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Acute Lymphoblastic Leukemia: Optimizing 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: Friday, Mar 09, 2018



Transcript: 

Mark R. Litzow, MD: I think I’ve heard a number of you say that we should be testing MRD whenever we’re testing a patient, whenever we’re doing a marrow transplant or at frequent times during their therapy. Anthony, what do you think?

Anthony S. Stein, MD: There are some drawbacks and pitfalls of testing MRD. When you send the specimen, you need to make sure that it’s your first pull, and not draw 20 cc from each tube and send part of that for your MRD because then you’re going to get a falsely negative result. So, the technique of drawing the marrow is very important, and also making sure that the first tube that you draw is actually sent for MRD testing and not sent for something else.

Mark R. Litzow, MD: That’s a good point. What is your perspective, though, on the time point when, as Aaron said, you want to make a change in therapy?

Anthony S. Stein, MD: I think that’s dependent on the regimens. From the Alliance protocol, I think MRD was significant at day 28. If you follow the German protocol, it becomes more significant around week 16. And discussing with the University of Texas MD Anderson Cancer Center people, I think for hyper-CVAD it would be after the third cycle, so it would already be part 2. That’s when it becomes significant, after part 2A of treatment. That’s why I think when you treat a patient with ALL, it’s best to pick 1 single regimen that you get used to, know how to use it properly and know all the pitfalls of using that regimen: toxicity, delaying treatment, and dose modifications. Then you know when to do your MRD when it’s going to be predictive, rather than switching between multiple regimens where you really become clueless. And the other thing is, to be able to treat an ALL patient, you need to be treating more than 1 or 2 patients per year to be able to do it correctly.
Mark R. Litzow, MD: Exactly.

Aaron C. Logan, MD, PhD: If we can convey any message today, it should be that ALL patients are rare, and the treatment is very, very important and very highly sophisticated now, particularly with all these new agents. So, I think all of us would be happy if ALL patients were referred to academic centers, at least for a consultation about how to achieve the best response. It doesn’t mean we’re going to have to give them all of their therapy, but they should see an academic hematologist very early on in the process.

Anthony S. Stein, MD: I just want to go back to MRD testing in the relapsed setting. From both the blinatumomab studies and the inotuzumab studies regarding those patients who became MRD-negative. A lot of those patients still relapsed within 3 months of becoming MRD-negative. In my mind, I don’t know how predictive MRD is in the relapsed setting. Using next-generation sequencing and going to a deeper level, that may be where it is very useful to know if you have a deeper level. That may be more predictive of outcome.

Aaron C. Logan, MD, PhD: I think that the achievement of an MRD-negative remission below 10-4 definitely has different impacts in the frontline setting versus the relapsed setting. And it’s true that any patient who relapses and does achieve an MRD-negative remission won’t relapse unless they’re transplanted. At least currently, we’re not aware of another therapy that’s going to cure that patient, but it’s still prognostic going to the transplant. Achievement of MRD-negativity, even in salvage, does predict for better outcome from the allogeneic transplant, so you still want to get that good response with your salvage therapy. And so, the salvage therapy you select is very important, particularly if they’re going to be going to transplant. You might as well not do the transplant if they’re in salvage and going in with MRD, because the transplant just typically won’t work that well.

Bijal D. Shah, MD: Although it wasn’t as relevant, there were still patients who relapsed despite being MRD-negative at 3 months. But when they compared the MRD-negative versus the MRD-positive patients, the MRD-positive patients clearly did much worse.

Transcript Edited from Clarity 

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Transcript: 

Mark R. Litzow, MD: I think I’ve heard a number of you say that we should be testing MRD whenever we’re testing a patient, whenever we’re doing a marrow transplant or at frequent times during their therapy. Anthony, what do you think?

Anthony S. Stein, MD: There are some drawbacks and pitfalls of testing MRD. When you send the specimen, you need to make sure that it’s your first pull, and not draw 20 cc from each tube and send part of that for your MRD because then you’re going to get a falsely negative result. So, the technique of drawing the marrow is very important, and also making sure that the first tube that you draw is actually sent for MRD testing and not sent for something else.

Mark R. Litzow, MD: That’s a good point. What is your perspective, though, on the time point when, as Aaron said, you want to make a change in therapy?

Anthony S. Stein, MD: I think that’s dependent on the regimens. From the Alliance protocol, I think MRD was significant at day 28. If you follow the German protocol, it becomes more significant around week 16. And discussing with the University of Texas MD Anderson Cancer Center people, I think for hyper-CVAD it would be after the third cycle, so it would already be part 2. That’s when it becomes significant, after part 2A of treatment. That’s why I think when you treat a patient with ALL, it’s best to pick 1 single regimen that you get used to, know how to use it properly and know all the pitfalls of using that regimen: toxicity, delaying treatment, and dose modifications. Then you know when to do your MRD when it’s going to be predictive, rather than switching between multiple regimens where you really become clueless. And the other thing is, to be able to treat an ALL patient, you need to be treating more than 1 or 2 patients per year to be able to do it correctly.
Mark R. Litzow, MD: Exactly.

Aaron C. Logan, MD, PhD: If we can convey any message today, it should be that ALL patients are rare, and the treatment is very, very important and very highly sophisticated now, particularly with all these new agents. So, I think all of us would be happy if ALL patients were referred to academic centers, at least for a consultation about how to achieve the best response. It doesn’t mean we’re going to have to give them all of their therapy, but they should see an academic hematologist very early on in the process.

Anthony S. Stein, MD: I just want to go back to MRD testing in the relapsed setting. From both the blinatumomab studies and the inotuzumab studies regarding those patients who became MRD-negative. A lot of those patients still relapsed within 3 months of becoming MRD-negative. In my mind, I don’t know how predictive MRD is in the relapsed setting. Using next-generation sequencing and going to a deeper level, that may be where it is very useful to know if you have a deeper level. That may be more predictive of outcome.

Aaron C. Logan, MD, PhD: I think that the achievement of an MRD-negative remission below 10-4 definitely has different impacts in the frontline setting versus the relapsed setting. And it’s true that any patient who relapses and does achieve an MRD-negative remission won’t relapse unless they’re transplanted. At least currently, we’re not aware of another therapy that’s going to cure that patient, but it’s still prognostic going to the transplant. Achievement of MRD-negativity, even in salvage, does predict for better outcome from the allogeneic transplant, so you still want to get that good response with your salvage therapy. And so, the salvage therapy you select is very important, particularly if they’re going to be going to transplant. You might as well not do the transplant if they’re in salvage and going in with MRD, because the transplant just typically won’t work that well.

Bijal D. Shah, MD: Although it wasn’t as relevant, there were still patients who relapsed despite being MRD-negative at 3 months. But when they compared the MRD-negative versus the MRD-positive patients, the MRD-positive patients clearly did much worse.

Transcript Edited from Clarity 
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