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Understanding MRD Testing in CLL

Insights From: Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center
Published Online: Monday, Sep 11, 2017



Transcript:

Thomas J. Kipps, MD, PhD: We’re looking at a number of approaches to assess for minimal residual disease. The use of flow cytometry is compelling, because every clinical pathology laboratory has the capacity to do flow cytometry. Provided they have more moderate instrumentation, reasonably they can get down to a sensitivity of 1 in 10,000 cells. It’s nice to be able to use a test that is available, and one that’s familiar to your pathologist. So, that has a really a big advantage.

We’re also doing next generation sequencing, and the revolution that we’ve had in sequencing technology allows us to sequence genomes for very little money and with a quick turnaround time. It’s really phenomenal. So, it’s possible to take the leukemia cells and get a genomic sequence on them very easily at low cost, and you can then look for traces in the sequence of the genes that are fingerprints for leukemia. And that can approach sensitivities of 1 in a million cells. I must say that there are some exceptions to that, because there are some sequences that may not be very easy to detect, even with next generation sequencing. Therefore, I would say for all-comers that maybe 1 in 100,000 would be our sensitivity level, and for some you can get down to 1 in a million.

There’s another technique called allele-specific primers, and they can go down to similar levels as next generation sequencing. However, there, the composition of the sequence becomes even more limiting. So, I think on average the sensitivity of that test will be a little bit less than 1 in 100,000, in my experience.

Now the big problem with the sequencing technology is that we need to have access to the leukemia cells prior to treatment. So, to be able to determine that we can’t detect the leukemic cells, we have to have the signature or the fingerprints of the leukemic cells identified. It’s almost as if you were to go on a search and do a very sensitive crime scene investigation and collect DNA samples and have the ability to sequence the DNA, but if you didn’t have a bank of what DNA belonged to whom, it wouldn’t make much sense—the information that you have. You need to have a database that is linking the fingerprints of the leukemia prior to treatment so you can identify those fingerprints in the detection of minimal residual disease.

And so, we have to have cells either processed or banked away ahead of time. This is not something that is impossible to do, but it does create some issues where you may have to have your blood sent off for testing, and maybe it’s stored and tested later. If you achieve a response and it’s something that you want to look at for minimal residual disease, then you can have it tested and compared back with your previous leukemia fingerprints. That represents, I think, a big limitation in those techniques.

I think we’ve come a long way. It’s very exciting to see, because the last few years have brought forth almost half a dozen new agents, new drugs, that can be used in the treatment of patients with chronic lymphocytic leukemia. And certainly, the treatment outlook is much brighter than it used to be even just a few short years ago. I must say that we still are facing the fact that patients are requiring therapy sometimes for years with these newer agents.

We have to worry about issues such as cost, and even minor side effects that might not bother you. But if it’s something you have to live with for a long period of time, if not forever, they can be sometimes a problem for patients. So, we are trying to stretch the envelope to find ways where we can achieve that complete remission and be able to get patients to where they no longer have to take continuous therapy.

Are there ways of either combining agents or bringing in newer agents that might be able to seal the deal and get a deeper clearance, so that we can clear minimal residual disease and actually try and achieve a cure for this disease? I really don’t find it satisfactory that we would want to just treat leukemia like we would treat diabetes or hypertension. I do believe we can actually cure these diseases by the appropriate use of the right type of therapy for the right type of patient, with the combinations of some of these newer therapies. With some of the newer therapies that are being developed, I think we should be able to eradicate the disease in a great majority of patients and hopefully have quite a few of those patients go on to live their lives without requiring continuous therapy.

That would be where I think the field is heading. I do know that we are treating patients; we’re one of the first to use venetoclax, because we were in the first clinical trial using that drug and we didn’t know what to expect. It’s always a heady thing when you first use it for the first time, and we were struck by how powerful it is. So, we’ve had patients on therapy for years now, and I know that sometimes patients who do not clear minimal residual disease may actually tend to develop recurrent disease or resistance to the drug over time. We’re seeing resistance develop to treatment with ibrutinib and some of these newer agents.

Sometimes, you get the impression that cancer is like this game of Whack-A-Mole—you have to get the disease down. And if we get it down here, it might tend to come back up again. So, I think aiming for these curative strategies where we can safely get into a complete remission without evidence of minimal residual disease is desirable. We have to be very careful, though, that we don’t end up throwing the baby out with the bathwater. What I mean is that it would be hardly of any use to somebody if you have to practically kill yourself in order to achieve that goal. If we have a high rate of patients having unacceptable toxicities or even mortalities in order to try and achieve that goal, I don’t think that would be acceptable either.

So, we need to try and keep stretching the envelope and define better tolerated therapies, and more effective therapies, so we can maybe tell patients, “OK, you have leukemia, you’ll be able to take care of it like you would a bad infection.” We’ll be able to cure the disease and have the patient go off and live their lives normally, without any mortality or morbidity.

Transcript Edited for Clarity
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Transcript:

Thomas J. Kipps, MD, PhD: We’re looking at a number of approaches to assess for minimal residual disease. The use of flow cytometry is compelling, because every clinical pathology laboratory has the capacity to do flow cytometry. Provided they have more moderate instrumentation, reasonably they can get down to a sensitivity of 1 in 10,000 cells. It’s nice to be able to use a test that is available, and one that’s familiar to your pathologist. So, that has a really a big advantage.

We’re also doing next generation sequencing, and the revolution that we’ve had in sequencing technology allows us to sequence genomes for very little money and with a quick turnaround time. It’s really phenomenal. So, it’s possible to take the leukemia cells and get a genomic sequence on them very easily at low cost, and you can then look for traces in the sequence of the genes that are fingerprints for leukemia. And that can approach sensitivities of 1 in a million cells. I must say that there are some exceptions to that, because there are some sequences that may not be very easy to detect, even with next generation sequencing. Therefore, I would say for all-comers that maybe 1 in 100,000 would be our sensitivity level, and for some you can get down to 1 in a million.

There’s another technique called allele-specific primers, and they can go down to similar levels as next generation sequencing. However, there, the composition of the sequence becomes even more limiting. So, I think on average the sensitivity of that test will be a little bit less than 1 in 100,000, in my experience.

Now the big problem with the sequencing technology is that we need to have access to the leukemia cells prior to treatment. So, to be able to determine that we can’t detect the leukemic cells, we have to have the signature or the fingerprints of the leukemic cells identified. It’s almost as if you were to go on a search and do a very sensitive crime scene investigation and collect DNA samples and have the ability to sequence the DNA, but if you didn’t have a bank of what DNA belonged to whom, it wouldn’t make much sense—the information that you have. You need to have a database that is linking the fingerprints of the leukemia prior to treatment so you can identify those fingerprints in the detection of minimal residual disease.

And so, we have to have cells either processed or banked away ahead of time. This is not something that is impossible to do, but it does create some issues where you may have to have your blood sent off for testing, and maybe it’s stored and tested later. If you achieve a response and it’s something that you want to look at for minimal residual disease, then you can have it tested and compared back with your previous leukemia fingerprints. That represents, I think, a big limitation in those techniques.

I think we’ve come a long way. It’s very exciting to see, because the last few years have brought forth almost half a dozen new agents, new drugs, that can be used in the treatment of patients with chronic lymphocytic leukemia. And certainly, the treatment outlook is much brighter than it used to be even just a few short years ago. I must say that we still are facing the fact that patients are requiring therapy sometimes for years with these newer agents.

We have to worry about issues such as cost, and even minor side effects that might not bother you. But if it’s something you have to live with for a long period of time, if not forever, they can be sometimes a problem for patients. So, we are trying to stretch the envelope to find ways where we can achieve that complete remission and be able to get patients to where they no longer have to take continuous therapy.

Are there ways of either combining agents or bringing in newer agents that might be able to seal the deal and get a deeper clearance, so that we can clear minimal residual disease and actually try and achieve a cure for this disease? I really don’t find it satisfactory that we would want to just treat leukemia like we would treat diabetes or hypertension. I do believe we can actually cure these diseases by the appropriate use of the right type of therapy for the right type of patient, with the combinations of some of these newer therapies. With some of the newer therapies that are being developed, I think we should be able to eradicate the disease in a great majority of patients and hopefully have quite a few of those patients go on to live their lives without requiring continuous therapy.

That would be where I think the field is heading. I do know that we are treating patients; we’re one of the first to use venetoclax, because we were in the first clinical trial using that drug and we didn’t know what to expect. It’s always a heady thing when you first use it for the first time, and we were struck by how powerful it is. So, we’ve had patients on therapy for years now, and I know that sometimes patients who do not clear minimal residual disease may actually tend to develop recurrent disease or resistance to the drug over time. We’re seeing resistance develop to treatment with ibrutinib and some of these newer agents.

Sometimes, you get the impression that cancer is like this game of Whack-A-Mole—you have to get the disease down. And if we get it down here, it might tend to come back up again. So, I think aiming for these curative strategies where we can safely get into a complete remission without evidence of minimal residual disease is desirable. We have to be very careful, though, that we don’t end up throwing the baby out with the bathwater. What I mean is that it would be hardly of any use to somebody if you have to practically kill yourself in order to achieve that goal. If we have a high rate of patients having unacceptable toxicities or even mortalities in order to try and achieve that goal, I don’t think that would be acceptable either.

So, we need to try and keep stretching the envelope and define better tolerated therapies, and more effective therapies, so we can maybe tell patients, “OK, you have leukemia, you’ll be able to take care of it like you would a bad infection.” We’ll be able to cure the disease and have the patient go off and live their lives normally, without any mortality or morbidity.

Transcript Edited for Clarity
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