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Importance of Monitoring Patients with Chronic Myeloid Leukemia

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 09, 2016


Transcript:

Jorge Cortes, MD:
So, David, Harry mentioned something that I just want to ask you to tell us a little bit more about, adherence. This is a chronic treatment. Patients take a pill and it goes on for a long time, indefinitely, we’re starting to assess discontinuation, but at least for a very, very long time. How relevant is assessing adherence? Does it matter? How do we do it?

David Snyder, MD, FACP: No, I think it is very important. As Harry said, there are studies showing somewhat intuitive, perhaps, that patients who don’t take their drugs don’t do as well as those who take it. There’s also data showing a very large proportion of patients, I think it’s something like 85% of patients with CML are not consistently adherent. And I think that’s an important issue we need to be aware of.

I think there are two sides of it. One is the patient who is feeling well, their disease is fully controlled, they’re not having side effects from the drugs. It’s almost like they don’t have a reminder that, aah, there’s something wrong here, I need to make sure I take my drug to remind them every day. And so people, busy with their daily lives, they tend to forget. Especially if it’s a drug that they have to take more than once a day, there’s even more chance that they’ll miss a dose here and there. So I think that’s one part of it.

The other part is about some of the issues that Harry mentioned about the ongoing kind of nagging side effects. For most of the patients, the side effects that occur, which are common, tend to be low grade, grade 1 or 2, and they tend to be transient. However, we know that some of the patients have ongoing low grade toxicity that’s kind of always there. That might be a reason for them to say, oh, I need to take a break; I need a little holiday. So, it’s important to be aware of that.

We do have choices of other TKIs. If there’s an issue about this kind of nagging ongoing side effects, that’s something to address, and potentially consider a change to allow them to be more adherent.

Jorge Cortes, MD: I think one of perhaps the most telling studies, these from David Marin, who showed among these patients who had been on treatment for a long time, and they measured adherence by this device in the cap and he showed that patients that had at least 10% of the dose, the probability of achieving these deeper responses, MR 4.5 was 0%. So it doesn’t take too many doses to miss and that’s why some of these recommendations actually tell us that when the patient is not reaching these endpoints, the first thing you do is check adherence and what is maybe interfering with adherence because it’s very important.

David Snyder, MD, FACP: I echo what Harry said about meeting on an ongoing basis with the patient. My patients know that I’m going to be checking the PCR and they often kind of confess to me. “Oh, I took that trip out of the country and I left my drug at home. Do you think that’s going to show up?” And likely it will and I think it’s important to emphasize that.

Jorge Cortes, MD: Okay. A lot of what we’ll be discussing has to do with monitoring the patient and all of these aspects that are so critical for assessing the response. How do you monitor patients, Kevin, in the clinic? I’m talking about like a newly diagnosed patient. How do you do the monitoring?

Kevin Kelly, MD, PhD: Yes, certainly. I tend to follow the NCCN Guidelines. For safety considerations, I check CBC and chemistry every two weeks for the first two months, and then I pay close attention to the three months BCR-ABL time point. This is a key milestone, as we alluded to earlier, because patients who achieve BCR-ABL, less than 10% at three months have a better overall survival. Of course, we don’t necessarily need to act immediately if they’re slightly above 10%. So we have that six-month time point, too, where we can make a change, particularly if they’re still above 10% at the six- month time point. And then I continue to check BCR-ABL every three months until the patient achieves a major molecular response.

You do have the option then to maybe extend it out to every six months, but, as Harry said, we like to see these patients on a frequent basis. So, typically, if they’re coming to the office anyhow, we continue to check their BCR-ABL, so every three months.

Then when the patient reaches BCR-ABL less than 1%, which we said was kind of equivalent to a complete cytogenetic response, we often times do a bone marrow biopsy to confirm the presence of a complete cytogenetic response. So we’ve moved away from doing a lot of bone marrow biopsies and I think a lot of patients are very grateful for that when we can check BCR-ABL. But there still is a role for bone marrow biopsies, particularly when the BCR-ABL is hovering above the 1% mark, and we want to confirm that they’ve lost a complete cytogenetic response.

Jorge Cortes, MD: Harry, how often do you do the BCR on your patients and does it change over time or is it constant?

Harry Erba, MD, PhD: Well, the first point I’d like to make about that is I always do it at baseline and it’s not to get a patient specific value. That’s not really the importance, although there is some data from Australia that how much it goes down by three months might be as important as this 10% level. But the real reason for doing it is that there will be rare patients who will have variant fusions of BCR and ABL where the commercially available PCR assays will not detect it efficiently. And so the best time to understand this is when the patient shows up and they have a white count of 100,000 and you get a BCR-ABL result of .1% or negative.

So I do all three assays at the beginning, chromosomes, FISH, and PCR because that’s the best time to have your baseline. Then you know the assay is informative, and then I do it every three months starting at three months. And I do it to make sure they’re meeting their milestones and I always also do it as a way of checking adherence.

Let’s say the patient has gotten into a major molecular remission, but one time they come in and it’s just a little bit higher. So it went from .02 to .08 and hasn’t gone up 10-fold, they haven’t lost an MMR, we’re not so worried, your nurse calls the patient and the patient gets the result and they’re worried. And they might say, eeh, I didn’t tell Doc Erba that I was not taking the drug. I’m going to make sure I’m a little bit more compliant. So I think using it also as a way of ensuring compliance can be very helpful for our patients, so at baseline and every three months. And I continue to do that. Patients who achieve a complete molecular remission who live far from our center, maybe every six months.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Jorge Cortes, MD:
So, David, Harry mentioned something that I just want to ask you to tell us a little bit more about, adherence. This is a chronic treatment. Patients take a pill and it goes on for a long time, indefinitely, we’re starting to assess discontinuation, but at least for a very, very long time. How relevant is assessing adherence? Does it matter? How do we do it?

David Snyder, MD, FACP: No, I think it is very important. As Harry said, there are studies showing somewhat intuitive, perhaps, that patients who don’t take their drugs don’t do as well as those who take it. There’s also data showing a very large proportion of patients, I think it’s something like 85% of patients with CML are not consistently adherent. And I think that’s an important issue we need to be aware of.

I think there are two sides of it. One is the patient who is feeling well, their disease is fully controlled, they’re not having side effects from the drugs. It’s almost like they don’t have a reminder that, aah, there’s something wrong here, I need to make sure I take my drug to remind them every day. And so people, busy with their daily lives, they tend to forget. Especially if it’s a drug that they have to take more than once a day, there’s even more chance that they’ll miss a dose here and there. So I think that’s one part of it.

The other part is about some of the issues that Harry mentioned about the ongoing kind of nagging side effects. For most of the patients, the side effects that occur, which are common, tend to be low grade, grade 1 or 2, and they tend to be transient. However, we know that some of the patients have ongoing low grade toxicity that’s kind of always there. That might be a reason for them to say, oh, I need to take a break; I need a little holiday. So, it’s important to be aware of that.

We do have choices of other TKIs. If there’s an issue about this kind of nagging ongoing side effects, that’s something to address, and potentially consider a change to allow them to be more adherent.

Jorge Cortes, MD: I think one of perhaps the most telling studies, these from David Marin, who showed among these patients who had been on treatment for a long time, and they measured adherence by this device in the cap and he showed that patients that had at least 10% of the dose, the probability of achieving these deeper responses, MR 4.5 was 0%. So it doesn’t take too many doses to miss and that’s why some of these recommendations actually tell us that when the patient is not reaching these endpoints, the first thing you do is check adherence and what is maybe interfering with adherence because it’s very important.

David Snyder, MD, FACP: I echo what Harry said about meeting on an ongoing basis with the patient. My patients know that I’m going to be checking the PCR and they often kind of confess to me. “Oh, I took that trip out of the country and I left my drug at home. Do you think that’s going to show up?” And likely it will and I think it’s important to emphasize that.

Jorge Cortes, MD: Okay. A lot of what we’ll be discussing has to do with monitoring the patient and all of these aspects that are so critical for assessing the response. How do you monitor patients, Kevin, in the clinic? I’m talking about like a newly diagnosed patient. How do you do the monitoring?

Kevin Kelly, MD, PhD: Yes, certainly. I tend to follow the NCCN Guidelines. For safety considerations, I check CBC and chemistry every two weeks for the first two months, and then I pay close attention to the three months BCR-ABL time point. This is a key milestone, as we alluded to earlier, because patients who achieve BCR-ABL, less than 10% at three months have a better overall survival. Of course, we don’t necessarily need to act immediately if they’re slightly above 10%. So we have that six-month time point, too, where we can make a change, particularly if they’re still above 10% at the six- month time point. And then I continue to check BCR-ABL every three months until the patient achieves a major molecular response.

You do have the option then to maybe extend it out to every six months, but, as Harry said, we like to see these patients on a frequent basis. So, typically, if they’re coming to the office anyhow, we continue to check their BCR-ABL, so every three months.

Then when the patient reaches BCR-ABL less than 1%, which we said was kind of equivalent to a complete cytogenetic response, we often times do a bone marrow biopsy to confirm the presence of a complete cytogenetic response. So we’ve moved away from doing a lot of bone marrow biopsies and I think a lot of patients are very grateful for that when we can check BCR-ABL. But there still is a role for bone marrow biopsies, particularly when the BCR-ABL is hovering above the 1% mark, and we want to confirm that they’ve lost a complete cytogenetic response.

Jorge Cortes, MD: Harry, how often do you do the BCR on your patients and does it change over time or is it constant?

Harry Erba, MD, PhD: Well, the first point I’d like to make about that is I always do it at baseline and it’s not to get a patient specific value. That’s not really the importance, although there is some data from Australia that how much it goes down by three months might be as important as this 10% level. But the real reason for doing it is that there will be rare patients who will have variant fusions of BCR and ABL where the commercially available PCR assays will not detect it efficiently. And so the best time to understand this is when the patient shows up and they have a white count of 100,000 and you get a BCR-ABL result of .1% or negative.

So I do all three assays at the beginning, chromosomes, FISH, and PCR because that’s the best time to have your baseline. Then you know the assay is informative, and then I do it every three months starting at three months. And I do it to make sure they’re meeting their milestones and I always also do it as a way of checking adherence.

Let’s say the patient has gotten into a major molecular remission, but one time they come in and it’s just a little bit higher. So it went from .02 to .08 and hasn’t gone up 10-fold, they haven’t lost an MMR, we’re not so worried, your nurse calls the patient and the patient gets the result and they’re worried. And they might say, eeh, I didn’t tell Doc Erba that I was not taking the drug. I’m going to make sure I’m a little bit more compliant. So I think using it also as a way of ensuring compliance can be very helpful for our patients, so at baseline and every three months. And I continue to do that. Patients who achieve a complete molecular remission who live far from our center, maybe every six months.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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