Central Nervous System (CNS) Lymphoma Transplant Program

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 here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined by Dr. Allison Winter, a member of the lymphoma and bone marrow transplant groups here at Cleveland Clinic. She is here today to talk to us about stem cell transplants for patients with primary CNS lymphoma. So welcome, Allison, maybe you could start by telling us a little bit about your role here at Cleveland Clinic?

Allison Winter, MD: Thanks for having me, Dr. Shephard. So my role here at Cleveland Clinic is primarily in the lymphoma group, but since we do several transplants for our lymphoma patients, I'm also a member of the bone marrow transplant group, which includes CAR T-cell immunotherapy, which is a pretty hot topic as well in lymphoma.

Dale Shepard, MD, PhD: Okay. Well, great. So maybe to start off, we have a diverse group that may be listening in, tell us what is central nervous system or CNS lymphoma?

Allison Winter, MD: Yeah. So when you're talking about CNS lymphoma, there's two things that you want to separate. So there's primary central nervous system lymphoma, which means it's lymphoma that's exclusive to the brain, spinal cord, leptomeninges and eyes, and has no systemic involvement. Sometimes though when you're talking about CNS lymphoma, it can be either synchronous with systemic lymphoma, or people who have systemic lymphoma can relapse into the central nervous system.

Dale Shepard, MD, PhD: When we think about treatments, there's a designation based on where the tumor is located. What's the impact on treatment choices?

Allison Winter, MD: So there's actually a pretty big impact on treatment choices. Primary central nervous system lymphoma is really a separate entity. And so how you approach that is going to be different than if you approach someone with systemic and synchronous CNS lymphoma, because you're going to want to focus on treatment for both areas. So if it's primary central nervous system lymphoma, you're worried about drugs that get into the central nervous system lymphoma, but you don't have to worry about lymphoma in the liver or lymph nodes or other locations. Whereas if it's synchronous CNS lymphoma, you need a regimen that's going to address both the central nervous system as well as the systemic disease.

Dale Shepard, MD, PhD: So how did you get interested in STEM cell transplants for CNS lymphoma?

Allison Winter, MD: Well, as training to be a lymphoma doctor, I had been in multiple clinics with autologous STEM cell transplants because we use that a lot for our systemic lymphoma patients. Here at Cleveland Clinic a lot of the primary central nervous system lymphoma is treated them the neuro oncology group. So I was in clinic with Dr. Kalaycio, who is a obviously well-known transplanter, and we had a consult for an autologous transplant in a patient with primary CNS lymphoma. And that's when I started asking questions about, "How often do we do this? Is there data for this? Are other centers doing this?" And started learning more about this process and this opportunity.

Dale Shepard, MD, PhD: And so where are we? You're putting together a CNS lymphoma transplant program, but tell me a little bit about that, where you are and what the goals are?

Allison Winter, MD: So there's increasing evidence to support the use of consolidative autologous STEM cell transplant for patients with primary CNS lymphoma. And so I think what I'm trying to do is create a multidisciplinary approach with our lymphoma doctors, neuro oncologists, and transplant program to offer this treatment modality to patients where it makes sense. And then that includes looking at various components of transplant. So when we think about autologous STEM cell transplant, the most important component is the high dose chemotherapy which comes before the infusion of the autologous STEM cells.

So in systemic lymphoma, the standard in most places of the country is a regimen called BEAM. But the CNS penetration of BEAM is probably not good enough if we're talking about primary central nervous system lymphoma. So one of the things that we have talked about as a group is which preparative regimen or high-dose chemo regimen we want to use for these patients. And that's a very important point. So not just collaboration, but also nuances of what drugs we're choosing when we're doing the transplant.

Dale Shepard, MD, PhD: And are these being tested in a trial setting or are you to the point where you're setting up research protocols?

Allison Winter, MD: There's no one trial that has said this preparative regimen is better than the rest. We can look at what's been published, but there's no comparison. There's no randomized comparison. So that's one of the limitations in this field is that we don't have a lot of big randomized studies. Most of the things that have been published to date are retrospective or are phase two studies. Now one of the big ones that we're looking to have results for, that we're all anxiously awaiting, is a CALGB study, which is actually randomizing patients to transplant, consolidate of autotransplant versus consolidative chemotherapy, in primary central nervous system lymphoma. So I think one of the big pushes in primary central nervous system lymphoma is to get people into trials so we can answer these questions in a more systematic approach.

Dale Shepard, MD, PhD: I'm going to guess that trial's been around a while if it's a CALGB trial.

Allison Winter, MD: Yeah. It's been around a while, but we just are still awaiting results. But like I said, there's growing evidence from non-randomized trials supporting the use of consolidative auto transplant. Nut there's a lot of other exciting research going on. So since I was first and foremost a lymphoma doctor and in the transplant program I obviously have a lot of interest in CAR T-cell, but patients with primary central nervous system lymphoma or even secondary CNS lymphoma were originally excluded from the CAR T-cell trials.

There's been some case reports and retrospective studies now looking at CAR T-cell for people who have relapsed secondary central nervous system lymphoma. And there are now clinical trials looking at CAR T-cell and primary central nervous system lymphoma. So I think that's some of the exciting stuff that's ahead of us.

Dale Shepard, MD, PhD: Was the limitation in the trials with CAR T-cells initially, was it concerned about neurotoxicity, or was it about penetration?

Allison Winter, MD: Neuro toxicity was one of the major concerns. There was a New England Journal of Medicine publication looking at one of the CAR T-cell products, Kymriah, in patients with secondary CNS lymphoma. And they did not see increased rates of neurotoxicity. I mean, take that for what it's worth. It's a case series of a handful of patients, but we're now approaching more systematic trials. For instance, Axi-cel is now in clinical trial for primary central nervous system lymphoma. And Axi-cel was the first product that was approved for diffuse large B-cell lymphoma systemically.

Dale Shepard, MD, PhD: Let I guess, as we've been talking about this, maybe for perspective, how many patients are we talking about? So primary CNS lymphoma, how many patients a year roughly? Sounds like probably a handful.

Allison Winter, MD: Yeah. So it's definitely a rare component of diffuse large B, it's usually diffused large B cell lymphoma when we're talking about primary central nervous system lymphoma, but it's definitely a much rarer than diffuse large B cell lymphoma as a whole. I don't know how many patients we see a year. That's a good question.

Dale Shepard, MD, PhD: But just in general, as an entity, it sounds like that might be a barrier to some of the trials being finished, is how many patients there are to put in the trials.

Allison Winter, MD: Yeah, that's definitely a barrier.

Dale Shepard, MD, PhD: Now you mentioned at the beginning that at least here at Cleveland Clinic, we're oftentimes seen by the neuro onc folks. Is that kind of a trend around the country that the primary lymphoma doctors aren't the ones seeing them? Or is this kind of a barrier to maybe making this work?

Allison Winter, MD: So it's institutional dependent. At some places, the lymphoma docs are the ones taking care of primary CNS lymphoma. Here at Cleveland Clinic, neuro oncology has taken care of a lot of these patients. But I think it makes sense to get lymphoma docs involved, especially when we're talking about future trials with drugs that we're very familiar with. So CAR T-cells I'm very familiar with, and then there's this new regimen called TEDDI-R, which is incorporating Ibrutinib, which is a novel therapy that I use all the time in CLL and mantle cell lymphoma, incorporating that into primary central nervous system lymphoma. So I think it makes sense to get the lymphoma docs involved.

Not that I want to like steal all the patients or anything, but I think collaboration makes sense too, because there are some nuances of having lymphoma in the central nervous system that I sometimes need help from the neuro oncologists, because it's obviously different than what I'm used to. So I think collaboration makes sense.

Dale Shepard, MD, PhD: Is there a particular patient profile that seems to make most sense for this kind of therapy? So oftentimes we think about newer therapies. You're like, "Well, who's going to benefit most?" Is this kind of all comers with primary CNS lymphoma? Or can you sort out sort of who's the most likely to benefit?

Allison Winter, MD: The most likely people to benefit are going to be the patients who have chemosensitive disease. So going into an auto transplant, we typically in all realms of lymphoma take people who have either a complete remission or a partial remission to induction therapy. And it's definitely going to be more beneficial for probably younger patients who can tolerate a STEM cell transplant. I hesitate to use the word younger, because age is a number, and performance status really goes a long way. So I transplant plenty of people with just good old-fashioned systemic diffuse large B-cell lymphoma in their 70s. So really I hate to say age, but a good performance status in being a transplant candidate is obviously very important, but I wouldn't necessarily discriminate on age alone.

Dale Shepard, MD, PhD: All right. How do we work on getting the word out? So are you working through educational programs, support groups? This sounds like an interesting new therapy, but given the small numbers, it's a matter of getting people here to get the therapy. So how do we spread the word?

Allison Winter, MD: I think the first part is education. So I was a third year fellow, ready to take a job as a lymphoma doc and I didn't really know the data very well for consolidative transplant for primary central nervous system lymphoma. So I want to get the word out that this is an option for some patients. And I would love to have referrals and talk to patients about this. It's the same case with say, mantle cell lymphoma, which is a rare lymphoma that we use consolidated auto transplant for. If we don't get the referrals, we can't offer the patients that therapy.

Dale Shepard, MD, PhD: Are there support groups, Facebook groups, something that sort of helps in terms of patient education?

Allison Winter, MD: That's a really good question. I know for my CLL patients, they often hear about all kinds of things, including even clinical trials in their Facebook groups. I don't know of any primary CNS lymphoma Facebook groups, but maybe we should start one.

Dale Shepard, MD, PhD: Well, yeah.

Allison Winter, MD: My first goal this year has been to look at which conditioning regimen should we choose? Who should we being referral? Now that we're up and running, you're right, we need to get the word out.

Dale Shepard, MD, PhD: So you mentioned a couple of times here about conditioning regimens being something that needs sorted out. What other gaps do you see? Where does the research need to point to make this an optimal therapy?

Allison Winter, MD: To make it an optimal therapy, you first have to get people in a good remission before you do the consolidative auto transplant. Some of the research coming out is looking at induction regimens to be honest. So we used to use rituximab and methotrexate, but now it's really a poly chemotherapy that we're using. Some of the common ones have been MPV. So methotrexate with procarbazine and vincristine. Not too long ago results about the matrix trial, which is incorporating thiotepa into your poly chemotherapy backbone, have come out. And now, even as I mentioned previously, the TEDDI-R regimen. So the preliminary data for the TEDDI-R regimen is very interesting. And I think we're all waiting anxiously the results of that. So that's one that's incorporating CNS penetrating drugs like temozolomide, traditional chemotherapies, etoposide, doxil, dexamethazone, but with this ibrutinib novel therapy.

So we're anxiously awaiting those induction studies because you need to get people into remission before you can consolidate them with a transplant.

Dale Shepard, MD, PhD: So as a solid tumor oncologists, I have not participated in any way, shape or form with transplants for a while. Is there anything about the transplant itself, like the cells, the number of cells, or anything about that transplant itself that is unique because of the blood-brain barrier, the need to get into a space that you don't ordinarily think about.

Allison Winter, MD: There's nothing unique about the autologous STEM cells. So when I talk to my patients, I explain that what we're really trying to do is give you high doses of chemo. High doses of chemo that can penetrate the blood-brain barrier, and having high doses is helpful for that. And it would just be too toxic on your bone marrow. So the autologous STEM cells, sometimes people call it an autologous STEM cell rescue, because you're rescuing your bone marrow from the toxicity of the high doses of chemo.

So the important part is that conditioning, preparative, high dose chemo regimen that I keep talking about. The STEM cells are to rescue from the toxicity. And that's kind of how I explain it.

Dale Shepard, MD, PhD: Looking forward, where do you see this going? Different settings of patients, or what do you think is the future for this?

Allison Winter, MD: So there's things that we can do better. Like I said, having induction regimens with better efficacy, we're also looking at chemo mobilization strategies. So when you come into a transplant we obviously have to mobilize your STEM cells so that we can collect them. In systemic lymphoma if you're not in a complete remission, we often do chemo priming or chemo mobilization with etoposide here at Cleveland Clinic. That didn't really make sense for the CNS lymphoma patients, and there's been some data published about using cytarabine chemo mobilization at Dana-Farber. So looking at other strategies to just make it successful induction, chemo mobilization, the preparative regimen, maybe there's a maintenance strategy that we could consider in the future, but not just one component, but all of them.

Dale Shepard, MD, PhD: Certainly bone marrow transplants, lymphoma, all cancer in general, but particularly transplants need a lot of support. I mean, you need a lot of sort of team players on a multidisciplinary way. Is there anything that seems to be unique with these patients in terms of the support required?

Allison Winter, MD: So I'm lucky to be part of the bone marrow transplant. It's a well-oiled machine, I would say. We have great nurses, social workers, schedulers, and they are really good about being a team, and making sure they get people through the transplant process. So I've thrown them a few curve balls because a lot of our things are very protocolized. And when I was hired and started saying, "Well, let's do chemo mobilization with cytarabine, and let's use thiotepa." We've never used thiotepa in our conditioning regimens. And there's some different protocols you have to use with thiotepa when you're giving it that are much different. So I'm throwing some curve balls, but the team has been great. Everyone's made changes, and we're just trying to improve it for future people.

Dale Shepard, MD, PhD: Any words of advice to people who might be listening and thinking about setting up a program?

Allison Winter, MD: Words of advice. I would say collaboration is very important. I don't hesitate to ask my colleagues in neuro-oncology for help. I don't hesitate to ask my department of transplant chair for help. I think teamwork and collaboration are the most important part.

Dale Shepard, MD, PhD: Excellent. Well, you've provided some great insight today and some novel therapies that we're developing. So any additional comments?

Allison Winter, MD: I'm very interested in CNS lymphoma, not just primary central nervous system lymphoma, but when it's synchronous CNS lymphoma or relapse into the central nervous system. I think there's opportunities to improve outcomes from these patients.

Dale Shepard, MD, PhD: Excellent. Well, thank you very much for being with us today.

Allison Winter, MD: Thank you for having me.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, ClevelandClinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget you can access real-time updates from Cleveland Clinics Cancer Center experts on our Consult QD website at consultq.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.