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Molecular Cytogenetic Risk Stratification in ALL

Panelists: Mark R. Litzow, MD, The Mayo Clinic; Jae Park, MD, Memorial Sloan Kettering Cancer Center; Bijal Shah, MD H. Lee Moffitt Cancer Center & Research Institute; Anthony Stein Gehr Family Center for Leukemia Research
Published: Tuesday, Jan 22, 2019



Transcript: 

Mark R. Litzow, MD:
  Hello. The introduction of novel immune-based approaches for adults with acute lymphoblastic leukemia are revolutionizing the treatment paradigm from one that until recently had mainly relied on combination chemotherapy. However, for older patients with ALL, survival still remains poor, and there is a need for less intensive but effective treatment strategies.

In this OncLive Peer Exchange® panel discussion we will be looking at new data, including from the ASH [American Society of Hematology] 2018 meeting, to shed light on how the most recent data will be used to shape the way we treat our patients.

I’m Dr Mark Litzow, a consultant in the Division of Hematology and professor of medicine in the College of Medicine [and Science] at the Mayo Clinic, located in Rochester, Minnesota.

Participating today on our distinguished panel are Dr Jae Park, a hematologist-oncologist and staff member at the Memorial Sloan Kettering Cancer Center [in New York, New York], specializing in the care of patients with leukemia.

Dr Bijal Shah is a hematologist-oncologist specializing in leukemia and lymphoma at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

Finally, Dr Anthony Stein, clinical professor and co-director of the Gehr Family Center for Leukemia Research within the Hematologic Malignancies and Stem Cell Transplantation Institute at City of Hope in Duarte, California, is with us. Thank you for joining us. Let’s begin.

I’d like to start by discussing the classification and molecular cytogenetic risk stratification for patients with ALL. And what current prognostic factors we think are most important. Bijal, can you lead off on that?

Bijal D. Shah, MD: Absolutely. I think it’s a great question and it’s very important to risk stratify as we think about how we prioritize care for our patients. I’m going to begin by saying there are 2 broad classes before we even begin to get into the cytogenetic molecular risk. And that is the unfit patient and the fit patient. Understanding that without question forms the intensity with which we’re ultimately able to approach our patient, and based on information from this meeting, potentially the application of novel agents, such as blinatumomab in that front-line setting as opposed to waiting until relapse.

As we move beyond fit and unfit, now what we’re really talking about again are the cytogenetic molecular features that may help to define therapeutics, first and foremost, and that’s the Philadelphia chromosome [Ph] translocation. Seeing that implies a need for the addition of tyrosine kinase inhibitors, whether that be imatinib, dasatinib, nilotinib, bosutinib, or ponatinib, all of these tyrosine kinase inhibitors are starting to generate data within the space. I should say on multiagent therapeutic backbones.

Moving beyond the Philadelphia-positive, I think the next big group that we need to better understand how to treat, though we certainly recognize it informs treatment outcomes, are the MLL rearranged leukemias and the hypodiploid, or p53 mutant leukemias. And these remain without question a treatment challenge even with the novel agents that we have in hand.

And more likely at this point in time it’s going to inform decisions like: Do I consider allogeneic transplant in post-remission rather than informing a specific therapeutic approach? And I say, perhaps. I don’t want to imply that we have definitive data, randomized data, to support that one approach is better than another in this group of patients.

The final group that was more recently described but for which I think we have more and more data is the Ph-like category. And these are going to be patients who have kinase rearrangements involving ABL, involving JAK [Janus kinase] and several others, that appear to be more prone to relapse over time. I think we’re still asking fundamental questions about how to treat them, whether the addition of kinase inhibitors such as ruxolitinib or dasatinib in these patients will improve outcome.

I think the other, perhaps now slowly, resolving issue is, how we define them. And the Ph-like ALLs in the past were strictly defined by a specific gene expression profile. I think more of us in the field are moving towards identifying them based on a cytogenetic, or in some cases at some institutions, even IHC [immunohistochemistry], expression profiles. So more specifically, overexpression of CRLF2.

And so as we see IGH/CRLF2 arrangements, JAK2 arrangements and others, I think more and more of us are feeling comfortable calling these Ph-like, even in the absence of gene expression profiling, to definitively call that.

In the T-ALLs [T-cell ALLs] it gets a little bit more complicated, and I think what we are left with in T-ALL are really immunophenotypic subcategorizations, early T-precursor, cortico-subtype and mature T-ALLs, with some data suggesting that early T-precursor ALL is going to behave in a much more inferior [manner] than its counterparts. Again, in the pediatric settings it may be a little bit different.

Digging a little bit deeper into the molecular phenotype, RAS/PTEN mutations may be another additive risk feature in this population, with those independent of MRD [minimal residual disease] showing a higher risk of relapse over time with that signature.

Mark R. Litzow, MD: Jae, could you comment about the age-related differences in some of these prognostic groups that Bijal just mentioned?

Jae Park, MD:  Sure. One important [piece of] information that we have [is that] the Philadelphia chromosome-positive incidence increases with age. So for the BCR-ABL transcript positive or translocator 1, the incidence increases over age. So if we see patients over the age of 60 or so I think the incidence, we can estimate about 40% will be Ph-positive. I think when we see newly diagnosed ALL patients in the older age group, that this is definitely one test that all patients should [get] because treatment is vastly different. But the incidence increases for Ph-positive ALL.

The Ph-like, I think this information that we’re gathering for adult ALLs, the incidence is higher in the pediatric patients, and it seems to plateau in the young adolescent age, and then the plateau seems to continue beyond that age group. So it doesn’t appear that there’s increased incidence as you get older beyond that group, but that also is another factor that should be considered to be tested.

Mark R. Litzow, MD: Well thank you, that was a very comprehensive assessment.

Anthony S. Stein, MD: The Ph-like ALL is also much more common in the Hispanic group of patients.

Mark R. Litzow, MD: It’s an important point to remember. Yes, thank you. That’s a very comprehensive overview of some of the important risk stratification that we need to think about when we see patients.


Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD:
  Hello. The introduction of novel immune-based approaches for adults with acute lymphoblastic leukemia are revolutionizing the treatment paradigm from one that until recently had mainly relied on combination chemotherapy. However, for older patients with ALL, survival still remains poor, and there is a need for less intensive but effective treatment strategies.

In this OncLive Peer Exchange® panel discussion we will be looking at new data, including from the ASH [American Society of Hematology] 2018 meeting, to shed light on how the most recent data will be used to shape the way we treat our patients.

I’m Dr Mark Litzow, a consultant in the Division of Hematology and professor of medicine in the College of Medicine [and Science] at the Mayo Clinic, located in Rochester, Minnesota.

Participating today on our distinguished panel are Dr Jae Park, a hematologist-oncologist and staff member at the Memorial Sloan Kettering Cancer Center [in New York, New York], specializing in the care of patients with leukemia.

Dr Bijal Shah is a hematologist-oncologist specializing in leukemia and lymphoma at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida.

Finally, Dr Anthony Stein, clinical professor and co-director of the Gehr Family Center for Leukemia Research within the Hematologic Malignancies and Stem Cell Transplantation Institute at City of Hope in Duarte, California, is with us. Thank you for joining us. Let’s begin.

I’d like to start by discussing the classification and molecular cytogenetic risk stratification for patients with ALL. And what current prognostic factors we think are most important. Bijal, can you lead off on that?

Bijal D. Shah, MD: Absolutely. I think it’s a great question and it’s very important to risk stratify as we think about how we prioritize care for our patients. I’m going to begin by saying there are 2 broad classes before we even begin to get into the cytogenetic molecular risk. And that is the unfit patient and the fit patient. Understanding that without question forms the intensity with which we’re ultimately able to approach our patient, and based on information from this meeting, potentially the application of novel agents, such as blinatumomab in that front-line setting as opposed to waiting until relapse.

As we move beyond fit and unfit, now what we’re really talking about again are the cytogenetic molecular features that may help to define therapeutics, first and foremost, and that’s the Philadelphia chromosome [Ph] translocation. Seeing that implies a need for the addition of tyrosine kinase inhibitors, whether that be imatinib, dasatinib, nilotinib, bosutinib, or ponatinib, all of these tyrosine kinase inhibitors are starting to generate data within the space. I should say on multiagent therapeutic backbones.

Moving beyond the Philadelphia-positive, I think the next big group that we need to better understand how to treat, though we certainly recognize it informs treatment outcomes, are the MLL rearranged leukemias and the hypodiploid, or p53 mutant leukemias. And these remain without question a treatment challenge even with the novel agents that we have in hand.

And more likely at this point in time it’s going to inform decisions like: Do I consider allogeneic transplant in post-remission rather than informing a specific therapeutic approach? And I say, perhaps. I don’t want to imply that we have definitive data, randomized data, to support that one approach is better than another in this group of patients.

The final group that was more recently described but for which I think we have more and more data is the Ph-like category. And these are going to be patients who have kinase rearrangements involving ABL, involving JAK [Janus kinase] and several others, that appear to be more prone to relapse over time. I think we’re still asking fundamental questions about how to treat them, whether the addition of kinase inhibitors such as ruxolitinib or dasatinib in these patients will improve outcome.

I think the other, perhaps now slowly, resolving issue is, how we define them. And the Ph-like ALLs in the past were strictly defined by a specific gene expression profile. I think more of us in the field are moving towards identifying them based on a cytogenetic, or in some cases at some institutions, even IHC [immunohistochemistry], expression profiles. So more specifically, overexpression of CRLF2.

And so as we see IGH/CRLF2 arrangements, JAK2 arrangements and others, I think more and more of us are feeling comfortable calling these Ph-like, even in the absence of gene expression profiling, to definitively call that.

In the T-ALLs [T-cell ALLs] it gets a little bit more complicated, and I think what we are left with in T-ALL are really immunophenotypic subcategorizations, early T-precursor, cortico-subtype and mature T-ALLs, with some data suggesting that early T-precursor ALL is going to behave in a much more inferior [manner] than its counterparts. Again, in the pediatric settings it may be a little bit different.

Digging a little bit deeper into the molecular phenotype, RAS/PTEN mutations may be another additive risk feature in this population, with those independent of MRD [minimal residual disease] showing a higher risk of relapse over time with that signature.

Mark R. Litzow, MD: Jae, could you comment about the age-related differences in some of these prognostic groups that Bijal just mentioned?

Jae Park, MD:  Sure. One important [piece of] information that we have [is that] the Philadelphia chromosome-positive incidence increases with age. So for the BCR-ABL transcript positive or translocator 1, the incidence increases over age. So if we see patients over the age of 60 or so I think the incidence, we can estimate about 40% will be Ph-positive. I think when we see newly diagnosed ALL patients in the older age group, that this is definitely one test that all patients should [get] because treatment is vastly different. But the incidence increases for Ph-positive ALL.

The Ph-like, I think this information that we’re gathering for adult ALLs, the incidence is higher in the pediatric patients, and it seems to plateau in the young adolescent age, and then the plateau seems to continue beyond that age group. So it doesn’t appear that there’s increased incidence as you get older beyond that group, but that also is another factor that should be considered to be tested.

Mark R. Litzow, MD: Well thank you, that was a very comprehensive assessment.

Anthony S. Stein, MD: The Ph-like ALL is also much more common in the Hispanic group of patients.

Mark R. Litzow, MD: It’s an important point to remember. Yes, thank you. That’s a very comprehensive overview of some of the important risk stratification that we need to think about when we see patients.


Transcript Edited for Clarity 
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