Non-Relapse Mortality Following CAR-T Therapy | Kai Rejeski, MD | ASH 2023

So my name is Kai Rogieski from Memorial Sloan Kettering Cancer Center and one of the abstracts that we presented at this year's ASH meeting concerned the incidence of non-relapse mortality. We performed a systematic review and meta-analysis of the incidence and the causes of non-relapse mortality after CAR T cell therapy. So what is non-relapse mortality? Non-relapse mortality is essentially all the reasons for a death after CAR T cell therapy that are not related to the lymphoma or progression of the lymphoma. And these are important because they essentially are very serious adverse events that occur. And we know a lot about the prototypical side effects of CAR T cell therapy, CRS and ICANs. I think what this analysis showed us is that there's also sort of other side effects that are very relevant and that also contribute to non-relapse mortality. And so I think one of the first findings that we observed is that infections are by far the most common cause of non-relapse mortality after CAR T cell therapy. And that's really observed across disease entities, across CAR products. We observe that the second most common cause of non-relapse mortality are cardiovascular or respiratory events. And the third most are actually secondary malignancies. So as we have patients that are responding to therapy, sort of natural events that occur in patients that are in remission can occur. And one of these can be also secondary malignancies. And this is something that we're on the lookout for when patients are sort of in long-term remission. Interestingly, the more CAR T specific side effects, CRS, ICANs and HLH only really were a minority of all non-relapse related or contribute to a minority of non-relapse related deaths. I think really highlighting the importance particularly of infections. What we're now also able to do with this analysis, which encompassed more than 7,000 CAR T patients across clinical trials and real world studies, is we were able to look at sort of what is the expected NRM rate across disease entities. We found that the NRM is actually increased in patients with multiple myeloma and mantle cell lymphoma compared to LBCL and indolent lymphoma. We also found that there are differences between CAR products and especially a higher non-relapse mortality rate with the axocaptogen xylolucil CAR product compared to TISA cell and lysis cell. And generally speaking, the CAR products that had a CD28Z co-stimulatory domain compared to a 4-1VB co-stimulatory domain, they had higher non-relapse mortality. So I think these types of analysis are really important to understand what types of side effects patients are at risk at after CAR T cell therapy. Understanding the risk factors, particularly for infections, we hopefully can develop strategies that mitigate the risk for severe infections after CAR T cell therapy.