Advances in Primary CNS Lymphoma

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 Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I'm happy to be joined again by Dr. Allison Winter, a member of the lymphoid malignancy and cellular therapy programs here at Cleveland Clinic, as well as Medical Director for VeloSano. She was most recently a guest on this podcast to discuss novel therapies for chronic lymphocytic leukemia and has also been on this podcast to talk about primary CNS lymphoma. She's here today to discuss advances in primary CNS lymphoma and give us some updates, so welcome.

Allison Winter, MD: Thanks for having me back.

Dale Shepard, MD, PhD: Absolutely. Give us a little bit of an idea again, what you do here at Cleveland Clinic.

Allison Winter, MD: Yeah, of course. I am a lymphoid malignancy specialist as well as cellular therapy specialist, which means I treat all things in terms of cancer of the lymphocyte, so that includes some chronic leukemias like CLL and hairy cell leukemia, as well as non-Hodgkin lymphomas. And then in terms of cellular therapy, that includes both bone marrow transplants and CAR T cell therapies.

Dale Shepard, MD, PhD: All right. A lot of different people with different backgrounds might be listening in, so we're going to talk about primary CNS lymphoma. Give us a little bit of an idea of what that is, how common it is, something people might not be as familiar with.

Allison Winter, MD: Primary CNS lymphoma is not very common. When we think about primary CNS lymphoma, it's important to distinguish it from another type of CNS lymphoma called secondary CNS lymphoma. And when we use the word primary CNS lymphoma, that's when we have a lymphoma that is limited to the central nervous system only. That includes brain parenchyma, the meninges, the spinal cord, the CSF fluid, and even the vitriol retinal space, so they do not have any lymphoma outside of that space, nothing in terms of systemic disease. I also see a lot of CNS lymphoma that would be categorized as secondary. This can be at time of diagnosis, people can have both CNS lymphoma as well as systemic lymphoma or this can happen in the relapse setting, people can relapse into the central nervous system.

And so that's how we distinguish. Now, it's very different from the way we talk about lymphoma usually, so if you talk to lymphoma doctors we're usually categorizing based on histology, so we use words like diffuse large B-cell lymphoma, mantle cell lymphoma. That's how we typically categorize. This is actually the only entity that we categorize based on location. And so the last thing I would point out is most primary CNS lymphoma is of the diffuse large B-cell lymphoma histology probably about 90%, but again, it really means just limited to that central nervous system location.

Dale Shepard, MD, PhD: Before we think about treating it, we have to diagnose it, so if you think about most systemic lymphomas, you develop something in the brain and you can think, well, okay, it's spread to the brain. This is something that starts in the brain, so what are the challenges to getting a good diagnosis of a primary CNS lymphoma?

Allison Winter, MD: The challenge of diagnosis is recognizing it on imaging that it could be a lymphoma. It's not uncommon that patients are misdiagnosed. I've seen things like multiple sclerosis or other demyelinating diseases as the diagnosis people are thinking, so really the standard of care is to do a brain biopsy. And again, it can often be misdiagnosed because I've seen patients be given steroids or things like rituximab. And so symptoms get better for a time if that misdiagnosis is made and then eventually progress, so the challenge is A, to recognize it as a possibility and to have a neurosurgeon who can do a brain biopsy because that is the standard of care diagnostic modality.

Dale Shepard, MD, PhD: When we think about historically, how have we treated these in the past?

Allison Winter, MD: Historically, treatment has been a little bit static in terms of the gold standard, so high dose methotrexate has been a long time gold standard for these patients. Now, what has not been static is what we combine with high dose methotrexate and then part B of treatment, which is consolidation. The way I talk about treatment is there's a part one and a part two, so part one is induction chemotherapy, and that's where your gold standard high dose methotrexate comes in for most patients. And then part B is consolidation, which ranges from things like whole brain radiation to just typical what I would call non-myeloablative chemotherapy, which is a big long word that means not high dose chemotherapy because when I use the word high dose chemotherapy, I mean high dose chemotherapy followed by an autologous stem cell transplant or stem cell rescue.

Dale Shepard, MD, PhD: Are there particular factors that play into how you go down a treatment path in terms of size of the tumor, histology of the tumor? You talked about this being more location-based instead of histology like we typically think or things like age and comorbidities. What are the factors that play into it, from the beginning and how you think about how you're going to manage this?

Allison Winter, MD: From the beginning, again, we still need to have a brain biopsy to confirm the histologic diagnosis because there are a small percentage of primary CNS lymphoma cases that are not diffuse large B-cell lymphoma. And if they are not, they're often a more indolent or a low-grade lymphoma. Like for instance, marginal zone lymphoma is another one that I will see and I manage completely differently, so establishing the histologic diagnosis and establishing that it truly is primary CNS lymphoma and not CNS lymphoma with systemic disease because that will automatically change the treatment paradigm. And then of course the performance status of the patient, what can the patient tolerate, is key. And when I talk about that, there's two distinguishing terms that I use. Performance status is how the patient is performing in areas of daily living. Are they able to walk? Are they able to get off the couch, can they drive, can they cook versus frailty?

Frailty is something I talk about in my older patients with lymphoma, and that's incredibly pertinent to primary CNS lymphoma because one of the risk factors of developing primary CNS lymphoma is just increasing age. And so a lot of patients are older. Now, frailty is something I can't change. If someone is what I would call frail at baseline, I'm not going to change that with treatment. Whereas performance status, this is something that is often due to the lymphoma and if I treat the lymphoma, I can improve it. Those are two different things that I use a lot of questioning of the patient and family member to see if I can determine the difference. Because if I think the performance status is poor from lymphoma, then I'm going to be more aggressive with my treatment because I think I can get that better versus the latter where I need to be maybe more gentle because I don't want to hurt the patient.

Dale Shepard, MD, PhD: Certainly as we've already discussed, there's an expertise on your part in terms of how to assess patients and what the therapy options are, need for brain biopsies, need to be able to administer things like high dose methotrexate. As you think about where these patients are and should be treated, are patients with this particular subset of lymphoma really need to come to a place that specializes in this disease?

Allison Winter, MD: This is an entity where I would say, yes, patients really need to come to a special center because it is so complicated. High dose methotrexate is not an easy regimen to give, which it's interesting because patients actually tolerate it really well if it's done right. When I compare it to my other chemotherapies, it doesn't cause that much myelosuppression, it doesn't cause hair loss or at least significant completely no hair, hair loss. I don't need a growth factor, so it's actually gentle in that regards, but the ability to give it safely is key, so you really need a center that is confident at the protocol to give methotrexate, which is an inpatient admission, a continuous sodium bicarb drip and checking of methotrexate levels.

You also need the specialty of a center like ours because if the methotrexate doesn't go well there is no standard second line regimen or relapsed regimen. And so how to choose the next line of therapy can be a challenge if you're not familiar with what is out there. Third, there's that consolidation piece. And so for older patients versus younger patients, it's going to be much different, but both are really probably better at again, a specialized center, whether that's transplant or maybe even a clinical trial because that's another area where we're seeing clinical trials starting to help revolutionize and improve the care of these patients.

Dale Shepard, MD, PhD: When we talked the last time we talked about transplants and so maybe give us a little bit of an update on where we are in terms of understanding the role of transplants and then what further therapies you're excited about.

Allison Winter, MD: When I came on to talk about transplants, that was shortly after I think I started as staff and we had increasing data to support the role of transplant in the consolidation phase. And at that time we had just started our transplant program for primary CNS lymphoma. And so I can say in that time we have certainly transplanted a number of patients and I can say that there is a firm role for transplant for those who are eligible, and that's the key word. For those who are not eligible for a transplant, what other options do we have? For instance, at our institution, my colleague, Dr. Peereboom, has been leading a clinical trial that is using a BTK inhibitor called Tirabrutinib, which is hopefully trying to improve both induction because the Tirabrutinib is combined with the induction chemotherapy. But also it could be a good option, I've done it for a couple of my patients who I don't think are a transplant candidate because there's also a maintenance phase, so after they complete induction therapy, if they can't get a transplant, at least on this study they can have Tirabrutinibs.

The other thing that I'm hopeful for is looking at diffuse large B-cell lymphoma. We use CAR T-cell therapy quite frequently, and one of the that we have done for older patients with diffuse large B-cell lymphoma, typically older, there's of course other reasons that can't be eligible for a transplant is utilized data from a trial called the Pilot trial, which used one of our products known as Liso-Cel, a CAR T cell product instead of transplant. And so there is a sponsored study that we're hoping to get open here very soon that will fill that gap in the treatment paradigm of patients who go through induction chemotherapy but aren't eligible for consolidation transplant that they could be eligible for this study, which is again, Liso-Cel or CAR T consolidation therapy.

Dale Shepard, MD, PhD: And so that's something maybe if you could elaborate on, because I think people that don't typically use these, either transplants of course or either CAR T's, what are some of the things that might make people able to tolerate or eligible for a CAR T therapy but not necessarily a transplant? Maybe just give us an overview because those are both potentially scary things for people who don't use them.

Allison Winter, MD: Exactly. Transplant eligibility, so one thing that drives me a little bit crazy in the primary CNS literature is they'll say age over 70 you can't get a transplant, which is not necessarily true. But I would say you do get to a certain age where you don't transplant, so someone 78, 79 or early eighties, you are getting to a level where we feel uncomfortable, but if you're not a fit 71, 72-year-old, of course you're not going to be eligible for a transplant. There's other things like renal function, cardiac function, lung function where we have stricter cutoffs for eligibility for transplant. Transplant is really a high dose chemotherapy, that's the purpose of an autologous transplant is to get any weeds, I call them with the high dose chemotherapy. It's tough. You're in the hospital for three weeks, blood counts go close to zero, and so there are plenty of people who are older or have comorbidities or maybe not quite the performance status to be eligible for a transplant.

Now, I think when CAR T was first coming out, we equated transplant eligibility to CAR T eligibility, but over the years as we've become more experienced with CAR T cell therapy, both in terms of managing the toxicity as well as having multiple products to choose from, we've learned that that is not true. There are, for instance, eighty-year-olds that I have given a type of CAR T called Liso-Cel two that I could not transplant. And so those patients were too old or they had comorbidities that would be really, really hard to transplant, it just wasn't going to be safe. But with Liso-Cel, which we're actually doing as an outpatient now at Cleveland Clinic in many locations across the country is not without side effects or logistics, but certainly much less toxic than a transplant. I think the message I want to get out there for all diffuse large B-cell lymphoma, not just primary CNS lymphoma, is that transplant eligibility and CAR T eligibility are not the same thing, and it's always better just to refer even if you're unsure.

Dale Shepard, MD, PhD: And age isn't a hard cutoff?

Allison Winter, MD: Age is not a hard cutoff. I have given CAR T to... I think my oldest CAR T to date was 86, but again, there are some nuances of which product you choose because there's not just one product for large B-cell lymphoma at this point.

Dale Shepard, MD, PhD: When we think about particularly primary CNS lymphoma, are there particular toxicities either short or long-term that you're most concerned about when you approach therapy?

Allison Winter, MD: That's a great question. Whole brain radiotherapy had an important place in primary CNS lymphoma for a long time, but I know myself and others have recognized the long-term neurocognitive side effects of whole brain radiotherapy, which is why the questions of what alternative consolidations can we consider to avoid those long-term effects have been raised in the first place. And so certainly there's been a trial that says transplant is as efficacious as whole brain radiotherapy, but has less of those long-term neurocognitive side effects. Now, CAR T-cell therapy, this was originally excluded from all diffuse large B-cell lymphoma trials because one of the main toxicities that we worry about with CAR T-cell therapy is something called ICANS or neurotoxicity. And so there was a great concern that if patients had CNS lymphoma their risk for neurotoxicity would be higher. There have been a shift in that thought process because they have since been included in trials. Although limited numbers, it does not seem as though there is increased risk of neurotoxicity in these patients.

Dale Shepard, MD, PhD: This is a type of lymphoma that you've mentioned a couple of times. It's really defined by being limited to the brain. If people have a patient that's diagnosed with a primary CNS lymphoma, there are neuro-oncologists that treat things in the brain as a location and people like yourself who treat lymphomas, how's the split in terms of who should see who?

Allison Winter, MD: That is a great question, and I'm not sure I know the answer. I was asking these types of questions when I was coming out of fellowship and answer is it seems to be institution dependent. In my opinion, I really think there's a role for collaboration of both specialties as we move forward, because of course, my neuro-oncology colleagues have been extremely helpful to me and I'm hoping to provide help and expertise to them. For things like CAR-T, which I've already been doing as a lymphoma specialist for many years.

Dale Shepard, MD, PhD: What are the things moving forward that excite you most in terms of either diagnosis or induction or consolidation? What's going to raise to a new plateau of care?

Allison Winter, MD: I'm most excited by the fact that there are clinical trials happening for these patients and clinical trials that are trying to move past standard chemotherapy with novel agents. I think we have some preliminary information on novel therapies of the past, like a ibrutinib or lenalidomide, but to really make any sort of difference we know that there really needs to be a combination therapy. At least that's my thought process. That's pretty true of any relapsed refracted diffuse large B-cell lymphoma that a single agent is not going to cut it. And then I think including patients with CNS lymphoma on studies like CAR-T cell studies and dedicating studies to just this population will be extremely helpful, so I'm just excited about anything novel, CAR-T novel agents to advance the field.

Dale Shepard, MD, PhD: Not a common tumor, but you're doing great work and appreciate you joining us today with some good insights.

Allison Winter, MD: Thank you very much. And I'm always happy to take a phone call from anyone from anywhere because this is a really big passion of mine, and I think increasing awareness that there are options for these patients is extremely important.

Dale Shepard, MD, PhD: Thank you.

Allison Winter, MD: Thank you.

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