ASH 2024 | An analysis of second primary malignancies in patients receiving CAR T-cell therapy

So in a follow-up meta-analysis to the one that we published on non-relapse mortality, earlier this year we took a really deep dive on the subject of second primary malignancies. Now this has been a really hot topic after the FDA issued a black box warning on this subject with CAR T-cell therapy, focusing specifically on the incidence of T-cell lymphomas arising after CAR T-cell therapy, positing potentially that insertional mutagenesis may play a role in this. And so we really looked at all the clinical trials, real-world studies, and took a deep dive in understanding SPM, the overall estimate of SPM after a median follow-up of about just more than a year. We find that SPM, indeed, they occur in about 6% of CAR T-cell recipients. And we do not see differences across disease entities or CAR T-cell products. However, when we perform meta-regression modeling, one of the factors that really came through was the number of prior treatment lines. That’s one. I’ll talk about that in a second. And the second was really the duration of follow-up and the treatment setting. So there’s really three factors. Now, treatment setting, as a patient is followed up in a clinical trial, they’re followed up more closely for these long-term events and that is not necessarily surprising. Also follow-up time, we know that as patients are followed longer or have a longer duration of follow-up, they have a higher likelihood for developing these types of long-term side effects like SPM. And then finally treatment lines, CAR T-cell patients, you know, they arrive to therapy currently in a state where they’ve received multiple lines of prior chemotherapy, systemic therapies. And so when we’re talking about the risk of SPM after CAR T-cell therapy, we’re actually talking about the risk of SPM after the first, second, third line of therapy, then CAR-T. How do we know which one of these therapies the SPM truly relates to? And so I think that this analysis really opens more questions. I think we need longer follow up on a lot of these trials to really understand this long term side effect better. We also are able to take a deeper dive into understanding what types of SPMs. We see that myeloid malignancies are actually quite common, whereas T-cell lymphomas, which have had high media attention, actually were exceedingly rare. And even in the cases where we identified them, a lot of times they were actually not CAR positive. And I think this study adds to the literature, understanding and contextualizing the risk of SPM for our patients moving forward. And probably the most important part of this analysis was actually a subgroup meta-analysis where we looked at CAR T-cell therapy relative to previous standard of care therapies. And we do not see that the SPM estimate is higher in the CAR T-cell arm relative to previous standard of care. So maybe a little bit of caution really about this hot topic of SPM with this analysis.

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