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Development of Secondary Acute Myeloid Leukemias

Panelists:Rafael Bejar MD, PhD, UCSD Moores Cancer Center; Elias Jabbour, MD, MD Anderson Cancer Center; Rami S. Komrokji, MD, Moffitt Cancer Center; Ruben A. Mesa, MD, FACP, Mayo Clinic Cancer Center
Published: Tuesday, Jan 12, 2016



Transcript:

Ruben A. Mesa, MD, FACP:
I think that idea, that not all the niches are the same, is really key. Certainly, as we look at the patients who have transformed from a myeloproliferative neoplasm to AML, there's that group of patients in whom the marrow itself is really quite fibrotic, and we’re not even sure there's hematopoiesis going on in there.

Yet, they'll have that 30% blast in the peripheral blood, and we think that the spleen can be an important harbor of those cells. And again, how well are drugs getting into that space? Are they really equally efficacious in that environment versus the marrow environment? A lot of opportunities.

So as we think about particularly secondary AML—that I view as a huge area of our unmet need in this group of patients. They tend to be older. It's quite prevalent in that group. By pretty much any metric, they tend to have a more challenging prognosis in a lot of ways.

Maybe, Elias, as we think about both kind of pre-leukemic disorders, chronic myeloid disorders, MDS, MPNs, what are we learning about how their path may be different than those with a de novo acute leukemia.

Elias Jabbour, MD: Well, Ruben, you’re touching a point that is very important because with population aging, we see more and more of this damage to the stem cell toward MDS happening. So, I think if we're giving an opportunity to live a lifetime, like eternally, we will all have MDS somehow. And then eventually we go into AML, but we will not be given this opportunity.

So as you mentioned, there are two kinds of AML. The de novo one, for which we have good results, decent results. But the secondary ones are horrible. But we're discovering today the hidden life of cancer. So you have somebody coming in with AML, but even if they have not had MDS, they had a certain period of time where they were acquiring something. And then they come to see you at the end where they have acute myeloid leukemias. This leukemia, they have very bad features, complex karyotype, multiple mutations, p53 mutation. We know they are very resistant to chemotherapy.

We did work on MDS, for example, and we reported that some patients will never transform, or at least will have a very late transformation, but some others do transform. And if we monitor this patient, for example, simply by doing a karyotype, we discover they can acquire certain abnormalities and they go into acute myeloid leukemia. And I think it's similar in myeloproliferative neoplasm, as well.

We know, for example, in women who had breast cancer, who had adjuvant chemotherapy, some of them will go into MDS and AML, and some will not. And then, definitely, they’ll have deficiency of some enzymatic repairs, and others that can trigger these events and push for cancer.

Now, whether there are techniques available today that can to do sequencing to identify certain targets—maybe we can intervene earlier, start this process, reverse it. Or we may fail. And we think we’re improving survival, but survival only of patients from what we know. But, hopefully, we can intervene earlier and get to a place better than today.

Rafael Bejar MD, PhD: I think that's a great point. You were mentioning pre-leukemic states, and they are the pre-leukemic states that we recognize and have a diagnosis and a name for, like MDS and MPNs. We are beginning to understand better what mutations will lead to progression, or are more likely to lead to progression, and that's helpful to help make decisions about patients. Does this patient require a transplant? Or maybe they don't need one. And knowing which mutations are actually prognostic is helpful in that regard. But your other point is also valid, that many people who have, what we call de novo AML, don't have a recognized preexisting condition.

But if you were to actually sequence them at that earlier time point, you might find that these mutations are already present and already evolving without giving them a clinical phenotype. And I think that's an exciting new area that we haven't really explored. And maybe we can identify these patients who aren't at high risk, like patients who have had treatment for breast cancer and other disorders.

Elias Jabbour, MD: Rafael, you mentioned something very important. I had a patient coming to see me in the clinic last week. She's a nurse at MD Anderson. She had Hodgkin disease diagnosed. And she's going to get her treatment. Her concern coming to see us wasn't about her Hodgkin disease treatment. Her concern was, well if I get Hodgkin disease treatment, will I acquire MDS down the road in 5, 10 years?

So now with the next-generation sequencing and all these techniques and the study samples, maybe we can identify a group of patients at the baseline, who have certain mutations that can evolve down the road. And, therefore, that will take us to the personalized therapy, identifying a group of patients. Maybe they do not need adjuvant therapy. Or, they need something minimal or different interventions.

Rami Komrokji, MD: So that brings us actually to the presentation by the Washington University Group at the plenary session at ASH where they tried to look at what triggers the development of secondary myeloid diseases. And obviously, the first impression that you will have, you will find more mutations and abnormalities in patients who had secondary MDS or AML. But that was not the case.

So then they rethought the hypothesis, there's probably preexisting clone or preexistent underlying abnormalities that will increase the risk. So they developed this ultrasensitive technique to look at minute clones of p53. And as a phenomenon of aging, we may acquire some minute clones of those. And it turns out that actually chemotherapy may eradicate the other cells. And what comes back as the recovery of those p53 mutant cells, they get subsequent hits, and how patients develop MDS, AML.

In the future, for this patient, maybe if there is a technique where you can tell and you have an option of avoiding chemotherapy, if this patient has a detectible p53 mutation and a small clone, maybe that's a patient in whom we can avoid chemotherapy.

Ruben A. Mesa, MD, FACP: I think that's very, very relevant. And one of my roles is overseeing our cancer practice for Mayo Clinic in the Southwest. So I’m very mindful of our solid tumor colleagues, as well. And again, there are situations where adjuvant therapies in various cancers, sometimes it's less clear how beneficial it will be if age is a factor or other components. So clearly if you were concerned about a high likelihood of triggering a myeloid disorder, that would be another important concern.
                                                                                                                                                                                                                                                                                                                  
Transcript Edited for Clarity

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Transcript:

Ruben A. Mesa, MD, FACP:
I think that idea, that not all the niches are the same, is really key. Certainly, as we look at the patients who have transformed from a myeloproliferative neoplasm to AML, there's that group of patients in whom the marrow itself is really quite fibrotic, and we’re not even sure there's hematopoiesis going on in there.

Yet, they'll have that 30% blast in the peripheral blood, and we think that the spleen can be an important harbor of those cells. And again, how well are drugs getting into that space? Are they really equally efficacious in that environment versus the marrow environment? A lot of opportunities.

So as we think about particularly secondary AML—that I view as a huge area of our unmet need in this group of patients. They tend to be older. It's quite prevalent in that group. By pretty much any metric, they tend to have a more challenging prognosis in a lot of ways.

Maybe, Elias, as we think about both kind of pre-leukemic disorders, chronic myeloid disorders, MDS, MPNs, what are we learning about how their path may be different than those with a de novo acute leukemia.

Elias Jabbour, MD: Well, Ruben, you’re touching a point that is very important because with population aging, we see more and more of this damage to the stem cell toward MDS happening. So, I think if we're giving an opportunity to live a lifetime, like eternally, we will all have MDS somehow. And then eventually we go into AML, but we will not be given this opportunity.

So as you mentioned, there are two kinds of AML. The de novo one, for which we have good results, decent results. But the secondary ones are horrible. But we're discovering today the hidden life of cancer. So you have somebody coming in with AML, but even if they have not had MDS, they had a certain period of time where they were acquiring something. And then they come to see you at the end where they have acute myeloid leukemias. This leukemia, they have very bad features, complex karyotype, multiple mutations, p53 mutation. We know they are very resistant to chemotherapy.

We did work on MDS, for example, and we reported that some patients will never transform, or at least will have a very late transformation, but some others do transform. And if we monitor this patient, for example, simply by doing a karyotype, we discover they can acquire certain abnormalities and they go into acute myeloid leukemia. And I think it's similar in myeloproliferative neoplasm, as well.

We know, for example, in women who had breast cancer, who had adjuvant chemotherapy, some of them will go into MDS and AML, and some will not. And then, definitely, they’ll have deficiency of some enzymatic repairs, and others that can trigger these events and push for cancer.

Now, whether there are techniques available today that can to do sequencing to identify certain targets—maybe we can intervene earlier, start this process, reverse it. Or we may fail. And we think we’re improving survival, but survival only of patients from what we know. But, hopefully, we can intervene earlier and get to a place better than today.

Rafael Bejar MD, PhD: I think that's a great point. You were mentioning pre-leukemic states, and they are the pre-leukemic states that we recognize and have a diagnosis and a name for, like MDS and MPNs. We are beginning to understand better what mutations will lead to progression, or are more likely to lead to progression, and that's helpful to help make decisions about patients. Does this patient require a transplant? Or maybe they don't need one. And knowing which mutations are actually prognostic is helpful in that regard. But your other point is also valid, that many people who have, what we call de novo AML, don't have a recognized preexisting condition.

But if you were to actually sequence them at that earlier time point, you might find that these mutations are already present and already evolving without giving them a clinical phenotype. And I think that's an exciting new area that we haven't really explored. And maybe we can identify these patients who aren't at high risk, like patients who have had treatment for breast cancer and other disorders.

Elias Jabbour, MD: Rafael, you mentioned something very important. I had a patient coming to see me in the clinic last week. She's a nurse at MD Anderson. She had Hodgkin disease diagnosed. And she's going to get her treatment. Her concern coming to see us wasn't about her Hodgkin disease treatment. Her concern was, well if I get Hodgkin disease treatment, will I acquire MDS down the road in 5, 10 years?

So now with the next-generation sequencing and all these techniques and the study samples, maybe we can identify a group of patients at the baseline, who have certain mutations that can evolve down the road. And, therefore, that will take us to the personalized therapy, identifying a group of patients. Maybe they do not need adjuvant therapy. Or, they need something minimal or different interventions.

Rami Komrokji, MD: So that brings us actually to the presentation by the Washington University Group at the plenary session at ASH where they tried to look at what triggers the development of secondary myeloid diseases. And obviously, the first impression that you will have, you will find more mutations and abnormalities in patients who had secondary MDS or AML. But that was not the case.

So then they rethought the hypothesis, there's probably preexisting clone or preexistent underlying abnormalities that will increase the risk. So they developed this ultrasensitive technique to look at minute clones of p53. And as a phenomenon of aging, we may acquire some minute clones of those. And it turns out that actually chemotherapy may eradicate the other cells. And what comes back as the recovery of those p53 mutant cells, they get subsequent hits, and how patients develop MDS, AML.

In the future, for this patient, maybe if there is a technique where you can tell and you have an option of avoiding chemotherapy, if this patient has a detectible p53 mutation and a small clone, maybe that's a patient in whom we can avoid chemotherapy.

Ruben A. Mesa, MD, FACP: I think that's very, very relevant. And one of my roles is overseeing our cancer practice for Mayo Clinic in the Southwest. So I’m very mindful of our solid tumor colleagues, as well. And again, there are situations where adjuvant therapies in various cancers, sometimes it's less clear how beneficial it will be if age is a factor or other components. So clearly if you were concerned about a high likelihood of triggering a myeloid disorder, that would be another important concern.
                                                                                                                                                                                                                                                                                                                  
Transcript Edited for Clarity
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