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Monitoring for Relapse in Acute Lymphoblastic Leukemia

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: Wednesday, Feb 13, 2019



Transcript:

Bijal D. Shah, MD:
How do you monitor for relapse in your patients with lymphoblastic lymphoma? So the typical T[-cell] lymphoblastic lymphoma patients.

Anthony S. Stein, MD: Well … obviously, if somebody comes with a lymph node we biopsy it; once somebody is in remission, I don’t think you have to do serial PET [positron emission tomography] scans every couple of months to see whether they stay in remission. And I think the lymphoma field, once you’re in remission, my understanding is you don’t keep doing restaging PET scans over and over again.

Bijal D. Shah, MD: That’s variable, depending on who you ask, meaning there is still a lot of overuse of PET scans. That’s really more what I’m trying to….

Anthony S. Stein, MD: Because … I don’t think for lymphoma, if you catch it a little bit earlier versus when you can feel a palpable lymph node, I don’t think it’s going to make all that much difference to the outcome of the patient.

Bijal D. Shah, MD: What do you think?

Jae Park, MD: During initial induction and consolidation, I usually do assess them at the time of the bone marrow biopsy. So, if I’m assessing their bone marrow, I usually do get the PET scan during that time if there was a detectable disease that I’m following. During the maintenance portion of it, there’s no standardization. But during the first 2 years, I usually either alternate CT [computed tomography] or PET scan every 6 months or so, twice a year that I would monitor them by imaging. Bone marrow, we typically do every 3 months during that time, the first 2 years, and during the maintenance, every 6 month thereafter. I think about how much imaging is too much, so we settled on every 6 months during the maintenance. But … and as you said, if it’s detectable as they caught it, what do you do for the small disease that’s appearing? What do you do with the information? But there’s some assurance there, too, and not checking too infrequently. That’s what we’ve been doing at MSK [Memorial Sloan Kettering Cancer Center].

Bijal D. Shah, MD: Mark, do you think there might be an advantage for NGS [next-generation sequencing] peripheral blood assessments in these patients?

Mark R. Litzow, MD: I think there could be. I honestly don’t know a lot of data in particular. I don’t know if you do.

Bijal D. Shah, MD: No.

Mark R. Litzow, MD: It would make sense to be able to utilize that approach, but I don’t know if there’s good data about that. What about time to MRD [minimal residual disease] negativity, how do you incorporate that into your practice? You have a patient who gets into MRD negativity after 1 cycle versus 2 or 3; do you change your approach to those patients, Bijal?

Bijal D. Shah, MD: Yes. If someone has persistent MRD, for example, after consolidation, I get very worried. And I’m talking about even very low levels by NGS. And I start thinking about intensifying therapy, where and how I can, and that’s going to be dependent on how the patient is coming to me. So maybe that means incorporating nelarabine into their front-line regimen. If they’re coming to me on hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone].

Mark R. Litzow, MD: With T-cell disease.

Bijal D. Shah, MD: With T-cell disease. If they’re coming to me on hyper-CVAD, then maybe that means incorporating PEG [pegylated]-asparaginase on the hyper-CVAD backbone, and we’ve done that as well. But the bottom line is I’m thinking very hard about what to do for these patients and following those patients very closely. This is the end of consolidation, persistent MRD. If they’re MRD-positive after induction but cleared after consolidation, that’s a much harder question to answer. Now I’m going back to the original genotype, and this is again why we try to sequence our patients frontline. If I’m seeing high-risk features that I don’t like, I’m more apt to take that patient to an allogeneic transplant. If I see what looks like a more benign genotype; I’m going to make something up, CDKN2A/2B without much else in the way of mutations, I might say, OK, then this is someone I’ll repeat an MRD assessment on at the end of therapy, just to make sure that the MRD remains negative before making any big decisions. And, if it does come back positive, now I have my BLIN [blinatumomab] and other approaches that I can think about in that context. But I don’t want to pretend I have the answers. This is really an institutionally driven approach, and I’d be curious to hear what others are doing.

Jae Park, MD: The early response, from the pediatric data, if you respond to .... steroid at day 14, I think we know there’s a good prognostic indicator, at least borrowing from the data from the pediatric. I think the kinetics are important. If you get early [response], then it’s kind of assuring that I’m getting more optimistic in the sense that maybe these patients may not be high-risk and therefore may not need allotransplant. So we often have the conversation with the patients. If they’re using pediatric-inspired regimen after induction [phase] 1, which is usually about day 28 to day 30, and if you repeat a bone marrow biopsy and they’re MRD-positive.… If they’re MRD-negative, good. But, if they’re MRD-positive then they move on to induction phase 2, which is about 6 to 8 weeks of a chemotherapy, and after that, which is now about 12 to 16 weeks, if they’re negative.

So that’s the hard part for me as well. Just because they converted negative, are they now good because they were positive at induction phase 1 and day 28, but now they’re negative  3 months after? Are those as good as minus-minus patients, meaning initially MRD-negative after induction 1 and then negative? I don’t know the answer, just that we’re looking into the database of the pediatric-inspired study, whether early response…. And I generally think those are assuring, but if you convert after induction 2 with a slightly different regimen, then what should I do with it in those patients? And then I think we have to factor in all the other factors, the genotypes, molecular features, and so forth to make a decision [whether to] take a similar approach. If I see something that I don’t like and that I consider to be a higher risk, then I will be much more aggressive in changing therapy or to allogeneic transplant. If not, then kind of staying on the current regimen.

Mark R. Litzow, MD: I think that’s a very important point that we shouldn’t rely on MRD alone. We need to look at the overall picture, the genetics in particular. I think those 2. In my mind, the genetics, whether it be the cytogenetics or the molecular plus the MRD assessment, need to be factored in to how your subsequent management is going to go.

Transcript edited for clarity.

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Transcript:

Bijal D. Shah, MD:
How do you monitor for relapse in your patients with lymphoblastic lymphoma? So the typical T[-cell] lymphoblastic lymphoma patients.

Anthony S. Stein, MD: Well … obviously, if somebody comes with a lymph node we biopsy it; once somebody is in remission, I don’t think you have to do serial PET [positron emission tomography] scans every couple of months to see whether they stay in remission. And I think the lymphoma field, once you’re in remission, my understanding is you don’t keep doing restaging PET scans over and over again.

Bijal D. Shah, MD: That’s variable, depending on who you ask, meaning there is still a lot of overuse of PET scans. That’s really more what I’m trying to….

Anthony S. Stein, MD: Because … I don’t think for lymphoma, if you catch it a little bit earlier versus when you can feel a palpable lymph node, I don’t think it’s going to make all that much difference to the outcome of the patient.

Bijal D. Shah, MD: What do you think?

Jae Park, MD: During initial induction and consolidation, I usually do assess them at the time of the bone marrow biopsy. So, if I’m assessing their bone marrow, I usually do get the PET scan during that time if there was a detectable disease that I’m following. During the maintenance portion of it, there’s no standardization. But during the first 2 years, I usually either alternate CT [computed tomography] or PET scan every 6 months or so, twice a year that I would monitor them by imaging. Bone marrow, we typically do every 3 months during that time, the first 2 years, and during the maintenance, every 6 month thereafter. I think about how much imaging is too much, so we settled on every 6 months during the maintenance. But … and as you said, if it’s detectable as they caught it, what do you do for the small disease that’s appearing? What do you do with the information? But there’s some assurance there, too, and not checking too infrequently. That’s what we’ve been doing at MSK [Memorial Sloan Kettering Cancer Center].

Bijal D. Shah, MD: Mark, do you think there might be an advantage for NGS [next-generation sequencing] peripheral blood assessments in these patients?

Mark R. Litzow, MD: I think there could be. I honestly don’t know a lot of data in particular. I don’t know if you do.

Bijal D. Shah, MD: No.

Mark R. Litzow, MD: It would make sense to be able to utilize that approach, but I don’t know if there’s good data about that. What about time to MRD [minimal residual disease] negativity, how do you incorporate that into your practice? You have a patient who gets into MRD negativity after 1 cycle versus 2 or 3; do you change your approach to those patients, Bijal?

Bijal D. Shah, MD: Yes. If someone has persistent MRD, for example, after consolidation, I get very worried. And I’m talking about even very low levels by NGS. And I start thinking about intensifying therapy, where and how I can, and that’s going to be dependent on how the patient is coming to me. So maybe that means incorporating nelarabine into their front-line regimen. If they’re coming to me on hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone].

Mark R. Litzow, MD: With T-cell disease.

Bijal D. Shah, MD: With T-cell disease. If they’re coming to me on hyper-CVAD, then maybe that means incorporating PEG [pegylated]-asparaginase on the hyper-CVAD backbone, and we’ve done that as well. But the bottom line is I’m thinking very hard about what to do for these patients and following those patients very closely. This is the end of consolidation, persistent MRD. If they’re MRD-positive after induction but cleared after consolidation, that’s a much harder question to answer. Now I’m going back to the original genotype, and this is again why we try to sequence our patients frontline. If I’m seeing high-risk features that I don’t like, I’m more apt to take that patient to an allogeneic transplant. If I see what looks like a more benign genotype; I’m going to make something up, CDKN2A/2B without much else in the way of mutations, I might say, OK, then this is someone I’ll repeat an MRD assessment on at the end of therapy, just to make sure that the MRD remains negative before making any big decisions. And, if it does come back positive, now I have my BLIN [blinatumomab] and other approaches that I can think about in that context. But I don’t want to pretend I have the answers. This is really an institutionally driven approach, and I’d be curious to hear what others are doing.

Jae Park, MD: The early response, from the pediatric data, if you respond to .... steroid at day 14, I think we know there’s a good prognostic indicator, at least borrowing from the data from the pediatric. I think the kinetics are important. If you get early [response], then it’s kind of assuring that I’m getting more optimistic in the sense that maybe these patients may not be high-risk and therefore may not need allotransplant. So we often have the conversation with the patients. If they’re using pediatric-inspired regimen after induction [phase] 1, which is usually about day 28 to day 30, and if you repeat a bone marrow biopsy and they’re MRD-positive.… If they’re MRD-negative, good. But, if they’re MRD-positive then they move on to induction phase 2, which is about 6 to 8 weeks of a chemotherapy, and after that, which is now about 12 to 16 weeks, if they’re negative.

So that’s the hard part for me as well. Just because they converted negative, are they now good because they were positive at induction phase 1 and day 28, but now they’re negative  3 months after? Are those as good as minus-minus patients, meaning initially MRD-negative after induction 1 and then negative? I don’t know the answer, just that we’re looking into the database of the pediatric-inspired study, whether early response…. And I generally think those are assuring, but if you convert after induction 2 with a slightly different regimen, then what should I do with it in those patients? And then I think we have to factor in all the other factors, the genotypes, molecular features, and so forth to make a decision [whether to] take a similar approach. If I see something that I don’t like and that I consider to be a higher risk, then I will be much more aggressive in changing therapy or to allogeneic transplant. If not, then kind of staying on the current regimen.

Mark R. Litzow, MD: I think that’s a very important point that we shouldn’t rely on MRD alone. We need to look at the overall picture, the genetics in particular. I think those 2. In my mind, the genetics, whether it be the cytogenetics or the molecular plus the MRD assessment, need to be factored in to how your subsequent management is going to go.

Transcript edited for clarity.
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