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Acute Lymphoblastic Leukemia: Challenges in MRD Testing

Panelists: Mark R. Litzow, MD, Mayo Clinic; Ryan D. Cassaday, MD, University of Washington School of Medicine; Aaron C. Logan, MD, PhD, University of California San Francisco Medical Sciences Building; Bijal D. Shah, MD, Moffitt Cancer Center; Anthony S. Stein, MD, Hematologic Malignancies and Stem Cell Transplantation Institute
Published: Tuesday, Mar 06, 2018



Transcript:

Mark R. Litzow, MD: Do you think we need to try to standardize MRD testing across the country?

Aaron C. Logan, MD, PhD: I don’t think it needs to be standardized. I think the individual providers of MRD testing can validate their tests, and they can apply for FDA approval of their test to show that it’s reproducible, that it’s valid. I don’t think we need to have everyone do the same MRD assay because flow cytometry, ASO-PCR, and next-generation sequencing correlate very, very well. So, I don’t think we need to standardize. I just want to enable MRD testing for all patients. And so, if you’ve got a flow-based assay in your hospital, by all means use it. You want to have as minimal a barrier to MRD testing as possible. But for the physicians who don’t have access to an internal flow-based MRD assay, I think you really need to set up a way to send it out, to adapt it for the clonoSEQ assay.

Mark R. Litzow, MD: Bijal, you’re saying, “I always wonder, could a test be too sensitive? Could we be picking up a few small clones that are ‘irrelevant?’ It’s not going to change the patient’s prognosis.”

Bijal D. Shah, MD: Exactly. That’s my point. We know that pushing beyond 10-4 in Philadelphia-positive ALL is relevant. I suspect—not just suspect, the UKALL data that were recently published also demonstrated it—that using a really specific PCR pushing below that 10-4 threshold was also prognostic. I have a sense that as we go deeper, it’s going to be relevant. But at some point, without question, the signal-to-noise ratio is lost. We start picking up on more noise than signal, and we also see that in the Philadelphia-positive patients. What do you do with a PCR of 0.000006? I’ll tell you what I do: I’d repeat it. We’re not really sure what to do when you approach that level.

Aaron C. Logan, MD, PhD: I think at those lower limits, it’s likely going to be stratified by the genomics of the disease. If a patient has a PH-like lesion and they get to 10-5, that could mean something different than somebody who has a normal karyotype with no genetic lesions identified on genetic profiling at diagnosis. We’re going to need very large studies to help disambiguate that, but there has to be some interaction between the genetics of the disease and their MRD achievements at various milestones.

We don’t understand that quite yet, so in some cases, we might have too much knowledge if we use a highly sensitive assay. In other cases, that knowledge about the residual disease at a low level is vital. An example is in the postallograft setting. We did a study when I was at Stanford showing that with any detectable disease, even at the 10-6 level forecast, those patients are all going to relapse. In that particular setting, if that patient relapses, it’s going to be very hard to capture them again and offer them anything meaningful. For long-term disease-free survival, that’s a scenario where I think the stakes are high and using the more sensitive test is very well justified.

Bijal D. Shah, MD: But I think we also need to talk about why we’re having this discussion. We’re going to get to it later as well, I hope. Because of what we’re seeing as it relates to blinatumomab in the context of MRD, because of what we’re seeing at it relates to CAR T-cell therapy in the context of MRD, we’re seeing superior outcomes with less toxicity, and I think we have to account for that. That’s the reason why we need to think about it. It’s not making transplant irrelevant, but it’s simply saying we have a technique that we can now utilize in the context of MRD.

Aaron C. Logan, MD, PhD: I think we’re getting into a very interesting era because historically, the presence of MRD at one of these milestones was used to intensify therapy, give some more chemotherapy, and make sure you get them to transplant. The BLAST study demonstrated that for MRD patients at week 16 who got 4 consecutive cycles of blinatumomab, they had 50% long-term disease-free survival without being allografted.

Now, that’s a small study. It needs to be repeated with a larger number, but it’s really compelling that there may be patients where, if we could identify them and treat them for MRD with an immuno-oncology agent like blinatumomab, perhaps we can actually save them the need to go to the transplant, which is very, very interesting. We’ll end up with these scenarios where patients who do well, achieve their MRD-negative milestones, and are actually going to stay on chemotherapy and chemotherapy maintenance for 2 to 3 years. Those who are MRD-positive at week 16 are going to switch tracks, get some blinatumomab, and be done earlier.

Bijal D. Shah, MD: Exactly.

Aaron C. Logan, MD, PhD: Is that right? I don’t know how we’re going to deal with that as a field, but that’s what the data are now telling us to do. It’s going to be really interesting.

Transcript Edited for Clarity 

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Transcript:

Mark R. Litzow, MD: Do you think we need to try to standardize MRD testing across the country?

Aaron C. Logan, MD, PhD: I don’t think it needs to be standardized. I think the individual providers of MRD testing can validate their tests, and they can apply for FDA approval of their test to show that it’s reproducible, that it’s valid. I don’t think we need to have everyone do the same MRD assay because flow cytometry, ASO-PCR, and next-generation sequencing correlate very, very well. So, I don’t think we need to standardize. I just want to enable MRD testing for all patients. And so, if you’ve got a flow-based assay in your hospital, by all means use it. You want to have as minimal a barrier to MRD testing as possible. But for the physicians who don’t have access to an internal flow-based MRD assay, I think you really need to set up a way to send it out, to adapt it for the clonoSEQ assay.

Mark R. Litzow, MD: Bijal, you’re saying, “I always wonder, could a test be too sensitive? Could we be picking up a few small clones that are ‘irrelevant?’ It’s not going to change the patient’s prognosis.”

Bijal D. Shah, MD: Exactly. That’s my point. We know that pushing beyond 10-4 in Philadelphia-positive ALL is relevant. I suspect—not just suspect, the UKALL data that were recently published also demonstrated it—that using a really specific PCR pushing below that 10-4 threshold was also prognostic. I have a sense that as we go deeper, it’s going to be relevant. But at some point, without question, the signal-to-noise ratio is lost. We start picking up on more noise than signal, and we also see that in the Philadelphia-positive patients. What do you do with a PCR of 0.000006? I’ll tell you what I do: I’d repeat it. We’re not really sure what to do when you approach that level.

Aaron C. Logan, MD, PhD: I think at those lower limits, it’s likely going to be stratified by the genomics of the disease. If a patient has a PH-like lesion and they get to 10-5, that could mean something different than somebody who has a normal karyotype with no genetic lesions identified on genetic profiling at diagnosis. We’re going to need very large studies to help disambiguate that, but there has to be some interaction between the genetics of the disease and their MRD achievements at various milestones.

We don’t understand that quite yet, so in some cases, we might have too much knowledge if we use a highly sensitive assay. In other cases, that knowledge about the residual disease at a low level is vital. An example is in the postallograft setting. We did a study when I was at Stanford showing that with any detectable disease, even at the 10-6 level forecast, those patients are all going to relapse. In that particular setting, if that patient relapses, it’s going to be very hard to capture them again and offer them anything meaningful. For long-term disease-free survival, that’s a scenario where I think the stakes are high and using the more sensitive test is very well justified.

Bijal D. Shah, MD: But I think we also need to talk about why we’re having this discussion. We’re going to get to it later as well, I hope. Because of what we’re seeing as it relates to blinatumomab in the context of MRD, because of what we’re seeing at it relates to CAR T-cell therapy in the context of MRD, we’re seeing superior outcomes with less toxicity, and I think we have to account for that. That’s the reason why we need to think about it. It’s not making transplant irrelevant, but it’s simply saying we have a technique that we can now utilize in the context of MRD.

Aaron C. Logan, MD, PhD: I think we’re getting into a very interesting era because historically, the presence of MRD at one of these milestones was used to intensify therapy, give some more chemotherapy, and make sure you get them to transplant. The BLAST study demonstrated that for MRD patients at week 16 who got 4 consecutive cycles of blinatumomab, they had 50% long-term disease-free survival without being allografted.

Now, that’s a small study. It needs to be repeated with a larger number, but it’s really compelling that there may be patients where, if we could identify them and treat them for MRD with an immuno-oncology agent like blinatumomab, perhaps we can actually save them the need to go to the transplant, which is very, very interesting. We’ll end up with these scenarios where patients who do well, achieve their MRD-negative milestones, and are actually going to stay on chemotherapy and chemotherapy maintenance for 2 to 3 years. Those who are MRD-positive at week 16 are going to switch tracks, get some blinatumomab, and be done earlier.

Bijal D. Shah, MD: Exactly.

Aaron C. Logan, MD, PhD: Is that right? I don’t know how we’re going to deal with that as a field, but that’s what the data are now telling us to do. It’s going to be really interesting.

Transcript Edited for Clarity 
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