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Optimizing Allogeneic Transplant Strategies in ALL

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: Wednesday, Feb 21, 2018



Transcript: 

Mark R. Litzow, MD: In the last couple of minutes of this segment, we’ll take the simple question of which of these patients, once they get into remission, should be transplanted. Anthony, you can take that on and give us your initial perspective on how you approach transplant now in both Ph-positive and Ph-negative ALL.

Anthony S. Stein, MD: When I evaluate a patient for transplant, it’s considering them either being Ph-positive or Ph-negative. For Ph-positive patients, there’s one randomized study from the Southwest Oncology Group that compared hyper-CVAD with dasatinib. Those patients who had a donor went on to transplant, and those patients who did not have a donor went on maintenance therapy with dasatinib. And from that study, it was shown that patients who went to transplant had a superior outcome compared to patients continued on chemotherapy. Up to the present time, at least for a Philadelphia-positive patient, my bias would still be to take that type of patient to transplant, unless the data from hyper-CVAD plus ponatinib can equal the survival that we currently get using a transplant.

Ryan D. Cassaday, MD: If you were referred a patient who was induced with hyper-CVAD and ponatinib, would you still recommend that they get a transplant?

Anthony S. Stein, MD: If the patient had a fully matched donor—a sibling donor, fully matched unrelated donor—yes. But any patient with a mismatch or a haploidentical donor, I would defer that for the future if a patient relapses.

Mark R. Litzow, MD: And we’re assuming their BCR-ABL

Anthony S. Stein, MD: They still need to be MRD-negative and PCR-negative.

Mark R. Litzow, MD: Right. What about the Ph-negative patients?

Anthony S. Stein, MD: With patients who are Ph-negative, there we look at what molecular and cytogenetics were up front. The main high-risk groups are basically hypodiploidy and translocation 4;11. Those would be the 2 main poorer cytogenetics. And then, depending on the regimen they got, you would look at the MRD status either after induction or at week 16, depending on which regimen is being used. So, for a patient who is MRD-negative and did not have a translocation 4;11 or was not hypodiploid, that patient I would continue on an AYA regimen. If I were to use hyper-CVAD, I think hyper-CVAD was designed more to take a patient to transplant. If a patient is going to continue on an AYA regimen, then I would not transplant that patient.

Aaron C. Logan, MD, PhD: If they achieve MRD-negativity.

Anthony S. Stein, MD: If they are MRD-negative.

Aaron C. Logan, MD, PhD: What about the BCR-ABL–like lesions and that normal karyotype, the older AYA population? How does that affect your decision making for transplant?

Anthony S. Stein, MD: With that, you get differing opinions. For somebody who is Ph-like, who’s MRD negative at the end of induction therapy, that sort of patient you may continue on chemotherapy, but that can be debated. And in the last Alliance study, those patients, the Ph-like patients, did worse than patients who were not Ph-like. If a patient had a fully matched donor—a sibling, an unrelated donor—I would take that kind of patient to a transplant. But if they have anything less than a fully matched donor, then the risk benefit ratio may not be in the favor of doing a transplant at that time.

Ryan D. Cassaday, MD:  I think the Ph-like story is certainly an interesting an evolving one.

Anthony S. Stein, MD: And also, they don’t all behave the same way.

Ryan D. Cassaday, MD: Right. The St. Jude’s group has done the lion’s share of the work in teasing out exactly what these lesions are and what the biology is. They published a study just a few years ago where they looked back and they found that if you’re Ph-like but achieve an early negative remission, your outcomes are just as good.

Anthony S. Stein, MD: Yes, that’s correct.

Ryan D. Cassaday, MD: Now again, that’s an extrapolation of children to adults, if we’re going to apply this to a young adult patient population. But to the point you made initially of, if you achieve an early MRD-negative remission and you know that they’re Ph-like, if they were a patient who I was treating, I would probably not refer that patient for transplant based on those small data. But I would recognize that because they’re Ph-like, they’re probably less likely to achieve that deep response, and that MRD is what’s going to trigger you to consider sending them for transplant.

Aaron C. Logan, MD, PhD: Yes, I agree. I think the biology frequently declares itself.

Ryan D. Cassaday, MD: Yes.

Aaron C. Logan, MD, PhD: They may not achieve the MRD-negative CR because of the Ph-like lesion. But I don’t think we can take pediatric data and just simply extrapolate them, because it’s very protocol-specific in terms of how those outcomes are achieved. I think, like anything, I struggle with it a bit, but I’m still compelled right now with the available data to probably transplant somebody, as long as they have a well-matched sibling or unrelated donor, if they have an identified Ph-like lesion. Because my concern is that if they do relapse—they’re obviously at higher risk for relapse—recapturing that patient is more difficult. And so, I think you’ve got to take your best shot on goal right up front.

Bijal D. Shah, MD: I think that’s what the data support in T-cell ALL—taking both genomic risk and MRD into account when making decisions, and in that case, the ICD-10 classification scheme—but also in B-cell ALL. Now the recently published data—I think Moorman was corresponding on that paper—in the UKALL paper showed that not only MRD, but also taking into account some of these very high risk genomic lesions that can influence the risk of relapse, were pivotal in driving that.

Mark R. Litzow, MD: Anthony, how do you decide whether to do a reduced intensity regimen or a full intensity regimen?

Anthony S. Stein, MD: That would depend on the age of the patients. At my institution, for a patient under the age of 60 who is otherwise fit and healthy, that patient would get a FTBI (fractionated total-body irradiation) etoposide regimen. We’ve shown that patients, when we use etoposide for patients in the Ph-positive setting, seemed to get better results than using cyclophosphamide. In a Ph-negative patient, we still use FTBI etoposide. It has become our standard regimen for the last 25 years. For somebody over the age of 60, we tend not to use whole-body radiation. Our go-to regimen has been using a reduced-intensity regimen with fludarabine and melphalan.

Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: In the last couple of minutes of this segment, we’ll take the simple question of which of these patients, once they get into remission, should be transplanted. Anthony, you can take that on and give us your initial perspective on how you approach transplant now in both Ph-positive and Ph-negative ALL.

Anthony S. Stein, MD: When I evaluate a patient for transplant, it’s considering them either being Ph-positive or Ph-negative. For Ph-positive patients, there’s one randomized study from the Southwest Oncology Group that compared hyper-CVAD with dasatinib. Those patients who had a donor went on to transplant, and those patients who did not have a donor went on maintenance therapy with dasatinib. And from that study, it was shown that patients who went to transplant had a superior outcome compared to patients continued on chemotherapy. Up to the present time, at least for a Philadelphia-positive patient, my bias would still be to take that type of patient to transplant, unless the data from hyper-CVAD plus ponatinib can equal the survival that we currently get using a transplant.

Ryan D. Cassaday, MD: If you were referred a patient who was induced with hyper-CVAD and ponatinib, would you still recommend that they get a transplant?

Anthony S. Stein, MD: If the patient had a fully matched donor—a sibling donor, fully matched unrelated donor—yes. But any patient with a mismatch or a haploidentical donor, I would defer that for the future if a patient relapses.

Mark R. Litzow, MD: And we’re assuming their BCR-ABL

Anthony S. Stein, MD: They still need to be MRD-negative and PCR-negative.

Mark R. Litzow, MD: Right. What about the Ph-negative patients?

Anthony S. Stein, MD: With patients who are Ph-negative, there we look at what molecular and cytogenetics were up front. The main high-risk groups are basically hypodiploidy and translocation 4;11. Those would be the 2 main poorer cytogenetics. And then, depending on the regimen they got, you would look at the MRD status either after induction or at week 16, depending on which regimen is being used. So, for a patient who is MRD-negative and did not have a translocation 4;11 or was not hypodiploid, that patient I would continue on an AYA regimen. If I were to use hyper-CVAD, I think hyper-CVAD was designed more to take a patient to transplant. If a patient is going to continue on an AYA regimen, then I would not transplant that patient.

Aaron C. Logan, MD, PhD: If they achieve MRD-negativity.

Anthony S. Stein, MD: If they are MRD-negative.

Aaron C. Logan, MD, PhD: What about the BCR-ABL–like lesions and that normal karyotype, the older AYA population? How does that affect your decision making for transplant?

Anthony S. Stein, MD: With that, you get differing opinions. For somebody who is Ph-like, who’s MRD negative at the end of induction therapy, that sort of patient you may continue on chemotherapy, but that can be debated. And in the last Alliance study, those patients, the Ph-like patients, did worse than patients who were not Ph-like. If a patient had a fully matched donor—a sibling, an unrelated donor—I would take that kind of patient to a transplant. But if they have anything less than a fully matched donor, then the risk benefit ratio may not be in the favor of doing a transplant at that time.

Ryan D. Cassaday, MD:  I think the Ph-like story is certainly an interesting an evolving one.

Anthony S. Stein, MD: And also, they don’t all behave the same way.

Ryan D. Cassaday, MD: Right. The St. Jude’s group has done the lion’s share of the work in teasing out exactly what these lesions are and what the biology is. They published a study just a few years ago where they looked back and they found that if you’re Ph-like but achieve an early negative remission, your outcomes are just as good.

Anthony S. Stein, MD: Yes, that’s correct.

Ryan D. Cassaday, MD: Now again, that’s an extrapolation of children to adults, if we’re going to apply this to a young adult patient population. But to the point you made initially of, if you achieve an early MRD-negative remission and you know that they’re Ph-like, if they were a patient who I was treating, I would probably not refer that patient for transplant based on those small data. But I would recognize that because they’re Ph-like, they’re probably less likely to achieve that deep response, and that MRD is what’s going to trigger you to consider sending them for transplant.

Aaron C. Logan, MD, PhD: Yes, I agree. I think the biology frequently declares itself.

Ryan D. Cassaday, MD: Yes.

Aaron C. Logan, MD, PhD: They may not achieve the MRD-negative CR because of the Ph-like lesion. But I don’t think we can take pediatric data and just simply extrapolate them, because it’s very protocol-specific in terms of how those outcomes are achieved. I think, like anything, I struggle with it a bit, but I’m still compelled right now with the available data to probably transplant somebody, as long as they have a well-matched sibling or unrelated donor, if they have an identified Ph-like lesion. Because my concern is that if they do relapse—they’re obviously at higher risk for relapse—recapturing that patient is more difficult. And so, I think you’ve got to take your best shot on goal right up front.

Bijal D. Shah, MD: I think that’s what the data support in T-cell ALL—taking both genomic risk and MRD into account when making decisions, and in that case, the ICD-10 classification scheme—but also in B-cell ALL. Now the recently published data—I think Moorman was corresponding on that paper—in the UKALL paper showed that not only MRD, but also taking into account some of these very high risk genomic lesions that can influence the risk of relapse, were pivotal in driving that.

Mark R. Litzow, MD: Anthony, how do you decide whether to do a reduced intensity regimen or a full intensity regimen?

Anthony S. Stein, MD: That would depend on the age of the patients. At my institution, for a patient under the age of 60 who is otherwise fit and healthy, that patient would get a FTBI (fractionated total-body irradiation) etoposide regimen. We’ve shown that patients, when we use etoposide for patients in the Ph-positive setting, seemed to get better results than using cyclophosphamide. In a Ph-negative patient, we still use FTBI etoposide. It has become our standard regimen for the last 25 years. For somebody over the age of 60, we tend not to use whole-body radiation. Our go-to regimen has been using a reduced-intensity regimen with fludarabine and melphalan.

Transcript Edited for Clarity 
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