EHA 2025 | Using mechanisms of resistance and clonal evolution to guide treatment decisions in R/R AML

Yeah, so this meeting I gave an educational presentation on the mechanism of relapse and progression in relapsed/refractory acute myeloid leukemia. I think the main message is that the genetics and cytogenetics typically change at the time of relapse. It’s really important to do both the cytogenetic analysis and also the whole genome, the genome NGS analysis, sequencing analysis to identify if there’s any targeted therapy that this patient can go in the setting of a clinical trial or off clinical trial. So I presented multiple examples where, for example, complex cytogenetics and TP53 mutations are being selected with intensive chemotherapy and maybe less so or with non-intensive therapy. I also have shown that in the context of targeted therapy, for example, with IDH inhibitors, BCL2 inhibitors, and FLT3 inhibitors, there’s common disappearance of the target lesion, such as IDH mutation, or NPM1 mutation, or FLT3 mutation. But there’s emergence of the clones with what we call signaling mutations, such as RAS mutations, FLT3 mutations, sometimes in the context of BCL2 inhibition. And so it’s really important to track those and to understand how to best manage that. 

So an additional point with the kind of approval of the menin inhibitors in the salvage setting, we now know that there are more subsets that can be sensitive to this therapy in addition to KMT2A rearranged and NPM1 mutated leukemia. And I showed the example of the NUP98 rearranged AML, which could be only diagnosed using the novel technology called optical genome mapping, or OGM, that can identify cryptic translocations and rearrangements at fairly high sensitivity. 

I also showed some other mechanisms of resistance, for example, to menin inhibitor therapy with mutations in the binding site, and also specific to, for example, IDH inhibitor therapy, some mutations, again, in the binding site of the inhibitor, isoform switching, but also non-targeted mechanisms, again, with RAS mutations and mutations in differentiation-associated genes, such as CEBPA. 

So the point is that the mechanisms of relapse are many, and they’re quite diverse. I have demonstrated with the use of a single cell DNA sequencing how we can better understand the clonal progression on the level of individual clones and how we can track those on the level of DNA and also the RNA levels, which of course requires additional studies and understanding. So it’s also the mechanisms of resistance are specific to the therapy that is being used, and now we’re learning more about escape from specific targeted therapies and how best to track those. Fortunately, we have more and more targeted therapies available and I think at relapse the goal is really to get the patient into remission and to go for the transplant if feasible. So I think using targeted therapy rather than the use of chemotherapy is becoming more and more prevalent at the time of relapse and so using the tools that we have is really important to understand molecular mechanisms of progression.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.