Treating Common Toxicities From CAR T Therapy

Transcript:

David Maloney, MD, PhD: Fred, these patients get the typical toxicities: cytokine release syndrome and neurologic toxicities. Would you like to discuss that?

Frederick Locke, MD: Yes. With CAR [chimeric antigen receptor] T-cell therapy, of course these patients are getting conditioning chemotherapy, so they may have transient hematologic toxicities. But there are really 2 main categories of toxicities with CAR T-cell therapy, and that’s cytokine release syndrome, or CRS, and neurological toxicities. Cytokine release syndrome is really characterized by elevation of high cytokines. Patients may develop fevers, hypoxia, hypotension. In severe cases, patients may need pressers to maintain blood pressure, or mechanical ventilation.

The neurological toxicities are often sort of characterized by expressive aphasia but can lead to confusion. Patients can develop seizures. Some patients have more serious neurological events, like cerebral edema, although these events are relatively rare and seem to be related to the type of construct used.

In general, the management of these toxicities for cytokine release syndrome include using the anti—IL-6 receptor antibody, tocilizumab, which is approved in the United States for the treatment of cytokine release syndrome. We also use corticosteroids for patients. In general, the use of these agents has moved into earlier lines.

For the neurological events, tocilizumab doesn’t seem to do a lot for neurological toxicities, although if they’re in conjunction with CRS, tocilizumab can be used. But corticosteroid therapy is the mainstay of treatment for the neurological toxicities.

David Maloney, MD, PhD: When the original data were published, there was a general reluctance to intervene with treatment for CRS or neurological toxicity because of fear of actually blunting the anti-tumor effect. I think the original trials really waited a long time—until patients were in the ICU [intensive care unit] or were on pressers. There’s kind of been an evolution of that. I think we saw that in the real-world data a little bit, right? The incidence of severe CRS and neurological toxicity, or at least the CRS anyway, seems to be less at grade 3, grade 4 than what we were seeing.

Do you see that this evolution is going to be able to make this easier to be done in the clinic?

Frederick Locke, MD: I do see across multiple clinical trials, and in the standard-of-care setting that people are using tocilizumab and corticosteroids for earlier grades of toxicity—CRS and neurological events—and it does appear that the earlier use leads to deceased incidence of the severe events and does not appear to be impacting response rates. We may need more time to look at durable responses, but I think that it’s giving us more confidence in the ability to use these therapies safely.

Jason Westin, MD: Early on, we had patients who were very savvy and who read about these therapies. Patients would actually say, “Please don’t give me steroids,” when they were getting their CAR T because of fear of potential loss in response. However, as more time has emerged, I think I agree with Fred. We’re seeing encouraging results that reveal that may not have an impact.

David Maloney, MD, PhD: That’s actually a dangerous position, and we have to be careful that we don’t convey that to the patient in the clinic. I, too, have had that situation where people are refusing, or won’t allow us to give them steroids, for fear that it’s going to blunt their anti-tumor effect. In reality, I think they need to understand that if they’re sick enough to need that, then we need to go forward. It’s an important message to explain to your patients: If we do have to intervene, it doesn’t mean that the CAR T therapy is not going to work.

Max Topp, MD: We could also say that if you actually treat a patient with grade 1 cytokine release syndrome or grade 2 neurotoxicity early onward, we may prevent them from grade 3, grade 4 events, where the algorithms actually suggest using not milligram doses of steroids but gram doses of steroids, which then obviously has more of an effect.

Caron Jacobson, MD: We may see some really small subset analyses show that sort of cumulative doses of steroids and things like that may impact overall outcomes. I think we have to be careful about those analyses though, and they really have to be palliative for multifactorial analysis. We do know that patients who have high tumor volume are also the ones who are more likely to have high-grade toxicity. Therefore, they will be the ones who are more likely to need more of these agents, but they are also the patients who are less likely to have durable responses. Whether it’s the treatment of the toxicity or their inherent disease that’s leading to the detriment and outcome, I think that really remains to be seen.

David Maloney, MD, PhD: That seems to be really true in ALL [acute lymphoblastic leukemia] with disease burden. Do you guys have any experience with that?

Frederick Locke, MD: Yeah. I think the data from published trials suggest a higher degree of CAR T-cell related toxicities.

David Maloney, MD, PhD: In the Memorial Sloan Kettering [Cancer Center] data, as well, patients who were less than 5% blast did substantially better in terms of long-term outcomes than people with greater disease burden.

Caron Jacobson, MD: We’re talking about pediatrics right now, but the ROCKET study that was taken into an industry-sponsored study in adults had 2 separate cohorts. They had the MRD [minimal residual disease]—positive cohort, where they didn’t have morphologically positive disease; and then they had everyone who had morphologically positive disease, who in early data, the degree of disease burden certainly looked like it predicted for response.

Transcript Edited for Clarity