big clinical trials that have led to the development of the standard treatments we have for DLBCL today. So for instance, the latest combination of chemotherapies that are given to people with diffuse large B -cell lymphoma right when they're diagnosed, so their first treatment was done in a study called the Polar X study, and it combined a new drug called Polatuzumab with standard chemotherapy plus Rituximab and compared it in a randomized way among many different hundreds of patients and compared it to our standard treatment that had been a standard for many decades called R -CHOP, so Rituximab plus a combination of chemotherapy drugs. And that trial led to sort of PolaR -CHIP, that new regimen becoming a new standard treatment for many patients with lymphoma. But people with HIV were excluded from that trial. People with HIV were also excluded from the randomized trial that compared that standard treatment of R -CHOP to actually the backbone chemotherapy regimen that we're gonna talk about today, but in that regimen called EPOC, E -P -O -C -H, with rituximab. There was another trial that showed that those two regimens were equivalent to each other. But our EPAC was more toxic than our CHOP. And both of those trials were very important trials that really set the standard for lymphoma, DLBCL treatment for the last more than five years. And people with HIV were specifically excluded from those trials. And so we don't know tons of information about those regimens compared to one another and people with HIV. And so all we can do is sort of extrapolate or like take that information. and apply it to people with HIV.

And in general, I think that's what we should do. In general, I think that people with HIV and lymphoma should be treated exactly the same way as people without HIV because we don't have a lot of information specifically in people with HIV. So I think that people with HIV should be included in clinical trials going forward and there's a lot of excitement about doing that among the collaborative groups in the United States and around the world and also in early phase trials. But there also might be some unique aspects that are associated with HIV lymphomas that might be able to be exploited as ways to improve outcomes specifically for people with HIV. So we talked about the fact that immunosuppression caused by HIV, so low T cells and immune dysregulation and chronic inflammation, are one of the things that lead to the development of lymphoma in people with HIV. Can we exploit that somehow or treat that or reverse those things to lead to better outcomes in people with HIV, since those don't occur in the general population to the same extent? Or can we do something about those viruses, EBV and KSHV, that lead to the development of lymphomas or something we can do to treat what those do to the body to reverse those effects and lead to better outcomes?

So I think there's two things that should happen to help people with HIV and lymphoma. First, we should improve the inclusion criteria of our clinical trials to allow for people with HIV to participate and also to think about ways specifically small trials that can sort of lead to bigger trials like the one we'll discuss today potentially leading to a research breakthrough specifically for people with HIV.

Kat: Thank you. So the reason for usually excluding HIV patients in studies, is that because they're considered too unhealthy to be in a study in general?

Kate Lurain: I think it's for a variety of reasons. That is one reason. So many people think about people with HIV back in the 80s and 90s before there was extremely effective antiretroviral therapy and patients frequently died of infections. And, you know, there was no opportunity to treat someone's HIV effectively. when patients developed lymphoma or other types of cancers, their curative treatment for lymphoma or other cancers wasn't even thought about because why would you give somebody very toxic chemotherapy drugs if they're just gonna die of an infection because of their HIV in the coming months anyway? Well, that's really not the case anymore. I think there's a lot of people, oncologists in particular, don't see a lot of people with HIV in their practice. They don't see what people with HIV look like, what their health actually is in the current era where you can take one pill once a day and HIV can be completely undetectable in someone's blood. And they're not really any higher risk for infection than the general population of people. I should mention that people with HIV, they face a lot of stigma in healthcare. So there's stigma against HIV itself, even in the modern era.

We have good treatment and HIV has been around now for more than 40 years. Also, we know that people with HIV tend to be from populations of people in our society who are stigmatized in healthcare in general. So minoritized patients, black patients, also patients who may not speak English, like Hispanic patients, also patients who may inject drugs who face a lot of stigma in the healthcare system. So you combine all of these things together and I think people, healthcare professionals, tend to not understand how to take care of patients like this or how to put their own biases aside to make sure that they're including these patients in clinical trials. And also there's just sort of this feeling that patients with HIV are we don't know how these drugs will affect people with HIV specifically. We don't know what the potential problems could be. Well, I would say that's true, but we're studying new agents, but we don't know how they're going to affect someone with maybe a heart problem or with diabetes or a number of other medical problems. And I think HIV really is a chronic medical problem that can easily be treated. And it should be easy to include people with HIV in the majority of trials.

Kat:Thank you for sharing that. Can you give us a brief description of the study design?

Kate Lurain: Yeah, so this study combines pomalidomide, which is a pill, along with a combination chemotherapy regimen that's standard that I mentioned earlier called EPOC, E -P -O -C -H. Each letter stands for a different chemotherapy drug plus prednisone, a steroid. And that's a standard chemotherapy regimen that combines standard drugs that we use for many different types of lymphomas.

In general, people who treat HIV -associated lymphomas, tend to use this regimen EPOC as sort of the backbone of the first line of treatment that we give our patients. It's not set in stone, but people with HIV tend to get very aggressive lymphomas, and many people will reach for a very aggressive regimen like EPOC over something like CHOP, potentially when people have advanced stage lymphoma like you see in HIV.

So we're using a standard chemotherapy regimen and EPOC is given every three weeks and it's given in a somewhat unique way, which sounds quite complicated and can be overwhelming to hear about it first, I think for some of our patients, but it's given as a continuous infusion for 96 hours, so four days. And you get sort of a drip, drip, drip of chemotherapy through an IV.

So it's an intravenous combination of drugs and it's given slowly over 96 hours for four days and you get one more chemotherapy drug, the C in the regimen, the cyclophosphamide at the end over 30 minutes through an IV at the end of that EPOC infusion. Some hospitals admit patients to the hospital to give them EPOC because you're giving continuous chemotherapy at our center at the NCI.

We're able to give this as an outpatient and many places are as well, but we give it so patients actually carry sort of like a black fanny pack sort of bag with them at all times while they're on this chemo and they come in and they get their pump and their bag set up with their chemo and it's infusing into their arm. And then they leave the hospital and 24 hours later they come back, they get their next bag changed new bag and then they leave the hospital and they come back every day just for that change of the bag until that 96 hours is done. That's given every that's on every three weeks every 21 days which we call one cycle and it's given for six total cycles. The pomalidomide pill is this pomalidomide is a drug we call it POM or P -O for short.

It's a pill that is FDA approved and has been used now for quite some time for another type of blood cancer called multiple myeloma. And pomalidomide has, it's an interesting drug. has many different things that it can do in the body and the ways it can act on the tumor. The first is that it can directly act on the tumor to kill the tumor cells. It does this by one of the most common pathways in our cells that get dysregulated in a DLBCL is a pathway called NF -kappa -B and that pathway gets turned on abnormally and allows the cells to grow. Well, pomalidomide can turn that off inside the cancer cells. The other way it works is by working on some of those bad effects of the viruses, EBV and KSHV, that I mentioned earlier. So in our lab, in our branch, Dr. Robert Yarshuin, his lab has shown that pomalidomide can reverse the negative effects of these viruses in cells in his lab. So these herpesviruses, once we're infected with them, we can never get rid of them. But most people who are infected with these viruses don't have any problem because their immune systems function normally. It's only a problem when you have an assault on your immune system like HIV that these viruses get out of control but they sit in our immune system and we can't get rid of them because they are very tricky at turning off what's going on in the cell to sort of hide for our immune cells. So normally when a cell is infected with a virus, the cell realizes it and it puts these signals or proteins on the outsides of cells to signal to our immune cells, come over here and kill me because I am infected with the virus and we should get rid of this before it spreads to another cell.

But these herpes viruses like EBV and KSHV can turn off those signals so that the immune system cannot recognize that the cell is infected and they can just sit there infected and cause potential problems when patients have and can potentially cause lymphoma. So what Dr. Yarshun has shown is that pomalidomide can reverse this process and can make it shown that these signals or these I'm infected signals on the outsides of cells. These signals are called, these proteins are called ICAM or MHC1. It can lead to sort of the upregulation or expression is what we call it scientifically on the outside of the cells. So to signal to the immune system, I am an infected cancer cell and you should attack me. The other thing that pomalidomide does is it can also activate tired or senescent cells, T cells in particular. So people with HIV, when they have chronic HIV infection or they have infection with one of these viruses like EPV or KSHV, the immune cells can get tired or senescent. And we've shown in our patients, we've published on this, that

We actually see this, that the cells in people with HIV and cancer are senescent or tired, and that pomalidomide can reverse that. So we've seen it in the lab with Dr. Yarshwin, and I've seen it in my patients, and some of our other clinical trials. So pomalidomide can work in several different ways, very long -winded answer about how it works, and why we're choosing it specifically in people who have HIV -associated lymphomas to add it to the standard regimen.

Kat: Thank you so much. And can you tell us what the goal or objective of the study is or what needs to be proven by this study?

Kate Lurain: So this is a small phase one clinical trial. So that means that we're looking for 18 patients or fewer. And our primary objective is to show the safety of this regimen of pomalidomide and EPOC. So while these are well -known drugs and have been used in lymphoma and other blood cancers, they haven't been used together before. So it's a new combination of standard drugs given together for a new type of diseases.

So all patients who have HIV -associated B -cell lymphomas of most different subtypes that occur at higher risk in people or higher frequency in people with HIV, those are the types of lymphomas that we're targeting for this study. So the primary objective is to look for safety of the combination in HIV -associated lymphomas.

And then the other things that we're gonna be looking at secondarily and in a sort of exploratory manner, we'll be looking at sort of what are the outcomes in patients? So do patients, how well does it work? What is the response rate? Is how we would refer to it in our clinical trial. We're also looking at some of, I told you that pomalidomide has immune effects. can excite T cells.

It can reverse the effects of the viruses. So we're gonna be looking at that. I think it's gonna be, you know, small studies. It's important to look at the sort of immune and research correlatives to figure out whether this would be important or something worth pursuing, you know, in a larger population of patients and see what we can learn among, you know, sort of these rare subtypes of lymphoma.

Kat: Perfect, thank you. Now I just have some feasibility questions about the study. How often are tests done for patients, whether that be blood or scans? How often is that done on the study?

Kate Lurain: So before enrolling on the study, we would do things that any oncologist would do when a patient came with a new diagnosis of lymphoma. So do we do blood tests to look at the blood counts, things like anemia, things like that, also to look at organ function, like kidney function and liver function. And then we would also do scans to look inside the body. So cat scans and also a scan called a PET scan, which is used frequently in people with lymphoma to look sort of at how active the lymphoma is in different areas of the body. We also want to make sure that the lymphoma is not involving the brain. So we do an MRI of the brain and we also look to see whether the lymphoma is involving the fluid around the brain, the cerebrospinal fluid. So we do a lumbar tap lumbar puncture or spinal tap to look at that fluid and see if lymphoma is there. We also look for a variety of different infections. So we wanna make sure that any infections that patients have, we know about them so we can treat them. We don't wanna start lymphoma treatment and not know about an infection that could get worse when we give chemotherapy. So those are sort of standard things. And then before we would start treatment, once a patient decides to enroll on the study, and we think it's a good treatment option for them, it would be safe for them. Then we do some research lab work, some of those extra sort of immune type tests I was talking about. You would have lab work to check sort of basic laboratory parameters like your blood counts and your organ function and your electrolytes or salts in your blood during the EPOC infusion at least once. And then twice a week, we would check your blood counts during that 21 day cycle to see how the chemotherapy is affecting your blood counts to see whether we need to adjust the dose for the next cycle, either up or down, depending on what your blood counts look like throughout the cycle. So that's done every cycle for six cycles. We check the blood work at least twice a week after completing that EPOC infusion. And then we do another PET scan and CT scan after two cycles to see how the treatment is working. If it looks like the treatment is working, we can continue on. If we think, look like the treatment is not working, we need to think about maybe switching treatments. That can also help us there before we get too far behind. And then we check another scan at the end of treatment. So after the six cycles of the pomalidomide plus the EPI.

Kat: How long after they finish treatment are they on follow up?

Kate Lurain: So we follow patients for up to five years on the study. So, you know, we've studied, we would happily see our patients in clinic beyond five years, but definitely for five years on the study. To start with, we see our patients once a month after completing treatment per the protocol requires us, but we obviously will see patients anytime if they still, if they need us in between them and then if everything's going great, after those three one -monthly visits, then we space visits out to every three months and then every six months after the first year.

Kat: And I'm assuming because this study is small, it's really just a local study at the moment.

Kate Lurain: So we are the only site at the National Cancer Institute for this study. However, at the NIH, we do pay for travel and we reimburse lodging. So we do have patients who come from all over the United States and occasionally the world to come for our studies.

Kat: Thank you. And what are some of the most important or the biggest inclusions and exclusions of the study?

Kate Lurain: The most important things to be included on the study are to have HIV and have an aggressive B -cell lymphoma. So diffuse large B -cell lymphoma or DLBCL, or the other subtypes are Burkitt lymphoma, plasma blastic lymphoma, or primary effusion lymphoma. Some patients with lymphoma might have heard about a performance score or ECOG performance score before.

And oftentimes clinical trials will have patients who are really sort of pretty healthy overall, other than having lymphoma and can kind of get up and go and are living close to their normal life prior to having lymphoma. So having a very low number of their ECOG, our patients can have any ECOG numbers, so any performance data. So even patients who are quite critically ill can be included in our study.

We want to make sure patients don't have involvement inside their brain by lymphoma. On this study, since we don't think this would be the best treatment for lymphoma that is inside the brain, we do allow patients to participate who have lymphoma that involves the fluid around the brain. We allow for participants who have bone marrow involvement by their lymphoma or other organ dysfunction by their lymphoma. So you don't have to have perfect kidney or liver function if the lymphoma is causing problems there since we hope that treatment will quickly reverse that. You have to have, you know, pretty stable cardiac function on the study since

Some of these drugs can affect the heart. We wanna make sure patients don't have serious cardiac issues that could cause problems if we gave them these drugs. And then patients can have infections since they do have HIV, but they can't be out of control. They have to be on some treatment for their infection. And then most importantly, should add, is that patients must be on antiretroviral therapy. There's no sort of they have to have been on antiretroviral therapy so they could start the day before if they had never been on antiretroviral therapy previously. Their HIV doesn't have to be controlled or undetectable in the blood. There's no virus level that we require, but you must take antiretroviral therapy when you start treatment. There's no CD4 T cell number cutoff. You can have any T cell number and be a participant on the study.

But those are some sort of common exclusion criteria for people when people with HIV are included on studies. Is there a T cell or HIV level cut off and we do not have that.

Kat: Perfect, thank you. Now I'll move on and ask some questions about the medications in the trial. I know you kind of already gave us a background on pomalidomide. Could you tell us a little more about all the other drugs used in there such as Rituximab and Prednisone and others?

Kate Lurain: Rituximab is a very common oncology drug. It is actually an immune therapy drug. It's not a type of chemotherapy. It's been part of the standard frontline regimen for patients who have DLBCL for a couple decades now since the 1990s. And it is a drug that's given by an IV. So it's intravenous and it is given very, very slowly during the first treatment. It's given on the first day of every cycle. And it's given very, very slowly because it's an immune or an antibody treatment. And it's an antibody treatment that comes from a rabbit. So patients can have reactions like allergic type reactions to the drug. So we give a lot of medicines before we give the rituximab to try to prevent that. And

So patients get Tylenol and Benadryl and some the prednisone before they get the rituximab to try to prevent any allergic reactions. And it's usually just an allergic reaction while the drug is being infused. It doesn't cause an allergic reaction later or in subsequent or following cycles. So it's pretty standard medicine. I think it sounds kind of scary to think you could have an allergic reaction to a medicine, but patients do really well. Nurses everywhere are really good at looking for the signs of an allergic reaction and acting and adding more medicines to treat that, Tylenol or Benadryl or steroids if patients have a reaction. And then the chemotherapy drugs are all sort of older chemotherapy drugs have been a long time in use for lymphoma. In addition to the prednisone, which is a steroid,

Steroids are given because they do several things. They deplete or get rid of our lymphocytes in our body. They lower lymphocyte levels and we know diffuse large B -cell lymphomas, those B -cells are lymphocytes. So it gets rid of some B -cells and is used to treat lymphomas very frequently. It also helps with nausea. So some of the chemotherapy drugs can cause nausea. And so the prednisone also helps with that. It's a really good drug for nausea.

And it helps with those rituximab reactions as well. The chemotherapy agents, so there's four of them. It's the E, O, C, and H in the EPOC regimen. It's etoposide, van -christine, cyclophosphamide, and doxorubicin. Don't get confused the fact that those letters don't match up with the names I just said. They're trade names versus generic names. So those drugs all work by killing dividing cells. know that lymphoma cells divide really, really quickly. And so those drugs target in different ways dividing cells to stop and kill any dividing cells in the body. So not only do they kill lymphoma cells, but they can also kill some of our normal healthy cells that divide very frequently. So cells like our hair cells, patients do lose their hair when they get Epoch. They also the cells that line our mouth and our intestines and our stomach, those cells divide a lot. And so those get damaged by the chemotherapy drugs. That's why patients can get sores in their mouth or can get diarrhea or nausea and vomiting. So those, we do a lot to try to prevent nausea and vomiting, to treat it, to treat diarrhea, to treat sores in the mouth. I think in general, the side effects of chemotherapy sound really, really scary. And it's always the first cycle of chemotherapy when it's totally new to people and to their caregivers, I think sounds really, really scary, which is why we're always there to sort of help with, you know, guiding people about, know, if you have a side effect, just let us know. There's lots of things that we can do to help you. Just let us know. There's nothing too small that you can't reach out about because everything's new.

These are really, these are powerful and potent drugs and it's important that patients know that they can reach out and ask questions when there's side effects that we can help with them. Cause there's a lot we can do for side effects from chemotherapy drugs.

Kat: And with these drugs, I know you said pomalidomide is a pill. Are all the others infusion?

Kate Lurain: They’re all given through an infusion and they have to be given through a special IV. So patients may have heard of a port before. It's a device that's placed on the chest usually that can be accessed with a needle by a nurse puncturing through the skin into the port because these drugs cannot be given through sort of what's called a peripheral vein or sort of a small vein in the arm. cannot be given through there. can affect the veins, they have to be given through bigger veins. And the way we get through the bigger veins is we place a port in the chest, or we often place what's called a pick line. So peripheral IV that is long, it goes in through the top of the arm, goes, and it's long inside the body, it goes into the bigger veins that are in the chest. So we usually do a pick line because it's easy to put in and put out ports are more permanent and require a surgery. But many places will use a port to give EPOC but it does require sort of a fancier IV than just a normal IV that you might get to have blood drawn or to be given fluids or something like that.

Kat: Thank you so much. I'm not sure if you can share on this question, especially since the study is so new, but are there any obvious trends you've seen so far?

Kate Lurain: We have enrolled five participants now, and I think that I can't divulge tons of information about the study so far. We don't have tons of information even about the study so far. But what I will say is that patients have had some good outcomes and we've had some bad outcomes. Our patients that we've enrolled on the study have had very, very aggressive lymphomas and the treatment has not worked for several of the patients. We've had one amazing success story in a patient who was quite sick at the beginning of treatment and looks like there's a complete response and treatment. But, you know, I think we have not had enough experience yet, I think, to see the biggest trends yet. So some really, really unfortunate lack of success, but some great success so far too.

Kat: Thank you. And how could you see potential results of this study changing the future of lymphoma treatment?

Kate Lurain: Since we're enrolling patients who have different types of HIV -associated lymphomas, we may see some good results in certain subtypes versus others. And there's a potential, I think, to do a bigger study in maybe certain subtypes where we see some good clinical activity that helps patients in a bigger study, maybe a multi -center study going forward in the future.

I think we'll also learn something about the immune effects of pomalidomide in HIV -associated lymphomas and see if we can sort of learn from that to sort of bring pomalidomide to either different combinations of drugs or in other, you know, on other clinical trials as well.

Kat: What are some expected challenges you expect to encounter with this study?

Kate Lurain: Well, I think we're already seeing that people with HIV are

They have aggressive lymphoma and people with HIV often are, as I mentioned before, face difficulties with getting good medical care because of stigma among medical providers and medical systems. And so we've gotten some patients on this trial and on other trials who had really aggressive lymphoma that had gone along had gotten worse because patients had put things off or hadn't wanted to participate in the medical system, didn't have the means to participate in the medical system, or once they did engage the medical system, didn't get fantastic care. So we've seen some patients where I think their lymphoma was extremely aggressive and it was very unfortunate that our treatment did not help them. I think other sort of difficulties is that it is a complicated regimen. is, EPOC is, you know, I've told you you have to come and go, you know, patients really need to put their lives on hold to get treatment. I don't know that that's particularly different from any type of lymphoma treatment, but it is complicated to be on a clinical trial and patients, it may be difficult for certain people to, you know, get transportation or to you know, find out even about our clinical trials since we are just one site. So we're always looking for physicians to refer their patients to us, but you know, we don't have an ER at the NIH, so patients can't just walk in and see us. They have to be referred either by themselves, their families and caregivers, or their, you know, their physicians.

Kat: And what is the timeline for this study? How long will it last? And do you predict more phases? And yeah, what is the timeline for it?

Kate Lurain: I think probably about five years or so. We are accruing about three participants per year. The study's been open about two years now. And so probably about five years to accrue all of the participants to the study. And then going forward after that, we follow all of the participants for at least five years. So it'll be a long time before we get the final, final, final results of the study.

I think that we will probably disseminate results by the time we've accrued all the participants, we don't have to wait five years. usually we like to sort of, I would expect we would have results in about five or six years.

Kat: Perfect, thank you so much. And I'm assuming if it went on to future phases, there would be more opportunity nationwide or even international to participate.

Kate Lurain: Yeah, I think so too. There's a consortium of people called the AIDS Malignancy Consortium. It's a group of hospitals and doctors who run clinical trials that are multi -center in the United States, as well as in certain sites on the continent of Africa and South America. And the AMC, or the AIDS Malignancy Consortium run sites specifically for people with HIV and they've done some big, you know, multi -center studies in lymphoma before and that would be potential collaboration with our colleagues there.

Kat: Thank you. had no idea about that. Now, since we have a little extra time, let's touch on your study called Pellmolidomide and Nivolumab for the treatment of virus -associated malignancies with or without HIV. If you'll just give us a brief description of the design of that study as well.

Kate Lurain: So this study was originally written to treat any virus associated cancer. So we've talked about EBV and KSHV today. There are other viruses that cause cancer. So hepatitis B and C virus, human papillomavirus or HPV. But all of these viruses, they have the same sort of immune dysregulation and sort of hide from the immune system in the same way I've described earlier.

And so that's why we're using pomalidomide again. Dr. Yarshwin showed in his lab effects on these viruses as well. then there's also, so nivolumab is an anti -PD -1 drug and this is a drug that's approved in other types of lymphomas, specifically classical Hodgkin lymphoma. And it works by activating T cells to fight cancer. So it actually works directly on the T cells instead of directly on the cancer like a chemotherapy agent, for instance. So we think this might specifically be helpful for people who have virus -associated cancers where the immune system might be tired or the virus might make the cells hidden from the immune system. We think pomelan, myon, and volemab will work together to make the cells more visible to the immune system, activate the T cells to then kill those virus -infected cancer cells.

So pomalidomide again is a pill and nivolumab is an infusion that you get through an IAB. Both drugs are approved by the Food and Drug Administration for a variety of different cancers, but they're not approved together. So that's why this is a phase one clinical trial. And we've completed the dose escalation portion of this trial. So we were doing escalating doses or increasing doses of the pomalidomide and we've completed that portion.

And now what we've done is we've expanded to two cohorts of participants. One for patients who have virus associated lymphomas. So that could include diffuse large B cell lymphoma or Burkitt lymphoma, as long as they're associated with EBV or KSHV. And to Kaposi's sarcoma, which is another type of, usually a skin cancer that's caused by KSHV. Patients can have HIV or they don't have to have HIV. So it's in the general population or in people with HIV. And this is for people who have had prior treatment of some kind for their cancer. So the last one we talked about was for patients who'd never had treatment before for their lymphoma. This is for patients where their first treatment for their lymphoma or their cancer didn't work or their lymphoma did work and then the cancer came back. And then we would, this treatment is something that they could potentially be on. So for to fuse large B -cell lymphoma, participants would be eligible if they had had a prior treatment, say with CHOP or with EPOC or another regimen like that previously.

Kat: And what is the objective of this study?

Kate Lurain: Again, it's to show safety of this combination together since they haven't been given together before. They definitely haven't been given together for these diseases. secondarily, we're looking at, again, lot of what is the response rate? How well does it work in our patients? And then we're also looking in exploratory way at some of the immune -based markers in the blood and in the tumors to see if these drugs are having the effects that we think that they might have, that we've seen in the lab and that we've seen in patients on other trials.

Kat: Thank you. What are some of the biggest inclusions and exclusions of this one?

Kate Lurain: There’s certainly more inclusion and exclusion criteria in this trial than in the one I just described. So patients here generally have to have pretty good organ function. They have to have that a pretty good performance status. So they have to be able to sort of get to clinic, walk into clinic on their own and not be sitting in a chair all of the day. That's sort of dividing line there. They have to have had the prior treatment and their tumor has to be positive for the virus. So there are people who have diffuse large B -cell lymphoma, but it's not infected with EBV. And so those patients would not, this trial would not be for them. Those are, can't have, you know, your cardiac function has to be good.

Those are sort of the, it's a little bit more stringent. There's a lot more inclusion and exclusion criteria for this trial since there's a wider variety of tumors and it's sort of a more experimental combination than the trial I just described.

Kat: What does the schedule look like while on the study and then follow up wise?

Kate Lurain: So we give treatment every, so a cycle is every four weeks. So the nivolumab, the infusinal drug is given on day one of a 28 day cycle. And we actually give it sort of up to two years. So you could get it once a month for up to two years. The pomalidomide is a pill again. It's given, so during that four weeks, it's given for the first three weeks. And then there's one week where you don't take the pomalidomide. The last week of the cycle and that's sort of to let your blood counts recover. Pomalidomide can cause some anemia, low platelets, some low neutrophils, just a type of white blood cell. So we give that week off of the pomalidomide, sort of let those blood counts recover to get ready for the next cycle.

Kat: Have you encountered any challenges with this study or expect to encounter any challenges?

Kate Lurain: I think this study has been accruing very quickly because we were accruing a wide variety of different tumors. And so now we're looking for more specific types of tumors, just lymphoma and that Kaposi's sarcoma. our accrual might be slower. So we're always looking for patients. I think the other challenge is that most patients who get these immune type therapies like nivolumab don't have side effects.

But about 20 % of patients, remember I told you that Nivolumab works by activating your T cells to attack the cancer cells. Well, in about 20 to 30 % of patients, those T cells, they get excited and activate and they attack your normal healthy tissues instead. And so we have to keep a lookout for those immune side effects that can be very, very serious if we don't catch them quickly. so, you know, and they can really attack any sort of part of the body, any organ, and so it can be a wide variety of things we're looking out for. So we have to keep in close communication with our patients to make sure they're telling us if anything is going on in between their appointments.

Kat: Thank you. And what is the timeline for this study?

Kate Lurain: This study has been open now for a few years, I think since the end of 2021. And so we are now doing our specific cohorts of patients in lymphoma and Kaposi's sarcoma. And so I expect probably for another three or four years we'll be accruing those cohorts.

Kat: Thank you so much. That is all of the questions I have today. Thank you for joining us. We're so grateful for your generosity with your time and your willingness to share your incredible expertise with us. We're excited about what's to come for you this year and we would love to have you on the show again in the future to share some more updates. Dr. Lurain, we wish you the best in your clinical practice and your research endeavors. Thank you again for coming today.

Kate Lurain: Thanks so much, Kat. I really enjoyed being here today and chatting with you. And I just want to thank all of our patients in the HIV and AIDS competency branch who really contribute to all of the research that I've discussed today, who put their faith in me and our clinical team. And I really do want to thank our clinical team, my colleague, Dr. Ramya Ramaswamy, the other physician in our group, as well as all of our research nurses and our patient care coordinators and advocates our trainees who work with us and help us take care of the patients. They take phenomenal care of all the patients who walk through our door and thank you again for inviting me today.

Kat: Of course, and thanks for listening to HealthTree Podcast for DLBCL. Join us next time to learn more about what's happening in lymphoma research and what it means for you. Once again, thank you to our sponsors, Regeneron and Bristol Myers Squibb, who made this event possible. Have a wonderful day.