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Role of CAR T-Cell Therapy in Relapsed/Refractory ALL

Panelists:Ryan D. Cassaday, MD, University of Washington School of Medicine; Mark R. Litzow, MD, Mayo Clinic; Aaron C. Logan, MD, PhD, University of California San Francisco; Bijal D. Shah, MD, Anthony S. Stein, MD, Gehr Family Center for Leukemia Research
Published: Wednesday, Apr 04, 2018



Transcript: 

Mark R. Litzow, MD: We can’t continue without talking about CAR T-cell therapy, recently approved, with outstanding response rates but significant toxicity issues. Bijal, can you give us your perspective on where this fits in?

Bijal D. Shah, MD: Absolutely. I think that CAR T-cell therapy, without question, is extremely potent. I think what we lack in the adult space is information to guide us on the durability of that response. We need that. We need that before we can really understand how we integrate this, not just for relapsed/refractory disease but also as consolidation perhaps following an induction for those MRD-positive patients, and perhaps even the MRD-negative patients. I understand the toxicities, and I’ll come to that in a minute. But treating a patient who’s MRD-positive with a very low disease burden with CAR T, the treatment is actually exceptionally well tolerated. I think Jae Park had presented these data from the Memorial Sloan Kettering experience. Not only that, but the patients who got CAR T without a transplant—again small numbers—visually did much better than those who got a transplant for MRD-positive disease, suggesting not so much that we need to exclude transplant for patients post-CAR T, but rather that we have an effective tool for treating those patients in the MRD-positive space. I’m going to say it here: My goal is to move it up front for all my patients, having treated several patients on the Kite Pharmaceuticals CAR T trial. It can be extremely effective.

I can elaborate on efficacy if you’d like. But coming back to the toxicity, when I went back and looked across all the trials that had been done—recognizing that we’re still waiting on data from Juno Therapeutics to emerge and be published—the overall risk of death is in line with an autologous transplant. It’s about 3% to 5%. The duration of hospitalization was also in line with an autologous transplant, anywhere from 2 to 4 weeks in the hospital and most patients are out. This is becoming a very effective tool, and I think we’re going to see it used more and more. You can tell I’m more than biased. I’m excited because we’ve really been compelled by some of our experiences administering this to our patients.

Aaron C. Logan, MD, PhD: It’s definitely exciting, but I think this particular generation of CAR T cells does carry a lot of toxicity, and it requires extreme expertise to administer this therapy to patients. I don’t think that 10 years from now, this is the format that CAR T cells will have. I think there’s going to be innovation in our ability to control the activity of those cells. If we start to recognize higher-grade CRS [cytokine release syndrome] or higher-grade neurotoxicity, we’ll be able to augment the activity of those cells so that we can shut them off, put them in a quiescent state, deal with the toxicity in real time, and hopefully then turn them back on. There are various technologies that are being developed to do that. I think we’re learning a lot, and it’s always the case that you see more toxicity post marketing than you saw in clinical trials—because there were strict eligibility criteria. I think we need to wait and see what the real-world experience with CAR T cells is going to be before we start thinking about moving it to earlier lines of therapy.
We have to think about the economics of it. If a therapy costs $500,000 just for the drug, and the hospitalization may even possibly double that, is that something we can afford to do for every ALL patient when we’ve actually been curing ALL patients—a substantial portion of them—with much cheaper therapy? I think what we need to do is figure out who’s going to fail that cheaper therapy. It would be great if we could move some of the other agents up front so that patients aren’t on therapy for 2 1/2 to 3 years and they can get back to their normal life earlier. But right now, I’m really skeptical that a CAR T-cell upfront therapy is going to be the way to go.

Anthony S. Stein, MD: Hopefully, over time, the cost will come down as well.

Bijal D. Shah, MD: But this is where I’ll challenge you, because you mentioned 5 courses of blinatumomab. It’s $90,000 a month. That’s just the cost, that’s not even the charge. That doesn’t include complications for hospitalization. If we’re talking about inotuzumab, for 3 weeks of therapy, we’re talking about something around $100,000 as well. We have to keep in mind, as we talk about the up-front cost, that we have to compare and contrast with what else is out there. Believe me, I’m the last person who wants my patient to pay $475,000. That’s not at all what I think any of us on this table want, but I just want to make sure we keep perspective with the other therapies that we’re actively administering right now, as it relates to cost. As it relates to toxicity, I completely agree. What we’re going to see off trial is likely to be more toxicity. I imagine that as autologous transplants were coming into phase at one point for breast cancer, we were also seeing more toxicity than we currently see. It took us years to achieve that basement of 3% to 5%.
When I express my excitement, it’s excitement that relates to the Kymriah, or tisagenlecleucel, experience. I’m not going to even try and say that again. It was the durability that was observed in that trial in a pediatric population for which I’m hopeful again, because it’s a similar mechanism for adults. We can approximate that.

Ryan D. Cassaday, MD: I’ll be the CAR T-cell skeptic voice in the world, at least at this table. I think we have to pump the brakes a little bit. It’s an exciting therapy, and there’s a lot to be optimistic about it, but we really don’t have much in terms of even remotely long-term follow-up, particularly in the adult experience. It’s really unclear how good these CRs really are. I think the other thing that is important to point out, at least in what is currently the labeled experience or the labeled indication for it in the relapsed/refractory setting, is if you look at the ELIANA study results that led to the approval of Novartis’s product, these are among the most highly selected patients maybe ever enrolled in clinical trials. These were incredibly selected patients, because there was such demand. Despite that selection—they’re really sick, but very selected—about half of them ended up going into the ICU because of cytokine release syndrome. I think about a quarter of them ended up on dialysis at some point, and these are kids. It looks like there may be a newer generation of CARs, better patient selection, better understanding of the biology, better intervention strategies, tocilizumab, and so forth. We’re going to get there, but I think we’ve got a long way to go before we’re going to be talking about replacing traditional consolidation chemotherapy with CAR T cells.

Aaron C. Logan, MD, PhD: We’re still not going to know whether they need the allotransplant after the CAR T cells.

Bijal D. Shah, MD: To be very clear, we already have a frontline study with blinatumomab and a frontline study with inotuzumab ozogamicin. We just completed the randomized study with inotuzumab ozogamicin. It was published in the New England Journal of Medicine about a year ago. I think we have to be prepared for the fact that as we generate these effective therapies, the goal is to integrate them.

Ryan D. Cassaday, MD: Yes, and I don’t disagree with that. I think the Children’s Oncology Group is doing a frontline CAR T-cell study, and it’s really in their ultra–high-risk patients.

Bijal D. Shah, MD: Which are the young adults, right, by definition?

Ryan D. Cassaday, MD: Right, and that’s true. But it’s going to take years for that study to read out, and that may give us the first point. With all due respect to my pediatric colleagues, treating pediatric ALL is always going to be easier than treating adult ALL.

Bijal D. Shah, MD: It’s true. Hopefully, the data that we share tomorrow night will convince you, how about that?

Mark R. Litzow, MD: I think we need to keep in mind also that this therapy is, in a sense, even more restricted right now, at least more than bone marrow transplant. It only can be done in specialized centers, and the physicians have to be certified to deal with some of these severe reactions; not only the cytokine release syndrome but also neurotoxicity and those kinds of issues.

Anthony S. Stein, MD: There are also limitations on how many products can be made over a given time. I don’t know if there are any limitations on how many products can be manufactured over a certain time period.

Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: We can’t continue without talking about CAR T-cell therapy, recently approved, with outstanding response rates but significant toxicity issues. Bijal, can you give us your perspective on where this fits in?

Bijal D. Shah, MD: Absolutely. I think that CAR T-cell therapy, without question, is extremely potent. I think what we lack in the adult space is information to guide us on the durability of that response. We need that. We need that before we can really understand how we integrate this, not just for relapsed/refractory disease but also as consolidation perhaps following an induction for those MRD-positive patients, and perhaps even the MRD-negative patients. I understand the toxicities, and I’ll come to that in a minute. But treating a patient who’s MRD-positive with a very low disease burden with CAR T, the treatment is actually exceptionally well tolerated. I think Jae Park had presented these data from the Memorial Sloan Kettering experience. Not only that, but the patients who got CAR T without a transplant—again small numbers—visually did much better than those who got a transplant for MRD-positive disease, suggesting not so much that we need to exclude transplant for patients post-CAR T, but rather that we have an effective tool for treating those patients in the MRD-positive space. I’m going to say it here: My goal is to move it up front for all my patients, having treated several patients on the Kite Pharmaceuticals CAR T trial. It can be extremely effective.

I can elaborate on efficacy if you’d like. But coming back to the toxicity, when I went back and looked across all the trials that had been done—recognizing that we’re still waiting on data from Juno Therapeutics to emerge and be published—the overall risk of death is in line with an autologous transplant. It’s about 3% to 5%. The duration of hospitalization was also in line with an autologous transplant, anywhere from 2 to 4 weeks in the hospital and most patients are out. This is becoming a very effective tool, and I think we’re going to see it used more and more. You can tell I’m more than biased. I’m excited because we’ve really been compelled by some of our experiences administering this to our patients.

Aaron C. Logan, MD, PhD: It’s definitely exciting, but I think this particular generation of CAR T cells does carry a lot of toxicity, and it requires extreme expertise to administer this therapy to patients. I don’t think that 10 years from now, this is the format that CAR T cells will have. I think there’s going to be innovation in our ability to control the activity of those cells. If we start to recognize higher-grade CRS [cytokine release syndrome] or higher-grade neurotoxicity, we’ll be able to augment the activity of those cells so that we can shut them off, put them in a quiescent state, deal with the toxicity in real time, and hopefully then turn them back on. There are various technologies that are being developed to do that. I think we’re learning a lot, and it’s always the case that you see more toxicity post marketing than you saw in clinical trials—because there were strict eligibility criteria. I think we need to wait and see what the real-world experience with CAR T cells is going to be before we start thinking about moving it to earlier lines of therapy.
We have to think about the economics of it. If a therapy costs $500,000 just for the drug, and the hospitalization may even possibly double that, is that something we can afford to do for every ALL patient when we’ve actually been curing ALL patients—a substantial portion of them—with much cheaper therapy? I think what we need to do is figure out who’s going to fail that cheaper therapy. It would be great if we could move some of the other agents up front so that patients aren’t on therapy for 2 1/2 to 3 years and they can get back to their normal life earlier. But right now, I’m really skeptical that a CAR T-cell upfront therapy is going to be the way to go.

Anthony S. Stein, MD: Hopefully, over time, the cost will come down as well.

Bijal D. Shah, MD: But this is where I’ll challenge you, because you mentioned 5 courses of blinatumomab. It’s $90,000 a month. That’s just the cost, that’s not even the charge. That doesn’t include complications for hospitalization. If we’re talking about inotuzumab, for 3 weeks of therapy, we’re talking about something around $100,000 as well. We have to keep in mind, as we talk about the up-front cost, that we have to compare and contrast with what else is out there. Believe me, I’m the last person who wants my patient to pay $475,000. That’s not at all what I think any of us on this table want, but I just want to make sure we keep perspective with the other therapies that we’re actively administering right now, as it relates to cost. As it relates to toxicity, I completely agree. What we’re going to see off trial is likely to be more toxicity. I imagine that as autologous transplants were coming into phase at one point for breast cancer, we were also seeing more toxicity than we currently see. It took us years to achieve that basement of 3% to 5%.
When I express my excitement, it’s excitement that relates to the Kymriah, or tisagenlecleucel, experience. I’m not going to even try and say that again. It was the durability that was observed in that trial in a pediatric population for which I’m hopeful again, because it’s a similar mechanism for adults. We can approximate that.

Ryan D. Cassaday, MD: I’ll be the CAR T-cell skeptic voice in the world, at least at this table. I think we have to pump the brakes a little bit. It’s an exciting therapy, and there’s a lot to be optimistic about it, but we really don’t have much in terms of even remotely long-term follow-up, particularly in the adult experience. It’s really unclear how good these CRs really are. I think the other thing that is important to point out, at least in what is currently the labeled experience or the labeled indication for it in the relapsed/refractory setting, is if you look at the ELIANA study results that led to the approval of Novartis’s product, these are among the most highly selected patients maybe ever enrolled in clinical trials. These were incredibly selected patients, because there was such demand. Despite that selection—they’re really sick, but very selected—about half of them ended up going into the ICU because of cytokine release syndrome. I think about a quarter of them ended up on dialysis at some point, and these are kids. It looks like there may be a newer generation of CARs, better patient selection, better understanding of the biology, better intervention strategies, tocilizumab, and so forth. We’re going to get there, but I think we’ve got a long way to go before we’re going to be talking about replacing traditional consolidation chemotherapy with CAR T cells.

Aaron C. Logan, MD, PhD: We’re still not going to know whether they need the allotransplant after the CAR T cells.

Bijal D. Shah, MD: To be very clear, we already have a frontline study with blinatumomab and a frontline study with inotuzumab ozogamicin. We just completed the randomized study with inotuzumab ozogamicin. It was published in the New England Journal of Medicine about a year ago. I think we have to be prepared for the fact that as we generate these effective therapies, the goal is to integrate them.

Ryan D. Cassaday, MD: Yes, and I don’t disagree with that. I think the Children’s Oncology Group is doing a frontline CAR T-cell study, and it’s really in their ultra–high-risk patients.

Bijal D. Shah, MD: Which are the young adults, right, by definition?

Ryan D. Cassaday, MD: Right, and that’s true. But it’s going to take years for that study to read out, and that may give us the first point. With all due respect to my pediatric colleagues, treating pediatric ALL is always going to be easier than treating adult ALL.

Bijal D. Shah, MD: It’s true. Hopefully, the data that we share tomorrow night will convince you, how about that?

Mark R. Litzow, MD: I think we need to keep in mind also that this therapy is, in a sense, even more restricted right now, at least more than bone marrow transplant. It only can be done in specialized centers, and the physicians have to be certified to deal with some of these severe reactions; not only the cytokine release syndrome but also neurotoxicity and those kinds of issues.

Anthony S. Stein, MD: There are also limitations on how many products can be made over a given time. I don’t know if there are any limitations on how many products can be manufactured over a certain time period.

Transcript Edited for Clarity 
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