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Anjali Advani, MD, Director of the Inpatient Leukemia Unit at Cleveland Clinic, joins the Cancer Advances Podcast to talk about the innovations in acute lymphoblastic leukemia (ALL). While chemotherapy has traditionally been the go-to treatment, advancements like blinatumomab and CAR-T cell therapy are reshaping care. Listen as Dr. Advani discusses the challenges and considerations in choosing these therapies, CAR-T re-challenge potential, and the future directions in ALL treatments.

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Beyond Chemotherapy: Advancements in ALL Treatment

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advance, 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 Shepherd, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today, I'm very happy to be joined by Dr. Anjali Advani. She's professor of medicine, Director of Inpatient Leukemia Unit and Vice Chair of the SWOG Leukemia Committee. She's here today to talk to us about innovations in the management of acute lymphoblastic leukemia. So welcome.

Anjali Advani, MD: Thank you.

Dale Shepard, MD, PhD: So give us a little bit of an idea. What do you do here at the clinic? I gave a couple titles, but what do you do while you're here at the clinic?

Anjali Advani, MD: Sure. So I do clinical research. I see patients, also do some teaching. Those are pretty much the main things.

Dale Shepard, MD, PhD: Here we go. Well, we're going to talk about ALL. You've done a lot of work in that area. Just for perspective, there's a lot of different people, different backgrounds, might be listening in. Let's start really, really basic. What is ALL?

Anjali Advani, MD: Sure. So ALL is the type of acute leukemia. So leukemia is a cancer of the blood or bone marrow, bone marrow is the factory where blood cells are produced. And so there are mainly two types of leukemia, acute and chronic. So with acute leukemia, these patients have too many blasts or very immature cells in their bone marrow. And basically those cells take over the normal production of the bone marrow so that the patients aren't able to make enough good white cells, platelets and red cells. And so, often these are patients that will end up admitted to the hospital because they'll come through the emergency room.

And then of the acute leukemias, there are two main types, ALL and AML, and that just refers to the type of white blood cell. So ALL, acute lymphoblastic leukemia, is basically the lymphoblast is the type of blast that is involved. And we can tell that by looking under the microscope and then also by doing a test called flow cytometry, where basically we run the cells through a machine and look at the markers.

Dale Shepard, MD, PhD: Okay. Give us an idea of the scope of this. Who gets it and how many cases a year?

Anjali Advani, MD: So, probably the most commonplace we see this is actually pediatrics, but there's a second peak actually in older adults. And because the disease is a little bit more complicated in terms of treatment, most of these patients are referred to tertiary and academic centers. So, I would say even though it is less common than AML, I think because of the complexity of treatment, and also I know we're going to talk about this in a little bit, some of the newer treatments, I think we end up seeing probably more than it may look like in the population just because of that referral bias. So, it doesn't tend to get treated as much in the community, I would say, as compared to some of the other diseases.

Dale Shepard, MD, PhD: Yeah, it seems like sometimes in our clinic, uncommon is relatively common.

Anjali Advani, MD: Yes, exactly.

Dale Shepard, MD, PhD: So historically, we are going to talk about the newer treatments and what the new innovations are going to be, but how has this been treated historically?

Anjali Advani, MD: So historically, really chemotherapy with what we call a BFM backbone has been the standard treatment which involves multiple chemotherapy drugs. Those have included anthracyclines, vincristine, steroids, cytoxin, PEG-asparaginase. And also these patients because there is a high risk of central nervous system involvement if they don't get CNS-directed therapy, they also get lumbar punctures with intrathecal chemotherapy.

And so for a number of years, that really was our standard and that's really, really changed a lot now, which has really been exciting. I think probably one of the other things that's happened over probably the last 20 years is in our young adults, which we define as really less than 40 years of age, in those patients, it's been shown that treating them with a pediatric-based or pediatric-inspired regimen is better than an adult regimen in terms of outcomes. And so that has been something that's been relatively new, I would say, over the last 10 years or so.

Dale Shepard, MD, PhD:

So, we're going to talk about some newer drugs, newer therapies, newer approaches. What was the primary driver for thinking about new therapies? Was it how satisfied we were with the response? Was it toxicity? Complexity of the drugs? Late effects? What drove the need to come up with new things?

Anjali Advani, MD: Yeah, that's a great question. So I think there are a few things. One is that for the older patients, many of them cannot tolerate those intensive regimens. And so, the question is what could we do to help those patients? The second thing is there are certain biologic subsets of disease such as Philadelphia Chromosome Positive disease or MLL, rearranged ALL, where our outcomes were not good, and so what can we do to improve outcomes? That is true regardless of age.

And then back in the past when really we looked at first relapse, there was a nice study done by Adele Fielding that was published really showing that even these patients that were candidates for salvage therapy and transplant, if you looked at the outcomes of relapsed patients, the overall survival was only maybe 10%, which is really poor. So in pediatrics with the upfront therapy, we cure a large percentage of patients. In adults, that percentage, again, depending on age, is probably maybe 50%. Again, things have changed and we'll talk about even in the upfront treatment, there's now been a lot of newer strategies to improve those outcomes.

So, I think for all those reasons, that's been a big push to try to really improve things both in the upfront setting so that hopefully patients don't relapse, and hopefully you take fewer patients to transplant, but then if they do relapse hopefully we can salvage them and have better outcomes with transplant.

Dale Shepard, MD, PhD: Excellent. So why don't we just go ahead and jump in? What are some of the newer approaches that have been developed in terms of, and we can start with upfront treatment, we can start any phase, any sort of state you like, but what are some of those newer approaches we've come up with?

Anjali Advani, MD: Yeah, no, great question. So, I think probably the most exciting thing, so for acute lymphoblastic leukemia, we look at it as Philadelphia chromosome negative and Philadelphia chromosome positive. So, the Philadelphia chromosome tends to occur more in older patients. So just starting with Philadelphia chromosome negative because that's probably a larger bucket of patients. And so, one of probably the most exciting presentations at a big leukemia hematology meeting was a late-breaking abstract presented by mark at ASH, and this was a clinical trial called ECOG 1910. This was done by the US National Cancer Groups as well as done internationally. And this study basically looked at adding a drug called blinatumomab, which is something called a BITE. It's an anti CD19 bispecific T-cell engaging antibody. So that drug is actually FDA approved in relapsed refractory, ALL, and also in patients that have minimal residual disease-positive ALL.

And so, because the drug has been so well tolerated and been so encouraging, the question in this trial was: what happens if you add this upfront treatment standard chemotherapy-based backbone in patients that are minimal residual disease negative. And this is probably one of the very few studies I would say overall in ALL to show not only a huge improvement in relapse-free survival, but overall survival.

And so, those results were so encouraging, the manuscript has not been published yet, it should be very soon, but those results were so great that actually the NCCN guidelines have actually now suggested this. Even though it's not approved in this setting, the results were just that impressive. And I just came off inpatient leukemia service and we actually had a patient that fit, 49, Philadelphia chromosome negative, and so she's getting treated with that treatment protocol and that really has now become a standard for our patients.

In the young adult population, there's still some debate because this trial really included ages 35 and up, which straddles a little bit that AYA population, but really it went from 35 to 70, and so that's I think really changed. And so, the other part that we're going to probably come to is that also may start to change what we do with these other therapies, because if we're now using this more upfront, that means we may be using some of these other therapies more in the setting of relapse.

Dale Shepard, MD, PhD: How do we think through that in a disease like ALL? So, you have these historic things that work first line, sometimes the setting that you use drugs matters. Do we think that as we move these other drugs up into earlier phases, do we just hope for the best and use those drugs? Or do we have to redo studies to look at them in later stages?

Anjali Advani, MD: Yeah, I think you've really, so this was a phase three trial, and I think ultimately you really need that to really see is there a relapse-free and overall survival benefit. I think one of the things you also have to be careful with with some of these other drugs, for example, inotuzumab, which is the anti CD22 immunoconjugate that is FDA approved in relapse disease, that drug can have some other toxicities such as hepatic toxicities. And so, there is a randomized phase three trial that is currently on hold that was looking at chemo in the AYA population with a pediatric backbone versus chemo plus inotuzumab. And that trial was actually halted because there were some late toxicity. So, it actually wasn't right with the inotuzumab, it was a little after.

And so I think that's the other piece, you do have to be careful because you're obviously in that regimen now combining it with other agents. And so you have to also look at the toxicities and be careful with that. And really have a good data safety and monitoring plan.

Dale Shepard, MD, PhD: You mentioned before MRD, and MRD has got a big role in ALL in many cases. We had a recent episode, we talked about MRD and CLL. How are these newer therapies changing our perspective on what is necessary in terms of measuring MRD, alternative, the duration of therapy when you resume therapy? How are these new drugs changing our perceptions of what we use MRD for?

Anjali Advani, MD: Yeah, no, great question. So, I would say it's interesting because for ALL, MRD by the pediatricians has been used for a long, long time.

Dale Shepard, MD, PhD: Right.

Anjali Advani, MD: And now we call MRD measurable residual disease rather than minimal residual disease because now we've found that really the more techniques we have, the more sensitive we're going. And so really the gold standard was, and still in some degree is, flow cytometry multicolor where we actually send it out. There are a couple of labs within the country that are really expertise at that approach, and so really if you're going to measure it.

But we've really seen in ALL that it is extremely prognostic. And so in the old days there were patients that we may have transplanted that now we don't transplant because MRD may actually override, for example, certain cytogenetic and molecular abnormalities. That's not true in all cases, but I think in ALL it's probably more so than in, for example, AML really changed which patients we transplant upfront. And we also use it, we know if it's positive, we also, they're now eligible for treatments such as blinatumomab, those patients CAR-T cell therapy is also starting to be moved upfront.

We don't use it really in ALL to make decisions about stopping treatment, although that may come at some point in the future. I'm not sure our outcomes in adults are at that point, but there's been some discussion in the pediatric groups about that. But definitely I think it helps us risk stratify patients a lot better, and also lets us know which patients should we think about for some of these novel therapies or clinical trials.

Dale Shepard, MD, PhD:

Does it seem like there may be a point where it's useful to know when to start a treatment?

Anjali Advani, MD: So, definitely for MRD-positive patients, yes. So, definitely that would be a place where blinatumomab has benefited and is FDA approved. There are also trials that have looked at, for example, CAR-T cell therapy in that space as well.

Dale Shepard, MD, PhD: All right, so I'm going to take the bait. You've mentioned CAR-T couple of times now. Tell me a little bit about what the role of CAR-T therapy is right now in ALL.

Anjali Advani, MD: So, right now for CAR-T cell therapy, there really are for adults two products approved. One is Kymriah, tisagenlecleucel, which is a mouthful. That is FDA approved for patients less than 26 years of age, so that's pediatric, and then our young adults that are less than 26. That CAR-T probably has the best data, so that is approved in relapsed refractory B-cell ALL, again, but only in that age group. In patients that are 18 years of age and older, there is Brexucabtagene or Tecartus that is approved, that has been more recent.

And then the third one that is not approved yet but hopefully will be approved as something called Obe-cell or autoleucel. And that is hopefully by July, maybe summer/fall going to be approved. All of these three CAR-T cells basically target CD19, but they have different co-stimulatory domains.

And the thing that is, although Obe-cell is not approved yet, probably the most exciting thing about that, again it's still just been in clinical trials, is that CAR-T cell seems to have less toxicity and potential, some more durability than say for example to Tecartus. The hope is that that may increase the number of patients that we're able to give CAR-T cell therapy to. Because one of the concerns have been toxicity such as cytokine release syndrome, neurotoxicity, and it's thought that with Obe-cell it's able to come off more quickly, and so you may not have the same toxicity you will with the others.

Kymriah or tisagenlecleucel is interesting because that particular car seems to have some durability and there actually is some data in the pediatric and AYA literature that you may have some durable responses without having to take patients to transplant.

I think with Tecartus or Brexucabtagene, there's been a little bit more debate how durable that CAR-T cell is, and I think most people are nervous unless they're going to bridge a patient to transplant. Ope-cell, again, the data is still new and it's not approved yet, but there's some thought that that CAR-T cell just from some of the preliminary data may be again, more durable.

So, one of the thoughts is you try to get the patient in remission with these CAR-T cells, but the second question, which is a huge debate, is then do you need to transplant every patient? Again, I think in the adult world generally we do, but it may be as we get CARs that are more persistent, it may be used as kind of a new immunotherapy. There is an ongoing children's oncology group trial basically trying to look at incorporating CAR-T cell therapy earlier in these kind of what we consider high risk patients. And so, the thought is then can you hopefully prevent them from relapse, and also not take them to transplant?

Dale Shepard, MD, PhD: I guess from the standpoint of trying to maximize therapies outside of transplant, is there work being done in ALL to re-challenge with CAR-T cell therapies? Either the same therapy or one of the alternate products

Anjali Advani, MD: That data is still very new. That's a great question. So I think there are a few issues. One is now we have other treatments like we have InO-Blina, then we have the CAR-Ts, only two CAR-Ts are really approved and most of the time we'll have patients for example, that are 26 or above, so you may only have the one CAR-T.

And then when these patients relapsed after CAR-T, they may, as we discussed, these are all CD19 directed. There are other CAR-Ts targeting, for example, CD22 or dual-CARs or targeting CD20. And so sometimes it's not uncommon when these patients relapse after CAR-T cell that they may lose their CD19 expression and then they may not be a candidate for CD19-directed therapy. And so then you really need to either look at something like Inotuzumab or trying to get them on a clinical trial with a different CAR-T cell

Dale Shepard, MD, PhD: And are drugs like Blina, which is also CD19 as a BITE, right? As directed.

Anjali Advani, MD: Mm-hmm.

Dale Shepard, MD, PhD: Are those as likely as well to lose CD 19 sensitivity and then maybe not be able to use a CAR-T directed towards CD19?

Anjali Advani, MD: That is the big debate. So there's a lot of debate. I mean, you can definitely lose CD19s. There have been several of the trials looking at CAR-T treatment have looked at whether prior blinatumomab exposure impacts outcomes and response. And it's a little bit of a mixed bag, but basically the thought is that you can still do it. How much it impacts things because those patients are more heavily pretreated because, again, this was more in the relapse setting that they received Blina.

So one of the problems with CAR-T cell therapy I would say right now is that we usually have to give patients something before the CAR-T. One, because it takes time to make the CAR-T cells, but two, because you also tend to get toxicity if you have a really, really high tumor burden.

Dale Shepard, MD, PhD: I guess how do you guys think through brand new patient comes in, has CD19 as a potential target for their treatment, what are the factors that make you wonder about doing a BITE therapy like Blina, doing a CAR-T therapy? What are the factors that would lead you down one path instead of the other?

Anjali Advani, MD: If they're relapsed, in the relapse setting?

Dale Shepard, MD, PhD: Yeah.

Anjali Advani, MD: So in the relapse setting, the other part that would help us is tumor burden. So, even for Blina, if a patient has a very high tumor burden and or extramedullary disease, CNS disease, that's a case we would actually look at notuzumab versus blinatumomab. I would say most of the time just because of logistics, we end up doing blinatumomab or inotuzumab first before CAR-T, just because again, most of these patients require something.

And the other piece becomes if it's a first relapse and they're going to go to transplant, it's also not clear at this point are any of these treatments better than the other? As long as you get them into an MRD negative remission and then are able to get them to transplant. So, I often will have patients evaluated by the CAR-T team so that you can get that process going, so that say you give them X and it's not working, you need to have things lined up to be able to have that treatment appropriate for them.

One thing that's a little off topic, but that is really exciting is that for T-cell ALL, which is a smaller proportion of ALL, makes up only about 20% of ALL, that has been a really greatly unmet need because we don't have CD19 or 22, we don't have drugs like Blina or Ino or the CAR-T cells we can target. We do have Nelarabine, which is FDA-approved for relapse disease. There are a couple of really exciting things in that realm where there is going to be a US intergroup trial looking at incorporating Venetoclax and Navitoclax, which are BCL-2 and BCL-XL inhibitors into upfront treatment again to hopefully prevent relapse because those drugs have looked very encouraging in the relapse setting. So, that's the trial that should hopefully be open in the next six months and that'll be a large randomized trial.

But the other thing that we have open here right now, which is really exciting, is we have a CAR-T cell trial for relapse refractory T-cell ALL, and that is targeting CD7. And so, it's been very interesting because although it's a small population of patients, there have been a lot of referrals for that because it's just such an unmet need. The tricky part is because it's still in the phase one setting and there only are very few slots at a time, those patients have to be stable enough to sometimes wait for that slot to be open, and so it's tricky trying to navigate that piece of it.

Dale Shepard, MD, PhD: Yeah, a whole new level of complexity. Well, it certainly sounds like there's some exciting things in the treatment of ALL and we'll continue to look forward to new development. So appreciate your insight today.

Anjali Advani, MD: Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.

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