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Advances in Treating Diffuse Large B-Cell Lymphoma

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Published on April 29, 2020

Key Takeaways

“Oncologists are always a little shy to use the cure word, but that's what it seems like for some of these patients. They've basically taken what we called an incurable disease, and for a significant proportion of patients it seems like they may be cured now,” says Dr. Joshua Brody, Director of the Lymphoma Immunotherapy Program at Mount Sinai School of Medicine, discussing recent advances in treating diffuse large B-cell lymphoma.
 
Dr. Brody explains how CAR T-cell therapy works, discusses recent FDA approvals and shares the latest treatment news. Watch now to learn from a lymphoma expert.

This program is sponsored by Karyopharm Therapeutics. This organization has no editorial control, and Patient Power is solely responsible for program content.

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Transcript | Advances in Treating Diffuse Large B-Cell Lymphoma

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:
Hello, Andrew Schorr with Patient Power, and joining me to talk about diffuse large B-cell lymphoma and the changing landscape for the people who are affected by that is Dr. Joshua Brody from the Mount Sinai School of Medicine in New York City where he is the director of the Lymphoma Immunotherapy Program. Dr. Brody, welcome back to Patient Power.

Dr. Brody:
Andrew, thank you very much for having me. I appreciate it.

Andrew Schorr:
Dr. Brody, first of all, within lymphomas, could you help us understand where diffuse large B-cell lymphoma fits in, how many people maybe or among all the different types of lymphoma, and then we'll talk about what's changing.

Dr. Brody:
Sure, absolutely. They told me right before the interview, don't use too many numbers, because people will fall asleep. I'll only give you a few numbers. So, lymphoma each year in America are about 80,000 plus new diagnoses and so a lot of those, 25,000 of those, are new diagnoses of diffuse large B-cell lymphoma. And the punchline is both good news and bad news. The good news is, of those 25,000 we probably cure with standard therapy 16,000, a little bit more, but that still leaves 8,000 or 9,000 that are incurable with standard therapies, 2020 therapies. But we have a real reason to think that the numbers will be better with 2021, 2022 therapies in the near future.

Andrew Schorr:
Okay. Now there've been lots of changes. So, for instance, there've been approved therapies for sort of a big gun, chimeric antigen receptor T-cell therapy, and I think the prospect of also maybe some oral therapies or combinations of medicines approved or experimental that are helping maybe more people, right?

Dr. Brody:
Sure. Absolutely. So yeah, we can do it in sort of the way you said. You eloquently said a mouthful—chimeric antigen receptor T cells. We just say CAR-T cells, chimeric antigen receptor, CAR-T cells. FDA approved now two different versions for DLBCL, diffuse large B-cell lymphoma, and a third one probably is going to be approved later this year. And that's a very big deal. All of these new approvals we talk about are usually approved for patients for whom standard therapies have failed. So we sometimes call those second- or third- or later-line therapies, usually third-line therapies. But all of these things that have been promising or proven to be effective, we eventually try to move some of them up into second-line and even to first-line therapy. So we can talk about the third-line advances and which of those we'll be able to try to get into earlier lines of therapy.

Andrew Schorr:
Okay. But these are big guns, if you will. Definitely immunotherapy, a lot to manage in the hospital, right? So do you feel that that is offering also the chance of a cure or a longer life for people where the more standard therapies haven't worked?

Dr. Brody:
Sure. Absolutely. So let's do this CAR-T cell one first. And this is one type of immunotherapy. And I got to tell you, Andrew, when I, when I describe this therapy to my family members, I have a grandma still who's not a young woman. I won't reveal any secrets. But I used to discuss some of these, and sometimes she would even come to these meetings if I would give a talk ,and she would take notes, although she doesn't have any formal training. And when I describe these therapies to my family members, they cannot believe it is real. It sounds like science fiction, it sounds like Star Trek therapy, but they are real, so when I described this CAR T-cell therapy, you're going to have to take my word on it.

This concept is that we take out a person's immune cells, just some of them. It doesn't actually make a big difference in what they're missing. We take out a few of their immune cells, specifically these things called T cells. These are some of the important soldiers of the immune system. We take out a few of their T cells. It's a fairly simple process, just like a long blood draw. We call it pheresis. And then into their own T cells, their own immune cells, we put a new gene, and this is a gene that does a couple of things, but the first thing that the gene does is recognize lymphoma cells, because it has actually got the genes for an antibody built into this we call it chimeric gene. This chimera, this chimeric gene has sort of five genes built into it. Two of the genes help it to recognize lymphoma cells and the other genes help it to send the signal to activate that T cell that it's now in.

So the punchline is we take the T cells out, we put this CAR gene into them and now it is a CAR-T cell, and then we reinfuse those CAR-T cells back into the person. The process is pretty complicated. It is, we say, personalized, individualized. We have to make a new product for every person, at least with the current technology. In the future, we're working on having sort of an off-the-shelf CAR-T cell, but that's a ways away, and we'll see if it's even as good as what we already have today.

But when we reinfuse these CAR-T cells back into the patient, I don't want to undersell what a big deal this is, because there can be side effects of that, and we can discuss it. But the good effects are that just as you hinted, we think this might cure a significant proportion of patients, probably not half but maybe a third or a little more might be cured. That's our estimation, because it seems like a third of patients have long remissions, and their lymphoma has not recurred even one and two years later. So it seems like they may be cured. And again the oncologists are always a little shy to use the cure word, but that's what it seems like for some of these patients. They've basically taken what we called an incurable disease, and for a significant proportion of patients it seems like they may be cured now.

Andrew Schorr:
Okay. So let me back up for just a minute, Dr. Brody. So that's immunotherapy we're talking about. You said many patients have been cured with even standard therapy you've had. So what has that been? Just so we understand for most people, what might they receive?

Dr. Brody:
Yeah, so the frontline therapy for DLBCL—and we're lucky, because it's been tested now many times and for many years. So it seems to be, at least today, the most effective and safest option is usually we call it chemoimmunotherapy, so it's part chemotherapy, part immunotherapy. The immunotherapy part is a standard medicine called rituximab (Rituxan), which you've heard about in the context of every type of non-Hodgkin's lymphoma just about every B-cell non-Hodgkin's lymphoma we use rituximab there.  So it's a combination of rituximab and chemotherapy. The chemotherapy is usually one called CHOP. So R, rituximab, CHOP. 

R-CHOP probably cures 50, 55 percent of patients with DLBCL. And then if it's not effective enough, we do have some second-line types of chemotherapy which can still be effective.

Andrew Schorr:
Okay, so you have those approaches, CAR T now approved and more coming. Maybe off-the-shelf CAR T that's maybe less expensive and simpler to be effective. And what about new therapies that are being tested, including oral therapies that could play a role? One I wanted to ask you about was a new class of medicine called selinexor (Xpovio), but I know there may be others as well.

Dr. Brody:
Sure. So yeah, these are great questions. You mentioned the CAR-T cells hopefully becoming more accessible and easier. In fact, that is probably a big advance that will happen this year, this third type of CAR-T cell that'll be FDA-approved this year. One thing that's exciting about it is it seems to be a bit safer and simpler to use than the ones we already have approved, so we may be able to use it as outpatient therapy. The current CAR-T cells, pretty much inpatient. You have to be stuck in the hospital for, it could be two or three weeks. It's variable. But the one that will get FDA-approved this year, we have a hope, maybe not on day one when it gets approved, but over time we'll able to use it in the clinic and then patients won't have to get admitted to the hospital. That'll make it much easier to use and a more pleasant experience for patients we think with possibly fewer side effects.

So that's this year's advance in CAR-T cells, one type of immunotherapy. As you said, we have other new therapies just recently approved including some oral therapies which are just on the verge of approval. So one of the newer therapies is an antibody drug conjugate like rituximab that many people are familiar with. This is an antibody but not against CD20 like rituximab is but by another lymphoma target called CD79. Andrew, there will be a quiz at the end of the interview, so you got to get all these numbers. CD79 is another molecule on the surface of almost all lymphoma cells or all B-cell non-Hodgkin's lymphoma cells. And this antibody targets to the lymphoma cell. But as you hear, it's an antibody drug conjugate. So then it actually brings a type of chemotherapy right to the lymphoma cell.

We already have antibody drug conjugates approved for breast cancer, for other types of lymphoma, but this past year we got one approved for DLBCL. The name of that antibody drug conjugate is polatuzumab vedotin (Polivy). Why can we have simple names? I can't speak to it. Polatuzumab vedotin is FDA-approved in combination with a couple of other therapies, but it seemed to give a real benefit, and it's a pretty elegant concept to just bring chemotherapy right to the lymphoma instead of treating the whole person in some sense with chemotherapy. So antibody drug conjugates are a new approved therapy for DLBCL. And as you hinted, we also have some promising oral therapies. The one that's furthest along actually has been around for years for another type of cancer, multiple myeloma. So this is a medicine called lenalidomide (Revlimid). And lenalidomide, we usually use it in combination with rituximab and that combination is pretty good for diffuse large B-cell lymphoma, probably gives responses in 30, 40 percent of patients.

But we have very exciting new data about a new antibody instead of rituximab targeting another molecule on the surface, CD19. So this is an antibody called tafasitamab (MOR208), and it's been used in combination with lenalidomide, an oral, a pill and that combination has been unbelievable in the Phase II data and will probably get approved this year because of that exciting data. It was inducing remissions in a majority of patients and complete remissions in a good proportion, about 40 percent. And those remissions seemed to last for a long time. We don't really know how long yet, but many of them were lasting more than a year.

So new immunotherapy tafasitamab antibody in combination with oral therapy, lenalidomide, and as you mentioned, we have others coming down the pipe. Selinexor, again, another medicine approved for myeloma, and it's been very promising there, an oral therapy. It's been studied a few years ago in DLBCL, and it will probably come back two more studies. In the initial studies, probably the dosage was not optimal, and there was probably more side effects in terms of sore mouth, nausea, things like that. So maybe now that myeloma has shown how to use this medicine safely, we'll be able to bring it back to DLBCL.

Andrew Schorr:
Okay. So for our viewers who receive a diagnosis of this diffused large B-cell lymphoma, it's a mouthful, or a family member, it sounds like Dr. Brody, you have more than ever before and great hope for people if not a cure, different lines of therapy that can offer a longer life.

Dr. Brody:
It's actually true. And we do, and again, since this is a common lymphoma, the highest incident lymphoma that we diagnose, you will meet people, friends, family members that will get diagnosed with it. And I guess my first piece of advice at the time of diagnosis is the standard therapies are pretty good as we say, but they still have a lot of room for improvement. So a big part of this for us as bringing new therapies in combination with the R-CHOP frontline therapy. So instead of trying to cure people, sometimes failing and then trying to do better later, if we could just cure more people right off the bat, that would be very preferable to us, of course, to our patients and their families. So we have a bunch of frontline trials in which we combine R-CHOP usually with other gentle or targeted therapies.

One example is that tafasitamab, the new antibody that we just described, will start a trial for frontline therapy. We have a BTK inhibitor, you've heard about these for CLL and some other lymphomas and leukemias that we'll be starting into a new trial for frontline patients with DLBCL. And we have other targeted therapies, a medicine called enzastaurin (DB102), which is being studied in the frontline. So although we do pretty well with the frontline therapies, I still think it's very worthwhile for every person that gets a new diagnosis of DLBCL to at least check at the nearby academic centers and see if they have exciting trials, so maybe we can do better than we've been doing so far for the frontline therapy.

Andrew Schorr:
Good point. So for our audience, I'll just underscore it. I've been in trials as a leukemia patient. Combination therapy is kind of basic to oncology and hematology now over a number of years, getting a bigger bang and hopefully a cure or a very long remission. So that's where you need to say when you're diagnosed, is there a combination, maybe the trials at an academic medical center down the road that could offer you that hope of a bigger bang, if you will?

Dr. Brody:
Absolutely. Bigger bang.

Andrew Schorr:
Okay. Dr. Joshua Brody from Mount Sinai in New York City. Thank you so much for all you do in moving research forward. And I hope our patients who are listening know we can be partners with you in getting answers that may help us and answers in your research that can help many more. Thanks for being with us.

Dr. Brody:
Andrew, I appreciate it. Thank you very much.

Andrew Schorr:
Andrew Schorr with Patient Power, with Dr. Joshua Brody, reminding you that knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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