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The Evolving Role of Transplant in ALL

Panelists: Mark R. Litzow, MD, The Mayo Clinic; Jae Park, MD, Memorial Sloan Kettering Cancer Center; Bijal Shah, MD H. Lee Moffitt Cancer Center & Research Institute; Anthony Stein Gehr Family Center for Leukemia Research
Published: Friday, Feb 22, 2019



Transcript:

Mark R. Litzow, MD:
Anthony, I wanted to ask you: Now that we have the ability to detect these low levels of disease—we’ve got an agent that’s approved to treat these low levels of disease—where does transplant fit into all of this? We haven’t talked about that very much. When do you think about transplant in ALL patients these days?

Anthony S. Stein, MD: So, my philosophy is if you’re using an AYA [adolescent and young adult] regimen, the patient does not have any high-risk cytogenetics such as—hypodiploidy, Philly-like, 4;11 are the main bad players. And, if they become MRD [minimal residual disease] negative, then I would not transplant that patient. I would just follow them. I would continue them on an AYA regimen and follow them over time. If somebody is MRD positive, if somebody has a poorer cytogenetic abnormality or mutational abnormality, then I would give them induction therapy, get them into remission. And, if they have an adequate donor, then I would take them to a transplant.
For somebody who is MRD positive at day 28 or after consolidation treatment, that patient, again, I would give blinatumomab to make them MRD negative. And if they have a good donor, then I would also take them to a transplant based on the German study for MRD, for the BLAST trial. In that study, I think the result, if you look down, if you look at the data for patients going to transplant, there was a higher transplant mortality rate—because if you look at the type of transplants that were done on these patients, a lot of them were 8 out of 10, 9 out of 10; a lot of centers were using cord blood—so you had a much higher transplant-related mortality. So, if you don’t have an ideal donor, then I would just rely on the [blinatumomab] and follow the patient and not transplant the patient.

Bijal D. Shah, MD: Sorry, I was going to say you just brought up a brilliant point, because when I talk to my transplant patients, their response is [that] everyone has a donor.

Anthony S. Stein, MD: Well, everybody has a donor, but I mean, a haplo [haploidentical] transplant nowadays, giving post-transplant [is] almost like doing a fully matched, unrelated transplant. But, when you’re moving down to the 8 or 9 out of 10 mismatched transplants, then the risk is much higher. If you have to go to a cord transplant where the cell dose is a little bit low and you have a big adult patient, then the risk of that transplant is much higher, yeah.

Mark R. Litzow, MD: What do you do with the patient that’s still positive after blinatumomab, still MRD positive?

Anthony S. Stein, MD: CAR [chimeric antigen receptor] T cells.

Jae Park, MD: Those are refractory to blinatumomab.

Anthony S. Stein, MD: Or if they’re CD22 and I don’t have my CAR T cells, then I might give that patient inotuzumab or this now new, novel…there may be new, novel agents coming along like venetoclax that also have a potential benefit. But that type of patient I would consider giving CAR T cells.

Jae Park, MD: I think those are the difficult questions, because sometimes…if we see MRD-positive patients, even if we decide to go to transplant, you want to turn [them] into MRD negative before going to transplant. But what if we’re not successful and they’re still MRD positive after that attempt? I think then, if we have an alternative option, should we pursue that option to try another type of MRD-negative…or would you say, “You know what, this is the best that we can do,” and then go to transplant with an MRD-positive disease and accept the risk that we will take? I think these are the difficult questions.

Anthony S. Stein, MD: If you transplant somebody with MRD-positive disease, the outcome is not zero. There is a…

Jae Park, MD: Correct.

Anthony S. Stein, MD: There is some survival.

Jae Park, MD: It’s not as good as MRD negative.

Anthony S. Stein, MD: Correct.

Jae Park, MD: But it’s the best we can do—I don’t think it’s off the table. But, [given] an alternative of better options that [had] a good option, then I think most of us will pursue that option before going to transplant, if we still have a shot at getting MRD negativity.

Bijal D. Shah, MD: MRD negative—how?

Jae Park, MD: You mean by which assays?

Bijal D. Shah, MD: So, in terms of the transplant decision making, there [were] data by Pulsipher and colleagues showing that the next-generation sequencing approach was able to—again, because of their lower methods of detection—[was] able to pick out, thinking in the pediatric space, patients with very, very low disease burdens who still had a heightened risk of relapse over time. And so do we use our conventional flow approach? And, again, this is a very different question I’m asking. It’s not about “Is there MRD risk or not?” but “Which method do we use for making a transplant go, no-go decision?”

Jae Park, MD: We definitely don’t have…prospective data to kind of guide us to that. I think, of course, deeper the better, but if somebody is 10-4, is that kind of good enough to go to transplant? I think it all depends on “Is this the best that we think I can do?” If somebody started with the blinatumomab first cycle, started with the 10-1 and they got to the 10-3, I may just give them another cycle to see if I can get it a little bit deeper to go to transplant. But, if somebody had kind of zero changes from the beginning to an end, I’m not so sure a further cycle is going to change anything. So I think a lot of factors are going to go into it. If there’s an option to go a little bit deeper, theoretically thinking there will be better retrospective support that, that will be [an] ideal [situation]. But there [are] also good data for the transplant; MRD negative better, but just because they’re MRD positive, to a certain degree—we’re talking about a little degree, 10-2 or [10]-3 or lower. They still have benefit for the transplant for those patients, assuming again [that] it’s kind of the best we can do at that time. We still don’t have an MRD-directed CAR T-cell therapy yet, so I think that’s kind of another thing that we’re not able to do.

Anthony S. Stein, MD: But I think most of the transplant data have used 10-4 as a cutoff, so until you know what the influence of like a 10-6 is—I mean, I would still use my 10-4 as my cutoff about prognosticating about a transplant.

Bijal D. Shah, MD: That’s fantastic. It’s amazing how far we’ve come. I remember when we were using morphologic CRs [complete remissions]—and I’m not that old, but when we were using morphologic CRs to make that determination of transplant. None of us are doing that anymore, exactly, but it wasn’t that long ago.

Mark R. Litzow, MD: So, Bijal, you’ve got this patient. Let’s say they failed blinatumomab. For one reason or another, CAR T is not an option. You’ve settled on giving them inotuzumab. Transplanters are telling you, “We’re ready to go, we’ve got a donor as soon as you can get this patient into remission or MRD negative.” How do you manage inotuzumab in a setting of a transplant-eligible patient?

Bijal D. Shah, MD: Very challenging—and what my transplanters are telling me now is [that] they want 4 to 6 weeks between the last dose of inotuzumab and the transplant, for fear of veno-occlusive disease emerging. And that is not always [a] sufficient time span in which to keep patients MRD negative—meaning, after you stop your inotuzumab, we still think that there’s residual disease [that] is going to percolate up and that is extraordinarily tough. Sometimes we’ll try.

Mark R. Litzow, MD: I remember the iNNOVATE trial, high rate of MRD negativity, but you look at that survival curve and it…

Bijal D. Shah, MD: It falls fast.

Mark R. Litzow, MD: It falls fast.

Bijal D. Shah, MD: And the thing to remember is, that was a flow cytometry-based MRD assessment, and the other thing to remember is, as we move in to salvage 1 and salvage 2 and salvage 2 and beyond scenarios, the impact of MRD negativity becomes less—meaning in spite of MRD negativity, we can see relapses occur more frequently than in the front-line setting when we achieve an MRD-negative endpoint. And [keep] in mind that they’re probably 6 logs below 1e6. So we’re probably, if we really wanted to eradicate disease, getting down to 1e12. I don’t know if we’re ever going to get there, but that’s really what we’re talking about in terms of eradicating leukemia. So, even achieving a 1e6 threshold, there’s still disease left behind. And, in these patients who may have very proliferative disease, going into their inotuzumab, boy, you have to act fast. And so what am I doing? Trying to bridge them however I can. Sometimes steroid, sometimes that’s POMP [6-mercaptopurine (6-MP), vincristine, methotrexate, and prednisone] without the 6MP, but [they’re] strategies to try [to] maintain that remission during that period off inotuzumab as we’re trying to get them to the allogeneic stem cell transplant. But there’s no easy way to do it.

One of the things that I’m looking at, not just pretransplant but now also for the post-transplant relapse, which is another extraordinarily challenging population to take care of, are some of the regimens that were presented at this 2018 American Society of Hematology annual meeting, , things that may allow me to fractionate the inotuzumab; essentially, expose them to lower doses in the hopes that perhaps we may have less of a hepatotoxicity signature with a preserved remission rate.

Transcript edited for clarity.

 

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Transcript:

Mark R. Litzow, MD:
Anthony, I wanted to ask you: Now that we have the ability to detect these low levels of disease—we’ve got an agent that’s approved to treat these low levels of disease—where does transplant fit into all of this? We haven’t talked about that very much. When do you think about transplant in ALL patients these days?

Anthony S. Stein, MD: So, my philosophy is if you’re using an AYA [adolescent and young adult] regimen, the patient does not have any high-risk cytogenetics such as—hypodiploidy, Philly-like, 4;11 are the main bad players. And, if they become MRD [minimal residual disease] negative, then I would not transplant that patient. I would just follow them. I would continue them on an AYA regimen and follow them over time. If somebody is MRD positive, if somebody has a poorer cytogenetic abnormality or mutational abnormality, then I would give them induction therapy, get them into remission. And, if they have an adequate donor, then I would take them to a transplant.
For somebody who is MRD positive at day 28 or after consolidation treatment, that patient, again, I would give blinatumomab to make them MRD negative. And if they have a good donor, then I would also take them to a transplant based on the German study for MRD, for the BLAST trial. In that study, I think the result, if you look down, if you look at the data for patients going to transplant, there was a higher transplant mortality rate—because if you look at the type of transplants that were done on these patients, a lot of them were 8 out of 10, 9 out of 10; a lot of centers were using cord blood—so you had a much higher transplant-related mortality. So, if you don’t have an ideal donor, then I would just rely on the [blinatumomab] and follow the patient and not transplant the patient.

Bijal D. Shah, MD: Sorry, I was going to say you just brought up a brilliant point, because when I talk to my transplant patients, their response is [that] everyone has a donor.

Anthony S. Stein, MD: Well, everybody has a donor, but I mean, a haplo [haploidentical] transplant nowadays, giving post-transplant [is] almost like doing a fully matched, unrelated transplant. But, when you’re moving down to the 8 or 9 out of 10 mismatched transplants, then the risk is much higher. If you have to go to a cord transplant where the cell dose is a little bit low and you have a big adult patient, then the risk of that transplant is much higher, yeah.

Mark R. Litzow, MD: What do you do with the patient that’s still positive after blinatumomab, still MRD positive?

Anthony S. Stein, MD: CAR [chimeric antigen receptor] T cells.

Jae Park, MD: Those are refractory to blinatumomab.

Anthony S. Stein, MD: Or if they’re CD22 and I don’t have my CAR T cells, then I might give that patient inotuzumab or this now new, novel…there may be new, novel agents coming along like venetoclax that also have a potential benefit. But that type of patient I would consider giving CAR T cells.

Jae Park, MD: I think those are the difficult questions, because sometimes…if we see MRD-positive patients, even if we decide to go to transplant, you want to turn [them] into MRD negative before going to transplant. But what if we’re not successful and they’re still MRD positive after that attempt? I think then, if we have an alternative option, should we pursue that option to try another type of MRD-negative…or would you say, “You know what, this is the best that we can do,” and then go to transplant with an MRD-positive disease and accept the risk that we will take? I think these are the difficult questions.

Anthony S. Stein, MD: If you transplant somebody with MRD-positive disease, the outcome is not zero. There is a…

Jae Park, MD: Correct.

Anthony S. Stein, MD: There is some survival.

Jae Park, MD: It’s not as good as MRD negative.

Anthony S. Stein, MD: Correct.

Jae Park, MD: But it’s the best we can do—I don’t think it’s off the table. But, [given] an alternative of better options that [had] a good option, then I think most of us will pursue that option before going to transplant, if we still have a shot at getting MRD negativity.

Bijal D. Shah, MD: MRD negative—how?

Jae Park, MD: You mean by which assays?

Bijal D. Shah, MD: So, in terms of the transplant decision making, there [were] data by Pulsipher and colleagues showing that the next-generation sequencing approach was able to—again, because of their lower methods of detection—[was] able to pick out, thinking in the pediatric space, patients with very, very low disease burdens who still had a heightened risk of relapse over time. And so do we use our conventional flow approach? And, again, this is a very different question I’m asking. It’s not about “Is there MRD risk or not?” but “Which method do we use for making a transplant go, no-go decision?”

Jae Park, MD: We definitely don’t have…prospective data to kind of guide us to that. I think, of course, deeper the better, but if somebody is 10-4, is that kind of good enough to go to transplant? I think it all depends on “Is this the best that we think I can do?” If somebody started with the blinatumomab first cycle, started with the 10-1 and they got to the 10-3, I may just give them another cycle to see if I can get it a little bit deeper to go to transplant. But, if somebody had kind of zero changes from the beginning to an end, I’m not so sure a further cycle is going to change anything. So I think a lot of factors are going to go into it. If there’s an option to go a little bit deeper, theoretically thinking there will be better retrospective support that, that will be [an] ideal [situation]. But there [are] also good data for the transplant; MRD negative better, but just because they’re MRD positive, to a certain degree—we’re talking about a little degree, 10-2 or [10]-3 or lower. They still have benefit for the transplant for those patients, assuming again [that] it’s kind of the best we can do at that time. We still don’t have an MRD-directed CAR T-cell therapy yet, so I think that’s kind of another thing that we’re not able to do.

Anthony S. Stein, MD: But I think most of the transplant data have used 10-4 as a cutoff, so until you know what the influence of like a 10-6 is—I mean, I would still use my 10-4 as my cutoff about prognosticating about a transplant.

Bijal D. Shah, MD: That’s fantastic. It’s amazing how far we’ve come. I remember when we were using morphologic CRs [complete remissions]—and I’m not that old, but when we were using morphologic CRs to make that determination of transplant. None of us are doing that anymore, exactly, but it wasn’t that long ago.

Mark R. Litzow, MD: So, Bijal, you’ve got this patient. Let’s say they failed blinatumomab. For one reason or another, CAR T is not an option. You’ve settled on giving them inotuzumab. Transplanters are telling you, “We’re ready to go, we’ve got a donor as soon as you can get this patient into remission or MRD negative.” How do you manage inotuzumab in a setting of a transplant-eligible patient?

Bijal D. Shah, MD: Very challenging—and what my transplanters are telling me now is [that] they want 4 to 6 weeks between the last dose of inotuzumab and the transplant, for fear of veno-occlusive disease emerging. And that is not always [a] sufficient time span in which to keep patients MRD negative—meaning, after you stop your inotuzumab, we still think that there’s residual disease [that] is going to percolate up and that is extraordinarily tough. Sometimes we’ll try.

Mark R. Litzow, MD: I remember the iNNOVATE trial, high rate of MRD negativity, but you look at that survival curve and it…

Bijal D. Shah, MD: It falls fast.

Mark R. Litzow, MD: It falls fast.

Bijal D. Shah, MD: And the thing to remember is, that was a flow cytometry-based MRD assessment, and the other thing to remember is, as we move in to salvage 1 and salvage 2 and salvage 2 and beyond scenarios, the impact of MRD negativity becomes less—meaning in spite of MRD negativity, we can see relapses occur more frequently than in the front-line setting when we achieve an MRD-negative endpoint. And [keep] in mind that they’re probably 6 logs below 1e6. So we’re probably, if we really wanted to eradicate disease, getting down to 1e12. I don’t know if we’re ever going to get there, but that’s really what we’re talking about in terms of eradicating leukemia. So, even achieving a 1e6 threshold, there’s still disease left behind. And, in these patients who may have very proliferative disease, going into their inotuzumab, boy, you have to act fast. And so what am I doing? Trying to bridge them however I can. Sometimes steroid, sometimes that’s POMP [6-mercaptopurine (6-MP), vincristine, methotrexate, and prednisone] without the 6MP, but [they’re] strategies to try [to] maintain that remission during that period off inotuzumab as we’re trying to get them to the allogeneic stem cell transplant. But there’s no easy way to do it.

One of the things that I’m looking at, not just pretransplant but now also for the post-transplant relapse, which is another extraordinarily challenging population to take care of, are some of the regimens that were presented at this 2018 American Society of Hematology annual meeting, , things that may allow me to fractionate the inotuzumab; essentially, expose them to lower doses in the hopes that perhaps we may have less of a hepatotoxicity signature with a preserved remission rate.

Transcript edited for clarity.

 
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