Predictors of CRS and Neurotoxicity in Lymphoma Patients

Hi everyone, my name is Rani Chaval. I'm attending on the cellular therapy and bone marrow transplantation service at Memorial Stone Kettering, where I'm also a physician scientist investigating mechanisms and determinants of efficacy and toxicity of cellular therapies. In this ash on behalf of the CIBMTR, I presented work on the landscape of toxicities of CAR T cell therapy. CAR T cell therapy has transformed the field of care in hematological malignancies, specifically in lymphoma. Patients that were previously refractory to chemotherapy have a chance for long remissions and even cure. However, the downside is that CAR T cell therapy is also associated with some significant toxicities. In our analysis on behalf of the CIBMTR, focused on the main two toxicities. One is cytokine release syndrome or CRS, and the other is immune effector cell associated neurotoxicity syndrome or neurotoxicity. We also call it ICANS. So what is CRS and what is ICANS? CRS is in fact a systemic response to the infusion of CAR T cell therapy. When we infuse the CAR T cells, they expand when they are exposed to the tumor antigen or to the tumor cells. And this leads to a systemic inflammatory reaction where patients develop fever and moreover their blood pressure could go down, they could become hypoxic, meaning they have difficulty breathing, and that could be a life-threatening complication. With neurotoxicity or ICANS, we have a broad range of manifestations starting from mild tremor or agitation up to a coma, seizures, and even could deteriorate to death. Luckily these severe complications or severe manifestations of these complications are not as frequent, but we still see considerable amounts of CRS and ICANS. What we did in the current analysis and published this ash is run one of the largest analysis of looking at CRS and neurotoxicity in patients treated with CND19 directed CAR T cells for large B-cell lymphoma in the United States. We had approximately 1900 patients from 97 centers. In this analysis, we looked at the incidence of cytokine release syndrome and neurotoxicity or ICANS. We actually had one of the largest cohorts to date of approximately 1900 patients from 97 centers reported to the CIBMTR, which is a national registry for cellular therapy and hematopoietic cell transplantation. We find that most patients either do not develop CRS or develop relatively low grades of CRS, meaning grade one or two, with approximately 67% developing these low grades. The more severe grades of CRS, meaning grade three or higher, were experienced by about 8% of patients. So this is not a very high rate and this is actually encouraging. With respect to neurotoxicity, again, most patients did not develop a neurotoxicity. So 56% did not have any ICANS at all. However, 21% of the patients developed severe ICANS, meaning grade three or higher. And this is a life-threatening complication, so we should keep that in mind and keep that in mind and try to prevent it. We then looked at what are the predictors of developing these toxicities. And for CRS, we found that a certain type of CAR T cell product was associated, we call it a certain type of CAR T cell product called axicotidin sololusso was more likely to be associated or induce CRS. We should also take in mind that we did not look at a response, which sort of is the other side, but it was associated with a slightly higher likelihood of CRS. With respect to ICANS, again, the CAR T cell product, axi-cell or axicotidin sololusso, was more likely to be associated with ICANS compared to tisagenicluso, which is another type of a CAR T cell product. Other risk factors for developing ICANS included an older age and a lower performance status at the time of administration of CAR T cells. Finally, we looked at the implication or the impact of having these toxicities on survival on these patients. We found that patients having low grade or no CRS or ICANS had longer survival to patients that developed more severe manifestations of ICANS and CRS after CAR T cell therapy. In conclusion, we see that there is still a substantial proportion of patients experiencing either CRS or ICANS following a CAR T cell therapy. The fact that these severe toxicities are also associated with shorter survival means that we should be very, very aggressive in preventing those and try to understand better who will develop these toxicities and again, how we can prevent them.