SOHO 2026 | The future of MRD-guided treatment in ALL: NGS and cell-free DNA approaches

So, you know, I think right now we’re at a point where we’re still using flow-based MRD, and that’s become the standard across many centers, and that’s a good thing. But it’s also a reflection of what we were doing five years ago, even 10 years ago, and it’s time for us to move forward. It’s not just that next-generation sequencing is more sensitive. It is. It’s going to get us down to 10 to the minus 6 level disease. But here’s the key. That is also predictive of therapeutic failure. I think that’s a message that we’re still working to tell. We’re going to see some data, I hope soon, from the ECOG-E1910 study with those biobank samples. Now, not just a flow-based MRD assessment, but an NGS-based assessment. And we’re also going to see NGS MRD embedded into our trials as we go forward. I can tell you with CAR T-cell immunotherapy, 10 to the minus 6 matters. If you’re 10 to the minus 6, you might as well be 10 to the minus 4 or 10 to the minus 3. Seeing any level of MRD is predictive of relapse. And actually, the degree to which you see it is going to give you a timeline, right? If you’re 10 to the minus 5, 10 to the minus 6, you’ve got about three months. 10 to the minus 4, 10 to the minus 3 is probably closer to two months. And if it’s higher, then quite frankly, you already have disease. So this is the nuance here. We get both a binary endpoint, positive or negative, but also a sense of how quickly we need to intervene to address that MRD, or we’re going to be fighting not MRD, but disease.

I think the other thing to talk about MRD, which is going to be too detailed for this interaction, is understanding how to interpret heavy chains, kappa light chains, lambda light chains, TCR alpha beta clones, TCR gamma delta clones, trying to understand what that means. Because you have to remember that when we’re talking about B-cell recovery or T-cell recovery, the uniqueness of the clone that’s, of the sort of sequence that’s being tracked, because really we’re just tracking a small part of the, you know, the T-cell or B-cell receptor. If it’s not a unique sequence, you wouldn’t want to rely on it for detecting MRD. And so sometimes we pick this up in the, you know, again, as part of our clinical tracking, but really understanding what it is and understanding what it means requires some nuance. And that’s something where we’re working with Adaptive. We’re working with others to try and help to make more sense of the MRD assessments. I’m hoping that as we go forward, it’s no longer a competition of flow versus NGS versus, by the way, we’ve got cell-free DNA approaches, right, from Signatera and others. We’re actually trying to ask, look, if we’re confused, if we don’t know what’s going on, how do we stack our testing to make sure that we’re getting an answer, a meaningful one? And if you can imagine, right, as we go into the cell-free DNA space, can we actually learn a little bit about what mutations that we’re enriching in that cell-free DNA space and think about how to target it? I mean, the future is really that wild. So I’m, you know, I think that forward-looking how we, oh, there’s a word for it, where we sort of combine modalities, but that’s essentially what I’m trying to get.

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