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When to Switch Therapy in Chronic Myeloid Leukemia

Panelists: Harry P. Erba, MD, Duke University; Jorge E. Cortes, MD, MD Anderson Cancer Center; Michael Mauro, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Aug 16, 2018


Transcript: 

Harry P. Erba, MD: But to help inform that discussion about switching, we need to talk about how we monitor these patients to know when to switch them. And so, Jorge, can you lay out what the guidelines are and how you monitor the patients who started on an ABL TKI? What are you looking for?

Jorge E. Cortes, MD: Yes. I think that it is very important, and the major agencies that have given us information on these, ELN and NCCN and all of these, they have very similar recommendations. And I think it is very clear to all of us that the close monitoring is critical to optimize the benefit. There’s no question that something is going to do well even if you’re not looking. But you are going miss the patients who are not, or you’re going to miss when you could have changed the impact of the outcome.

So, basically, what I do is pretty close to what these guidelines recommend. I do every 3 months for the first year. Once the patient gets a deep, at least a major, molecular response and that’s stable, I go to every 6 months, and I stay with every 6 months. Some have recommended that later on you should continue with every 3 months. For example, the ELN says every 3 to 6 months. I think once a patient has a very stable response, every 6 months is fine. I may do every 3 months if I reduce the doses or there is a question mark about a value we took earlier that is a small variation. I may want to check it a little bit sooner if it’s going in the wrong direction, etc.

We can do that with PCR alone. I still think there is value of doing after start of treatment an occasional cytogenetic analysis early on. I think 6, 12 months could be valuable because there’s a small subset of patients who develop chromosomal abnormalities in the PD-L–negative metaphases. And it’s about 10% to 15% of patients, and those patients may have both a different outcome from the CML and the potential of developing rare but occasionally MBSs and AMLs that are not blast phase II, a different disease. But those things will occur early. So, after the initial year or two, maybe doing 1 or 2 bone marrows and making sure that those haven’t appeared, and if the patient has a good response, then just the PCR is important.

But again, in the first year, some important time points where we know where you want to be for having an optimal response at 3 months, 6 months, and 12 months are very important, and then 18 months. So, those are time points that we should not miss on any patient. Everybody should be monitored at those time points. And then, of course, continue every 6 months after that.

Harry P. Erba, MD: Mike?

Michael Mauro, MD: I use 2 terms: Play in the zone, but we don’t want to be developing PCR-itis. But I think once a patient gets into response, I agree that molecular response is the workhorse. I actually use molecular response as a reinforcement to continue to engage the patient. You’re continuing to do well; you’re continuing to show stable deep remission or it’s deepening. You don’t want to overdo it; that’s where the PCR-itis comes from. You can look at it too much and then you’re looking at lab variability and disease variability as it’s probably distinguishing over time. And it’s true. The good news is that most patients may do well without more intensive monitoring. So, you’ve got to strike a balance, I think, of what’s going to serve the patient the best.

And probably to remind everybody that in the United States and abroad, we actually don’t monitor as much as we should as a community. We’ve seen data on that, that even just the bare minimum—as you just mentioned, Jorge, they’re key milestones, the really molecular response, looking at cytogenetics within the first year, or molecular testing within the first year sometimes—doesn’t happen. But I think the molecular data collected over time help us have confidence about TFR, which is really a new agenda item. We don’t have to have reams of data, but we do need sufficient data to really judge a patient to be eligible. We have to marry those agendas.

Jorge E. Cortes, MD: Adding to this, one expression I use when I talk about these things is that to me, the molecular responses are not a measure of failure; they’re a measure of success.

A patient who hasn’t achieved an MR4.5 but has an MR4, they’re doing pretty good. If they have an MMR, they’re doing great, they’re going to live a normal life expectancy. Now they’re a measure of success because if you want TFR, you want to get deeper. But that patient is not failing therapy; they’re doing well. So, are you going to transplant that patient? Of course not. Are you going to change therapy? Well, yes, it depends. If you want to get deeper, maybe you just need to optimize their dose, whatever. But speaking about the PCR, you don’t want to overdo these things. Not everybody has to be negative in the PCR.

Harry P. Erba, MD: I’d like to add in a few things. In terms of monitoring, I think it’s important to understand why we’re monitoring. If we tell people that you have to come in for monitoring and don’t tell them why, then you’re going to lose it. And again, it has to do with education, the patient education of our referring physicians, people out there treating patients. The reason why we check at 3 months is that there are very good data that started from the Hammersmith, with 280 patients treated with imatinib, showing that the BCR-ABL to ABL ratio at 3 months was informative regarding progression-free and overall survival. Roughly, if it was above 10%, those patients had a PFS and OS of about 57%, and it was 93% if it was under 10%. So, that has been adopted into the ELN and NCCN guidelines.

At 1 year, this is where it gets a little confusing because people like us confuse people, and recommendations confuse people. You know, how deep of a response do you need? And my opinion is, if a patient is tolerating the drug, being compliant with the drug, and they achieve a complete cytogenetic remission at 1 year or a BCR-ABL ratio of 1% or lower, to me, that’s sufficient. And I would then continue to monitor them, making sure that that’s stable and getting better over time. Because those patients will do as well long term as patients who have a major molecular response.

Now if you achieve a major molecular response by 12 or 18 months, you’re less likely to lose that complete cytogenetic remission. But in terms of survival or progression, there’s really no difference between a CCyR at 1 year and a major molecular response.

So, in terms of my goal, my goal is for patients. Until now, it has been achieved, compliant with the drug, tolerating it, achieving a complete cytogenetic remission, and hopefully, you’ll see that BCR-ABL ratio go down over time. Now I think we have a new endpoint that is different, and that’s the MR4.5 that we’ll talk about later in terms of treating free remission.

The only other thing I would add to the discussion is I fully agree with all your comments about the risk of Philadelphia chromosome–negative cytogenetic changes. They do occur. I don’t personally repeat a marrow to look for those because, as you know, we don’t really know what to do with that data. We’ll monitor those patients by their blood counts. We’re not going to send them to transplant. So, it’ll really be a change in their blood counts that would trigger me doing it. So, I understand what it’ll show, but in my clinical practice, I don’t do it.

Transcript Edited for Clarity 

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Transcript: 

Harry P. Erba, MD: But to help inform that discussion about switching, we need to talk about how we monitor these patients to know when to switch them. And so, Jorge, can you lay out what the guidelines are and how you monitor the patients who started on an ABL TKI? What are you looking for?

Jorge E. Cortes, MD: Yes. I think that it is very important, and the major agencies that have given us information on these, ELN and NCCN and all of these, they have very similar recommendations. And I think it is very clear to all of us that the close monitoring is critical to optimize the benefit. There’s no question that something is going to do well even if you’re not looking. But you are going miss the patients who are not, or you’re going to miss when you could have changed the impact of the outcome.

So, basically, what I do is pretty close to what these guidelines recommend. I do every 3 months for the first year. Once the patient gets a deep, at least a major, molecular response and that’s stable, I go to every 6 months, and I stay with every 6 months. Some have recommended that later on you should continue with every 3 months. For example, the ELN says every 3 to 6 months. I think once a patient has a very stable response, every 6 months is fine. I may do every 3 months if I reduce the doses or there is a question mark about a value we took earlier that is a small variation. I may want to check it a little bit sooner if it’s going in the wrong direction, etc.

We can do that with PCR alone. I still think there is value of doing after start of treatment an occasional cytogenetic analysis early on. I think 6, 12 months could be valuable because there’s a small subset of patients who develop chromosomal abnormalities in the PD-L–negative metaphases. And it’s about 10% to 15% of patients, and those patients may have both a different outcome from the CML and the potential of developing rare but occasionally MBSs and AMLs that are not blast phase II, a different disease. But those things will occur early. So, after the initial year or two, maybe doing 1 or 2 bone marrows and making sure that those haven’t appeared, and if the patient has a good response, then just the PCR is important.

But again, in the first year, some important time points where we know where you want to be for having an optimal response at 3 months, 6 months, and 12 months are very important, and then 18 months. So, those are time points that we should not miss on any patient. Everybody should be monitored at those time points. And then, of course, continue every 6 months after that.

Harry P. Erba, MD: Mike?

Michael Mauro, MD: I use 2 terms: Play in the zone, but we don’t want to be developing PCR-itis. But I think once a patient gets into response, I agree that molecular response is the workhorse. I actually use molecular response as a reinforcement to continue to engage the patient. You’re continuing to do well; you’re continuing to show stable deep remission or it’s deepening. You don’t want to overdo it; that’s where the PCR-itis comes from. You can look at it too much and then you’re looking at lab variability and disease variability as it’s probably distinguishing over time. And it’s true. The good news is that most patients may do well without more intensive monitoring. So, you’ve got to strike a balance, I think, of what’s going to serve the patient the best.

And probably to remind everybody that in the United States and abroad, we actually don’t monitor as much as we should as a community. We’ve seen data on that, that even just the bare minimum—as you just mentioned, Jorge, they’re key milestones, the really molecular response, looking at cytogenetics within the first year, or molecular testing within the first year sometimes—doesn’t happen. But I think the molecular data collected over time help us have confidence about TFR, which is really a new agenda item. We don’t have to have reams of data, but we do need sufficient data to really judge a patient to be eligible. We have to marry those agendas.

Jorge E. Cortes, MD: Adding to this, one expression I use when I talk about these things is that to me, the molecular responses are not a measure of failure; they’re a measure of success.

A patient who hasn’t achieved an MR4.5 but has an MR4, they’re doing pretty good. If they have an MMR, they’re doing great, they’re going to live a normal life expectancy. Now they’re a measure of success because if you want TFR, you want to get deeper. But that patient is not failing therapy; they’re doing well. So, are you going to transplant that patient? Of course not. Are you going to change therapy? Well, yes, it depends. If you want to get deeper, maybe you just need to optimize their dose, whatever. But speaking about the PCR, you don’t want to overdo these things. Not everybody has to be negative in the PCR.

Harry P. Erba, MD: I’d like to add in a few things. In terms of monitoring, I think it’s important to understand why we’re monitoring. If we tell people that you have to come in for monitoring and don’t tell them why, then you’re going to lose it. And again, it has to do with education, the patient education of our referring physicians, people out there treating patients. The reason why we check at 3 months is that there are very good data that started from the Hammersmith, with 280 patients treated with imatinib, showing that the BCR-ABL to ABL ratio at 3 months was informative regarding progression-free and overall survival. Roughly, if it was above 10%, those patients had a PFS and OS of about 57%, and it was 93% if it was under 10%. So, that has been adopted into the ELN and NCCN guidelines.

At 1 year, this is where it gets a little confusing because people like us confuse people, and recommendations confuse people. You know, how deep of a response do you need? And my opinion is, if a patient is tolerating the drug, being compliant with the drug, and they achieve a complete cytogenetic remission at 1 year or a BCR-ABL ratio of 1% or lower, to me, that’s sufficient. And I would then continue to monitor them, making sure that that’s stable and getting better over time. Because those patients will do as well long term as patients who have a major molecular response.

Now if you achieve a major molecular response by 12 or 18 months, you’re less likely to lose that complete cytogenetic remission. But in terms of survival or progression, there’s really no difference between a CCyR at 1 year and a major molecular response.

So, in terms of my goal, my goal is for patients. Until now, it has been achieved, compliant with the drug, tolerating it, achieving a complete cytogenetic remission, and hopefully, you’ll see that BCR-ABL ratio go down over time. Now I think we have a new endpoint that is different, and that’s the MR4.5 that we’ll talk about later in terms of treating free remission.

The only other thing I would add to the discussion is I fully agree with all your comments about the risk of Philadelphia chromosome–negative cytogenetic changes. They do occur. I don’t personally repeat a marrow to look for those because, as you know, we don’t really know what to do with that data. We’ll monitor those patients by their blood counts. We’re not going to send them to transplant. So, it’ll really be a change in their blood counts that would trigger me doing it. So, I understand what it’ll show, but in my clinical practice, I don’t do it.

Transcript Edited for Clarity 
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