Minimal Residual Disease in ALL

Transcript:Raoul Tibes, MD, PhD: There are several ways to measure MRD. One is by measuring by PCR reactions, immunoglobulins, and T-cell receptor gene rearrangements. The other way is by measuring MRD by multi-color flow cytometry. I would say, at this point, both of those techniques are roughly equivalent, but it depends on the expertise of the laboratory offering those tests. So, unfortunately, MRD monitoring has not quite penetrated clinical practice here in the US. We have several reference laboratories, which use either immunoglobulin or T-cell gene receptor rearrangements or MRD monitoring blood flow, where physicians practicing ALL treatment can send the samples to those reference laboratories. European countries have validated and standardized the MRD monitoring and the reference laboratories throughout Europe as well.

Why is MRD important? Because MRD is one of the most important prognostic factors in the outcome of adult patients treated for their ALL. The two assays roughly have the same sensitivity, so the PCR and the multi-color flow cytometry. We can detect cells at a threshold of 10-4 to 10-5. And hopefully, in the future it will go even deeper. This means you can detect very few cells, and those assays can be done from the bone marrow but also from the peripheral blood. The MRD monitoring by PCR techniques essentially takes the patient’s blood and develops a specific primer to the patient. So, you do need to have a baseline sample, which is important. Flow cytometry monitoring of MRD uses common ALL antibodies or common antigens that are found on the ALL cells, and by 6 or 8-color flow, measures the level of the threshold of how many cells are left, and the sensitivity is very high as well. I would say both techniques of MRD monitoring are comparable at this point, and it’s more important to have a laboratory that the provider works with, trusts, and gets reliable results back.

Stefan Faderl, MD: The question is about the role of minimal residual disease and its importance in significance in treatment of patients with ALL. Minimal residual disease is primarily a very good measure of the quality of response that patients are able to achieve. It does predict outcome quite well in children, and more also obvious in acute lymphoblastic leukemia of adult patients. And it has become a frequent, almost standard, endpoint in clinical studies in children and adult studies with acute lymphoblastic leukemia. I think from a practical perspective, the major purpose or usefulness of minimal residual disease is the question of whether to intensify or deescalate therapy, in other words, whether or not patients may require stem cell transplant or have an equivocal outcome with chemotherapy or even notwithstanding stem cell transplants. If you just talk about chemotherapy, whether doses need to be intensified, additional intensified cycles added. Or if you talk about Ph-positive ALL, you can talk about the dosing of a kinase inhibitor. So, in that sense, minimal residual disease is quite useful and I think will become very important.

You may look at MRD as an endpoint of many, so pretreatment prognostic factors, be they known or unknown, in combination with the response to treatment after effect. It is a great equalizer that just gives you a very good idea as to how patients respond whatever their pretreatment prognostic markers may be and what you can or cannot do or should do with those patients.

Bijal D. Shah, MD: Minimal residual disease has now been recognized as an incredibly important endpoint for predicting treatment efficacy in the long run in adult acute lymphoblastic leukemia. We know now that patients who were previously recognized as high-risk, based on presenting features like white blood cell count who achieve an MRD negative status, may still do very, very well in the long run. The challenge is, as I see it, to the assessment of MRD, is when do we measure it? Is it after an induction and consolidation? Or are there other time points where we need to be continuously reassessing minimal residual disease?

A good example actually came out of the augmented BFM studies where they found that after the induction, while they certainly could show that they could predict outcome, it was actually more predictive when they measured around a 70 after the consolidation. We’re starting to see the same questions emerge in the context of hyper-CVAD. When is the best time? And I don’t think any of us knows.

A broader question is what is the best technology? I think that we’re limited in some regards by what’s commercially licensed across the United States. I think that multicolor flow cytometry is likely to become a standard of care. Whether we’ll see other things, like next-generation sequencing come into the space and either be used in concert with flow cytometry or whether we see one technology supplant the other, it’s too hard to predict at this stage. From our perspective, we’ve been using flow cytometry for some time. When I talk about multicolor flow cytometry, we have been using 4-color flow cytometry, which gets us down to about .1%. We know if we’re talking about MRD, we need to get down to the .01% level to be able to gauge progresses. We’ve been working with partners in the private space. I know there are also universities who are accepting these specimens and running them within their own labs to, again, help us provide that guidance, so that we can better predict how to treat our patients.

Things get even more confusing when we talk about what to do with MRD. We know that it’s an important endpoint for predicting the overall treatment outcome. But what we don’t know, is how will the intensification of therapy in the presence of minimal residual disease, whether that be adding agents on to the chemotherapy backbone or whether that be including things, like allogeneic transplant consolidation. How will those improve the outcome for patients who are MRD-positive? These are all things that we still have to look for from prospective clinical trials.

Transcript Edited for Clarity