ICML 2025 | Tracking responses with ctDNA in patients with FL receiving treatment in the LEVERAGE trial

Yeah so this is work done by my collaborator at Peter MacCallum Cancer Center, Piers Blombery, and his lab. And the Leverage study was a Phase I/II investigator-initiated trial of obinutuzumab, lenalidomide, and venetoclax in first-line high tumor burden follicular lymphoma. And I presented the clinical results at ASH last year and we saw a very high response rate, about 83%, with the two-year PFS of about 92%, so it looks active, but we did see some difficulties with myelosuppression. At this meeting, we are presenting the MRD data, and for this, Piers used a phase-seq-like MRD platform, not quite exactly phase-seq, but using phase variant detection, and we measured it at multiple time points at baseline and after each cycle of therapy, and I think the key take-homes are that we were able to see 96% of the 50 patients had a variant suitable for longitudinal reporting. The most frequently mutated genes for reported variants were BCL2 and immunoglobulin genes, as you would imagine, and based on that, we were able to longitudinally track variants in the vast majority of patients. We were able to see quite nice changes in kinetics of MRD after each successive cycle of therapy, and we were able to show rapid MRD clearance in the majority of patients relatively early on during treatment. We were also able to see some patients who cleared their, they became MRD negative very early and then had a positive end-of-treatment PET that looked like they were a non-responder. However, we did see in this case the utility of ctDNA to actually tell us that perhaps that a patient with a false positive PET could not have a biopsy if they didn’t subsequently progress, and there’s the MRD in the peripheral in the ctDNA in the peripheral blood was negative, it infers that the PET scan was actually a false positive, and that the actual response assessment was probably incorrect, so I think it highlights one potential utility of ctDNA to assist in the management of patients who have FDG-avid sites of potential disease that maybe for whatever reason are inaccessible for biopsy at the end of treatment and helping to make treatment decisions. We also saw a patient who clearly progressed clinically and had biopsy-proven progression who was MRD, apparently MRD negative at the end of their treatment, and when we went back and recalibrated the MRD measurement based on the post-relapse biopsy, there had been clonal evolution in the tumor such that when we reset and when we recalibrated the MRD to the new variants present in the clonal evolution, the MRD became positive. So I think, and that highlights that that’s also a false negative ctDNA result, not really false negative, but negative because there’s been clonal evolution in the tumor. So really, I think we’re learning a lot more about how to use MRD in the management of patients with B-cell lymphomas. And it remains an imperfect tool, which has room for improvement, but it remains a very interesting research tool in the management of patients with follicular lymphoma. And probably the most interesting thing about this is that there is not a lot of MRD phase-seq data about follicular lymphoma, so our abstract is relatively novel in that sense.

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