Relapsed/Refractory B-Cell ALL: CAR-T Safety Profiles

Elias J. Jabbour, MD: My last question regarding CAR [chimeric antigen receptor] T cells is about the toxicities. We’re learning on the job. Things are better. If you look at the data from the ELIANA trial, the rate of cytokine release syndrome [CRS] and neurological events were higher than they were in the consortium data. Tell me about the acute and delayed safety concerns.

Jae Park, MD: Acute toxicity usually happens within the first 2 or 3 weeks of the CAR T-cell infusion. There are 2: CRS, or cytokine release syndrome, and neurotoxicity. The first cytokine release syndrome usually happens fairly early. The median time for some of the products is about 1 to 2 days, so it happens in the first week. The predominant symptoms are fever, chills, hypotension, tachycardia, and hypoxia. It’s very similar to SIRS [systemic inflammatory response syndrome] or sepsis-like syndrome due to the release of proinflammatory cytokines.

The second toxicity, neurotoxicity, usually comes following the CRS, either concomitantly immediately following or after resolution of a CRS. Those are also usually acute toxicity, meaning it happens in the first 7 to 14 days. There are differences in the rate of these adverse effects in patients with lymphoma, myeloma, or ALL [acute lymphoblastic leukemia]. The group that tends to get the most toxicity is patients with adult ALL, unfortunately. Although they’re becoming much more manageable with brexucabtagene, about 25% of the patients are experiencing grade 3 and higher CRS and neurotoxicity, which typically means that they need to be in the ICU [intensive care unit] level or high acute level setting to manage this toxicity.

However, things are getting better, and we’re learning. The field has learned a great deal the last 10 years or so about managing the CAR T-cell–related toxicity. One thing is we’re intervening early with tocilizumab, which is an IL-6 receptor inhibitor approved for managing the CRS that’s related to CAR T-cell therapy. It’s highly effective in reversing very rapidly, within hours of infusion of tocilizumab. For neurotoxicity, steroid treatment is a mainstay of our therapy. With tocilizumab and steroids, we’re able to treat and prevent those severe or grade 5 events.

We also recently presented the data for anakinra, an IL-1 receptor inhibitor, at ASH [American Society of Hematology Annual Meeting], not in patients with ALL necessarily but in patients with lymphoma who were also at high risk of developing such adverse effects. We may be able to prevent the neurotoxicity, given the role of interleukin-1 in the generation or pathophysiology of a neurotoxicity. There are also many others, including itacitinib, JAK inhibitors, and GM-CSF [granulocyte-macrophage colony-stimulating factor] inhibitors. The field is evolving greatly at a very fast speed to reduce such toxicities.

Transcript edited for clarity.