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Understanding the Recent WHO MDS Classification Updates

Panelists: Vinod Pullarkat, MD, City of Hope Medical Center; Jamile Shammo, MD, Rush University Medical Center; Rami S. Komrokji, MD, Moffitt Cancer Center; Thomas Prebet, MD, PhD, Yale Cancer Center; Ellen K. Ritchie, MD, New York Presbyterian Hospital
Published Online: Thursday, Jan 05, 2017



Transcript:

Vinod Pullarkat, MD:
Hello, and thank you for joining us today for this OncLive Peer Exchange® on the topic of “Myelodysplastic Syndrome: Managing Risk and Complications.” Myelodysplastic syndrome is a heterogeneous disease that necessitates an individualized treatment approach and careful monitoring in an effort to slow disease progression and prevent complications. In this OncLive Peer Exchange®, a panel of experts in oncology and hematology will discuss some of the challenges in managing the disease, including accurate risk stratification, complications associated with transfusion-dependence, and practical considerations in the use of disease-modifying therapies and in stem cell transplantation.

I am Dr. Vinod Pullarkat, and I am associate clinical professor of hematology and hematopoietic cell transplantation at the City of Hope Medical Center in Duarte, California. Participating today on our distinguished panel are: Dr. Rami Komrokji, clinical director, senior member, and professor of oncologic sciences for the Malignant Hematology Department at the Moffitt Cancer Center in Tampa, Florida; Dr. Thomas Prebet, assistant director of Myeloid Malignancy Research and associate professor of hematology at the Yale Cancer Center in New Haven, Connecticut; Dr. Ellen K. Ritchie, an assistant professor of clinical medicine at Weill Cornell Medical College affiliated with New York Presbyterian Hospital; and Dr. Jamile Shammo, associate professor of medicine and pathology at the Rush University Medical Center in Chicago, Illinois. Thank you all for joining us. Let’s begin.

First, Dr. Shammo, could you discuss a little bit about the heterogeneity of MDS and the changes to the new WHO classification?

Jamile Shammo, MD: Absolutely. So, there has been a variety of advances in the understanding of MDS biology, particularly when it comes to mutational analysis. And some recent data about the importance of identifying single versus multilineage dysplasia—which I suppose had been in the 2008 WHO classifications. The update is not a complete overhaul of all disease entities, but is perhaps refinement of those categories. And, more importantly, I think I should say that the word “cytopenia” has been eliminated. For example, we don’t usually say “refractory anemia” or “refractory cytopenia” with multilineage dysplasia. This has been eliminated, and now you could utilize the term “MDS”, and then right after that, “single lineage dysplasia” or “multilineage dysplasia.” You identify it in sideroblasts and whether or not it’s also associated with single or multilineage dysplasia.

The other thing is that MDS also has been split into 2 groups: excess blast 1, which is 5% to 9% blasts, and then MDS excess blast 2, which is 10% to 19% blasts. Interestingly, in order to make a diagnosis of MDS ring sideroblast, in the old classification at least, you must have more than 15% ring sideroblasts in order to call it that. But, now, if you have SF3B1 mutation, which is the most common mutation in this patient population, you could have as few as 5% ring sideroblasts and still be able to call it MDS with ring sideroblast. Of course, there’s always a group of MDS unclassified, which continues to be the issue, and hopefully that will get refined over time. That’s a very quick wrap-up of what the 2016 WHO means.

Vinod Pullarkat, MD: Does this have prognostic implications with relation to survival and risk of AML transformation?

Jamile Shammo, MD: I think when you talk about survival in AML evolution, it’s always something that’s tied into other prognostic scoring systems. Generally speaking, we feel that MDS with single lineage, multilineage dysplasia, or even ring sideroblasts, all those categories have less than 5% blasts in the bone marrow. And, generally speaking, less than 5% blast category, irrespective of many other cytogenetic abnormalities, etc—which will come out through the IPSS (International Prognostic Scoring System)—have a better prognosis in general. But again, the WHO 2016 classification is a morphological assessment, and you need a little bit more information to come up with survival in leukemia evolution. I don’t know how others feel about that.

Rami S. Komrokji, MD: If I may add, Jamile, I think the ramification in the past system was a little bit confusing because, as you mentioned, we were talking about cytopenias. And you would say somebody that had a refractory cytopenia or multilineage dysplasia, they will have anemia. So, every time, there is discordance between what you see, cytopenia and the dysplasia. And since, as you mentioned, it’s a pathologic classification, the naming is more geared in the new classification, to look at the dysplasia in the bone marrow. Because, again, you could have refractory anemia and that patient could only have thrombocytopenia in the peripheral blood. So, I think it’s a little bit easier. The other thing would also be probably mentioning the threshold to erythroleukemias, that the suggestion to count the blasts out of the non-erythroid cells is going away because those categories did as good as MDS rather than the true erythroleukemias. And maybe also we are starting to, again, pay attention to the ring sideroblasts, whether they are in the setting of multilineage dysplasia or not, because now we are starting to see active therapies in clinical trials in patients with ring sideroblasts.

Jamile Shammo, MD: I’m so glad you brought up this point about erythroleukemia because a lot of times, people will get diagnosed with M6 simply because the percentage of blasts is greater than 20% in the non-erythroid, where now you look at it as a whole, which we will have a lot more MDS cases in this situation.

Thomas Prebet, MD, PhD: We still need to give a lot of credit to the pathologists, because it’s still a much more challenging diagnosis to make.

Jamile Shammo, MD: Absolutely.

Thomas Prebet, MD, PhD: That’s one point. This is maybe a little bit more easy now with the WHO 2016 classification to see exactly where we are, but it’s still a pretty challenging diagnosis.

Vinod Pullarkat, MD: Rami, you brought up this issue of treatment modification. Does this new classification have any implications for treatment?

Rami S. Komrokji, MD: That’s a good question. I think in the erythroleukemia it may be because some of those patients in the past were automatically looked at as acute myeloid leukemia and could have probably received induction chemotherapy. There is some experience that had been already available and published, that those patients do pretty well on hypomethylating agents, actually probably even better than MDS. I think now we’re going start looking at those, as Jamile was mentioning, as MDS. I think what happened with the prior version of the WHO, if you had multilineage dysplasia, those patients did not do well. So, refractory cytopenia with multilineage dysplasia and ring sideroblasts got collapsed into that group, and we started calling them all RCMDs (refractory cytopenias with multilineage dysplasia). We did not pay attention much to the ring sideroblasts. Now we are finding that a subset of ring sideroblast patients are a little bit unique. There are some available treatment options for them. In fact, there are phase III clinical trials targeting that population. We are talking about the mutation that Jamile mentioned, the SF3B1, that’s particular in that population, and now the splicing factor inhibitors are going in trial. So, I think we are going to pay attention to the ring sideroblasts among those categories. Those are the initial thoughts on how the therapy will be based on this classification.

Vinod Pullarkat, MD: So, for all ring sideroblasts, all the MDS ring sideroblasts are not the same. That’s what you’re saying. There may be a prognostic implication for that.

Transcript Edited for Clarity

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Transcript:

Vinod Pullarkat, MD:
Hello, and thank you for joining us today for this OncLive Peer Exchange® on the topic of “Myelodysplastic Syndrome: Managing Risk and Complications.” Myelodysplastic syndrome is a heterogeneous disease that necessitates an individualized treatment approach and careful monitoring in an effort to slow disease progression and prevent complications. In this OncLive Peer Exchange®, a panel of experts in oncology and hematology will discuss some of the challenges in managing the disease, including accurate risk stratification, complications associated with transfusion-dependence, and practical considerations in the use of disease-modifying therapies and in stem cell transplantation.

I am Dr. Vinod Pullarkat, and I am associate clinical professor of hematology and hematopoietic cell transplantation at the City of Hope Medical Center in Duarte, California. Participating today on our distinguished panel are: Dr. Rami Komrokji, clinical director, senior member, and professor of oncologic sciences for the Malignant Hematology Department at the Moffitt Cancer Center in Tampa, Florida; Dr. Thomas Prebet, assistant director of Myeloid Malignancy Research and associate professor of hematology at the Yale Cancer Center in New Haven, Connecticut; Dr. Ellen K. Ritchie, an assistant professor of clinical medicine at Weill Cornell Medical College affiliated with New York Presbyterian Hospital; and Dr. Jamile Shammo, associate professor of medicine and pathology at the Rush University Medical Center in Chicago, Illinois. Thank you all for joining us. Let’s begin.

First, Dr. Shammo, could you discuss a little bit about the heterogeneity of MDS and the changes to the new WHO classification?

Jamile Shammo, MD: Absolutely. So, there has been a variety of advances in the understanding of MDS biology, particularly when it comes to mutational analysis. And some recent data about the importance of identifying single versus multilineage dysplasia—which I suppose had been in the 2008 WHO classifications. The update is not a complete overhaul of all disease entities, but is perhaps refinement of those categories. And, more importantly, I think I should say that the word “cytopenia” has been eliminated. For example, we don’t usually say “refractory anemia” or “refractory cytopenia” with multilineage dysplasia. This has been eliminated, and now you could utilize the term “MDS”, and then right after that, “single lineage dysplasia” or “multilineage dysplasia.” You identify it in sideroblasts and whether or not it’s also associated with single or multilineage dysplasia.

The other thing is that MDS also has been split into 2 groups: excess blast 1, which is 5% to 9% blasts, and then MDS excess blast 2, which is 10% to 19% blasts. Interestingly, in order to make a diagnosis of MDS ring sideroblast, in the old classification at least, you must have more than 15% ring sideroblasts in order to call it that. But, now, if you have SF3B1 mutation, which is the most common mutation in this patient population, you could have as few as 5% ring sideroblasts and still be able to call it MDS with ring sideroblast. Of course, there’s always a group of MDS unclassified, which continues to be the issue, and hopefully that will get refined over time. That’s a very quick wrap-up of what the 2016 WHO means.

Vinod Pullarkat, MD: Does this have prognostic implications with relation to survival and risk of AML transformation?

Jamile Shammo, MD: I think when you talk about survival in AML evolution, it’s always something that’s tied into other prognostic scoring systems. Generally speaking, we feel that MDS with single lineage, multilineage dysplasia, or even ring sideroblasts, all those categories have less than 5% blasts in the bone marrow. And, generally speaking, less than 5% blast category, irrespective of many other cytogenetic abnormalities, etc—which will come out through the IPSS (International Prognostic Scoring System)—have a better prognosis in general. But again, the WHO 2016 classification is a morphological assessment, and you need a little bit more information to come up with survival in leukemia evolution. I don’t know how others feel about that.

Rami S. Komrokji, MD: If I may add, Jamile, I think the ramification in the past system was a little bit confusing because, as you mentioned, we were talking about cytopenias. And you would say somebody that had a refractory cytopenia or multilineage dysplasia, they will have anemia. So, every time, there is discordance between what you see, cytopenia and the dysplasia. And since, as you mentioned, it’s a pathologic classification, the naming is more geared in the new classification, to look at the dysplasia in the bone marrow. Because, again, you could have refractory anemia and that patient could only have thrombocytopenia in the peripheral blood. So, I think it’s a little bit easier. The other thing would also be probably mentioning the threshold to erythroleukemias, that the suggestion to count the blasts out of the non-erythroid cells is going away because those categories did as good as MDS rather than the true erythroleukemias. And maybe also we are starting to, again, pay attention to the ring sideroblasts, whether they are in the setting of multilineage dysplasia or not, because now we are starting to see active therapies in clinical trials in patients with ring sideroblasts.

Jamile Shammo, MD: I’m so glad you brought up this point about erythroleukemia because a lot of times, people will get diagnosed with M6 simply because the percentage of blasts is greater than 20% in the non-erythroid, where now you look at it as a whole, which we will have a lot more MDS cases in this situation.

Thomas Prebet, MD, PhD: We still need to give a lot of credit to the pathologists, because it’s still a much more challenging diagnosis to make.

Jamile Shammo, MD: Absolutely.

Thomas Prebet, MD, PhD: That’s one point. This is maybe a little bit more easy now with the WHO 2016 classification to see exactly where we are, but it’s still a pretty challenging diagnosis.

Vinod Pullarkat, MD: Rami, you brought up this issue of treatment modification. Does this new classification have any implications for treatment?

Rami S. Komrokji, MD: That’s a good question. I think in the erythroleukemia it may be because some of those patients in the past were automatically looked at as acute myeloid leukemia and could have probably received induction chemotherapy. There is some experience that had been already available and published, that those patients do pretty well on hypomethylating agents, actually probably even better than MDS. I think now we’re going start looking at those, as Jamile was mentioning, as MDS. I think what happened with the prior version of the WHO, if you had multilineage dysplasia, those patients did not do well. So, refractory cytopenia with multilineage dysplasia and ring sideroblasts got collapsed into that group, and we started calling them all RCMDs (refractory cytopenias with multilineage dysplasia). We did not pay attention much to the ring sideroblasts. Now we are finding that a subset of ring sideroblast patients are a little bit unique. There are some available treatment options for them. In fact, there are phase III clinical trials targeting that population. We are talking about the mutation that Jamile mentioned, the SF3B1, that’s particular in that population, and now the splicing factor inhibitors are going in trial. So, I think we are going to pay attention to the ring sideroblasts among those categories. Those are the initial thoughts on how the therapy will be based on this classification.

Vinod Pullarkat, MD: So, for all ring sideroblasts, all the MDS ring sideroblasts are not the same. That’s what you’re saying. There may be a prognostic implication for that.

Transcript Edited for Clarity
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