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A Conversation on MRD in ALL

Panelists: David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center; Caron Jacobson, MD, Harvard Medical School; Frederick Locke, MD, Moffitt Cancer Center; Max Topp, MD, University Hospital of Wuerzburg; Jason Westin, MD, The University of Texas MD Anderson Cancer Center
Published: Thursday, Jan 23, 2020



Transcript: 

David Maloney, MD, PhD: One of the emerging areas is the use of MRD [minimal residual disease] testing, and this is a rapidly moving field. Do you want to give us a…?

Max Topp, MD: Sure. MRD is something shown to be the most prognostic factor for both pediatric and adult ALL [acute lymphocytic leukemia]. But the question really is, what technology to use. We traditionally have been using flow cytometry. There are more genetically based technologies, such as using the IgG rearrangement to track the B cells in these patients, and there’s emerging technology using NGS [next-generation sequencing], for example. But overall, the data set is actually really compelling that this is the strongest predictive matter for survival in patients with ALL.

Jason Westin, MD: I think the NGS technologies are fascinating and are the most clinically utilized technology that’s not flow based, that’s based on sequencing—the heavy chain gene rearrangement is the adaptive technology so far. There’s another technology that is looking at a panel of new patients. It’s selected for the most common mutations for that disease and then sequenced over time to look for the initial clone as well as emerging other clones that may be relevant for ALL as well as for other lymphomas in the future.

Caron Jacobson, MD: There are some data in diffuse large B-cell lymphoma with response to frontline chemotherapy that was very, very promising. I’m not saying they’re the same data for ALL, but you can imagine it would translate.

David Maloney, MD, PhD: Now that we have those tests, how often should we be doing them in the course of someone’s disease?

Max Topp, MD: For ALL, frequently. After the induction phase and after the conservation phase, you test for MRD. The majority of clinical trials use pediatric-based protocols in adults and, obviously, in young children. A time point of still being MRD positive at week 10, week 12, week 14 is highly predictive of a patient actually having the truly chemotherapy-insensitive clone. Even with maintenance, there is always a risk for relapse for those patients.

David Maloney, MD, PhD: Tisagenlecleucel is approved in the multiple relapsed setting or refractory disease setting. Do we see that moving forward at this point? Or how do we sequence? Where does it come into the treatment of patients with this disease?

Caron Jacobson, MD: Right now it’s approved in the setting of chemotherapy-refractory disease. It is for patients who don’t respond to their frontline chemotherapy or relapse after frontline chemotherapy and then don’t respond to a second line of therapy. I think more and more leukemia doctors are using it ahead of transplant. There’s an emerging question of whether patients who have a good response after CAR [chimeric antigen receptor] T-cell therapy need to go on to have a consolidative transplant.

There is a planned, randomized study for tisagenlecleucel looking at CAR versus inotuzumab versus blinatumomab. Once that study gets off the ground, it will hopefully read out and let us know how we should sequence this with respect to the other CD19-targeted agents. It’s an unanswered question, but we all really have to think hard about giving a patient a CD19-directed strategy ahead of a CD19 CAR T, because we are all worried about potential antigen loss leading to deceased efficacy.

David Maloney, MD, PhD: That’s a really good point, but we also have to remember we cure most pediatric and young adult patients with ALL with conventional chemotherapy. We have now seen studies with blinatumomab and inotuzumab in the relapsed/refractory setting, which have relatively limited utility, I would guess, in that setting. But I think that blinatumomab is now approved as an adjuvant in MRD-positive patients as well. So it’s really interesting to figure out how to sequence CAR-T cells if you’re going to use a CD19-directed therapy just beforehand, and partly because of the risk of potentially augmenting antigen-negative escape; although I don’t think we have much data on that at this point. Right now, how do you fit blinatumomab into the strategy?

Max Topp, MD: The data on treating MRD-positive ALL are established in that field. Inotuzumab is an agent that has been explored to be combined with frontline chemotherapy, and there are some very compelling data, at least from the phase II trial, showing that we could use that combination. In my mind, both of those agents would be somewhere integrated into frontline therapy. When a patient relapses or still remains MRD positive, the CAR T-cell therapy might come in to take care of business.

David Maloney, MD, PhD: Jason, how do we incorporate transplant? Is this going to be a road to eliminating transplant? In the ELIANA trial, I can’t remember the exact number, but it was more than half the patients had already failed an allogeneic stem cell transplant when they were eligible to get this. We do know that, at least in the adult population, going on to a second allogeneic transplant after it failed myeloablative allogeneic stem cell transplant certainly has higher transplant-related mortality. What do you think about this?

Jason Westin, MD: This is a big unmet need. We don’t yet know the answer to this. As you said, going for a second allotransplant is quite dangerous. We don’t have a lot of data to suggest that’s required. However, for ALL patients who get a response and are relapsed/refractory already responding to CAR T, it’s quite tempting to consolidate them with an allogeneic stem cell transplant. I think this is an area for which we don’t have an answer, but the risk of relapse without consolidation is tempting for many people to consider an allogeneic transplant in that space.

David Maloney, MD, PhD: Although I think in the ELIANA trial, again, the majority of patients did not get second transplants. We are truly looking at some long-term outcomes in patients who did not get a second allotransplant. I can just comment that in our adult population we have looked at this. Our policy at the Fred Hutchinson Cancer Research Center is to transplant patients who have not had a prior transplant if they have a donor and are transplant eligible. We think that with maybe the exception of patients we consider to have low-risk disease, which will be low LDH [lactate dehydrogenase], high platelet counts, and MRD kind of going into the CAR T, that’s the only group for which maybe we think could not get a transplant and have the same outcome, although we know that’s quite controversial.

Jason Westin, MD: It’s controversial, and we don’t know. As we get better MRD technology, perhaps we could look at not doing that in people who are truly deeply MRD negative, but that’s controversial.

Transcript Edited for Clarity

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Transcript: 

David Maloney, MD, PhD: One of the emerging areas is the use of MRD [minimal residual disease] testing, and this is a rapidly moving field. Do you want to give us a…?

Max Topp, MD: Sure. MRD is something shown to be the most prognostic factor for both pediatric and adult ALL [acute lymphocytic leukemia]. But the question really is, what technology to use. We traditionally have been using flow cytometry. There are more genetically based technologies, such as using the IgG rearrangement to track the B cells in these patients, and there’s emerging technology using NGS [next-generation sequencing], for example. But overall, the data set is actually really compelling that this is the strongest predictive matter for survival in patients with ALL.

Jason Westin, MD: I think the NGS technologies are fascinating and are the most clinically utilized technology that’s not flow based, that’s based on sequencing—the heavy chain gene rearrangement is the adaptive technology so far. There’s another technology that is looking at a panel of new patients. It’s selected for the most common mutations for that disease and then sequenced over time to look for the initial clone as well as emerging other clones that may be relevant for ALL as well as for other lymphomas in the future.

Caron Jacobson, MD: There are some data in diffuse large B-cell lymphoma with response to frontline chemotherapy that was very, very promising. I’m not saying they’re the same data for ALL, but you can imagine it would translate.

David Maloney, MD, PhD: Now that we have those tests, how often should we be doing them in the course of someone’s disease?

Max Topp, MD: For ALL, frequently. After the induction phase and after the conservation phase, you test for MRD. The majority of clinical trials use pediatric-based protocols in adults and, obviously, in young children. A time point of still being MRD positive at week 10, week 12, week 14 is highly predictive of a patient actually having the truly chemotherapy-insensitive clone. Even with maintenance, there is always a risk for relapse for those patients.

David Maloney, MD, PhD: Tisagenlecleucel is approved in the multiple relapsed setting or refractory disease setting. Do we see that moving forward at this point? Or how do we sequence? Where does it come into the treatment of patients with this disease?

Caron Jacobson, MD: Right now it’s approved in the setting of chemotherapy-refractory disease. It is for patients who don’t respond to their frontline chemotherapy or relapse after frontline chemotherapy and then don’t respond to a second line of therapy. I think more and more leukemia doctors are using it ahead of transplant. There’s an emerging question of whether patients who have a good response after CAR [chimeric antigen receptor] T-cell therapy need to go on to have a consolidative transplant.

There is a planned, randomized study for tisagenlecleucel looking at CAR versus inotuzumab versus blinatumomab. Once that study gets off the ground, it will hopefully read out and let us know how we should sequence this with respect to the other CD19-targeted agents. It’s an unanswered question, but we all really have to think hard about giving a patient a CD19-directed strategy ahead of a CD19 CAR T, because we are all worried about potential antigen loss leading to deceased efficacy.

David Maloney, MD, PhD: That’s a really good point, but we also have to remember we cure most pediatric and young adult patients with ALL with conventional chemotherapy. We have now seen studies with blinatumomab and inotuzumab in the relapsed/refractory setting, which have relatively limited utility, I would guess, in that setting. But I think that blinatumomab is now approved as an adjuvant in MRD-positive patients as well. So it’s really interesting to figure out how to sequence CAR-T cells if you’re going to use a CD19-directed therapy just beforehand, and partly because of the risk of potentially augmenting antigen-negative escape; although I don’t think we have much data on that at this point. Right now, how do you fit blinatumomab into the strategy?

Max Topp, MD: The data on treating MRD-positive ALL are established in that field. Inotuzumab is an agent that has been explored to be combined with frontline chemotherapy, and there are some very compelling data, at least from the phase II trial, showing that we could use that combination. In my mind, both of those agents would be somewhere integrated into frontline therapy. When a patient relapses or still remains MRD positive, the CAR T-cell therapy might come in to take care of business.

David Maloney, MD, PhD: Jason, how do we incorporate transplant? Is this going to be a road to eliminating transplant? In the ELIANA trial, I can’t remember the exact number, but it was more than half the patients had already failed an allogeneic stem cell transplant when they were eligible to get this. We do know that, at least in the adult population, going on to a second allogeneic transplant after it failed myeloablative allogeneic stem cell transplant certainly has higher transplant-related mortality. What do you think about this?

Jason Westin, MD: This is a big unmet need. We don’t yet know the answer to this. As you said, going for a second allotransplant is quite dangerous. We don’t have a lot of data to suggest that’s required. However, for ALL patients who get a response and are relapsed/refractory already responding to CAR T, it’s quite tempting to consolidate them with an allogeneic stem cell transplant. I think this is an area for which we don’t have an answer, but the risk of relapse without consolidation is tempting for many people to consider an allogeneic transplant in that space.

David Maloney, MD, PhD: Although I think in the ELIANA trial, again, the majority of patients did not get second transplants. We are truly looking at some long-term outcomes in patients who did not get a second allotransplant. I can just comment that in our adult population we have looked at this. Our policy at the Fred Hutchinson Cancer Research Center is to transplant patients who have not had a prior transplant if they have a donor and are transplant eligible. We think that with maybe the exception of patients we consider to have low-risk disease, which will be low LDH [lactate dehydrogenase], high platelet counts, and MRD kind of going into the CAR T, that’s the only group for which maybe we think could not get a transplant and have the same outcome, although we know that’s quite controversial.

Jason Westin, MD: It’s controversial, and we don’t know. As we get better MRD technology, perhaps we could look at not doing that in people who are truly deeply MRD negative, but that’s controversial.

Transcript Edited for Clarity
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