Jason Westin, M.D. Hi, I'm Dr. Jason Westin, a professor in the department of

Lymphoma-Myeloma at MD Anderson Cancer Center. And today, I'm thrilled to be joined by Dr. Sairah Ahmed, who's also a professor in the department of Lymphoma-Myeloma at MD Anderson. And this is the Cancerwise Podcast. Dr. Ahmed, thanks for being here. Today, we're going to dive into why it's so important to get an accurate lymphoma diagnosis, because obviously the right treatment starts with having that diagnosis. First, for someone who's just heard the term lymphoma for the first time, what does that mean, and what are the main types people should know about?  

Sairah Ahmed, M.D. So, I think it's really hard when you get the diagnosis of cancer to try to understand all the different types. The first thing I think that we should discuss is that lymphoma is a blood cancer. And so, that is a very different type of cancer compared to, say, breast cancer or lung cancer. Because it comes from the blood, the main way that we are going to try to look for it is by biopsies, blood work and potentially a bone marrow biopsy. Oftentimes, we will talk about the type of lymphoma that it is. And one of the most common ways that people have heard about lymphomas is either Hodgkin lymphoma or non-Hodgkin lymphoma. I think some ways to think about lymphomas are what cell does it come from? Another way is how is it acting? Is it aggressive? Is it growing fast or is it slowgrowing and indolent? Because that, often, will make the determination of what are the next steps that we are going to do for that particular diagnosis?  

Jason Westin, M.D. Yeah, I think that's very important to recognize that there's lots of different types of lymphoma. And so, if someone says you have lymphoma, that's not really enough information to know what to do with that. You need the subtype. It's kind of like someone saying, "I like music." It's like, well, there's lots of different types of music. Which type do you like, classical or heavy metal? A little bit of difference in between those. And so, having that accurate diagnosis really is critical because the treatments are informed by the type of diagnosis somebody has. Could you give an example of if somebody were to get a diagnosis that was unclear about, sort of, the treatment choices that might be on the table, and perhaps somebody could get a wrong treatment if they didn't have the right diagnosis?  

Sairah Ahmed, M.D. Yeah. So, I think that today the way that we treat lymphoma is very different compared to 30 years ago. And part of that difference is targeted therapy and immunotherapy, which greatly depends on markers that sit on top of the lymphoma cell. So, if you don't have the right diagnosis with the right markers, then potentially you're either over-treating or mistreating a patient because you're not using the right drugs. A really classic example of that is Hodgkin lymphoma versus a B-cell lymphoma. So, Hodgkin lymphoma is a distinct subtype of lymphoma that is CD30 positive, and that is very exquisitely sensitive to a type of drug called a checkpoint inhibitor. And so, that type of lymphoma is often very curable, and we want to make sure that we're treating the right lymphoma at the right time with the right drugs. And so, getting that diagnosis is critical. And one of the things that we are extremely blessed to have are very expert hematopathologists. Oftentimes, when you are talking about a diagnosis, it comes down to what your pathologist is going to tell you is on that slide, what they're looking at under the microscope. And so, that's where it comes into play that someone who has seen a certain type of lymphoma 1,000 times versus someone who's seen it 10,000 times, they can nuance it a little bit differently and give us more information about that lymphoma.  

Jason Westin, M.D. I think that's so important. And that pathology part is something that patients, if they're at a center that doesn't do a lot of lymphoma, may not really know if the pathologist is that experienced, because that kind of happens behind the scenes. They see the doctor in the clinic and the doctor says, here's what the pathologist said, but the patient may not really know much about that pathologist or the experience of the center in treating that disease. And so, if you're being diagnosed with a new cancer like lymphoma and you're not at a major cancer center, it's possible that the people who are giving you that diagnosis may know a lot about the disease. It's also possible that they see this very rarely, and they may not have that expertise you just talked about to really get into the weeds for what is the specific diagnosis or what subtype of a type of lymphoma. And as you mentioned, that could be absolutely critical to get the latest therapies. If you get a generic chemotherapy, it may not matter so much if you get kind of the exact category A and then subcategory III and kind of drill down a couple of levels information-wise. But if you're moving into the more modern therapies, like you mentioned, checkpoint antibodies, targeted therapies, getting that subtype-specific information is really critical. And that's why getting a second opinion may be a good idea. What do you do if somebody has a prior diagnosis of cancer like lymphoma and they get a treatment, but then it comes back? Is there a benefit to get a repeat biopsy, or is that something that you just trust the old biopsy?  

Sairah Ahmed, M.D. Yeah. So, I think lymphoma is an interesting type of cancer because it can sometimes change. You can have an indolent lymphoma turn into a more aggressive subtype. Sometimes you can have a person have two completely different kinds of lymphoma. And so, that first biopsy was correct, but a second biopsy may show a different kind of lymphoma. But I think, again, we come back to the treatments that we are able to offer today. Many of them are targeted towards the markers sitting on top of that cell. And so, that repeat biopsy helps us home in on what is going to be the next treatment that's best for this particular kind of lymphoma that we're seeing today.  

Jason Westin, M.D. I completely agree. Getting that repeat biopsy is critical because sometimes, as you mentioned, tumors might change. And the next targeted therapy you're going to choose could go after a target that's not there anymore. And it's not going to work if the cancer cell's not making that target. So, repeat biopsies -- doesn't sound very fun if you've already had a biopsy a year ago to get another one, but it could be absolutely critical to get the right treatment on time. I know that many people who are listening to this podcast may be listening because they already have a diagnosis of lymphoma, and their doctor's talking to them about, you need to get a new treatment, the treatment you've received before it may have worked, but the cancer came back and now we're considering next treatments. Dr. Ahmed, tell us about this new breakthrough therapy, which is not new anymore. It's been around for a while called CAR T cell therapy. What is CAR T cell therapy?  

Sairah Ahmed, M.D. Yeah. So, I think, you know, a lot of people have heard about CAR T cell therapy. It is, the CAR stands for an acronym: chimeric antigen receptor. T cells are part of everyone's immune system. And so, what this particular type of treatment does is it takes someone's T cell and it manipulates it to be able to recognize CD19, which sits on top of lymphoma cells and actually normal lymphocytes as well. The CD19 CAR T's are what have been approved, but there's lots of different targets that you could potentially go after. And CAR T cell therapy has allowed us to be able to use someone's own immune system against the lymphoma quite effectively. And you've led some of the pivotal trials that have gotten these therapies approved. The really exciting thing about actually being a lymphoma and cellular therapy doctor right now is that CAR T cell therapy in the last seven years, eight years has actually changed the way that we treat lymphoma forever. And it has brought about the opportunity to cure a population of patients that otherwise would not have been cured. Cure is a four letter word in cancer. We don't like to say it because we often are worried about how accurate it's going to be. But with the kind of long term data that we have, I think that we can, you know, pretty confidently say that functionally, there are a group of people who have been cured by CAR T cell therapy who would not have had that potential opportunity before. I'll ask you, kind of, what your thoughts are in terms of how CAR T cell therapy is being utilized for lymphoma right now?  

Jason Westin, M.D. CAR T cell therapy does cure patients, but unfortunately, not enough patients get access to CAR T cell therapy. And this is because it's complicated to give a CAR T cell therapy. Giving chemotherapy or giving an antibody therapy, those are usually available at any cancer center, any oncologist office. CAR T cell therapies, because of the potential for side effects and the need for a multidisciplinary team to watch for those side effects, is only given at specialized centers, places like MD Anderson. And we've probably treated, what, 3,000 patients, something like that over the past seven years. So, 3,000 patients gives you a lot of experience versus somebody who's doing their first couple of patients. And having that institutional knowledge really allows you to anticipate problems, manage complicated things, and really have a better outcome, even for people who are quite sick. But as you asked, how is it being used right now? Unfortunately, a very small percentage of people who should get CAR T cell therapy are actually receiving it, and there's a lot of people that estimate it's something like 15% of all the people who should get CAR T cell are actually getting it. And part of that is because sometimes patients don't know about CAR T cell therapy. Their cancer comes back, the lymphoma has relapsed, and their doctor talked to them about a few different treatment options. But sometimes that's treatment options that could be given at the doctor's office, not necessarily something that could be given down the road. And so, CAR T cell therapies are a true breakthrough. As you mentioned, they are curing patients. And that's a term that we don't use lightly. That's somebody who's in remission for years after their disease that should have been potentially fatal and now has gone away. But it's really an access problem. And that's why getting referred to a comprehensive cancer center is so important. So, Dr. Ahmed, can you tell us a little bit about what side effects somebody could have with CAR T cells, and why going to a place with a lot of experience to manage those side effects could be important.  

Sairah Ahmed, M.D. Yeah. So, when we, kind of, talk about cancer treatment in general with patients, including chemotherapy or immunotherapy, one of the things that's pretty common is immune suppression. So, an increased risk of infection. And a lot of times we'll add in other medications to help prevent infection or drugs to help push up the white cell count, to decrease the time period where you're at the most risk for infection. CAR T cell therapy has all of those risks. It has a couple of additional unique side effects that we don't see necessarily with other chemotherapy drugs. So, essentially that T cell that we're putting back into a patient is a revved-up T cell. And so, it can cause the immune system to really get worked up. And one of the things that happens is you can have release of cytokines. And those cytokines have their own special side effects. So, cytokine release syndrome can have fevers, low blood pressure, sometimes low oxygenation. Another side effect is neurotoxicity. So, those same cytokines can cross the blood brain barrier and cause confusion, sometimes an increased risk of seizures. Now those sound like really big scary side effects. We've gotten exceptionally good at managing those side effects. And products have gotten better at, kind of, diminishing those really severe toxicities. But part of it is identifying the side effect. And if you're in a place that doesn't do a lot of CAR T cell therapy, then potentially that's where there's a gap, because you're not identifying that low risk toxicity and preventing it from becoming a high risk toxicity. The other part of it is, you know, when we talk about oncologists, you know, we're important, but we're not as important as our nurses, as our ER physicians, as our consulting services, because it's having that whole, kind of, umbrella of experts that helps cancer centers like MD Anderson do CAR T cell therapy and have really good outcomes. So, it's that, you know, that side effect that you have at 2:00 in the morning on a Saturday. And if you come into our emergency room, those people who are going to see you know you had CAR T cell therapy. You're confused. They're not going to do a stroke workup. They're going to make sure that you're getting treated for the side effect of the CAR T cell therapy.  

Jason Westin, M.D. Yeah, I think that's exactly right. And you need a team. If you've got a superstar quarterback, but you don't have an offensive line or wide receivers, you can't succeed in a sport like football. Same for CAR T cell, where if you have a physician that may know about side effects, but you don't have all the supporting cast of having the emergency room, or the ICU, or neurology, or infectious disease, or, as you mentioned, the bedrock, the nursing team that knows how to manage the side effects and anticipate them, it's not surprising that things could go badly and you could have a worse outcome. And so, getting a place that has a wealth of experience by treating thousands of patients, just like the next person who comes into our clinic ,and knowing what could go right or what could go wrong, and being a step ahead is critical. And so, getting that second opinion if you're suffering from relapsed lymphomas is absolutely critical to see if CAR T cell therapy might be right for you, especially at a place that has that expertise. So, as you mentioned, CAR T cells have been around for quite a while. Obviously, we're not satisfied with what we have yet. We're always trying to strive to do more. Could you tell us a little bit about some research that's ongoing for new advances in cell therapies?  

Sairah Ahmed, M.D. Yeah. So, actually I think one of the really important things is knowing that CAR T cell therapy works better the sooner you do it. And these are some of the trials that you have led and actually are leading right now, is doing CAR T cell therapy not, kind of, way down the road when you've had several different treatments, but doing it at the first time when the lymphoma comes back, leads to more people having that longterm remission and potentially doing it even before chemotherapy in the first line, right, when somebody gets newly diagnosed may also improve outcomes, or using it as a way to decrease the risk of lymphoma coming back. Those are all really exciting, kind of, clinical trials that are upcoming. But I think the other thing that we want to say is that there's a continuous strive to get better. We have one target that we know that works CD19. What are other targets that we can add to CD19 like CD20? That particular construct is now being tested in multiple clinical trials, trying to target both CD19 and CD20 at the same time. And then also looking at potentially other targets that haven't really been explored very frequently. So, at MD Anderson, Dr. Sattva Neelapu is actually looking at a novel target, CD79, to see if that will actually be the next CAR T cell to allow us to get rid of lymphoma that has come back. One of the other things at a comprehensive cancer center that does research is looking at different cells altogether. And so, MD Anderson is also exploring looking at natural killer CAR cells. Those are still in clinical trials and early phase studies. But that potentially could be another platform that would help treat lymphomas.  

Jason Westin, M.D. That's exciting to hear all these great new things coming along. And for somebody who's listening to this podcast, who's kind of considering, should they get CAR T cell therapy or not? Sometimes it can sound daunting of clinical trials with all these new things. Am I a candidate? Am I eligible? I'm a little bit older or I've got some medical problems. Is CAR T cell therapy restricted for Olympic athletes, or is this something that normal people could get?  

Sairah Ahmed, M.D. Yeah. So, that's one of the areas of my research, is actually looking at large registry studies of people who have received CAR T cell therapy to try to find how we can better identify toxicity, as well as see who is most eligible for getting this treatment.

As you said, a very low percentage of people actually have access to CAR T cell therapy. And part of that is because it's hard to get to. Part of it is because of some of the guidelines that were put around CAR T cell therapy, having to stay near a center for four weeks, not being able to drive for eight weeks. That has recently changed. The FDA has removed those guidelines. And so, you actually only have to come to a CAR T center for two weeks, and you only have to not drive for those two weeks, as long as you don't have any side effects. But I think the other part of being able to decide whether somebody is eligible for CAR T cell therapy is looking at how their organ function is, and how well they're going to be able to tolerate CAR T cell therapy. Age doesn't really matter. So, patients as old as 94 years old have received CAR T cell therapies, both here at MD Anderson as well as in other centers. That's registry data. And, you know, oftentimes when someone asks me who is eligible for CAR T cell therapy, we can give lots of different guidelines. But the analogy that I use is that even though I'm a doctor and I've done, you know, training in internal medicine and in cardiology and way back, you know, took surgery rotations, if I have a patient who's being considered for heart surgery, I'm not going to make that decision. I'm going to send that patient to a cardiothoracic surgeon who's going to do sophisticated testing to see if they are eligible for that surgery. So, my job is to make sure that they get that evaluation by an expert. And I kind of think of CAR T cell therapy the same. It is a procedure that's really complicated. And so, having a patient evaluated by a specialist is probably the best way to figure out whether they're eligible for that treatment or not.  

Jason Westin, M.D. So well said. And if you don't know about CAR T cell therapy, you may not know to ask for that referral, which is why podcasts like this raising awareness for CAR T cell are so important. But if you're diagnosed and you're watching this and you're not sure, you can always ask your doctor, what about CAR T cell therapy? And if your doctor says, "Oh, I don't know much about that", that may be a great opportunity for you to refer to get an opinion from somebody like yourself on what is the best treatment for me, and might that be CAR T cell therapy? For folks who are watching this because they are diagnosed newly with lymphoma or their lymphoma has come back, I think hopefully today's podcast will have really cemented what you should ask for in terms of having an accurate diagnosis. Are we sure about the subtype? Should I get a second opinion? And that could be both a second opinion for a biopsy as well as for a treatment recommendation. That's so important to make sure you get the right diagnosis and the right treatment, and coming to a place like MD Anderson may ensure that you get that correct diagnosis. How to advocate for that accurate diagnosis? Sometimes people may feel like they're putting on to their physician, or they're being pushy or being annoying if they ask, "Can we get a second opinion?" This happens all the time. A lot of our patients who come see us or coming for a second opinions, and often the referring physician or the original doctor is glad to get that either confirmation or fine-tuning. So, I've had patients that tell me they're relieved when we tell them that we agree with the original diagnosis, because they were worried they were going to upset their doctor back home. Doctors are people, but they're happy to get better information. And so, I don't think patients have to be fearful of going for a second opinion to hurt somebody's feelings. It's your life. You're the one who's going to get the treatments. And getting that diagnosis is absolutely critical. And then, why getting expert lymphoma care early makes a big difference. As you mentioned, getting that treatment at the right time can save you from getting a surgery or the wrong chemotherapy, and can be life-changing. So, any final thoughts?  

Sairah Ahmed, M.D. Yeah. So, I think you stated it really well. And the second opinion and having someone else take a look at the diagnosis. You know, oftentimes my patients will come to me with questions about, you know, oh my sister has breast cancer or oh my, you know, someone has lung cancer. And I tell them you don't want to talk to me. I am not the person who's an expert in those types of cancers. And so, you know, local oncologists are seeing lots of different kinds of patients. And that's incredibly hard. But particularly when you have a rare diagnosis, that's where we can be helpful, and we can give recommendations. Lots of my patients don't get treatment with me, but get treatment at home with my recommendations to their local oncologists. And just as you said, you know, it's often really nice to hear validation of what they were going to do. And sometimes, you know, you just need a little bit of help to say, this is the right path to go down and that we'll follow along with you. But the, the major, I think, thing that we want to make sure that patients realize is that particularly if you live close to us, we're a resource. We're the number one cancer center in the United States. And if you have the ability to, kind of, have access to that kind of level of care for a diagnosis of cancer, then we want to be able to facilitate that. And cancer centers are there so that people can get access to clinical trials and new drugs and breakthrough research sooner and have better outcomes. And ultimately, that's our goal. We want to make sure that we are treating cancer the best way that we can.  

Jason Westin, M.D. Well said. And I think that's so important, especially now as we've learned so much about cancer over the past few decades. And there are so many new treatments that may even be available at your local doctor's office. But getting that direction of what is the best treatment for me specifically? Sometimes we can give that recommendation of, you should not do treatment A or B, but you should treatment C. And the good news is treatment C is available in your hometown. That's wonderful. And so, getting that second opinion and that accurate diagnosis is absolutely critical. Well Dr. Ahmed, thank you so much for such an engaging conversation today. Hopefully this has been useful to the audience. Thank you to the audience for listening to the Cancerwise Podcast from MD Anderson. If you enjoyed this episode, don't forget to follow or subscribe on Apple Podcasts, Spotify, YouTube, or wherever you get your podcasts. And be sure to comment or review. For more information or to request an appointment at MD Anderson, call 1-877-632-6789 or visit MDAnderson.org.