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Bone Marrow Assessment in CML Management

Panelists:Jorge E. Cortes, MD, University of Texas MD Anderson Cancer Center; Harry P. Erba, MD, PhD, University of Alabama; Kevin Kelly, MD, PhD, University of Southern California; Javier Pinilla-Ibarz, MD, PhD, Moffitt Cancer Center; David S. Snyder, MD, FACP, City of Hope
Published: Tuesday, Feb 16, 2016


Transcript:

Javier Pinilla-Ibarz, MD, PhD:
Jorge, I would like to add to Harry’s comment. A quite important fact that I experienced in my practice at some point in the last year is, as he suggests, the importance of doing a bone marrow diagnosis. There’s a trend to use PCR alone as a diagnosis of this entity. And, in fact, I have anecdotal cases where there have been patients diagnosed with false-positive PCR low levels, where, in fact, they were not having any problem in the bone marrow with cytogenetics. So, I think this is quite important. I want to emphasize the importance to do a baseline bone marrow assessment to really have a truly good diagnosis of this entity.

Harry Erba, MD, PhD: Right, and the bone marrow at diagnosis might give you some hint if the patient is already slipping into an accelerated phase, if you see fibrosis, clustering of blasts.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, many, many things.

Harry Erba, MD, PhD: It doesn’t happen that often, but it does happen. Or if they have clonal evolution, you may not be able to do cytogenetics on the peripheral blood at diagnosis. So, if they have clonal evolution, you might say, ‘Well, so what.” Well, you might pick a different dose of your ABL TKI up front. So, unusual situations, but I guess the things that we see referred into us are these patients that don’t quite fit with what you might expect.

Jorge Cortes, MD: So, Javier brought up the issue of the bone marrow. David, can I ask you how often, baseline? I fully agree that baseline bone marrow is, to me, mandatory. After the diagnosis, do you do bone marrows? How often do you do bone marrows? Do we need bone marrows? When?

David Snyder, MD, FACP: Right. First of all, I agree completely with the importance of doing it at diagnosis, as has been mentioned. You can perhaps underestimate the staging of the disease just by relying on peripheral blood. I think it’s a little controversial about how often you need to do bone marrow biopsy after diagnosis. As Kevin mentioned, you might want to do it to document complete cytogenetic remission.

There is still value in that endpoint in terms of predicting survival. And I think NCCN has kind of struggled a little bit with it. I think PCR, of course, has become a very valuable test and the level of MMR, for example. To some extent, I think it’s taken the place of following cytogenetics and doing bone marrow biopsies. So, to me, if the patient is meeting the molecular endpoints that you’re looking for, it’s reasonable not to do a bone marrow biopsy again after that initial diagnosis.

Of course, if they fail to reach milestones or if they lose their initial response, that’s another story. I think that relying on peripheral blood FISH— which is another way to document cytogenetic remission—that’s a little controversial. But I think you can use that and the peripheral blood PCRs, and not have to do more bone marrow biopsies.

Harry Erba, MD, PhD: Actually, Kevin said it earlier that if a patient doesn’t have a BCR-ABL ratio of less than 1% or MMR, that he would do a bone marrow biopsy at one year. And, actually, I think NCCN says that if your patient is in an MMR or you already know they’re in a cytogenetic remission, you don’t have to do a bone marrow at that point. So, I think most of us have gotten away from many of the follow-up bone marrows that we were doing.

Jorge Cortes, MD: The follow-up, I agree. One thing that still worries me is that there’s a small subset of patients, about 10%, 15% of patients that may develop these chromosomal abnormalities in the Philadelphia-negative metaphases. Of course, that you wouldn’t find by a PCR. You wouldn’t even find by a FISH unless you did a FISH for every chromosome. Do you worry about them? Do you look for them?

Harry Erba, MD, PhD: Do you know how the best way not to worry about them, Jorge. Don’t do the bone marrow biopsy? Because…

Jorge Cortes, MD: Write that down.

Harry Erba, MD, PhD: Yeah, right. No, actually, Jorge, I already know from my patients who go to MD Anderson that before they can see you, they get a bone marrow biopsy. So, I understand that it’s mandated. That was so funny I forgot what I was going to say.

Javier Pinilla-Ibarz, MD, PhD: Additional cytogenetic abnormalities.

Harry Erba, MD, PhD: We don’t know what to do. So, it’s 5% to 10% of patients will have a Ph-negative clone that has these cytogenetic changes. I remember when I sat on the NCCN committee and people around the table brought this up as a reason to continue to do the yearly exam. And my argument against it was not only don’t we know what to do with it, but there have been patients who had been referred for allogeneic stem cell transplant based on these clones which may come and go over time. So, maybe the best [way] not to worry is not to do it.

Javier Pinilla-Ibarz, MD, PhD: So, I remember the paper Jorge published and many others. It’s true that maybe only deletion of chromosome 7; very, very few situations. I remember it was one case or two cases that may also really give you some warning because you may have an unexplained anemia or some kind of prolonged cytopenia. You may once you miss the gate, but for the overall cases, I agree that’s something different.

Jorge Cortes, MD: Let me tell you my approach, and I think it’s very compatible with what you all have said. I do worry about these things because we’ve shown that the overall survival for all of them is a little bit inferior. But, on the other hand, these abnormalities tend to happen early on. So, I do bone marrows at the beginning. Once they get to a stable MMR, if they haven’t developed these abnormalities, it’s very rare that they’ll develop them later. So, I do stop doing bone marrows as long as there’s changes on the counts, of course.

Javier Pinilla-Ibarz, MD, PhD: So, how many you will do?

Jorge Cortes, MD: Well, the patient will end up getting maybe two or three bone marrows afterall and then only as needed. But I do want to know when they develop these abnormalities because they do have a little bit of implication. True, there’s no clear indication of what to do with those patients, but those patients I may want to keep a closer eye [on] and have a lower threshold for when things change because they may be developing an occasional MDS and an AML. I think that’s something that I think we just need to be aware [of]. I think that it is definitely a fact that we are not doing as many bone marrows and we don’t need to be doing bone marrow as much. And definitely a patient that has reached a stable MMR, bone marrows are just as-needed based on other factors.

Harry Erba, MD, PhD: Like if the patient is in a good remission and they develop new cytopenias, it shouldn’t be assumed it’s due to the drug.

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Harry Erba, MD, PhD: You have to worry that it’s either losing response, that their disease is moving into a blast crisis, or they’ve got this secondary myelodysplastic syndrome. Or just keep in mind these patients are living longer and they could develop some other cause of anemia. But it has to be evaluated, not just assumed it’s the drug and cut back on the dose of the drug because that’s how we handle hematologic toxicity. It’s different when you see it later on.

Jorge Cortes, MD: Absolutely. Javier, let me ask you: we talked a little bit about the early molecular responses and this 10% threshold, and whatever, and then patients going deeper. And we have some guidelines as to how deep they have to go at what time, that all these NCCN and ELN tell us these values. What happens when you go in the opposite direction? You’re monitoring a patient and there’s a change in their transient levels. You have whatever volume and then next time they’re a little higher. When do you start worrying? When is a change just a variation and when is a change a real change?

Javier Pinilla-Ibarz, MD, PhD: To start with, I will have to say again that we are using very, very sensitive techniques that have intrinsic variability in the fact that you can repeat it and you have different values. And it is something that people may not really understand much in the community because we are the ones who see these problems more often. But there is no doubt that there are other scenarios that we can encounter with these variabilities of the PCR.

One of the scenarios is the fact that some patients may really go all the way down to almost a complete molecular response, undetectable disease, and [that this] is not really unusual. Many times when you see these blips, what you see really, is the detectable disease. In my opinion, this really should not be considered a failure of therapy by any means. Sometimes it’s a variability that may be related, adherence, or even biology of the disease. But by any means, that doesn’t really have any problems.

Of course, there are several guidelines about the fact that if a patient has reached these responses and loses the major molecular response; away from 4.5 and to less than 3.5, will be a reason of concern in my opinion, a reason to really say, well, is this patient leading or going to cytogenetic relapse. Maybe a time, at some point, if really these things continue to be consistent, a bone marrow evaluation will be indicated to really see what’s going on.

So, once again, the variability of the PCR may happen at different levels. I always remember your talks about if the PCR is going well, it’s the same: leave it alone. If it’s going down, it’s perfect, and if it’s going up, well, watch more carefully. So, you really want to anticipate the farther relapses and the fact that you need to really discuss the possibility to change therapies.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Javier Pinilla-Ibarz, MD, PhD:
Jorge, I would like to add to Harry’s comment. A quite important fact that I experienced in my practice at some point in the last year is, as he suggests, the importance of doing a bone marrow diagnosis. There’s a trend to use PCR alone as a diagnosis of this entity. And, in fact, I have anecdotal cases where there have been patients diagnosed with false-positive PCR low levels, where, in fact, they were not having any problem in the bone marrow with cytogenetics. So, I think this is quite important. I want to emphasize the importance to do a baseline bone marrow assessment to really have a truly good diagnosis of this entity.

Harry Erba, MD, PhD: Right, and the bone marrow at diagnosis might give you some hint if the patient is already slipping into an accelerated phase, if you see fibrosis, clustering of blasts.

Javier Pinilla-Ibarz, MD, PhD: Absolutely, many, many things.

Harry Erba, MD, PhD: It doesn’t happen that often, but it does happen. Or if they have clonal evolution, you may not be able to do cytogenetics on the peripheral blood at diagnosis. So, if they have clonal evolution, you might say, ‘Well, so what.” Well, you might pick a different dose of your ABL TKI up front. So, unusual situations, but I guess the things that we see referred into us are these patients that don’t quite fit with what you might expect.

Jorge Cortes, MD: So, Javier brought up the issue of the bone marrow. David, can I ask you how often, baseline? I fully agree that baseline bone marrow is, to me, mandatory. After the diagnosis, do you do bone marrows? How often do you do bone marrows? Do we need bone marrows? When?

David Snyder, MD, FACP: Right. First of all, I agree completely with the importance of doing it at diagnosis, as has been mentioned. You can perhaps underestimate the staging of the disease just by relying on peripheral blood. I think it’s a little controversial about how often you need to do bone marrow biopsy after diagnosis. As Kevin mentioned, you might want to do it to document complete cytogenetic remission.

There is still value in that endpoint in terms of predicting survival. And I think NCCN has kind of struggled a little bit with it. I think PCR, of course, has become a very valuable test and the level of MMR, for example. To some extent, I think it’s taken the place of following cytogenetics and doing bone marrow biopsies. So, to me, if the patient is meeting the molecular endpoints that you’re looking for, it’s reasonable not to do a bone marrow biopsy again after that initial diagnosis.

Of course, if they fail to reach milestones or if they lose their initial response, that’s another story. I think that relying on peripheral blood FISH— which is another way to document cytogenetic remission—that’s a little controversial. But I think you can use that and the peripheral blood PCRs, and not have to do more bone marrow biopsies.

Harry Erba, MD, PhD: Actually, Kevin said it earlier that if a patient doesn’t have a BCR-ABL ratio of less than 1% or MMR, that he would do a bone marrow biopsy at one year. And, actually, I think NCCN says that if your patient is in an MMR or you already know they’re in a cytogenetic remission, you don’t have to do a bone marrow at that point. So, I think most of us have gotten away from many of the follow-up bone marrows that we were doing.

Jorge Cortes, MD: The follow-up, I agree. One thing that still worries me is that there’s a small subset of patients, about 10%, 15% of patients that may develop these chromosomal abnormalities in the Philadelphia-negative metaphases. Of course, that you wouldn’t find by a PCR. You wouldn’t even find by a FISH unless you did a FISH for every chromosome. Do you worry about them? Do you look for them?

Harry Erba, MD, PhD: Do you know how the best way not to worry about them, Jorge. Don’t do the bone marrow biopsy? Because…

Jorge Cortes, MD: Write that down.

Harry Erba, MD, PhD: Yeah, right. No, actually, Jorge, I already know from my patients who go to MD Anderson that before they can see you, they get a bone marrow biopsy. So, I understand that it’s mandated. That was so funny I forgot what I was going to say.

Javier Pinilla-Ibarz, MD, PhD: Additional cytogenetic abnormalities.

Harry Erba, MD, PhD: We don’t know what to do. So, it’s 5% to 10% of patients will have a Ph-negative clone that has these cytogenetic changes. I remember when I sat on the NCCN committee and people around the table brought this up as a reason to continue to do the yearly exam. And my argument against it was not only don’t we know what to do with it, but there have been patients who had been referred for allogeneic stem cell transplant based on these clones which may come and go over time. So, maybe the best [way] not to worry is not to do it.

Javier Pinilla-Ibarz, MD, PhD: So, I remember the paper Jorge published and many others. It’s true that maybe only deletion of chromosome 7; very, very few situations. I remember it was one case or two cases that may also really give you some warning because you may have an unexplained anemia or some kind of prolonged cytopenia. You may once you miss the gate, but for the overall cases, I agree that’s something different.

Jorge Cortes, MD: Let me tell you my approach, and I think it’s very compatible with what you all have said. I do worry about these things because we’ve shown that the overall survival for all of them is a little bit inferior. But, on the other hand, these abnormalities tend to happen early on. So, I do bone marrows at the beginning. Once they get to a stable MMR, if they haven’t developed these abnormalities, it’s very rare that they’ll develop them later. So, I do stop doing bone marrows as long as there’s changes on the counts, of course.

Javier Pinilla-Ibarz, MD, PhD: So, how many you will do?

Jorge Cortes, MD: Well, the patient will end up getting maybe two or three bone marrows afterall and then only as needed. But I do want to know when they develop these abnormalities because they do have a little bit of implication. True, there’s no clear indication of what to do with those patients, but those patients I may want to keep a closer eye [on] and have a lower threshold for when things change because they may be developing an occasional MDS and an AML. I think that’s something that I think we just need to be aware [of]. I think that it is definitely a fact that we are not doing as many bone marrows and we don’t need to be doing bone marrow as much. And definitely a patient that has reached a stable MMR, bone marrows are just as-needed based on other factors.

Harry Erba, MD, PhD: Like if the patient is in a good remission and they develop new cytopenias, it shouldn’t be assumed it’s due to the drug.

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Harry Erba, MD, PhD: You have to worry that it’s either losing response, that their disease is moving into a blast crisis, or they’ve got this secondary myelodysplastic syndrome. Or just keep in mind these patients are living longer and they could develop some other cause of anemia. But it has to be evaluated, not just assumed it’s the drug and cut back on the dose of the drug because that’s how we handle hematologic toxicity. It’s different when you see it later on.

Jorge Cortes, MD: Absolutely. Javier, let me ask you: we talked a little bit about the early molecular responses and this 10% threshold, and whatever, and then patients going deeper. And we have some guidelines as to how deep they have to go at what time, that all these NCCN and ELN tell us these values. What happens when you go in the opposite direction? You’re monitoring a patient and there’s a change in their transient levels. You have whatever volume and then next time they’re a little higher. When do you start worrying? When is a change just a variation and when is a change a real change?

Javier Pinilla-Ibarz, MD, PhD: To start with, I will have to say again that we are using very, very sensitive techniques that have intrinsic variability in the fact that you can repeat it and you have different values. And it is something that people may not really understand much in the community because we are the ones who see these problems more often. But there is no doubt that there are other scenarios that we can encounter with these variabilities of the PCR.

One of the scenarios is the fact that some patients may really go all the way down to almost a complete molecular response, undetectable disease, and [that this] is not really unusual. Many times when you see these blips, what you see really, is the detectable disease. In my opinion, this really should not be considered a failure of therapy by any means. Sometimes it’s a variability that may be related, adherence, or even biology of the disease. But by any means, that doesn’t really have any problems.

Of course, there are several guidelines about the fact that if a patient has reached these responses and loses the major molecular response; away from 4.5 and to less than 3.5, will be a reason of concern in my opinion, a reason to really say, well, is this patient leading or going to cytogenetic relapse. Maybe a time, at some point, if really these things continue to be consistent, a bone marrow evaluation will be indicated to really see what’s going on.

So, once again, the variability of the PCR may happen at different levels. I always remember your talks about if the PCR is going well, it’s the same: leave it alone. If it’s going down, it’s perfect, and if it’s going up, well, watch more carefully. So, you really want to anticipate the farther relapses and the fact that you need to really discuss the possibility to change therapies.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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