EHA 2021 | The role of MRD in AML regulatory decision making

There are a number of studies over, you know, over a decade that have shown that MRD is strongly associated with, you know, relapse and survival in AML. And this is really across different types of MRD detection tools, so whether it’s flow cytometry or PCR, whether you’re looking at different subtypes of AML, different timings of assessment. The studies are pretty clear that, you know, having residual disease as detected by MRD is always worse than being MRD-negative.

Our group recently published a collaborative, looking at the impact of MRD in a large meta-analysis of 81 studies. And not surprisingly, this confirmed the strong prognostic benefit of achieving MRD negativity in AML, with double the five-year overall survival for patients who are MRD-negative, versus those who are MRD-positive.

And so with that, I think there’s been a lot of questions about, you know, could we use MRD as a surrogate endpoint, in clinical trial design and for regulatory approval. And so, the FDA has given some guidance for this. First of course, you need to show that there’s a plausible association between MRD and outcomes, and that’s pretty, that’s pretty obvious. And then to show kind of robust association in some of these retrospective studies. And I think we’ve seen that across studies, and in the meta-analysis.

I think one thing that is still lacking are prospective studies, that clearly show that as therapies change, and along with them MRD status changes, that also impacts overall survival. So, that’s something that hasn’t really been looked at a lot in a prospective manner, and I think that that’s one barrier to using this as a clinical trial endpoint, and in regulatory approval.

That being said, I think it’s a very important thing to investigate because, you know, using MRD as a surrogate endpoint for survival, which I think, you know, we will see, but I think the data will support that, would allow for much more rapid assessment of combination therapies in drugs and clinical trials, because you can assess MRD after one or a few cycles of therapy, as opposed to some large studies that, you know, where you want to see an overall survival benefit. These studies accrue for five plus years before, and mature, before we can get an overall survival benefit.

So, if we can get MRD to be accepted as a regulatory endpoint, for a surrogate endpoint, that will allow for more rapid assessment of new drugs and combination therapies, and mainly to regulatory approval. And ultimately, if we have effective therapies that are good at clearing MRD and ultimately improving survival, we’ll know that sooner, and we’ll be able to treat more patients with those earlier, rather than waiting years and years for studies to accrue. So, that’s a very key next step, I think, in the field of MRD and hopefully one that we’ll see soon, in terms of regulatory approval for MRD as an endpoint.