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Mutation Analysis in 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: Thursday, Jan 14, 2016


Transcript:

Jorge Cortes, MD:
Hello, and thank you for joining this OncLive TV Peer Exchange on Chronic Myeloid Leukemia. The use of tyrosine kinase inhibitors targeting the BCR-ABL protein is the hallmark of therapy for patients with chronic myeloid leukemia and, as you know, it has transformed this disease from a life-threatening to a chronic one for most patients.

We continue to refine our approaches to monitoring of CML and treatment of resistance to further improve outcomes for our patients. In this panel discussion, my colleagues and I will discuss the latest advances in the field, as well as how to apply the new data to clinical practice.

My name is Jorge Cortes from the Department of Leukemia at MD Anderson Cancer Center. Joining me today are my colleagues; Dr. Harry Erba, a professor of medicine and director of Hematologic Malignancy Program at The University of Alabama in Birmingham; Dr. Kevin Kelly, an associate professor of clinical medicine at the USC Norris Comprehensive Cancer Center at the University of Southern California; Dr. Javier Pinilla-Ibarz, an associate professor for the Department of Malignant Hematology at the Moffitt Cancer Center in Tampa, Florida; and Dr. David Snyder, the associate chair for the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

Welcome, and let’s get started. Kevin, can you tell us what is the importance or how important is it to have an early prompt diagnosis in CML in terms of treatability and prognosis?

Kevin Kelly, MD, PhD: Yes, certainly Jorge. It’s important to make a prompt diagnosis early so that these patients can get started on definitive treatment for their CML. The sooner they start on definitive treatment, the sooner they’ll reach their treatment milestones, and this can have an impact on their overall survival.

Jorge Cortes, MD: Harry, when we make the diagnosis, we know patients by definition will have their BCR-ABL. We’ve heard about mutation analysis a lot and that’s part of what our armamentarium of the tests that we do. When do we conduct the mutation analysis? How do we do that?

Harry Erba, MD, PhD: Well, you should consider it because we know that the various tyrosine kinase inhibitors have variable activity against BCR-ABL when there are different mutations there. So it may help in choosing treatment in a patient who has failed to achieve the primary milestones at 3 months, 6 months, 12 months set by ELN Guidelines or the NCCN Guidelines.

If a patient has a cytogenetic or molecular response, and then loses that response, doing a sequence analysis of the BCR-ABL fusion and looking at these kinase domain mutations may help you select the next drug that you’re going to use based on that sensitivity analysis. We don’t do it at baseline though. We don’t do it at the time of diagnosis because these commercially available assays for the BCR-ABL or ABL kinase domain mutations have not actually been shown to be useful in choosing first-line therapy.

Jorge Cortes, MD: Excellent. Now, that brings me to the next question. The sequencing that you describe has a level of sensitivity. Now we have better tools or more sensitive tools that can detect these mutations at lower levels, like next-generation sequencing, and things like that. So, Javier, is there a role? Do we use them now? What is the role of these next-generation sequencing for mutations in CML?

Javier Pinilla-Ibarz, MD, PhD: Sure, Jorge. As you know, technology has been changing dramatically in the last years and the acquisition in our practice of next-generation sequencing is really there now. So I think from the classical Sanger sequencing, right now it’s commonly ordered, these next-generation sequencing, specifically after amplification of BCR-ABL and the sequencing of the ABL gene or domain mutation areas, as Harry was mentioning.

There is recent evidence of this work that has been presented at this meeting, what seems like with these very sensitive techniques, there are some investigators that are able to detect even a very, very low level of mutations and even at diagnosis, something that we had not seen much in the past or at least have increased the sensitivity of Sanger techniques.

Jorge Cortes, MD: So does that mean we should start sending our patient samples for next-generation sequencing or is it not quite ready for clinical use yet?

Javier Pinilla-Ibarz, MD, PhD: I don’t think we are quite there yet. I think we are really looking at these data. I think there’s very early information that we have, but I guess it’s an area that we’re going to continue to investigate. At this point, as Harry said, I think it’s very well set up in the research setting, but we should really do these assays. Most of the time these assays can be done by next-generation sequencing.

Jorge Cortes, MD: Well, thank you. We obviously do monitoring routinely by PCR in all our patients and that’s been available for many years. There’s also an evolving field and now there is this digital PCR, which has advantage of being more sensitive, and so it’s been brought up in some of the studies to try to detect disease at even lower levels. David, how do you see the potential of digital PCR now and in the future?

David Snyder, MD, FACP: So, as you said, it’s a more sensitive way of detecting the BCR-ABL transcript. There’s less variability in the results and there’s a benefit to that. We know with the standard qPCR technique, especially at the low levels, there can be quite a lot of variability. The potential is to detect much lower levels of residual transcript, so now the standard lower threshold is MR 4.5, and it really comes into play when you talk about discontinuation trials.

The criteria for patients to be eligible for those trials generally uses a threshold of MR 4.5, and we know that maybe half the patients or so will relapse. With this newer technique, we can potentially get down to MR 5, MR 5.5 and it may be that people who can reach those lower levels will have a higher success rate after discontinuation.

And I say, maybe because that’s not been shown to be the case yet, but with this technique it allows us to look at a much deeper level of sensitivity that might be relevant in making those decisions about discontinuation.

Jorge Cortes, MD: Yes. It’s interesting because in that context of this continuation, some of the studies have assessed the patients who discontinue therapy and they even still have holding the response after discontinuation. So these tests are still positive, so we’re still trying to understand what exactly that means and find the role. But it is very interesting technology that is available.

David Snyder, MD, FACP: I think the question of the clinical relevance, of having the ability to detect the transcript at a lower threshold, remains to be seen because, as you said, patients may have residual transcript, but clinically, that may not be relevant.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Jorge Cortes, MD:
Hello, and thank you for joining this OncLive TV Peer Exchange on Chronic Myeloid Leukemia. The use of tyrosine kinase inhibitors targeting the BCR-ABL protein is the hallmark of therapy for patients with chronic myeloid leukemia and, as you know, it has transformed this disease from a life-threatening to a chronic one for most patients.

We continue to refine our approaches to monitoring of CML and treatment of resistance to further improve outcomes for our patients. In this panel discussion, my colleagues and I will discuss the latest advances in the field, as well as how to apply the new data to clinical practice.

My name is Jorge Cortes from the Department of Leukemia at MD Anderson Cancer Center. Joining me today are my colleagues; Dr. Harry Erba, a professor of medicine and director of Hematologic Malignancy Program at The University of Alabama in Birmingham; Dr. Kevin Kelly, an associate professor of clinical medicine at the USC Norris Comprehensive Cancer Center at the University of Southern California; Dr. Javier Pinilla-Ibarz, an associate professor for the Department of Malignant Hematology at the Moffitt Cancer Center in Tampa, Florida; and Dr. David Snyder, the associate chair for the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

Welcome, and let’s get started. Kevin, can you tell us what is the importance or how important is it to have an early prompt diagnosis in CML in terms of treatability and prognosis?

Kevin Kelly, MD, PhD: Yes, certainly Jorge. It’s important to make a prompt diagnosis early so that these patients can get started on definitive treatment for their CML. The sooner they start on definitive treatment, the sooner they’ll reach their treatment milestones, and this can have an impact on their overall survival.

Jorge Cortes, MD: Harry, when we make the diagnosis, we know patients by definition will have their BCR-ABL. We’ve heard about mutation analysis a lot and that’s part of what our armamentarium of the tests that we do. When do we conduct the mutation analysis? How do we do that?

Harry Erba, MD, PhD: Well, you should consider it because we know that the various tyrosine kinase inhibitors have variable activity against BCR-ABL when there are different mutations there. So it may help in choosing treatment in a patient who has failed to achieve the primary milestones at 3 months, 6 months, 12 months set by ELN Guidelines or the NCCN Guidelines.

If a patient has a cytogenetic or molecular response, and then loses that response, doing a sequence analysis of the BCR-ABL fusion and looking at these kinase domain mutations may help you select the next drug that you’re going to use based on that sensitivity analysis. We don’t do it at baseline though. We don’t do it at the time of diagnosis because these commercially available assays for the BCR-ABL or ABL kinase domain mutations have not actually been shown to be useful in choosing first-line therapy.

Jorge Cortes, MD: Excellent. Now, that brings me to the next question. The sequencing that you describe has a level of sensitivity. Now we have better tools or more sensitive tools that can detect these mutations at lower levels, like next-generation sequencing, and things like that. So, Javier, is there a role? Do we use them now? What is the role of these next-generation sequencing for mutations in CML?

Javier Pinilla-Ibarz, MD, PhD: Sure, Jorge. As you know, technology has been changing dramatically in the last years and the acquisition in our practice of next-generation sequencing is really there now. So I think from the classical Sanger sequencing, right now it’s commonly ordered, these next-generation sequencing, specifically after amplification of BCR-ABL and the sequencing of the ABL gene or domain mutation areas, as Harry was mentioning.

There is recent evidence of this work that has been presented at this meeting, what seems like with these very sensitive techniques, there are some investigators that are able to detect even a very, very low level of mutations and even at diagnosis, something that we had not seen much in the past or at least have increased the sensitivity of Sanger techniques.

Jorge Cortes, MD: So does that mean we should start sending our patient samples for next-generation sequencing or is it not quite ready for clinical use yet?

Javier Pinilla-Ibarz, MD, PhD: I don’t think we are quite there yet. I think we are really looking at these data. I think there’s very early information that we have, but I guess it’s an area that we’re going to continue to investigate. At this point, as Harry said, I think it’s very well set up in the research setting, but we should really do these assays. Most of the time these assays can be done by next-generation sequencing.

Jorge Cortes, MD: Well, thank you. We obviously do monitoring routinely by PCR in all our patients and that’s been available for many years. There’s also an evolving field and now there is this digital PCR, which has advantage of being more sensitive, and so it’s been brought up in some of the studies to try to detect disease at even lower levels. David, how do you see the potential of digital PCR now and in the future?

David Snyder, MD, FACP: So, as you said, it’s a more sensitive way of detecting the BCR-ABL transcript. There’s less variability in the results and there’s a benefit to that. We know with the standard qPCR technique, especially at the low levels, there can be quite a lot of variability. The potential is to detect much lower levels of residual transcript, so now the standard lower threshold is MR 4.5, and it really comes into play when you talk about discontinuation trials.

The criteria for patients to be eligible for those trials generally uses a threshold of MR 4.5, and we know that maybe half the patients or so will relapse. With this newer technique, we can potentially get down to MR 5, MR 5.5 and it may be that people who can reach those lower levels will have a higher success rate after discontinuation.

And I say, maybe because that’s not been shown to be the case yet, but with this technique it allows us to look at a much deeper level of sensitivity that might be relevant in making those decisions about discontinuation.

Jorge Cortes, MD: Yes. It’s interesting because in that context of this continuation, some of the studies have assessed the patients who discontinue therapy and they even still have holding the response after discontinuation. So these tests are still positive, so we’re still trying to understand what exactly that means and find the role. But it is very interesting technology that is available.

David Snyder, MD, FACP: I think the question of the clinical relevance, of having the ability to detect the transcript at a lower threshold, remains to be seen because, as you said, patients may have residual transcript, but clinically, that may not be relevant.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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