The Evolving Role of CAR T Cell Therapy in Hematological Malignancies - Episode 10
David Maloney, MD, PhD: We’ve seen really exciting data with both commercially approved agents, but now there’s a third agent that finally made the scene, I guess. Many of us are very excited about this. This was lisocabtagene maraleucel, which was presented by Dr Jeremy Abramson. And this was about 269 patients treated with this agent. It’s a 4-1BB CAR [chimeric antigen receptor], but it’s manufactured slightly differently. There are actually 2 streams. They first select CD4 and CD8 cell populations, then make 2 CARs, then combine them back in a 1:1 ratio at the exact prescribed dose.
We’re very excited about this. Many of us participated in those clinical trials. The take-home from that, from my perspective, was that the response rate was high. I think 75% of patients had an overall response rate. And 55% of them had a complete remission, which seems pretty much in line with the other studies with the follow-up that was presented so far. Again, this looks almost identical to axicabtagene ciloleucel, although there’s clearly not the long-term follow-up. The thing that was quite striking about this agent was the perception that it was less toxic. Now, this is always a tricky thing. It’s the third study to be done. People have learned a lot about how to treat CRS [cytokine release syndrome]. However, there’s only 2% grade 3 CRS, and less than 50% of the patients had any CRS. And what Fred was just saying, that’s about 90% with axicabtagene ciloleucel. There certainly is a perception that there’s less toxicity, less IC [intensive care] usage, less tocilizumab usage, less steroid usage, but there still was neurological toxicity.
Caron Jacobson, MD: Can I ask you about the ICU [intensive care unit] usage? This was something that was glossed over in the presentation, but 7% of patients did go to the ICU. I don’t know what everyone else’s experience is, but at our center I don’t think we exceed 10% of patients who go to the ICU with the currently available products. That ICU admission did not match the grade 3 or higher CRS or the grade 3 or higher neurotoxicity.
David Maloney, MD, PhD: Well, we have to remember that a lot of these were done in smaller centers. If you get a sick patient, they go to the ICU. They’re not all done at university hospitals.
Jason Westin, MD: On the study, there was 10% grade 3 or 4 neurotoxicity. There was some neurotoxicity. It was a little greater than what we’ve seen for CRS, and it’s possible that that might have been some of the ICU stay. Or in early days, before you knew how to manage CAR T-cell therapy, it was often more common to send someone to the ICU for what looked like maybe emerging CRS or emerging neurotoxicity. As we get more comfortable, we feel more confident to keep people on the floor and out of the ICU. I saw that as well, and I thought that was interesting. But it seems with the rate of toxicities, this is impressive.
Frederick Locke, MD: I would just add on to that and say that I agree, David. That ICU usage is a difficult variable and is highly utilized differently across centers. To the point about severe toxicities, yes, the rates of severe toxicity are different. But it’s important to recognize that the management of toxicities may have been different. When to use tocilizumab or corticosteroids in these trials may have been different. And also to acknowledge that the treatment-related mortality on the TRANSCEND study was 3%, and that’s in line with what we’ve seen in the ZUMA-1 and JULIET studies. Even though the rates of severe toxicity are lower, these are therapies that have the opportunity to have patients get really sick, and you really have to build up that experience to treat these patients.
Jason Westin, MD: And the toxicities seen from axicabtagene ciloleucel and tisagenlecleucel are largely reversible toxicities. These severe toxicities we saw in the other studies largely washed out pretty quickly. There’s a difference, but these are not long-term toxicities that we see.
David Maloney, MD, PhD: I also think there’s a big opportunity for healthcare utilization. We reported that 44 patients, I believe, were treated in the outpatient setting with lisocabtagene maraleucel. Surprisingly, 45% of them never required any hospitalization. If you look then at the median days that they did spend in the hospital compared with the people treated in the hospital, it was 6 or so days shorter. The healthcare utilization was considerably less. And so I think at some point we’ll probably be taking the big picture here. For my patients treated with axicabtagene ciloleucel, the median hospitalization is 14 days, and we still have a considerable number of patients who still end up in the ICU. I don’t know what the experience is at your centers, but we don’t have economic analyses yet. That was 1 thing that was quite interesting.
Frederick Locke, MD: I agree. It’s not only a healthcare utilization, it’s also potentially a reimbursement issue. If you infuse CAR T-cell therapy in the inpatient setting or in the outpatient setting and admit to the hospital within 72 hours, that falls upon the DRG [diagnosis-related group]—based billing of the lymphoma diagnosis for that patient. Unfortunately, that has led to some economic issues for the administration of these therapies.
David Maloney, MD, PhD: The average admission was day 5, if I remember, for the patients who were treated in the outpatient setting, which might be an opportunity.
Caron Jacobson, MD: I think this is a health policy issue, though, because our reimbursement pattern should not be dictating what we do for our patients, right? That’s not what we should be making our decisions based on, and I think that has to be communicated.
Frederick Locke, MD: I totally agree. But at a price tag of close to $400,000, hospitals may not be able to afford to...
David Maloney, MD, PhD: To not get paid.
Caron Jacobson, MD: It’s not an issue to bring to the hospitals. It’s an issue to bring to Medicare and Medicaid.
Frederick Locke, MD: Exactly. But it’s a problem that needs to be addressed and solved; otherwise, we’re going to make the decisions based on these issues.
David Maloney, MD, PhD: I’ll just point out a small abstract that we presented, which was an interesting attempt to develop patient-reported outcomes for people receiving CAR T-cell therapy. This has been a limited approach so far. There have been a little data with Kymriah [tisagenlecleucel], but we actually tried to incorporate this into the study. I think 190 patients we saw did this. What we basically saw was there was a dip at 1 month in terms of patient-reported quality of life that then improved steadily throughout treatment. Things to keep in mind are that you can’t fix things that preexist. Many of these patients had neuropathy. They had prior therapy. They had prior transplants. If you carry a lot of baggage coming into treatment, you’re not going to cure that with the treatment.
The second thing is, they all had active disease. You would expect the quality of life to continue to deteriorate if you can’t treat their disease. What we did find was if you look at responders versus nonresponders, there’s a marked difference in improvement in quality of life, which is not surprising. I’m not sure about the value of these kinds of things in somebody with a fatal illness. But I think it does show that we’re not hurting their quality of life by the long-term toxicities with CAR T-cell therapy.
Frederick Locke, MD: Yeah, and I enjoyed your presentation on the patient-reported outcomes. We actually conducted a single-center look at patient-reported outcomes with axicabtagene ciloleucel. We presented this at last year’s ASH meeting and had similar findings. During the acute phase of the therapy, patients were reporting more fatigue and other issues. But as time went on, they actually felt better than they did before CAR T-cell therapy. That’s likely related to the fact that these patients are in durable remissions. It is important to note that many of these patients, within months after treatment, are feeling back to their precancer baseline, or at least pre—CAR T-cell therapy baseline, and return to work and things like that.
Jason Westin, MD: This is critical for the success of CAR T cells long-term, especially as they move into the second line—to be looking at these quality-of-life issues. Going back to the idea of healthcare utilization, as a third-line therapy it’s very important if the second-line clinical trials, which we’ll talk about in a moment, are positive. Then the number of patients who may be eligible for CAR T cells may skyrocket, and that may have an even greater taxing on the healthcare utilization and the need to look at this as a health policy from government payers.
Transcript Edited for Clarity