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CLL and CAR-T Cell Therapy: Is It Right for Me?

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Published on July 22, 2020

How Do You Decide if CAR-T Cell Therapy Could Work To Treat CLL?

In Part 2 of our recent CLL Answers Now program, host Andrew Schorr and Dr. Nitin Jain of the University of Texas MD Anderson Cancer Center discuss CAR-T Cell Therapy for CLL and how to manage side effects such as cytokine release syndrome. Two CLL survivors who underwent CAR-T Cell therapy, David Garcia and Larry Saltzman, share their stories. Watch as they share how they managed side effects and the cost of this experimental treatment.

Watch Part 1: CLL Survivors Share Their CAR-T Cell Experience.

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Transcript | CLL and CAR-T Cell Therapy: Is It Right for Me?

What Can Make CLL More Aggressive?

Andrew Schorr:
We CLL patients have been learning, do we have different, are we mutated or unmutated, do we have the 17P deletion that could be more aggressive? Dave, do you know anything about the characteristics of your CLL that made your CLL more aggressive?

Dave Garcia:
I believe I am a 17.

Andrew Schorr:
17P. Okay. And Larry, how about you?

Dr. Saltzman:
Yeah, so I'm a 13Q deletion, an 11Q deletion, and I am IVGH unmutated.

What Is CAR T-Cell Therapy?

Andrew Schorr:
Okay. All right. And we've always heard mutated is better which never quite made sense to me. Okay. So just briefly to you Dr. Jain, Larry just said it's not for the faint of heart, right? So this is a big gun and you're still learning about it. And we should say that, like I've known somebody who passed away during CAR T-cell therapy and I know people who it wasn't lasting. Where are we now with our understanding of it?

Dr. Jain:
Yeah. So certainly I think those stories are obviously true stories, and I think it kind of makes you feel, I think certainly how the therapy is evolving and has helped patients, but as Larry pointed out, it can lead to certain complications. So I think a few things, one is that our awareness of these complications and our knowledge of how to handle these complications has improved. So the CAR T trials have been in the last four or five years. And I can say that, at least for our group and I'm sure for other groups as well, how do we manage patients? How do we understand the complications? When to use the steroids? These are the therapies we use to treat cytokine release syndrome. There are other drugs such as tocilizumab (Actemra), all those things have improved and evolved over the course of last few years I would say. So I think our understanding as a physician, how to manage the patients has improved. But certainly I think as we saw in these two stories to say, patients who have high-risk genetic markers.

So for David, it looks like deletion 17P, for Larry, it looks like 11Q deletion and unmutated IGVH. That's kind of the group of patients we do tend to relapse on newer therapies, especially with chemotherapy. And what we saw was that the disease was quite aggressive. And I can certainly see that the options were extremely limited at that time when you got the CAR T-cell therapy, and thankfully for both of you it has worked so far. So certainly I think it's an approach. We don't take it lightly. Many times patients ask me on their first visit to the clinic and they are untreated before and they are wanting to have the next best therapy and they say, "Hey, what about CAR T? Can I get CAR T and be done with it? And they have no therapy ever. So certainly that's not the patient population where CAR T right now is geared towards. But I think for patients who have failed multiple lines of therapy, failed ibrutinib (Imbruvica), failed venetoclax (Venclexta), I think that's certainly a strategy we should be pursued and can have very dramatic results in terms of long remissions.

What is Cytokine Release Syndrome?

Andrew Schorr:
Okay. Well, we hope, and we hope for these guys and anybody else who's been through it. I'm going to fire some questions at you and then I want to go back to Larry and Dave to get into the going through it stuff, particularly what they know about this neurologic problems or cytokine, if they even know, cytokine release syndrome. Cytokine release syndrome and we've been hearing about it lately related to complications of COVID-19 and you mentioned steroids. But we heard about it earlier way before the pandemic related to CAR T. So what is it? Is it like you're being in a coma and your immune system is just like the furnace is turned up, what's going on? And you said you've been learning how to control it Dr. Jain.

Dr. Jain:
Yeah. So cytokine release syndrome. So cytokine are different so-called chemicals to say in our body, which gets released when these CAR T-cells are in a way trying to attack the cancer cells. So generally we see it a few days after receiving the cells, many times it's like day five, day six, day seven in that ballpark. And if you measure the cytokine levels, sometimes we see high number of cytokine levels and there are different cytokine levels we check. But what we have realized now is that what happens is, from a patient standpoint is that you start having fever. That's one of the common things, your blood pressure may drop, you may start requiring oxygen, especially when you start requiring, where your blood pressure drops, you start requiring oxygen that becomes a bit more serious and that sometimes can evolve into transferring to ICU because you need medications to improve the blood pressure and things can get more complicated as well.

Andrew Schorr:
Larry is nodding his head. I think he's been through it. Yeah.

Are There Treatments for Cytokine Release Syndrome?

Dr. Jain:
Right. So I think what we are doing these days, and I think what has evolved is how do we manage patients? So there is a drug called tocilizumab which is blocks the IL-6, which is now under medication FDA approved for cytokine release syndrome. So it's used quite commonly by the centers which do CAR T. Steroids which very originally were taught to be that we should not be using steroids at all for patients with CAR T because it can kill the CAR T. I think what we have realized more and more is that there are certain patients who have this cytokine release syndrome and also the brain complication, the neurotoxicity where steroids can help actually very much. So I think there's some change in our management algorithm to say, as physicians, how we manage patients to use steroids a bit earlier than what maybe we used to do three, four years ago. So that's in a nutshell briefly as a cytokine release syndrome.

Andrew Schorr:
Okay. So you're refining your approach and that's what happens during a trial. You're learning as you go in this case.

Dr. Jain:
Right.

CLL Patients Share Their CAR T-Cell Therapy Experiences

Andrew Schorr:
All right. So let's see what the experience was. So first Dave, you told me on the phone a couple of weeks ago, there were some days you were just out of it, just gone, right?

Dave Garcia:
Right. Every day they would come in and I would have to write a sentence. It is a sunny day today, every single day. And by day four after the injection, I just could not do it. I was pretty much out of it for about three, four days. It was rough. It was rough. It wasn't easy but you get through it. It lasted for about three, four days. I was in the hospital for three weeks and then I had to stay there on campus for a week. So the whole process, I was there for one month.

Andrew Schorr:
And Larry, you went through it twice and you said at one point your brain was like, you felt like was jelly and your wife Sharon was with you through all this. So what has she told you about what was going on with Larry?

Dr. Saltzman:
In the beginning stages, the cytokine release syndrome was, as they say, I was febrile for days and I did require oxygen. My heart went into AFib. But at that point, I never lost my mind. I was writing the sentences every day too they wanted me to ask. And actually, by the third or week or so, we thought we had bypassed neurotoxicity, that it wasn't going to happen. All of a sudden, I'm having dinner talking to a friend making no sense at all on the phone. And I was talking gibberish and so we took a nice ambulance ride to the hospital and for 24 hours, I really wasn't speaking normally to anybody and it was very scary. You mentioned my wife Sharon, I knew who she was but I couldn't form any words. And the other subsequent problems, I had headaches from this and I also had tremors. So this is a highly technical thing. I have an Apple Watch, like many people do, and my Apple Watch is password protected.

And when you put the watch on, you have to enter the code to make the watch work. My hands were so trembly kind of like a Parkinson's tremor that I could not get my fingers for many days to be able to unlock the watch. This was part of the neurotoxicity. I couldn't sign my name. And that took weeks to resolve which it has now. So that was a scary deal.

What Makes Someone a Candidate For CAR T-Cell Therapy?

Andrew Schorr:
Right. So I think folks we’re making it really clear, this is a big gun right now. All right. So Dr. Jain, people are asking, well who would qualify for this? Is it age limiting? So for patients who, say myself or mom or dad maybe need this at a major center like yours, some of the NCI centers doing these trials, what are the factors to qualify?

Dr. Jain:
Yeah, I think certainly for CLL trials, patients who have had prior therapy. So many times, the trials may say that you have to have something like ibrutinib which has been one of the common medications. For patients with CLL that you have to have failed ibrutinib or have had ibrutinib in the past. Now we have more recently acalabrutinib (Calquence). So one of those drugs, or you could have ibrutinib and then have venetoclax and maybe failed both or could not tolerate both. So that would be certainly a patient we should be looking at. In terms of the age group, I don't think there's a true upper age limit.

Certainly, there is some suggestion that older patients, but I could say above 80 that becomes sometimes challenging in terms of the side effect management. I think individual trials have different cutoffs of age and I know some trials do not have any age cutoffs. So I think it's more related to performance status which is how active the patient is, how well they're doing, how their kidney function, liver function is. And as I said you certainly need to have failed at least one of the newer therapies, namely ibrutinib, acalabrutinib, or venetoclax before I think most trials would consider you eligible for CAR T-cell therapy.

Andrew Schorr:
So you said that you have patients who are newly diagnosed and they said, "I want the latest thing." But with a patient who comes in and you do some analysis and they haven't had ibrutinib, they haven't had acalabrutinib, they haven't had anything but you see some really high-risk factors, would you still want to try the other drugs first?

Dr. Jain:
Yes, for sure at this time, because again, you have to see a risk benefit of one approach versus other. So even if you have deletion 17P and we treat you with ibrutinib or acalabrutinib or maybe a venetoclax-based therapy, we still know that from the trials which have been done that maybe 70 to 80% of the patients will be in remission five years down the line with these new starting right away, which is amazing, which is much better than what we achieved with chemotherapy. And because of the CAR T-cell therapy and just what we discussed with the complications so far what we are seeing. Now in future if the CAR T-cell therapies were to become safer, and I hope that's where the field is moving towards, that could be envisioned that the patients who have high risk disease, maybe not as a first line therapy but maybe once the disease is better controlled with some therapies such as ibrutinib or venetoclax and they have a minimal amount of disease left, at that time they could be consolidated or a CAR T could be done as a consolidation strategy.

But again, those trials specifically in terms of CLL, I think are a bit far away just because the drugs you mentioned just now are quite effective, ibrutinib, acalabrutinib, venetoclax, and certainly they are much safer than CAR T-cell therapy. So right now the scenario is you go to a target therapy. If you fail that, then yes, consider a CAR T trial.

How Long Do The Benefits of CAR T-Cell Therapy Last?

Andrew Schorr:
You cancer doctors talk about the durability of the therapy. How long does it last? Do we know?

Dr. Jain:
So that's an extremely good question. So one thing you have to realize is that CAR T-cell therapy does not work for 100% percent of the patients and some patients may not respond to CAR T-cell therapy, but the recent data suggests that it may work for maybe 70 to 80, 90 in that 70 to 80% percent of the patients. But the CAR T-cell therapy for the 70 to 80% of the patients where it works, some of the folks can have a disease coming back after they received the CAR T few months down the line to one to two years down the line. So in terms of durability of the remission, how long it's going to last, I think that's something which is still being studied in clinical trials and it's early. But it's fair to say that just majority of the patients are responding. But certainly there are patients who may not respond or patients who’s disease may relapse after receiving CAR T.

But still, I think you have to realize that this is a kind of a therapy we are using where there's no other option left practically for most patients. So if this therapy was not there, then whatever benefit we are seeing now, it's not going to be there. So certainly a very effective therapy for the patients with such a refractory disease.

Can CAR T-Cell Therapy Cure CLL?

Andrew Schorr:
Okay. So here's a question that came in. So Larry mentioned sometime later gibberish on the phone with his friend, and Dave has been doing well. So at some point, can you tell a CAR T survivor they're out of the woods? Or could there be, if you will, another shoe that drops sometime weeks or months later?

Dr. Jain:
Yeah. So I think that's still not really clear that how far you have to go before we say that the risk of relapse is extremely low. Certainly the longer you go, the better it is. From some of the other lymphomas and the leukemia trials, it seems that if you're out one, one and a half years, maybe two years out of the CAR T-cell therapy, then the risk of relapse decreases. I don't think that's truly established yet in the context of CLL trials. So I think that's something maybe in the next one to two years, we will know more. But certainly that's true that longer you go, and I think especially if you go more than one year, the risk of relapse certainly decreases.

Is CAR T-Cell Therapy Expensive?

Andrew Schorr:
All right. A lot of people are asking about costs, and you alluded to this Larry. So I believe you're on Medicare, right? I think so. You have gray hair like me. Okay. So what were your costs? Because I know you and Sharon are not from Seattle but that's where you chose to go. So you mentioned there's a cost factor that could go with it. Maybe sometimes their foundations and other support that comes in, but what would you say to people about cost?

Dr. Saltzman:
So our medical costs were honestly and happily, mostly taken care of by our Medicare and we have a secondary open PPO insurance. So they took care of most everything except for copays on some pharmaceuticals and yes, copays on hospitalizations. It added up into the tens of thousands of dollars. The real cost for us was the living costs. We did not have a home in Seattle and so we rented a hotel room that was three blocks away from the clinic that I was attending. And so ended up staying in a hotel for four months and food, et cetera and then that's where the cost comes. And there is, okay, so full disclosure, the clinical trial did reimburse for some out of pocket transportation costs, but not nearly to the level that covered our experience.

Andrew Schorr:
Okay. And Dave, how about you related to cost? You're from Las Vegas. You're up at City of Hope near Los Angeles.

Dave Garcia:
Yes. I had to go back and forth quite a bit. I was going back and forth weekly for a while. Yeah, the cost of the trial were picked up, the drugs in the hospitalization were picked up by the trial, but there are a lot of costs involved with follow ups, tests. Like Larry mentioned, the trial sponsor did reimburse me for the cost of staying because I had to stay on campus after the therapy and I was reimbursed for that. So that helped but it is expensive.

How Will I Know if My CLL is in Remission?

Dr. Jain:
I think one of the things which have been studied actually reported from Fred Hutch group is actually what happens after the CAR T. So meaning that once you reach day 30, a month after the CAR T. Many times a bone marrow is done, and then there's a test called MRD which is assessed in the bone marrow and there are various way to assess it. But if you are what is called MRD negative. So 30 days after the CAR T, there is no evidence of leukemia in the bone marrow. This can be done in the blood as well. That's really what they have shown is a very, very good sign that your leukemia is likely going to stay in remission much longer than for a matter if you are MRD positive at that time.

Andrew Schorr:
But at the front end though.

Dr. Jain:
Yeah. But at the front end, I think so far, not a large number of patients have been treated with CAR T, and I think hopefully what we expect at this ASH meeting which is a big hematology meeting, probably virtual now, in December we'll hear some updates of the data with the CAR T. But with the front end, do we know which specific patients may respond? I think that's still under investigation. You have to realize most patients right now being considered for CAR T are high risk patients, meaning that they have either division 17P, they may have failed multiple lines of chemotherapy or ibrutinib or with venetoclax. They may be unmutated for this IGVH. So most of the patients are generally high risk getting into the CAR T. So we need kind of a spectrum of patients, multiple hundred plus patients enroll in trials then we can kind of analyze, yes, this subgroup of patients respond the best. I think eventually that data will come through, maybe in December we may see something but that's still not really clear.

Am I at Risk for Another Cancer if I Have Chronic Lymphocytic Leukemia?

Andrew Schorr:
If CAR T works, can the CLL jump to lymphoma or PLL, prolymphocytic leukemia? In other words, can the CLL outwit the T-cells and become another cancer?

Dr. Jain:
Nothing that has been described are known. CAR T certainly as a strategy has been, for CLL is still not approved but it is as a strategy is approved for lymphomas and hundreds and probably thousands plus patients have been treated with lymphoma trials with CAR T, and nothing of that sort has been described where another lymphoma or our so-called Richter's transformation of CLL, or a PLL transformation could occur. So that's something that has not been described or known to occur.

Will I Still Need a Stem Cell Transplant?

Andrew Schorr:
Okay. Before I forget Dr. Jain, I mentioned that Dave was scheduled for a transplant. So does CAR T even in the experimental phase now supersede transplant? So CLL doctors are not talking about transplanting more and if they're talking about some big gun, they would talk about a CAR T trial.

Dr. Jain:
Yeah. So I think that's another very valid question. And this comes up for discussion all the time in our group with our transplant colleagues here whether to pursue a CAR T or a transplant for an individual patient. I think because of the toxicities which historically has been associated with stem cell transplant and the CAR T, yes the first 30 days can be tough and with the complications we just heard. But once you go past the 30 days and few months down the line, it is very easy as we heard, they're not taking any medications and things like that. And with the transplant, there are still these complications of graft versus host disease and things like that which could occur later.

So I think there's a journal kind of push I think in the field and that I think CAR T therapies should may be preferred over stem cell transplant for individual patients. Certainly, there is no solid medical data to back that up. And there are patients where the doctor may recommend that you get to a CAR T, you get your disease under good control, and for certain situations, a transplant may still be recommended at the back end to hopefully control the disease hopefully forever. And that's certainly true for more like acute leukemia patients who are getting CAR T. For the CLL still not entirely clear whether you really need a transplant at the backend of getting a CAR T-cell therapy.

Final Thoughts on CAR-T Cell Therapy For CLL

Andrew Schorr:
Okay. So just to underscore, it's experimental, here are two gentlemen with us, Dave and Larry, though alive today, wasn't easy, wasn't a walk in the park. We'd certainly say that about transplant as well.

Many of us will never need CAR T, I think, with some great therapies, but some people will or whatever follows in the refinements that are going on with it. Dr. Nitin Jain, I want to thank you. I said this to you before, you and your colleagues, you're our angels pushing research forward. Thank you for all the work you do. Thanks for the expertise you bring to our patient power programs. Dave Garcia, thank you. I'm not going to put money down on the table because you told me the house usually wins. So I'll bet I'll see you in Las Vegas.

Larry, when this whole COVID thing subsides, I'm going to give you a big hug and I hope we get to have dinner together like we've done as couples before. All the best to you my friends and I hope this has been informative for our audience. Look at all our programs on patientpower.info. Larry has been an executive with Leukemia & Lymphoma Society. Loads of information there too. Thank you for joining us. I'm Andrew Schorr. Remember, knowledge can be the best medicine of all. We'll see you.

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