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Monitoring Response to CML Therapy

Insights From: Kendra Sweet, MD, Moffitt Cancer Center; Naval Daver, MD, University of Texas MD Anderson Cancer Center; Javier Pinilla-Ibarz, MD, PhD, Moffitt Cancer Center
Published Online: Monday, Mar 20, 2017



Transcript:

Naval Daver, MD:
For up-front therapy at this time, the way we would monitor these patients is, at baseline, do a bone marrow analysis along with peripheral blood, and we usually get cytogenetics in addition to a RT-PCR (reverse transcription polymerase chain reaction) for BCR-ABL. Then we would be following these patients every 3 months for a clinical evaluation. We do it every 3 months for about 1 year, then we drop it to once every 6 months for the next 2 years, and then we usually go to once a year.

Some of the areas that are still under discussion, and it’s not clear yet, is whether we should be looking at mutational analysis at the baseline. There are some data showing that even in chronic-phase CML, some patients may have baseline molecular mutations, such as T315I or E255K, which may make them resistant to particular TKIs and make us select others. However, the incidence seems to be small, anywhere between 2% to 4%. And so, based on this at this time, it’s not in the standard guidelines to do baseline tyrosine kinase inhibitors. So, I think the standard would be baseline cytogenetics RT-PCR every 3 months and cytogenetics and RT-PCR for the first year, then every 6 months for 2 years, and then once a year after that.

Javier Pinilla-Ibarz, MD, PhD: The definition of early molecular response comes from a serial trial that was performed on frontline treatment of CML with a first-generation or second-generation TKI and really looked for the achievement of less than 10% pCR by pCR testing on an international scale. This early molecular response definition of less than 10% has been adopted by NCCN and also by other guidelines, like ELN, as a cutoff, as a threshold for which we can consider which patients are going to do better or worse. It’s no doubt there is always a small number of patients who may be in a gray zone. I’m talking about a small percentage of patients who may not achieve these early molecular responses at 3 months, but maybe they achieve it at 6 months. However, it is very clear that patients who do not achieve early molecular response (EMR) at 3 months, they may be at higher risk of transformation later on. And, of course, this is mostly associated with the Sokal score. It means that less than or lack of obtention of less than 10% by pCR at 3 months in a high-risk patient is a very, very important red flag that we need to consider and really discuss to change the therapies.

Obtention of EMR at 3 months is a very important milestone in the treatment of patients with CML under tyrosine kinase inhibition. The goal is to truly get all patients, or most of our patients, of less than 10%. However, we know there is a certain amount of patients who may not achieve this less than 10% pCR. This is not a magic number. I think we need to be flexible, as the new NCCN guidelines state, and sometimes it’s not really a black-and-white situation. Maybe it’s a gray situation in certain areas where it may be worth it to repeat the pCR to really make sure that these goals are not achieved at 3 months. However, as I mentioned before, if I have a patient who definitely did not achieve this less than 10%, has been started on a first-generation TKI, and may be at intermediate or high risk, this is the kind of patient where we really will be very, very fast in considering switching therapy early on. Because, in my opinion, they are the patients who may have higher risk of transformation in the first year.

Naval Daver, MD: Additional mutation testing in CML is an area of evolution. We’re not 100% sure of the exact timing. In general, I think the accepted guidelines, or accepted time points to do the additional mutation analysis, are if there is a patient who’s having an increase in his RT-PCR for BCR-ABL, especially if it is confirmed on 2 consecutive analyses. So, for example, if I see a patient in the clinic who had been on dasatinib for 7 to 8 years, he had achieved a major molecular response—however, when he comes to see me, let’s say his BCR levels have gone up to 0.5 or 0.6—we usually would not clinically act on that at this time. I would probably bring him back after 1 month or 6 weeks and repeat it. If the repeat confirms that his BCR for BCR-ABL level remains at 0.5 or 0.6, or even goes up, then I would add on a mutation testing to see if the reason he’s losing the response to dasatinib is because of acquisition of a secondary mutation that caused resistance.

One important thing to consider in this scenario is to always take a very good history and make sure that the patient is actually compliant on the medication. Because what we have learned in CML, the main reason for treatment failure is not really acquisition of resist in mutations, but it’s actually compliance. And often, patients, after many years, will start missing a few doses or stopping it. This has been shown for other drugs, such as tamoxifen in breast cancer, where almost 70% to 75% of patients, when they were screened, did own up that they had actually stopped or started interrupting medications after 5 years. So, in that situation, if the patient does say he has been very compliant or at least 95% compliant, and his BCR is going up, I would check for a resistant mutation.

The other scenario is, of course, if there’s a clear morphological progression to a blast phase or accelerated phase. So, if a patient comes back to me and he has now bone marrow or peripheral blasts that are above 5% or if he’s having enlarging spleen, worsening anemia, thrombocytopenia, or other changes in his blood counts or white blood cell count, then I would definitely repeat a BCR for BCR-ABL. But I would also do a mutational testing at that time because we have seen that at the time of progression from chronic phase to blast or accelerated phase, or to FLT3-positive AML, there’s often acquisition of secondary mutations that could drive resistance and could help us select the appropriate TKI.

And the third scenario where we would consider it is in newly diagnosed accelerated phase or blast phase or AML with FLT3-positive mutations. It has been shown that in the newly diagnosed patients who come into more advanced phases of CML, almost between 5% to 15% of them could harbor a baseline resistant mutation. Identification of that mutation may help us select TKIs that work and are not going to be resistant.

In a patient who has been in a complete molecular remission, if the transcript levels become detectable on a routine surveillance follow-up PCR for BCR-ABL, the first thing we would do is repeat a PCR for BCR-ABL, usually with an interval of somewhere between 3 to 6 weeks. There can be minor small fluctuations in these levels because the PCR for BCR-ABL is a very sensitive test. So, we usually will not make any changes based on 1 increased value. But on 2 subsequent values, if we do see that the transcript levels are going up, and especially if they have come up above 0.1, then that would be an indication for consideration of switching to another TKI after making sure that the patient has been compliant at the appropriate dose.

Transcript Edited for Clarity
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Transcript:

Naval Daver, MD:
For up-front therapy at this time, the way we would monitor these patients is, at baseline, do a bone marrow analysis along with peripheral blood, and we usually get cytogenetics in addition to a RT-PCR (reverse transcription polymerase chain reaction) for BCR-ABL. Then we would be following these patients every 3 months for a clinical evaluation. We do it every 3 months for about 1 year, then we drop it to once every 6 months for the next 2 years, and then we usually go to once a year.

Some of the areas that are still under discussion, and it’s not clear yet, is whether we should be looking at mutational analysis at the baseline. There are some data showing that even in chronic-phase CML, some patients may have baseline molecular mutations, such as T315I or E255K, which may make them resistant to particular TKIs and make us select others. However, the incidence seems to be small, anywhere between 2% to 4%. And so, based on this at this time, it’s not in the standard guidelines to do baseline tyrosine kinase inhibitors. So, I think the standard would be baseline cytogenetics RT-PCR every 3 months and cytogenetics and RT-PCR for the first year, then every 6 months for 2 years, and then once a year after that.

Javier Pinilla-Ibarz, MD, PhD: The definition of early molecular response comes from a serial trial that was performed on frontline treatment of CML with a first-generation or second-generation TKI and really looked for the achievement of less than 10% pCR by pCR testing on an international scale. This early molecular response definition of less than 10% has been adopted by NCCN and also by other guidelines, like ELN, as a cutoff, as a threshold for which we can consider which patients are going to do better or worse. It’s no doubt there is always a small number of patients who may be in a gray zone. I’m talking about a small percentage of patients who may not achieve these early molecular responses at 3 months, but maybe they achieve it at 6 months. However, it is very clear that patients who do not achieve early molecular response (EMR) at 3 months, they may be at higher risk of transformation later on. And, of course, this is mostly associated with the Sokal score. It means that less than or lack of obtention of less than 10% by pCR at 3 months in a high-risk patient is a very, very important red flag that we need to consider and really discuss to change the therapies.

Obtention of EMR at 3 months is a very important milestone in the treatment of patients with CML under tyrosine kinase inhibition. The goal is to truly get all patients, or most of our patients, of less than 10%. However, we know there is a certain amount of patients who may not achieve this less than 10% pCR. This is not a magic number. I think we need to be flexible, as the new NCCN guidelines state, and sometimes it’s not really a black-and-white situation. Maybe it’s a gray situation in certain areas where it may be worth it to repeat the pCR to really make sure that these goals are not achieved at 3 months. However, as I mentioned before, if I have a patient who definitely did not achieve this less than 10%, has been started on a first-generation TKI, and may be at intermediate or high risk, this is the kind of patient where we really will be very, very fast in considering switching therapy early on. Because, in my opinion, they are the patients who may have higher risk of transformation in the first year.

Naval Daver, MD: Additional mutation testing in CML is an area of evolution. We’re not 100% sure of the exact timing. In general, I think the accepted guidelines, or accepted time points to do the additional mutation analysis, are if there is a patient who’s having an increase in his RT-PCR for BCR-ABL, especially if it is confirmed on 2 consecutive analyses. So, for example, if I see a patient in the clinic who had been on dasatinib for 7 to 8 years, he had achieved a major molecular response—however, when he comes to see me, let’s say his BCR levels have gone up to 0.5 or 0.6—we usually would not clinically act on that at this time. I would probably bring him back after 1 month or 6 weeks and repeat it. If the repeat confirms that his BCR for BCR-ABL level remains at 0.5 or 0.6, or even goes up, then I would add on a mutation testing to see if the reason he’s losing the response to dasatinib is because of acquisition of a secondary mutation that caused resistance.

One important thing to consider in this scenario is to always take a very good history and make sure that the patient is actually compliant on the medication. Because what we have learned in CML, the main reason for treatment failure is not really acquisition of resist in mutations, but it’s actually compliance. And often, patients, after many years, will start missing a few doses or stopping it. This has been shown for other drugs, such as tamoxifen in breast cancer, where almost 70% to 75% of patients, when they were screened, did own up that they had actually stopped or started interrupting medications after 5 years. So, in that situation, if the patient does say he has been very compliant or at least 95% compliant, and his BCR is going up, I would check for a resistant mutation.

The other scenario is, of course, if there’s a clear morphological progression to a blast phase or accelerated phase. So, if a patient comes back to me and he has now bone marrow or peripheral blasts that are above 5% or if he’s having enlarging spleen, worsening anemia, thrombocytopenia, or other changes in his blood counts or white blood cell count, then I would definitely repeat a BCR for BCR-ABL. But I would also do a mutational testing at that time because we have seen that at the time of progression from chronic phase to blast or accelerated phase, or to FLT3-positive AML, there’s often acquisition of secondary mutations that could drive resistance and could help us select the appropriate TKI.

And the third scenario where we would consider it is in newly diagnosed accelerated phase or blast phase or AML with FLT3-positive mutations. It has been shown that in the newly diagnosed patients who come into more advanced phases of CML, almost between 5% to 15% of them could harbor a baseline resistant mutation. Identification of that mutation may help us select TKIs that work and are not going to be resistant.

In a patient who has been in a complete molecular remission, if the transcript levels become detectable on a routine surveillance follow-up PCR for BCR-ABL, the first thing we would do is repeat a PCR for BCR-ABL, usually with an interval of somewhere between 3 to 6 weeks. There can be minor small fluctuations in these levels because the PCR for BCR-ABL is a very sensitive test. So, we usually will not make any changes based on 1 increased value. But on 2 subsequent values, if we do see that the transcript levels are going up, and especially if they have come up above 0.1, then that would be an indication for consideration of switching to another TKI after making sure that the patient has been compliant at the appropriate dose.

Transcript Edited for Clarity
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