ASH 2025 | POD36 as a prognostic marker and clinical tool in frontline CLL

This is something that I’m really excited about. It’s been kind of a long time coming. Early event status or early disease progression is a robust prognostic marker for survival in other indolent non-Hodgkin lymphomas, most remarkably, I guess, follicular lymphoma, where POD24 or early disease progression within 24 months of chemoimmunotherapy, really separates out a high-risk group of patients. This has been previously shown actually in CLL patients as well who had received first-line chemoimmunotherapy, and about one out of four patients in that group have this early disease progression within 24 months. 

We have now seen that there are a subgroup of patients that actually with targeted therapies still have a shorter than expected duration of benefit from these very effective classes of drugs. And so that led to looking, can we identify a thus far unquantified with our current prognostics, our current molecular testing, an additional high-risk group that we should be focusing on. 

And so we looked at a large cohort, nearly 800 patients treated at Mayo Clinic with a targeted agent as first-line therapy. This could be continuous BTKi or time-limited BTKi, BCL-2 inhibitor, or BCL-2 inhibitor and CD20, mostly venetoclax and obinutuzumab in that group, and identified where is the cut point, what is the early event status that makes sense in the contemporary era. And so this, fortunately, things are getting better. This stretches out to about 36 months, but if you use a cut point of 36 months, about 15% of people have an early progression event in that time. And that is independently associated with a fourfold increased risk of death. The only baseline feature that was associated with POD36 was TP53 disruption. But then again, when we’re looking at multivariable analysis on a time to event basis, all of these patients, it was independently associated with a fourfold increased risk of death. I think that warrants it saying again. 

So where do we from here? It needs validation certainly but I think looking this way and that: look to the beginning can we identify these patients up front and potentially then have novel approaches even in the first line can we better, can we find out how we can predict this high risk presentation early progression events. Secondly the patients who have a POD36 event, they need to be the high-risk subgroup that is being prioritized for innovative strategies and clinical trials right then. This is not a scenario where we should be waiting until you have double-resistant disease and now triple-resistant disease to covalent and non-covalent BCL2. If you have a patient that has early disease progression on their first targeted agent, they need to be prioritized for clinical trial at that juncture. And we as a community need to be coming up with innovative strategies for that.

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