MRD Timepoints in CLL

Insights From: Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center


Thomas J. Kipps, MD, PhD: We check for MRD, or minimal residual disease, after treatment with a finite regimen such as a chemoimmunotherapy regimen, or any regimen that has a defined course of treatment cycles. It also could be used to define whether or not you can shorten up on the treatment cycles. For example, it’s not one-size-fits-all. In other words, if you have a patient who has chemoimmunotherapy, we say one of the best predictors of a favorable respond is how they respond to the first 1 or 2 cycles of treatment. Generally speaking, it’s a saying that good patients do well. And so, if you have a very dramatic response within the first couple of cycles, that’s a good thing because it indicates your trajectory to clearing the cells in the marrow is actually pretty high. That’s different than if you take maybe 5 or 6 cycles, and you’re still not clearing the cells.

Of those patients who achieve a very good response in the first few cycles of therapy, we could say, “Well, when is it enough?” If we get to a point where we can’t find any leukemic cells in the blood and we can’t find them by exam, then testing for minimal residual disease at that point might be very useful. Looking at the marrow, a very sensitive site, and finding no cells there may allow you to say, “I have had 3 cycles of therapy, maybe I have had enough,” and not go with 6 cycles of therapy, allowing you to stop therapies sooner than if you didn’t have testing for MRD before. That makes a lot of sense to me.

Now, with the newer therapies that are going on and on and on, it’s very seldom—in fact, almost never—that you find patients clearing all the leukemic cells with BTK inhibitors, ibrutinib or acalabrutinib, by themselves. However, we’re seeing patients clear minimal residual disease with the drug venetoclax, and this is quite astounding, because this drug can be taken for a prolonged period. But we’re finding that, after several months of therapy, some of these patients may have a complete response. And if we look even into the bone marrow, we don’t see any leukemic cells with very sensitive tests. This is quite exciting, because then it could be allowed, just like we mentioned earlier for chemoimmunotherapy, to provide us with a means to say enough is enough. Maybe we could stop therapy at this point and be able to go on for a period of time before we require therapy again, and therefore define the course of treatment.

Some of our newer protocols are trying to double up on that, because when we look for minimal residual disease, we’re not looking at all the cells in the body. As a good analogy, let’s say you had a draw full of socks, you had maybe 1000 white socks, and in there you had 1 red sock. You reached in for a fistful and you pull it out, and all you saw is white socks. Well, your test can be more sensitive than the number of socks you have in your fist. And so, if you went and reached for all the socks, you’d find that 1 red sock.

To maximize our chance for not missing disease, we’re looking at strategies where we look for minimal residual disease in patients treated, say, with a venetoclax-based regimen, and if we don’t find it, then we may continue therapy for a few more months just to seal the deal. And then we look again. If we don’t find it again, then chances are we come to a very good response and patients may then at that point opt to stop therapy. We’re looking at patients who stop therapy versus continue therapy, and whether or not there’s difference in outcome. I think that patients who’ve achieved that level of response may actually do quite well without requiring continuous therapy, and that could be very useful for them.

Transcript Edited for Clarity
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