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MRD Testing for Acute Lymphoblastic Leukemia

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Published on June 17, 2021

The Importance of MRD Testing for Patients With ALL

Measurable residual disease (MRD) testing is allowing for more personalized care and informing treatment decisions for acute lymphoblastic leukemia (ALL). Follow along as Patient Power co-founder Andrew Schorr is joined by Susan O'Brien, MD, of UC Irvine Health, to discuss the importance of MRD testing and when these tests should be repeated. They also cover how MRD results can impact treatment decisions, including if and when a patient is eligible for stem cell transplant.

Support for this series has been provided by Adaptive Biotechnologies. Patient Power maintains complete editorial control and is solely responsible for program content.

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Transcript | MRD Testing for Acute Lymphoblastic Leukemia

Andrew Schorr: Hello and welcome to Patient Power. I'm Andrew Schorr and joining us once again on Patient Power is Dr. Susan O'Brien from UC Irvine. She's the Associate Director for Clinical Sciences there at the Chao Family Comprehensive Cancer Center. Dr. O'Brien, welcome back to Patient Power.

Dr. O'Brien: Thank you. Good to be here, Andrew.

Andrew Schorr: Dr. O'Brien, let's talk about MRD as you call it, some call it minimal residual disease, some call it measurable residual disease, and let's focus it on acute lymphoblastic leukemia. You've been a treating expert in that for many years. So where does MRD come in now? And why is it important?

How Does MRD Testing Impact ALL Treatment Decisions?

Dr. O'Brien: It's something we actually learned originally from the pediatricians treating pediatric ALL, but it's certainly applicable to all patients with ALL. And what it does, is it... Well, let's back up and look at how we define remission or response in ALL. What we call a CR, complete remission, means that the bone marrow looks normal under the microscope, so the pathologist does not see acute leukemia cells, and the blood counts normalize. Well, you can imagine how much bone marrow a person has in them, and we're taking a tiny little piece and looking at it under the microscope. So, it's probably a rather gross assessment of what we're defining as complete remission. What MRD does is it is a more sensitive assay, the typical one that we use now in clinical trials or in practice, but there are more sensitive assays coming out or available.

But the typical one that you see is an assay where it can look at or detect one in 10,000 leukemia cells. So, that's obviously a much more sensitive indicator of potential residual disease. Does that make any difference? Well, now we know it absolutely does. So, if a patient appears to be in complete remission, but their MRD assay is positive, their disease will come back unless we intervene to prevent that from happening. So, before we had MRD, we did use prognostic factors to try and predict which patient would be likely to have their ALL recur. And if we thought that that was likely, let's say based on chromosome abnormalities in the ALL, then we would generally refer those patients for allogeneic stem cell transplant in first remission, before the disease could have a chance to come back. And if the prognostic factors suggested maybe this is a lower risk patient, we might just treat them with some maintenance chemo and not refer them for stem cell transplant.

Well, now we still use the prognostic factors, but now we have a more refined way. I'm trying to figure out what to do after a patient enters remission, which is that we assess for minimal residual disease. And it doesn't have to be right after the first cycle. Some people still have disease after just one cycle of chemo, and then it goes away after two, but after two or three, if we can still detect disease using that sensitive assay, we know we need to change gears and either switch to alternate therapy, which we generally would do, and/or probably now define that person as high-risk and try and get them MRD undetectable, where the test is negative, but also most likely if they're able to go, send them for transplant.

Andrew Schorr: Okay, let me just go over that with you to make sure we all understand. So, this allows you, with MRD testing, to really get a clear picture of what's going on and how well treatment has knocked back the disease? And that helps determine how aggressively you need to treat the disease or not going forward at that time. Did I get it right?

Dr. O'Brien: Yes. I don't know if I would call it aggressively except for the transplant, but we need to switch gears and stop using the chemo we're using because obviously it's not getting rid of the disease. So, we have to take an alternative treatment approach.

What Are the Levels of Measurable Residual Disease Testing?

Andrew Schorr: Okay. Let's talk about levels of testing. So, you said you look now for one in 10,000 cells, and I understand that's typically through flow cytometry, is the testing-

Dr. O’Brien: There’s more than one way.

Andrew Schorr: -but you have newer tests coming on.

Dr. O'Brien: Sorry, Andrew. Yes, you can do it by flow cytometry. And that, as you said, is a very common way to do it. You can also do it, and maybe you were going to say this, by next generation sequencing.

Andrew Schorr: Mhmm (affirmative).

Dr. O’Brien: Which is a newer test that you were probably just alluding to.

Andrew Schorr: Right.

Dr. O’Brien: You can do it by something called PCR. So, there's a number of techniques that are all reasonable. It's the level of sensitivity that's important. And the standard is one in 10,000.

Andrew Schorr: Right. And so, where we're headed though is with, for instance, next generation sequencing, I think it can get much deeper. For me as a patient, working with you, I want to know that the treatment that I've been receiving has knocked it back to undetectable levels with a pretty sophisticated survey now.

Dr. O'Brien: Yes. Could it be too sophisticated? Probably not, but let's look at that. So, let's say we had... Well, we do have. Let's say we're talking about an assay where you could detect one in a million cells. Well, yeah, if I'm the patient I'm thinking, well, I don't want one in the million cells, I want no cells. But we also have to know, does that actually predict for a recurrence of the disease? So why would it not? Well, there is a thought that if you have very, very low levels of cells, that the body's own immune system might be able to get rid of those. So, we might not want to treat more aggressively or change treatments if it turned out that the outcome was going to be good.

This is all somewhat hypothetical, because as you alluded to, these newer tests that could detect one in a million cells are so new that we haven't actually correlated the presence of disease at that level with outcomes, we don't have a lot of data. But we do know from some other diseases where you can detect low level disease, that people still can stay in remission for many, many, many, many years. So, we have to find what is the tipping point where you want to get as deep as you can because you want to get rid of all the cells, but if it's an amount of cells that would not have led to recurrence, then we don't want to switch gears and send somebody to a transplant in that setting.

Andrew Schorr: So MRD testing, in trying to determine if your patient is undetectable with a sensitive test at whatever level, this is becoming more standard. You're at a university center, patients of course may be watching this who are treated all over, but is it your feeling that MRD testing for ALL has a firm place and is important for the doctor and the patient to determine where you are and what's needed?

Dr. O'Brien: There's no question about that. Nowadays, in ALL, MRD is standard of care. It's not considered investigational. Looking at the higher, the deeper levels, is probably investigational and is being looked at in clinical trials in academic centers. But if we just use that one in 10,000 level, that is standard of care and should be assessed in all patients with ALL.

How Often Should ALL Patients Receive MRD Testing?

Andrew Schorr: So now let's talk about serial testing, if you will. So as a blood cancer patient myself, I get regular blood tests and sometimes I've gotten bone marrow biopsies, and it needs to be done at different places in my journey with my illness. In ALL MRD testing, does it need to be done more than once? Or how do you determine when?

Dr. O'Brien: Yes. So, as I said, we usually will look right at the end of the first chemo, but sometimes people are positive and become negative later. So, you don't necessarily have to change treatment right at that point. But if you do it at that point and they're negative, that's great, right. But if you recall, the way ALL gets treated, it's that you generally have a number of somewhat more intensive cycles of chemo, and it varies a bit from regimen to regimen, but the concept is the same. And then patients generally go on maintenance, which can last two to three years.

So there's quite a long journey of therapy, maintenance therapy generally being therapy that doesn't impact quality of life. So, people can be working, can be going about their business, sometimes taking just pill chemotherapy, but the therapy is long. The intensive therapy is generally in the beginning. So yes, it's important to periodically reassess the MRD status because if, for example, somebody was on maintenance and their MRD, which had been undetectable, is now detectable, that's telling me that if I continue that maintenance their disease is going to recur. So, I've got to change my therapy at that point.

Andrew Schorr: Okay. So, it sounds like MRD testing is a real advance for... We're not at the Star Trek age where you can use some gizmo and just look inside the body at the micro-level, but we've made a lot of progress for you as a hematologist to know what's going on.

Dr. O'Brien: Absolutely. A huge amount of progress, Andrew.

Andrew Schorr: So for people with ALL today, when you look at it with MRD testing and the treatments you have, do you feel there's more hope for people in being able to manage ALL?

Dr. O'Brien: Absolutely. We have, in the past couple of years, two new agents that we didn't have before that we can use in ALL, both are what we call antibody-based therapies. Blinatumomab (Blincyto) is one and inotuzumab (Besponsa) is the other. And the big advantage of them is that they're very tolerable and they're not chemo. So up until we had some of these options, it was a bit trickier to know what to do with MRD detectability. In other words, I just got finished saying, "Well, if we detect it, we need to change gears." Well, if all we had was chemo and we were already using chemo, what do we change to? What we used to do is try and send those patients for transplant because we knew they would recur. But ironically, if a patient goes into a stem cell transplant MRD positive, they're more likely to recur after transplant.

They still may be cured, so it's worth doing it, but they're also more likely to recur than a patient who goes to the transplant MRD undetectable. So, a little bit, it was frustrating because your hands were tied, in terms of, you had this important data suggesting that the disease is going to come back if we keep doing what we're doing, but then the question would be, well now, what do you do about it? Well, here we have these antibodies which have allowed us to have options for switching gears and not just trying to, say, intensify chemotherapy.

Andrew Schorr: Dr. O'Brien, for someone who, where you and the patient agreed transplant might be beneficial, where does MRD negativity or not play a role in how you decide to proceed?

Dr. O'Brien: Ideally you would like the patient to be MRD undetectable before they go to the transplant. But sometimes that doesn't happen. If a patient has relatively resistant disease, you might try one of the antibodies. And if they still… So, you've switched gears already. You said, "Chemo is not getting me there, let me try another approach." And it's ineffective. Then what do you do? Well, in an ideal world, you get the patient MRD undetectable before transplant, but in the real world you might not have any other options to get that patient MRD undetectable. So, should you throw out the transplant? One option that could be looked into are the CAR Ts, so the chimeric antigen receptor trials, and there is a commercially available antibody for pediatrics, not yet one for adults. So that's why I said trials in the adult setting where the CAR T may be able to get the patient MRD undetectable, and then you send the patient to transplant.

If you've explored different options and the patient, you just can't get that patient to a point of being MRD undetectable, should you say, "Well, then they might as well not go to transplant?" No. We know that there's a higher risk for recurrence after transplant, but not everybody who goes in with MRD detectable disease relapses. And we've already discussed that if the patient is MRD positive, they are going to relapse, which we certainly don't want to happen. So going into the transplant is still better than not going, but this is where I think the CAR Ts also can come in, because generally they have been very effective, in many cases, at making people MRD undetectable. As I said, there is approved CAR T, FDA approved, out there for pediatrics and young adults. We do not yet have an FDA approved CAR-T for adults with ALL, but there are ongoing clinical trials.

Can CAR-NK or CAR T-Cell Therapies Help Patients Reach MRD Status?

Andrew Schorr: Let me ask you about CAR T just while we're talking about it. So, Dr. O'Brien there's research going on about different kinds of CAR T, different approaches, and also even CAR-NK research as well, not T cells, but natural killer cells. Will you think that any of this may apply in ALL, and also allow you to infuse these cells more quickly for people who are very sick and maybe don't have the time to wait maybe weeks for something to be made for them?

Dr. O'Brien: Right. So just to expand on that a little bit and remind people, all of the CAR Ts that we have that are commercially available, meaning FDA approved, use the patient's own T cells. So, the T cells are removed from the patient. The company, or the clinical trial, inserts the CAR, and that takes time. And then they have to expand those T cells. And then finally they're given back to the patient. So, as you're alluding to, there are some patients whose disease is so aggressive that in that time period, they progress so much that they get sick and can't even really get the CAR T.

We now are starting to have clinical trials with what are called off the shelf CAR Ts. So, these are CAR Ts that are pre-made, if you will, they're not using the patient's own T cells, which may actually be an advantage in that many people who've had a lot of chemo, et cetera, their T cells may not be that functional. So, these off the shelf products are promising because you also won't have that lag time where we lose some patients because their disease is just too aggressive. As I said, none of those are yet FDA approved, but they are in clinical trials and there's more than one company that's doing this. And that's also happening for the NK CAR Ts. So, these quote unquote off the shelf CAR Ts are also very promising. And as I said, clinical trials are ongoing.

Andrew Schorr: So if you put it all together, more sophisticated testing that can be repeated and a broader range of treatments to give you more options, or as you say, more ability to switch gears in ways that may be right for that patient.

Dr. O'Brien: Absolutely.

What Does the Future Hold for Acute Lymphoblastic Leukemia Patients?

Andrew Schorr: Yeah, I think that's all good news. So where are we headed, Dr. O'Brien, when you look at ALL, the testing and the treatments? You know, being at a university center, what could be next. So, are you hopeful looking into your crystal ball going forward?

Dr. O'Brien: Yes. One thing that's being done now by various centers, as well as the cooperative groups is asking the question, well, if these antibodies are great for treating minimal residual disease or even full-blown relapse, well, might we have better outcomes right upfront if we can incorporate them into frontline therapy, in addition to chemotherapy? And another question is can we incorporate them and do better, i.e., cure more people, but also could we decrease the amount of chemo that we give with all of the side effects that we know from chemotherapy, short-term as well as long-term? So, these are very exciting trials, and I would encourage any ALL patients to look into them, incorporating these antibodies upfront instead of saying, "Well, we'll use them if we have MRD positivity or if the disease recurs." Well, if we can incorporate them upfront, maybe we'll have less chance of MRD positivity and cure more people without having to send them to stem cell transplant to be cured.

Andrew Schorr: So if you put it all together, we have more sophisticated testing and a broader range of treatments. And now looking at where do those treatments, and the testing along with it, where do they fit in in the treatment journey? That's what you're working on now?

Dr. O'Brien: Yes, absolutely. Incorporating them earlier in the treatment and seeing if we can improve outcomes.

Andrew Schorr: Okay. One last thing. You said at the very beginning that there was learning for the treatment of adult ALL from pediatric, you were talking about it related to MRD testing. So, everything you're saying now, would you say that that is more broadly applying to anybody with the ALL diagnosis, whether it's a younger person or an older person?

Dr. O'Brien: A hundred percent. All I was really pointing out is that the first trials looking at MRD and its association with outcome were done by the pediatrics years ago. But in terms of where are they now, they are standard for any patient, child, or adult with ALL.

Andrew Schorr: Okay. So, for a patient who might not be at a university center, but might be more in the community, is there a question a patient or a family member should ask about whether MRD testing might give them and their doctor some insight?

Dr. O'Brien: Well, yes, they should ask their doctor, "What is my MRD status?" And if the doctor doesn't know, then there's a bit of a problem. Those tests, you don’t have to be… Some universities run them themselves, but you don't have to be at a university because many of the major labs will run those tests. So just like a doctor in practice will often send out, when a patient's diagnosed, to look if that leukemia has any chromosome abnormalities, the same labs that you would send those types of tests to, for the most part, all do MRD testing also. So, it's certainly really accessible everywhere, not just in a university setting.

Andrew Schorr: Okay. Well, I think for our audience who want to be empowered patients, it's a very hopeful time, I think, with ALL and what you're working on, what you're doing, and your ability to assess where a patient is. Dr. Susan O'Brien, thank you so much for explaining this to us, and we look forward to hearing about the research on what treatments might be used earlier along with testing to really help you and your patient know what to use when, and as you say, switching gears for maximum effectiveness. Thanks for being with us once again on Patient Power.

Dr. O'Brien: Always happy to be here. Good to see you, Andrew.

Andrew Schorr: Okay. Andrew Schorr with Dr. Susan O'Brien from UC Irvine, near me in Southern California. We wish all of our patients the best of health. Remember, knowledge can be the best medicine of all.

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