<p>Assessing the depth of response in patients with chronic lymphocytic leukemia (CLL) using measurable residual disease (MRD) testing is a topic of ongoing research. Achieving undetectable MRD is an important prognostic factor in CLL, and its role in directing treatment in clinical practice is being evaluated in clinical trials.</p>

MRD has been developed to give us a measurement of residual CLL after treatment. We can do this using different methods that provide different levels of sensitivity. Flow cytometry, traditionally the most commonly used method, is generally able to detect an MRD level of up to 10^-4, or 1 in 10,000 cells. Now, we also have next-generation sequencing methods that are able to reach 10^-6, which is a very low level of residual disease. The measurement of MRD guides us in predicting duration of response because we know that disease relapse is related to 2 factors. One is disease kinetics, which is dependent on prognostic factors such as IGHV mutational status. The second factor is how deep the remission is after treatment.

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I use MRD often because I work in a research setting. It helps me to anticipate the behavior of a patient’s cancer after—and even during—treatment. I find it particularly valuable for younger patients and for patients whom we are treating with curative intent. These are cases in which we want to not only control the CLL and allow the patient to live a normal life but also eliminate the disease and allow the patient to have a long treatment-free interval.

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Comparing MRD at different time points can sometimes be difficult with flow cytometry when there are small differences in the number of cells detected. With the development of newer techniques and a higher level of sophistication, the usefulness of the test will also continue to improve.

MRD is a moving target. As Dr Ferrajoli explained, flow cytometry typically detects up to 10^-4, and next-generation sequencing can go up to 10^-6. However, even 10^-6 is not 0, and there could still be billions of cancer cells left. So, MRD is a measure of the depth of remission, which is very important, especially in clinical trials in which you may use it to determine whether a patient with CLL should receive time-limited therapy or continuous therapy. We now have clinical trial data indicating that MRD correlates with progression-free survival, so it may be a very useful biomarker.

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However, there are some drugs, such as BTK inhibitors, that rarely lead to MRD clearance. Other treatments, such as CAR T cells and BCL-2 inhibitor combinations, are more likely to clear MRD, but this does not mean that BTK inhibitors are ineffective, as they can still control the disease.

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I have a love-hate relationship with MRD because, in many patients with CLL, I do not know what to do with the information when my goal is just to control their disease. In clinical trials, particularly CAR T-cell therapy trials, we test for MRD in every patient. It is very important to do that in this setting because we are trying to achieve long-term remission and to potentially even cure their CLL.

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It is important to note that there are some compartmental effects. MRD clearance in the blood does not necessarily mean that the MRD has also been cleared from the bone marrow or the lymph nodes. For instance, some patients can be MRD negative in the blood but still have bulky lymphadenopathy after receiving antibody-based therapy. However, overall, I think that MRD will become a very effective way of determining how deep a remission is.

Most clinical trials in CLL now assess MRD, and we know from trials of venetoclax-based regimens that a patient who is MRD positive at the end of time-limited therapy will likely relapse sooner. In clinical practice, data are still emerging on how to treat patients who remain MRD positive after 1 or 2 years of therapy. Personally, I assess MRD when I am stopping therapy. If MRD is undetectable, it is reassuring to the patient that they have achieved a remission and are likely to stay in remission for a long time.

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The big questions in the field that have still not been addressed are: Can we act on MRD beyond using it as information for prognosis, and should it inform treatment? There are currently mixed data in that regard, with some studies suggesting that continuing treatment longer, especially in the context of combination therapy such as acalabrutinib plus venetoclax, increases the likelihood that MRD will become undetectable. However, whether this benefits patients long-term remains to be seen. So, in the context of time-limited approaches, I think that MRD has a role, at least in prognostication.