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ALL: Therapy for Post-Induction MRD-Positivity

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, Mar 14, 2018



Transcript: 

Mark R. Litzow, MD: We made the point that when the best time is to measure MRD with a newly diagnosed patient is somewhat protocol dependent. Once you’ve decided when that time point is, what do you do if you’ve got a patient who’s MRD-positive, Ryan, and you’ve decided you need to make a change?

Ryan D. Cassaday, MD: I think it depends a little bit on the context of the regimen, at least for me. With hyper-CVAD, whether it’s a selected younger patient or an older patient who I don’t think can tolerate a pediatric-inspired regimen, my usual time point where I’m making sure they cleared MRD is similar to what Anthony said before. It’s usually after cycle 2B. If you haven’t cleared MRD and I’m treating you with hyper-CVAD—you’ve gotten to cycle 2B and you’re still MRD-positive—I’m usually thinking of switching. I think at that point, particularly with the hyper-CVAD regimen where it’s basically the same drugs over and over again, it’s unlikely that cycles 3A and 3B, which are basically the same things that you’ve been given over the last 3 months, are really going to make much of a difference. In that circumstance, I like to extrapolate from the BLAST study, and I’ll typically consider blinatumomab there. It’s a little bit of a hoodwink on the label, but in my opinion, that’s refractory disease. It may not necessarily be 6% blast, but it’s there and refractory to chemotherapy. In that case, I think it’s appropriate and it’s in the NCCN guidelines. That’s the usual approach I’ll take.

I have in selected circumstances, recognizing that it’s a bit of an extrapolation from some of the pediatric literature, used a high-dose methotrexate-based interim maintenance regimen for the young adults who I’m treating, according to a COG [Children’s Oncology Group] backbone. There’s maybe some suggestion in subgroup analyses that it might be able to rescue some of the patients who have persistent MRD after consolidation. That’s at about 12 weeks. But in general, if it’s a patient in first morphologic remission who has chemotherapy-refractory minimal residual disease, the drug I’m going to use for most patients is blinatumomab.

Aaron C. Logan, MD, PhD: I think it’s important that you change therapy rather than continue hyper-CVAD, just because they’re going to be transplanted in 2 months. It has been shown that if you go into the transplant MRD-positive, transplant has a very low likelihood of benefitting the patient. Just yesterday, Nicola Gökbuget presented some data from the GMALL (German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia) group where they looked at all of their patients in the ALFA-0703 study as well as a registry in Germany, and they demonstrated that when patients were MRD-positive or were negative and became positive—they called that a molecular relapse—the best salvage therapy was blinatumomab. High-dose methotrexate actually achieved an MRD-negative remission in about a third of those patients, but the only one that had a high rate of achieving a MRD-negative state was blinatumomab. So, I conceptualize blinatumomab right now as being an excellent bridge to transplant for those patients who are MRD-positive, and usually you’ll give 2 cycles while you’re waiting to identify your donor. Hopefully, you’ve already started the donor search, so it might be no longer than that. But then again, the BLAST study is out there and begs the question, are there patients who can be treated to a state of long-term disease-free survival with just blinatumomab and not with the transplant? Hopefully, we can better understand that. Is it something about the genetics of the disease? Is it something about the patient? Even though I do transplants, I would love to avoid doing transplants if at all possible, because I don’t like giving patients graft versus host disease.

Bijal D. Shah, MD: I think this harkens back to what you said earlier. The problem is we keep talking about MRD as though it’s different from remission. Really, it’s not, and what we need to do is refine our response criteria. The concepts of CR and Cri (complete remission with incomplete blood count recovery) are antiquated in the world of MRD.

Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: We made the point that when the best time is to measure MRD with a newly diagnosed patient is somewhat protocol dependent. Once you’ve decided when that time point is, what do you do if you’ve got a patient who’s MRD-positive, Ryan, and you’ve decided you need to make a change?

Ryan D. Cassaday, MD: I think it depends a little bit on the context of the regimen, at least for me. With hyper-CVAD, whether it’s a selected younger patient or an older patient who I don’t think can tolerate a pediatric-inspired regimen, my usual time point where I’m making sure they cleared MRD is similar to what Anthony said before. It’s usually after cycle 2B. If you haven’t cleared MRD and I’m treating you with hyper-CVAD—you’ve gotten to cycle 2B and you’re still MRD-positive—I’m usually thinking of switching. I think at that point, particularly with the hyper-CVAD regimen where it’s basically the same drugs over and over again, it’s unlikely that cycles 3A and 3B, which are basically the same things that you’ve been given over the last 3 months, are really going to make much of a difference. In that circumstance, I like to extrapolate from the BLAST study, and I’ll typically consider blinatumomab there. It’s a little bit of a hoodwink on the label, but in my opinion, that’s refractory disease. It may not necessarily be 6% blast, but it’s there and refractory to chemotherapy. In that case, I think it’s appropriate and it’s in the NCCN guidelines. That’s the usual approach I’ll take.

I have in selected circumstances, recognizing that it’s a bit of an extrapolation from some of the pediatric literature, used a high-dose methotrexate-based interim maintenance regimen for the young adults who I’m treating, according to a COG [Children’s Oncology Group] backbone. There’s maybe some suggestion in subgroup analyses that it might be able to rescue some of the patients who have persistent MRD after consolidation. That’s at about 12 weeks. But in general, if it’s a patient in first morphologic remission who has chemotherapy-refractory minimal residual disease, the drug I’m going to use for most patients is blinatumomab.

Aaron C. Logan, MD, PhD: I think it’s important that you change therapy rather than continue hyper-CVAD, just because they’re going to be transplanted in 2 months. It has been shown that if you go into the transplant MRD-positive, transplant has a very low likelihood of benefitting the patient. Just yesterday, Nicola Gökbuget presented some data from the GMALL (German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia) group where they looked at all of their patients in the ALFA-0703 study as well as a registry in Germany, and they demonstrated that when patients were MRD-positive or were negative and became positive—they called that a molecular relapse—the best salvage therapy was blinatumomab. High-dose methotrexate actually achieved an MRD-negative remission in about a third of those patients, but the only one that had a high rate of achieving a MRD-negative state was blinatumomab. So, I conceptualize blinatumomab right now as being an excellent bridge to transplant for those patients who are MRD-positive, and usually you’ll give 2 cycles while you’re waiting to identify your donor. Hopefully, you’ve already started the donor search, so it might be no longer than that. But then again, the BLAST study is out there and begs the question, are there patients who can be treated to a state of long-term disease-free survival with just blinatumomab and not with the transplant? Hopefully, we can better understand that. Is it something about the genetics of the disease? Is it something about the patient? Even though I do transplants, I would love to avoid doing transplants if at all possible, because I don’t like giving patients graft versus host disease.

Bijal D. Shah, MD: I think this harkens back to what you said earlier. The problem is we keep talking about MRD as though it’s different from remission. Really, it’s not, and what we need to do is refine our response criteria. The concepts of CR and Cri (complete remission with incomplete blood count recovery) are antiquated in the world of MRD.

Transcript Edited for Clarity 
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