VIDEO: Early relapse after initial chemotherapy major unmet need in follicular lymphoma

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Unmet need of follicular lymphoma that's here and present and very clear today, clear for the past decade, is these patients, might be 20, 25% of patients we meet who are early relapsers after initial chemotherapy. We first called these the POD-24 patients after getting R-CHOP they relapsed within 24 months. And it's sort of a similar story with patients that relapse within two or probably even three years of Bendamustine. You know, whether those patients really have the same biology or maybe they just had sort of an early transformed disease that is, you know, not responding in the long term to frontline chemotherapy, it's possible. Regardless, they're an unmet need because the outcomes are quite poor. You know, when we first described these POD-24 patients in this great and seminal paper by Carla Casulo, we saw that median survivals of those patients are approaching about five years, whereas most patients with follicular lymphoma median survivals are well beyond a decade. The survivals are so long we can't even measure them accurately, 'cause as we get newer therapies newer groups of patients have even longer survivals. So, clearly the POD-24 patients have been the primary unmet need over the past decade, and probably still are. How well those patients all do with newer therapies like Lenalidomide, and certainly the new targeted therapies like Tazemetostat, maybe PI3K inhibitors, and certainly with immunotherapies like and other bispecifics in CAR-T cells, we don't really know yet. Those therapies weren't well utilized when we first described these high-risk patients. So that is one unmet need still, the POD early relapsers after chemotherapy. I would say there's a new unmet need that is just revealing itself now, which is again I think, one of the most promising new therapies, immunotherapies with bispecifics. Elegant, highly effective, durable remissions for many patients. But, a common weakness that's shared with most immunotherapies is that the target that the immune system's going after, in this case CD-20 with , target can disappear. CD-20 is not critical to the survival of most of these lymphoma cells, and we have CD-20 loss and causing patients to relapse. We call this antigen escape. Same exact concept with CAR T-cells. CD-19, not usually critical for the survival of the cell in patients. It's well described in DLBCLN acute leukemia, but still the significant proportion of those patients relapsing with CD-19 negative disease after CAR-T cells. We don't know the exact frequency of this antigen escape problem yet. But the very early studies in bispecifics, in one of the publications from a couple of years ago now, the first nine relapsers, six of them had CD-20 negative disease after CD-3 by CD-20 bispecific antibodies. So, I don't know if it's really gonna be 60 plus percentage of patients that relapse with antigen escape, but it's gonna be a large number, so we need to consider that an upcoming critical unmet need. Luckily, we're kind of already trying to address that problem. One way is with novel bispecific antibodies. Instead of targeting CD-20, we target other surface antigens like CD-22. And that could treat patients who've already experienced antigen escape. And some very novel approaches are looking at trispecific antibodies. For example, one that's targeting CD-20 and CD-79 and CD-3. So, maybe if the CD-20 antigen escape is about to occur, we can prevent that by targeting CD-79 concurrently. So, I think antigen escape is going to be an increasingly prevalent, more observed problem over the next couple of years as we use more of these immunotherapies earlier in the lines of treatment. And so, thankfully, we already have some folks trying to address those unmet needs.