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Classification and Characteristics of MDS

Insights From:Thomas Prebet, MD, PhD, Yale Cancer Center; Heather Leitch, MD, PhD, St. Paul’s Hospital;Vinod Pullarkat, MD, City of Hope Medical Center
Published: Friday, Oct 07, 2016


Transcript:

Vinod Pullarkat, MD:
Molecular testing is now becoming commonplace in MDS, as well as many other hematologic disorders. There are two particular areas where this is useful. From a diagnostic standpoint, there are patients who have cytopenias, but they still don’t have obvious morphologic dysplasia in the marrow. And the molecular testing in that setting may allow you to make a diagnosis of MDS in that patient. One should, however, be careful, because there are patients who are otherwise normal who may have some of these mutations. And so, it has to be in the right clinical context of cytopenias. Finding these abnormalities on genomic testing may allow you to make a diagnosis of MDS and follow those patients closely.

From a prognostic standpoint, based on the genomic profile, the risk stratification will be different. For example, when we are applying some treatments, like hematopoietic stem cell transplant, there are patients who if they have certain genomic abnormalities, their outcomes will be very poor. And the risk/benefit ratio of transplantation in those patients could be different. So, it will allow us to choose appropriate treatment for patients based on their risk.

Heather Leitch, MD, PhD: In lower-risk MDS, about 50% of patients have cytogenetic abnormalities. And as they progress to higher-risk MDS, they may develop additional abnormalities. Now that we’re in the era of molecular testing, there are an increasing number of genetic abnormalities that cannot be detected by cytogenetics that are being recognized.

In MDS, we also, though, have an influence of epigenetic factors and micro RNAs. So, the story is complex and we don’t yet fully understand it. It has been shown recently in AML. There was a publication in The New England Journal of Medicine showing that different molecular abnormalities are present and they influence each other depending on which other ones are present in either a favorable or adverse prognostic manner.

The IPSS Score, and also other scores, take into account the number of cytopenias, the cytogenetic risk category, and the number of blasts in the marrow. And so, the weighting between the different scores is a little bit different. Some of the newer scores incorporate factors that are more recently recognized to be adverse prognostic factors, such as transfusion dependence in the WPSS. And the Cytogenetic Scoring System, of course, takes into account many more cytogenetic abnormalities than the original IPSS does. We do like to classify patients as lower risk or higher risk, which makes a difference not only in terms of prognosis, but also in terms of treatment decisions, as well.

In Canada, we developed a tool, which is available online, called the MDS Clear Path. It walks one through the workup diagnosis and management of MDS and can be applied to individual patients. This includes the prognostic systems for MDS, and when we do classify patients, we like to stratify them into lower risk and higher risk MDS. Since the majority of clinical trials have been based on the IPSS Score, that’s what we mainly use—although we’re now using the IPSS Revised Score more often and some of the other scores, as well.

Vinod Pullarkat, MD: MDS patients are classified mostly based on the International Prognostic Scoring System, and there is also a revised version of it, the IPSSR. But these scoring systems are not perfect. Sometimes a patient may be having a low- or intermediate-risk score by the IPSS, but, in fact, they may have some bad prognostic features. One example is a transfusion-dependent patient who is otherwise considered a low-risk patient. Clinically, that patient is at a higher risk for having complications. The same applies to patients who have very severe thrombocytopenia, for example. And now with the advent of molecular testing being done on all these patients, there are subsets of patients who have adverse prognostic molecular abnormalities who may otherwise be a low-risk or an intermediate 1-risk patient, but they actually will behave like a higher-risk patient. So, the risk stratification may have to be revised, taking into account what we know right now with genomic data that’s coming in.

Restaging of a patient should be done on an ongoing basis. The IPSS prognostication is done at diagnosis, and all those scoring systems apply to the diagnostic bone marrow specimen. But patients’ clinical behavior would dictate when you would restage the patient, and the risks will change based on the restaging.

We’ve always known that MDS is a heterogeneous disease. There are many cytogenetic and molecular subgroups that are all classified together as MDS. Now that we know more about genomics, we are understanding that the mutations that are seen in MDS may group the patients together into certain subgroups. For example, there are MDS patients who have mutations in various components of the spliceosome, so that may be one subset of patients. And there may be therapies that may work more in that group as opposed to somebody else who may have a DNA methylation abnormality. These mutations are now grouping patients into subgroups based on their disease biology. And there is implication for research, as well, because before there were large studies done where all the MDS patients were grouped together and the drug was tested. Now, we may have to move to a situation where we may test a particular drug in a subset of patients in a much smaller study. It has major implications for research and even for treatment. The certain subtypes may have a particular sensitivity toward particular treatment, so we may have to use that in our decision making.

Transcript Edited for Clarity
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Transcript:

Vinod Pullarkat, MD:
Molecular testing is now becoming commonplace in MDS, as well as many other hematologic disorders. There are two particular areas where this is useful. From a diagnostic standpoint, there are patients who have cytopenias, but they still don’t have obvious morphologic dysplasia in the marrow. And the molecular testing in that setting may allow you to make a diagnosis of MDS in that patient. One should, however, be careful, because there are patients who are otherwise normal who may have some of these mutations. And so, it has to be in the right clinical context of cytopenias. Finding these abnormalities on genomic testing may allow you to make a diagnosis of MDS and follow those patients closely.

From a prognostic standpoint, based on the genomic profile, the risk stratification will be different. For example, when we are applying some treatments, like hematopoietic stem cell transplant, there are patients who if they have certain genomic abnormalities, their outcomes will be very poor. And the risk/benefit ratio of transplantation in those patients could be different. So, it will allow us to choose appropriate treatment for patients based on their risk.

Heather Leitch, MD, PhD: In lower-risk MDS, about 50% of patients have cytogenetic abnormalities. And as they progress to higher-risk MDS, they may develop additional abnormalities. Now that we’re in the era of molecular testing, there are an increasing number of genetic abnormalities that cannot be detected by cytogenetics that are being recognized.

In MDS, we also, though, have an influence of epigenetic factors and micro RNAs. So, the story is complex and we don’t yet fully understand it. It has been shown recently in AML. There was a publication in The New England Journal of Medicine showing that different molecular abnormalities are present and they influence each other depending on which other ones are present in either a favorable or adverse prognostic manner.

The IPSS Score, and also other scores, take into account the number of cytopenias, the cytogenetic risk category, and the number of blasts in the marrow. And so, the weighting between the different scores is a little bit different. Some of the newer scores incorporate factors that are more recently recognized to be adverse prognostic factors, such as transfusion dependence in the WPSS. And the Cytogenetic Scoring System, of course, takes into account many more cytogenetic abnormalities than the original IPSS does. We do like to classify patients as lower risk or higher risk, which makes a difference not only in terms of prognosis, but also in terms of treatment decisions, as well.

In Canada, we developed a tool, which is available online, called the MDS Clear Path. It walks one through the workup diagnosis and management of MDS and can be applied to individual patients. This includes the prognostic systems for MDS, and when we do classify patients, we like to stratify them into lower risk and higher risk MDS. Since the majority of clinical trials have been based on the IPSS Score, that’s what we mainly use—although we’re now using the IPSS Revised Score more often and some of the other scores, as well.

Vinod Pullarkat, MD: MDS patients are classified mostly based on the International Prognostic Scoring System, and there is also a revised version of it, the IPSSR. But these scoring systems are not perfect. Sometimes a patient may be having a low- or intermediate-risk score by the IPSS, but, in fact, they may have some bad prognostic features. One example is a transfusion-dependent patient who is otherwise considered a low-risk patient. Clinically, that patient is at a higher risk for having complications. The same applies to patients who have very severe thrombocytopenia, for example. And now with the advent of molecular testing being done on all these patients, there are subsets of patients who have adverse prognostic molecular abnormalities who may otherwise be a low-risk or an intermediate 1-risk patient, but they actually will behave like a higher-risk patient. So, the risk stratification may have to be revised, taking into account what we know right now with genomic data that’s coming in.

Restaging of a patient should be done on an ongoing basis. The IPSS prognostication is done at diagnosis, and all those scoring systems apply to the diagnostic bone marrow specimen. But patients’ clinical behavior would dictate when you would restage the patient, and the risks will change based on the restaging.

We’ve always known that MDS is a heterogeneous disease. There are many cytogenetic and molecular subgroups that are all classified together as MDS. Now that we know more about genomics, we are understanding that the mutations that are seen in MDS may group the patients together into certain subgroups. For example, there are MDS patients who have mutations in various components of the spliceosome, so that may be one subset of patients. And there may be therapies that may work more in that group as opposed to somebody else who may have a DNA methylation abnormality. These mutations are now grouping patients into subgroups based on their disease biology. And there is implication for research, as well, because before there were large studies done where all the MDS patients were grouped together and the drug was tested. Now, we may have to move to a situation where we may test a particular drug in a subset of patients in a much smaller study. It has major implications for research and even for treatment. The certain subtypes may have a particular sensitivity toward particular treatment, so we may have to use that in our decision making.

Transcript Edited for Clarity
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