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Importance of MRD Testing in Acute Lymphoblastic Leukemia

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 02, 2018



Transcript: 

Mark R. Litzow, MD: Let’s turn now and talk about really a pivotal topic that has emerged as one of the most important, if not the most important, prognostic factors. That’s testing for minimal residual disease. Some people say measurable residual disease. I’d like to turn to Aaron and ask you to talk a little bit about the importance of this and some of the nuances and issues that we’re facing, particularly in the adult population, and how we utilize this tool.

Aaron C. Logan, MD, PhD: As you mentioned, MRD has long been conceived as signifying minimal residual disease, and this was originally built into several Children’s Oncology Group studies at particular milestones during the course of induction and consolidation therapy. And then, not long thereafter, the European groups started incorporating MRD even into the care of adult patients with ALL. We in the United States who do adult medicine have learned an awful lot from our pediatric colleagues worldwide, as well as our adult colleagues in Europe. And as the technologies have evolved, what we’re simply doing is deepening our knowledge about the patient’s response to initial therapy. And so, MRD really should signify measurable residual disease. We’re just simply changing the dynamic range of our knowledge. We used to define complete remission as there being less than 5% lymphoblast.

Not a single person at this table is happy if our patient has 3% lymphoblast at week 16 of therapy. And so, with these technologies like multiparameter flow cytometry or allele-specific oligonucleotide PCR, the next-generation sequencing approaches, we can deepen our knowledge about how that patient is responding to their therapy. Have they gotten to a point where there are less than 10-4 leukemia cells? That’s 1 leukemia cell out of 10,000 cells in the bone marrow, which has been recognized now through various COG studies—as well as European studies, as we can discuss—as an important threshold to achieve, because that’s very prognostic for whether a patient is going to relapse. We can debate what the right time point is. Is it the end of induction? Is it week 16? I would say it’s all of them, and we learned this from one of the German multicenter ALL group studies where they looked at MRD at every single point of therapy on their BFM backbone—at day 11, day 24, and at subsequent time points—as patients receive consolidation chemotherapy. And at every single time point, the presence of MRD greater than 10-4 remains prognostic.

What the regulatory, or should I say the advisory, agencies such as the NCCN and the European equivalent have done in the guidelines is they now state that MRD is the most important prognostic feature that we can assess in a patient who has received therapy for ALL. And both of those guidelines now recommend that every patient, regardless of their age, has an MRD assessment at some point. Now fortunately, the availability of MRD assessment has caught up to the point where every physician who takes care of a patient with ALL has one or more mechanisms by which they can assess disease, and I think that’s very important to do.

Mark R. Litzow, MD: Bijal, how should we assess MRD?

Bijal D. Shah, MD: That’s a great question. You brought up the cutoff of 10-4, which has really been our base with multiparameter flow cytometry. But it’s becoming clear, at least based on the UKALL data, but also in our experience in treating Philadelphia-positive leukemia, that when we get deeper than that it is still prognostically relevant. And so, as we start to develop these molecular techniques—you mentioned next generation sequencing, allele-specific PCR, and so on—it’s going to be critical that we apply them in the same way that the COG did.

I think that we’re going to have to begin to start looking at this at multiple time points throughout their chemotherapy regimen. If we have that high-risk patient with early T-cell precursor who’s MRD positive at week 4, because we are changing our therapies as we move to the consolidation phase, what can we expect after consolidation? What can we expect after interim maintenance, and so on and so forth?

I think we have to have that understanding. Right now, we don’t, and that’s why we have a lot of guesswork. Is induction important? Is consolidation important? Is it 10-5? What about 10-6? How confident can we be that that’s a real value? These are all things that we critically need in the context of clinical trials, Alliance-type cooperative group studies.

Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: Let’s turn now and talk about really a pivotal topic that has emerged as one of the most important, if not the most important, prognostic factors. That’s testing for minimal residual disease. Some people say measurable residual disease. I’d like to turn to Aaron and ask you to talk a little bit about the importance of this and some of the nuances and issues that we’re facing, particularly in the adult population, and how we utilize this tool.

Aaron C. Logan, MD, PhD: As you mentioned, MRD has long been conceived as signifying minimal residual disease, and this was originally built into several Children’s Oncology Group studies at particular milestones during the course of induction and consolidation therapy. And then, not long thereafter, the European groups started incorporating MRD even into the care of adult patients with ALL. We in the United States who do adult medicine have learned an awful lot from our pediatric colleagues worldwide, as well as our adult colleagues in Europe. And as the technologies have evolved, what we’re simply doing is deepening our knowledge about the patient’s response to initial therapy. And so, MRD really should signify measurable residual disease. We’re just simply changing the dynamic range of our knowledge. We used to define complete remission as there being less than 5% lymphoblast.

Not a single person at this table is happy if our patient has 3% lymphoblast at week 16 of therapy. And so, with these technologies like multiparameter flow cytometry or allele-specific oligonucleotide PCR, the next-generation sequencing approaches, we can deepen our knowledge about how that patient is responding to their therapy. Have they gotten to a point where there are less than 10-4 leukemia cells? That’s 1 leukemia cell out of 10,000 cells in the bone marrow, which has been recognized now through various COG studies—as well as European studies, as we can discuss—as an important threshold to achieve, because that’s very prognostic for whether a patient is going to relapse. We can debate what the right time point is. Is it the end of induction? Is it week 16? I would say it’s all of them, and we learned this from one of the German multicenter ALL group studies where they looked at MRD at every single point of therapy on their BFM backbone—at day 11, day 24, and at subsequent time points—as patients receive consolidation chemotherapy. And at every single time point, the presence of MRD greater than 10-4 remains prognostic.

What the regulatory, or should I say the advisory, agencies such as the NCCN and the European equivalent have done in the guidelines is they now state that MRD is the most important prognostic feature that we can assess in a patient who has received therapy for ALL. And both of those guidelines now recommend that every patient, regardless of their age, has an MRD assessment at some point. Now fortunately, the availability of MRD assessment has caught up to the point where every physician who takes care of a patient with ALL has one or more mechanisms by which they can assess disease, and I think that’s very important to do.

Mark R. Litzow, MD: Bijal, how should we assess MRD?

Bijal D. Shah, MD: That’s a great question. You brought up the cutoff of 10-4, which has really been our base with multiparameter flow cytometry. But it’s becoming clear, at least based on the UKALL data, but also in our experience in treating Philadelphia-positive leukemia, that when we get deeper than that it is still prognostically relevant. And so, as we start to develop these molecular techniques—you mentioned next generation sequencing, allele-specific PCR, and so on—it’s going to be critical that we apply them in the same way that the COG did.

I think that we’re going to have to begin to start looking at this at multiple time points throughout their chemotherapy regimen. If we have that high-risk patient with early T-cell precursor who’s MRD positive at week 4, because we are changing our therapies as we move to the consolidation phase, what can we expect after consolidation? What can we expect after interim maintenance, and so on and so forth?

I think we have to have that understanding. Right now, we don’t, and that’s why we have a lot of guesswork. Is induction important? Is consolidation important? Is it 10-5? What about 10-6? How confident can we be that that’s a real value? These are all things that we critically need in the context of clinical trials, Alliance-type cooperative group studies.

Transcript Edited for Clarity 
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