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Measuring Response in Chronic Myeloid Leukemia Treatment

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: Thursday, Feb 04, 2016


Transcript:

Jorge Cortes, MD:
Javier, there are many analyses that have shown that this 10% threshold, at three months, is important in predicting progression-free survival and overall survival. And I guess one of the questions is, how tight is that?

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Jorge Cortes, MD: Is that something that I should really obsess about?

Javier Pinilla-Ibarz, MD, PhD: No, I fully agree with you. I think there is no doubt that this exact time point assessment with these exact numbers are being kind of paranoid. I think we need to recognize that the techniques that we are using are extremely sensitive. They have some variability between them and every one (of them) is different.

I think as always discussed with you guys, that we have a general guideline that we need to keep as close as we can. But this doesn’t mean that at exactly three months, if the PCR result is 12%, we should make a dramatic change of the TKI. It’s important rather to be aware that there’s a reason why we should maybe repeat this PCR or maybe be more aware that this patient may not do as well. I fully agree that these are general guidelines. I think that the 10% level has been very well reproduced from trial to trial, but, of course, the real-life practicality of this approach is a different story.

The more I discuss this with patients and with colleagues, the more I think we should be aware that it is at least, a signal. If you don’t obtain this PCR level at three months, I will repeat it, but maybe I won’t wait for three months. I will repeat it in like three, four weeks and assess the patient’s status.

Jorge Cortes, MD: Yes. I think to me one of the biggest values of this finding is to emphasize the importance of the monitoring itself.

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Jorge Cortes, MD: And to be following your patients very closely because you can detect early signs of warning or a flag or something that make you be alert. At the very least, make sure that you are on top of this situation.

Harry Erba, MD, PhD: So, Jorge, I agree with what’s been said here and, specifically, the second-generation drugs do lead to a higher proportion of patients achieving these milestones at three months, or at six months, or at 12 months, and is one of the reasons why I choose second-generation drugs as first-line therapy, because that seems to translate into a lower risk of progression which is more common as we start therapy.

However, I just want to spend a second talking about the other side of the coin, and, that is, what if your patient at 12 months hasn’t achieved that major molecular remission at 12 months? And I want to just remind people that ELN and NCCN Guidelines do not consider lack of an MMR a failure. In the ELN, it’s a suboptimal response, but in both, failure is only if you don’t achieve a complete cytogenetic remission, which is a PCR level of about 1%. And I think that’s important because if you go back to the Tim Hughes paper published on the IRIS data, patients who had a BCR-ABL ratio between .1 and 1% had the same progression-free survival as patients who are in an MMR.

The difference between the two was that patients who were in that range of .1 to 1% had a higher rate of losing a complete cytogenetic remission, but not necessarily progressing. So it’s a time when you can assess adherence to the drug and making sure patients are taking their drug correctly, optimizing dose, but I don’t think it’s necessarily a time when we would just switch to something else if they’re in a complete cytogenetic remission.

Jorge Cortes, MD: Absolutely. And I think that brings an important issue that you’re starting to address, that when we’re assessing a patient, we’re not just evaluating a PCR of a patient. It’s not an issue about a PCR, it’s an issue about a patient. So, Harry, I’ll send back the question to you. Tell me a little bit about how important is it to assess then, any side effects that may be affecting how the patient is feeling, despite what the PCR is, quality of life. Do you use any quality of life assessments, formal or informal? How much should we emphasize those things when we see the patients?

Harry Erba, MD, PhD: Well, this is critically important. I mean, there have been multiple studies that have shown that adherence to your ABL TKI correlated with responses in outcomes to therapy. And so we need to consider all of the barriers to patients taking their drugs on time and as scheduled. These might be financial barriers. They might be barriers in terms of the side effects of the therapies that aren’t being managed well. And so I continue to see my patients even when they’ve been on therapy for five years and they’re doing great. I continue to see them every three months, and I do that because it’s a good time to assess those things. Has something changed in your ability to afford these drugs or get them? Are you now in that donut hole or you’ve lost insurance and you’re afraid to tell anybody? Are patients starting to take their drug on an alternate schedule because of this, or if they’re having toxicities that are getting in their way of taking it.

It’s really important for us, as oncologists treating these patients, to look at the toxicities that they’re having and manage them appropriately, instead of just quickly saying, well, that’s okay, we’ve got four other ABL tyrosine kinase inhibitors. We’re just going to switch to another one. Just keep in mind, if your patient has had side effects to one, they might not have the same side effect to the next one, but they’re likely to have some side effect that will be nagging and grade 1 or 2, and they’ll have to be managed. So managing toxicities is key to keeping your patients on their therapy. So seeing them off and doing that is much more important than a PCR result. They could just go to the lab and get the PCR result and your nurse could call them, but that would be missing the boat.

Jorge Cortes, MD: So you mean I should just not see the patient and say to them, here’s your prescription, see you later?

Harry Erba, MD, PhD: No.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Jorge Cortes, MD:
Javier, there are many analyses that have shown that this 10% threshold, at three months, is important in predicting progression-free survival and overall survival. And I guess one of the questions is, how tight is that?

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Jorge Cortes, MD: Is that something that I should really obsess about?

Javier Pinilla-Ibarz, MD, PhD: No, I fully agree with you. I think there is no doubt that this exact time point assessment with these exact numbers are being kind of paranoid. I think we need to recognize that the techniques that we are using are extremely sensitive. They have some variability between them and every one (of them) is different.

I think as always discussed with you guys, that we have a general guideline that we need to keep as close as we can. But this doesn’t mean that at exactly three months, if the PCR result is 12%, we should make a dramatic change of the TKI. It’s important rather to be aware that there’s a reason why we should maybe repeat this PCR or maybe be more aware that this patient may not do as well. I fully agree that these are general guidelines. I think that the 10% level has been very well reproduced from trial to trial, but, of course, the real-life practicality of this approach is a different story.

The more I discuss this with patients and with colleagues, the more I think we should be aware that it is at least, a signal. If you don’t obtain this PCR level at three months, I will repeat it, but maybe I won’t wait for three months. I will repeat it in like three, four weeks and assess the patient’s status.

Jorge Cortes, MD: Yes. I think to me one of the biggest values of this finding is to emphasize the importance of the monitoring itself.

Javier Pinilla-Ibarz, MD, PhD: Absolutely.

Jorge Cortes, MD: And to be following your patients very closely because you can detect early signs of warning or a flag or something that make you be alert. At the very least, make sure that you are on top of this situation.

Harry Erba, MD, PhD: So, Jorge, I agree with what’s been said here and, specifically, the second-generation drugs do lead to a higher proportion of patients achieving these milestones at three months, or at six months, or at 12 months, and is one of the reasons why I choose second-generation drugs as first-line therapy, because that seems to translate into a lower risk of progression which is more common as we start therapy.

However, I just want to spend a second talking about the other side of the coin, and, that is, what if your patient at 12 months hasn’t achieved that major molecular remission at 12 months? And I want to just remind people that ELN and NCCN Guidelines do not consider lack of an MMR a failure. In the ELN, it’s a suboptimal response, but in both, failure is only if you don’t achieve a complete cytogenetic remission, which is a PCR level of about 1%. And I think that’s important because if you go back to the Tim Hughes paper published on the IRIS data, patients who had a BCR-ABL ratio between .1 and 1% had the same progression-free survival as patients who are in an MMR.

The difference between the two was that patients who were in that range of .1 to 1% had a higher rate of losing a complete cytogenetic remission, but not necessarily progressing. So it’s a time when you can assess adherence to the drug and making sure patients are taking their drug correctly, optimizing dose, but I don’t think it’s necessarily a time when we would just switch to something else if they’re in a complete cytogenetic remission.

Jorge Cortes, MD: Absolutely. And I think that brings an important issue that you’re starting to address, that when we’re assessing a patient, we’re not just evaluating a PCR of a patient. It’s not an issue about a PCR, it’s an issue about a patient. So, Harry, I’ll send back the question to you. Tell me a little bit about how important is it to assess then, any side effects that may be affecting how the patient is feeling, despite what the PCR is, quality of life. Do you use any quality of life assessments, formal or informal? How much should we emphasize those things when we see the patients?

Harry Erba, MD, PhD: Well, this is critically important. I mean, there have been multiple studies that have shown that adherence to your ABL TKI correlated with responses in outcomes to therapy. And so we need to consider all of the barriers to patients taking their drugs on time and as scheduled. These might be financial barriers. They might be barriers in terms of the side effects of the therapies that aren’t being managed well. And so I continue to see my patients even when they’ve been on therapy for five years and they’re doing great. I continue to see them every three months, and I do that because it’s a good time to assess those things. Has something changed in your ability to afford these drugs or get them? Are you now in that donut hole or you’ve lost insurance and you’re afraid to tell anybody? Are patients starting to take their drug on an alternate schedule because of this, or if they’re having toxicities that are getting in their way of taking it.

It’s really important for us, as oncologists treating these patients, to look at the toxicities that they’re having and manage them appropriately, instead of just quickly saying, well, that’s okay, we’ve got four other ABL tyrosine kinase inhibitors. We’re just going to switch to another one. Just keep in mind, if your patient has had side effects to one, they might not have the same side effect to the next one, but they’re likely to have some side effect that will be nagging and grade 1 or 2, and they’ll have to be managed. So managing toxicities is key to keeping your patients on their therapy. So seeing them off and doing that is much more important than a PCR result. They could just go to the lab and get the PCR result and your nurse could call them, but that would be missing the boat.

Jorge Cortes, MD: So you mean I should just not see the patient and say to them, here’s your prescription, see you later?

Harry Erba, MD, PhD: No.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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