What is the significance of minimal residual disease and guiding ALL treatment decision?

What is the significance of minimal residual disease in guiding ALL treatment decisions?

Minimal residual disease, or measurable residual disease, or MRD, is a really key component of monitoring patients with acute lymphoblastic leukemia.

One thing that we've learned decades ago in treating patients with ALL is that you need to treat the patient far beyond the point that the leukemia is detectable. If you just stop treating the leukemia the moment the leukemia becomes undetectable, there's a high risk of relapse.

And so with minimal residual disease testing, we're able to identify components of the leukemia at a much lower level than we'd be able to see under the microscope. There are a few ways to assess MRD. One of them is called flow cytometry and involves using antibodies to identify markers on the surface of the cells, and to pick out small populations of cells that look like the original leukemia. Generally, this is sensitive to a level of 1 in 10,000, though at some centers, including MSK, we're able to do even a little bit better than that. And so, for example, that sensitive to the level of 0.01%, whereas looking at it, the microscope might get you to the level of just kind of a few percent that you'd be able to tell.

There are other methods that actually take a look, either at the DNA sequence associated with the abnormal lymphocyte itself, the abnormal B cell, or the abnormal T cell, or that actually use the gene fusion, such as the BCR-ALB fusion. In patients with Philadelphia chromosome positive disease as a marker of MRD. in patients with Philadelphia chromosome positive disease as a marker of MRD.

Sometimes I will hear patients or I'll hear providers refer to ALL broadly as MRD positive or MRD negative. And the advice that I would give in general to colleagues is to just be specific when you're talking about MRD in ALL. At one time point, Are you assessing the MRD? What technique are you using to assess the MRD? What's the sensitivity of that particular assay? All of those pieces of data are important in understanding what the significance of that patient's MRD might be.

Broadly, we use MRD to determine how likely it is that a patient will remain in a deeper mission if they continue on their current treatment strategy. Sometimes this can help us to identify patients who may not benefit from an allergenic hematopoietic cell transplant, because their risk of relapse is relatively low, or patients that are at a higher risk of relapse. If we just continue their current treatment paradigm without making a change.

However, it's important when you are evaluating this information to know what the technique was and when it was tested, because for example, having low level minimal residual disease following induction is different than having a low level minimal residual disease by, let's say, flow cytometry after consolidation, after someone has completed a longer period of therapy.

What happens if I'm still MRD positive after treatment?

Treatment of ALL has a number of different components, in part to help eradicate MRD, and many patients will not have full MRD negativity by the very most sensitive assays after just a few weeks of treatment, for example, particularly in the adult world.

There are a number of therapies that are out there, including the bispecific T-cell engager, blinatumomab, for example, that are very active in patients that have low level residual leukemia that has persisted after standard treatment. And so there are ways that we can eradicate MBD.

Finally, as we get better and better at our MRD techniques, we are realizing that sometimes we need to take a step back when we're looking at MRD assays and see and thoroughly think about what they what they mean.

For example, for patients that have Philadelphia chromosome positive acute lymphoblastic leukemia, some patients may have residual evidence of the abnormal gene fusion. But we and others have found that sometimes that can actually come from even outside the ALL clone. And so if someone is negative by all of the other techniques, such as flow cytometry or looking for the abnormal gene sequence associated with that abnormal B cell, we're less worried about an MRD positive result by the BCR-ABL test. And so it's important to talk with your oncologist about the significance of these results.

I'll also just note that as our testing gets more and more sensitive, sometimes we're in a position with these very low values MRD, where we're unclear if they're clinically significant. And so oftentimes we'll follow closely over time to see if a levels changing, going up, going down, etc. in order to determine whether we really think that that test result is ultimately going to predict an adverse outcome, such as a relapse in that particular patient.

As it turns out, especially with some of the tests like clonoseq, that are very sensitive to the level of one in 100,000 or 1 million, a positive test result at a low level after a few months of therapy does not necessarily mean that someone is going to relapse, although it does mean that they should be should be vigilant. And so it's important to talk with your oncologist or hematologist about what the best monitoring strategy is to make sure that we're continuing to meet our goals.