iwCAR-T 2025 | Mitigating non-relapse mortality in patients receiving CAR T-cells and bispecifics

So my name is Kai Rejeski from the LMU University Hospital in Munich. I think the first question is sort of what is non-relapse mortality? Non-relapse mortality really refers to any case of death event not related to lymphoma or myeloma recurrence or progression. These are really the most devastating side effects of cell therapy. And so initially, when CAR T-cell therapy was developed, the events that were observed that resulted in lethality were CRS, ICANS, or para-inflammatory events, essentially. What we’ve seen, though, now in a large meta-analysis that we published last year is that with advances in therapeutic management, these events actually are not the main drivers of non-relapse mortality anymore. It’s the events that are actually well-known to hematologists for more than 70 years. It’s cytopenias, infections, and secondary malignancies. And so to a certain extent, we’ve come full circle now in terms of understanding what types of side effects patients receiving CAR T-cell therapies are at risk for. So I think for CRS and ICANS, one of the big advances was really the development of a consensus grading framework to move away from describing these as sort of syndromes of encephalopathy, fever, but to really give it a name. And giving it a name was the basis for then developing consensus-based grading systems that defined specific severity grades. Now, that then was the basis for developing some type of metric to look at therapeutic advances, so giving toci early, giving corticosteroids. And that, I think, really set the frame for reduction in the overall toxicity burden. However, in the last five years, what we’ve gained a better understanding of is that it’s not just CRS and ICANS that we have to be on the lookout for. We have to think about cytopenias or what we call now immune effector cells associated hematotoxicity or ICAT. We have to be aware of infectious complications that arise due to sort of a multifactorial net state of immune suppression in CAR T-cell patients and aware of toxicities such as ICHS and others. And so I think now we are standing at a similar precipice where we’re trying to develop grading systems consensus reporting standards that then hopefully also allow us to make similar advances in therapeutic management and a reduction of the overall toxicity burden for these emerging side effects of high clinical interest. So in the talk today, I think I really tried to highlight that there are really three main NRM drivers that we have to think about. It’s hematotoxicity, infections, which are closely related to hematotoxicity, and secondary malignancies. So we think about the unmet needs for each one of these specifically. For hematotoxicity or for ICAD, we’ve now developed a grading system that can be employed, the EHA-EBMT consensus grading framework. I think what we have to do as a community is bring this grading system into clinical trials, into registries, to really have comparability of cytopenias across products, across disease entities. So I think there it’s about improving the reporting within an already existing grading framework. For hematoxicity I think it’s also important that we understand the underlying pathogenesis better so that we can develop the next generation of therapeutics. For infections it’s also about reporting. We have to do a better job at defining the type of infection, the site of infection, the timing of infection, the types of infection mitigation strategies that were used because that really provides the context to understand the infection rates that we observe in one clinical trial versus another. And so I think better reporting is really paramount for infectious complications. And then thinking about the type of prophylactic agents, thinking about mitigation strategies such as immunoglobulin, and really generating good evidence that can guide our further therapeutic management. And then finally, for the secondary malignancies, I think one main question is how much of this is actually CAR T-cell related or associated. And I think understanding better the link between CAR T-cells and the associated inflammation and the development of SPMs, I think that’s really a high area of unmet need in our field. So we’ve learned a lot about here, and I’ve talked here about non-relapse mortality with CAR T-cell therapy. But of course, another big question in the field is what about these other immunotherapies, T cell-based immunotherapies that are out there in the field now? And one of these that’s quite promising is obviously bispecific antibodies. And so with bispecific antibodies, the conventional logic is that these are better tolerated, lower rates of CRS, lower rates of ICANS. Oftentimes these can actually be sufficiently provided also in an outpatient setting. However, what we did here in this meta-analysis looking at both real-world studies and clinical trials is we’ve tried to look at the specific causes of death and essentially develop a similar framework for defining non-relapse mortality with bispecific antibodies. I think the first thing to highlight is really that when we account for many different study level confounders, the overall estimated NRM was actually similar for bispecifics and CAR T-cell therapy, which I think is a little bit against the conventional wisdom that is out there. And that has to do a lot with infectious complications. So they actually accounted for more than 70% of all NRM deaths. I think that resulted in an overall high NRM estimate observed with bispecific antibodies of about 5%, which is actually similar to that that is observed with CAR T-cell therapy. So much to do when it comes to bispecifics in terms of identifying infections, reporting infections, and mitigating infections. I think that that’s going to be a key area of interest moving forward for this important T-cell-based immunotherapy as well.

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