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Time Points in the Assessment of MRD

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:

Mark R. Litzow, MD:
Anthony, when do you think we should be measuring MRD?

Anthony S. Stein, MD: I think it also depends which regimen you’re using. I know if you use the Alliance AYA [adolescents and young adults] regimen, then they do it. I think what was most significant was after the induction therapy, which showed the greatest risk of predicting for outcome. If you’re using a German ALL protocol, they do it at week 16, which would be after the consolidation treatment, and that’s where all their data have been generated. If you use hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone], I think it’s after Part B, after cycle 1. I’m not sure if it’s….

Bijal D. Shah, MD: They have 2 time points for assessment. They say basically on, once hematological recovery occurs, so within about 30 days or so of cycle 1a, usually before cycle 1b, and then they do another assessment at month 3, on average. How that addresses the number of cycles for patients is not something … but I suspect it’s going to be after 3b or so for most patients.

Anthony S. Stein, MD: Basically, you have to learn what regimen you’re using, and then at what time point your MRD is significant enough to make a change in treatment.

Jae Park, MD: I think an important point also is that we’re making sure not to consider regular flow. We all talk about MRD and that it has to be a certain sensitivity for the MRD, the definition to be met in 10-4. So I think the 1 thing that could potentially happen is that when you get a regular flow, which is not to the level of sensitivity, they’ll assume the flow is negative, and then you’ll assume that it’s MRD-negative when in fact it’s really not because you’re not achieving that level of sensitivity.

So the 1 thing that we should be aware of is it true MRD that all the publications are talking about, or is it convention of flow and with less sensitivity that you’re assessing? I think that’s making sure that everybody is talking about the same definition. Of course you can go deeper with an NGS and then the prognostic implication of that.

And the NGS, I think another factor to remember is you need diagnostic material in order to follow the clone. So if you don’t send it at the time of diagnosis, unless you can retrieve it, which is possible and you can definitely do, but I think these are factors to consider when you’re seeing newly diagnosed patients that these are critical components to look for this kind of division of clone so that you can follow these patients. For flow you don’t need them, but I think these are the benefits of both, but I strongly believe they should be tested, because we all do, but these are the factors to consider I think can only see new patients.

Especially when there’s an MRD-directed therapy available and then there’s significance at the end of consolidation, for sure it’s a very important point. Induction, I think at that point is more data and depending on the regimen, but….

Anthony S. Stein, MD: I agree. It needs to be sent, if you’re looking for MRD, it needs to be sent to a reputable flow lab that deals with looking at MRD analyses and experience. I wouldn’t just send it to any new lab that just popped up.

Jae Park, MD: The flow is so complicated.

Bijal D. Shah, MD: Correct.

Jae Park, MD: It took many months and years before in our center they established that. So … there’s no false assurance. And then it also depended on when you send the flow … it has to be from the first pull to get the best results.

Anthony S. Stein, MD: Yes, that’s the most important factor to get a reliable flow.

Jae Park, MD: And if you send it at the fourth pull, then it’s meaningless; exactly.

Anthony S. Stein, MD: That’s meaningless.

Jae Park, MD: So I think these are the kind of details that need to be discussed.

Bijal D. Shah, MD: And also it’s not just the number of colors. It’s also the number of events. And that means you have to be very careful about asking MRD questions on very hypocellular marrows. And I think that’s something else that often gets lost in the shuffle.

Mark R. Litzow, MD: I think we’re talking about standardization of the assay, and our pediatric colleagues have the advantage of, you’re using 2 flow labs in the United States. They have cross-referenced each other. So they have standardization, where that’s a challenge in our adult world....

Anthony S. Stein, MD: But in the future NGS is going to probably take over because, 1, you probably can send the test from the peripheral; you won’t have to repeat bone marrows, they can send it from the peripheral blood. I mean the sensitivity may be 1 log lower than what you would get off the bone marrow. It’s easier to send from the blood and you can send it at the different timing. I’m not sure what the cost differential would be.

Bijal D. Shah, MD: That’s the bigger issue, and that’s why I brought up the difficulty with having to order it before you know what the marrow shows. And what does it mean if you’re ordering this NGS MRD assay and then your pathologist says there’s 20% blasts. OK, I just wasted a lot of money here.

Anthony S. Stein, MD: I think you’re able to cancel; hopefully the pathologist can look at the morphology the same day. The other one you have to ship out. So you may be able to cancel.

Bijal D. Shah, MD: We try, we try.

Jae Park, MD: I think the turnaround time is important because when you need to make a real-time decision very soon, the flow is very useful to do that. NGS sensitivity is very useful during maintenance consolidation when you’re monitoring them. So there may need to be a different value, the one assay may serve the better purpose during the later part of the day when you when you can actually tolerate 7-day or even longer turnaround time. The flow has an advantage, and because of expression of 19 and 22, at least for the B [B-cell] ALL, I think it’s an important factor. We’re still doing both at the same time, but eventually, as we get more data, perhaps at one point in time, one test may be better and then the other time, the NGS may take over. Especially in the peripheral blood monitoring, the later time point is very attractive and useful with good sensitivity during the consolidation of the maintenance portion, where you’re simply trying to monitor the patient’s progress there.

Transcript edited for clarity.

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Transcript:

Mark R. Litzow, MD:
Anthony, when do you think we should be measuring MRD?

Anthony S. Stein, MD: I think it also depends which regimen you’re using. I know if you use the Alliance AYA [adolescents and young adults] regimen, then they do it. I think what was most significant was after the induction therapy, which showed the greatest risk of predicting for outcome. If you’re using a German ALL protocol, they do it at week 16, which would be after the consolidation treatment, and that’s where all their data have been generated. If you use hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone], I think it’s after Part B, after cycle 1. I’m not sure if it’s….

Bijal D. Shah, MD: They have 2 time points for assessment. They say basically on, once hematological recovery occurs, so within about 30 days or so of cycle 1a, usually before cycle 1b, and then they do another assessment at month 3, on average. How that addresses the number of cycles for patients is not something … but I suspect it’s going to be after 3b or so for most patients.

Anthony S. Stein, MD: Basically, you have to learn what regimen you’re using, and then at what time point your MRD is significant enough to make a change in treatment.

Jae Park, MD: I think an important point also is that we’re making sure not to consider regular flow. We all talk about MRD and that it has to be a certain sensitivity for the MRD, the definition to be met in 10-4. So I think the 1 thing that could potentially happen is that when you get a regular flow, which is not to the level of sensitivity, they’ll assume the flow is negative, and then you’ll assume that it’s MRD-negative when in fact it’s really not because you’re not achieving that level of sensitivity.

So the 1 thing that we should be aware of is it true MRD that all the publications are talking about, or is it convention of flow and with less sensitivity that you’re assessing? I think that’s making sure that everybody is talking about the same definition. Of course you can go deeper with an NGS and then the prognostic implication of that.

And the NGS, I think another factor to remember is you need diagnostic material in order to follow the clone. So if you don’t send it at the time of diagnosis, unless you can retrieve it, which is possible and you can definitely do, but I think these are factors to consider when you’re seeing newly diagnosed patients that these are critical components to look for this kind of division of clone so that you can follow these patients. For flow you don’t need them, but I think these are the benefits of both, but I strongly believe they should be tested, because we all do, but these are the factors to consider I think can only see new patients.

Especially when there’s an MRD-directed therapy available and then there’s significance at the end of consolidation, for sure it’s a very important point. Induction, I think at that point is more data and depending on the regimen, but….

Anthony S. Stein, MD: I agree. It needs to be sent, if you’re looking for MRD, it needs to be sent to a reputable flow lab that deals with looking at MRD analyses and experience. I wouldn’t just send it to any new lab that just popped up.

Jae Park, MD: The flow is so complicated.

Bijal D. Shah, MD: Correct.

Jae Park, MD: It took many months and years before in our center they established that. So … there’s no false assurance. And then it also depended on when you send the flow … it has to be from the first pull to get the best results.

Anthony S. Stein, MD: Yes, that’s the most important factor to get a reliable flow.

Jae Park, MD: And if you send it at the fourth pull, then it’s meaningless; exactly.

Anthony S. Stein, MD: That’s meaningless.

Jae Park, MD: So I think these are the kind of details that need to be discussed.

Bijal D. Shah, MD: And also it’s not just the number of colors. It’s also the number of events. And that means you have to be very careful about asking MRD questions on very hypocellular marrows. And I think that’s something else that often gets lost in the shuffle.

Mark R. Litzow, MD: I think we’re talking about standardization of the assay, and our pediatric colleagues have the advantage of, you’re using 2 flow labs in the United States. They have cross-referenced each other. So they have standardization, where that’s a challenge in our adult world....

Anthony S. Stein, MD: But in the future NGS is going to probably take over because, 1, you probably can send the test from the peripheral; you won’t have to repeat bone marrows, they can send it from the peripheral blood. I mean the sensitivity may be 1 log lower than what you would get off the bone marrow. It’s easier to send from the blood and you can send it at the different timing. I’m not sure what the cost differential would be.

Bijal D. Shah, MD: That’s the bigger issue, and that’s why I brought up the difficulty with having to order it before you know what the marrow shows. And what does it mean if you’re ordering this NGS MRD assay and then your pathologist says there’s 20% blasts. OK, I just wasted a lot of money here.

Anthony S. Stein, MD: I think you’re able to cancel; hopefully the pathologist can look at the morphology the same day. The other one you have to ship out. So you may be able to cancel.

Bijal D. Shah, MD: We try, we try.

Jae Park, MD: I think the turnaround time is important because when you need to make a real-time decision very soon, the flow is very useful to do that. NGS sensitivity is very useful during maintenance consolidation when you’re monitoring them. So there may need to be a different value, the one assay may serve the better purpose during the later part of the day when you when you can actually tolerate 7-day or even longer turnaround time. The flow has an advantage, and because of expression of 19 and 22, at least for the B [B-cell] ALL, I think it’s an important factor. We’re still doing both at the same time, but eventually, as we get more data, perhaps at one point in time, one test may be better and then the other time, the NGS may take over. Especially in the peripheral blood monitoring, the later time point is very attractive and useful with good sensitivity during the consolidation of the maintenance portion, where you’re simply trying to monitor the patient’s progress there.

Transcript edited for clarity.
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