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MPNs: Differentiating Between ET, PV, and MF

Panelists: Harry P. Erba, MD, PhD, Duke University; Rami Komrokji, MD, Moffitt Cancer Center; Ruben A. Mesa, MD, FACP, The Mays Cancer Center, the newly named center of UT Health San Antonio MD Anderson Cancer Center; Jamile M. Shammo, MD, FASCP, FACP, Rush University Medical Center; Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center
Published: Tuesday, Jul 10, 2018



Transcript: 

Harry P. Erba, MD, PhD: It does bring up this question: if they all have these things in common, how do we distinguish the major MPNs from each other, specifically essential thrombocythemia, polycythemia vera, and myelofibrosis? Jamile, would you like to talk about that?

Jamile M. Shammo, MD, FASCP, FACP: I think that we’ve all had patients who have a classical presentation for ET with isolated thrombocytosis and JAK2 positivity; or, you’ve had a patient who has erythrocytosis with very high hematocrit and JAK2 positivity. I think some cases are certainly very easy to make a diagnosis with, but obviously when it comes to the MPNs, there’s a great deal of overlap among all entities. I think to some respect, that’s why the WHO 2016 classification emphasized the role of a bone marrow biopsy and placed a little bit more pressure on pathologists, so that they can actually make the distinction among the 3 entities. In a way, it makes sense.

As you had said, a JAK2 mutation puts all 3 entities together, but I think we need to separate them out. Obviously, you may end up with a patient who has PV but who is iron deficient, so they’re not going to manifest with a very high hematocrit or hemoglobin and hence, the diagnosis may be in question. I think that’s where the bone marrow biopsy may come in handy. Obviously, if you see panmyelosis, you can maybe see a karyocytic clustering, plus granulocytic proliferation. Then you’d be more inclined to call this PV as opposed to just seeing clusters of megakaryocytes and thrombosis, in which case you may favor ET.

On the other hand, there’s this new entity of prefibrotic myelofibrosis, which also needs to be distinguished from ET because those patients will not have fibrosis on their bone marrow biopsy. That is typically the case in cases of primary myelofibrosis, for both PV and ET myelofibrosis as well. I think that’s an important entity to distinguish from ET because it has a worse prognosis.

Rami Komrokji, MD: If I may add to that. I think nowadays, what we are learning is that this is a spectrum of myeloid diseases referring to what we call chronic diseases. We have MDS, myeloproliferative neoplasms, and the MDS MPNs. The hallmark of myeloproliferative diseases is probably that activation of the JAK/STAT pathway. We know that there are phenotypic driver mutations that drive the clinical features we see such as the JAK2 mutation, the calreticulin mutation, and the MPL mutation. Probably what distinguishes those diseases, or what makes something look like ET or polycythemia-vera sometimes, is the sequence and combination of those somatic mutations that we see that would lead to a certain clinical phenotype. Back to your point, I think now we are understanding much more about the biology that leads to those different presentations or manifestations. But the common thing is really the overactivation of the JAK/STAT pathway.

Harry P. Erba, MD, PhD: Srdan?

Srdan Verstovsek, MD, PhD: We now know much more about biology, and we all agree that activation of JAK/STAT pathway is the underlying biological problem of all 3 classic Philadelphia chromosome-negative MPNs. But when we talk about diagnosis, emphasis is about and should be about the bone marrow biopsy. The diagnostic criteria still exist. That means we don’t have 1 test. The bone marrow is not the 1 test. There is no molecular test. It’s a combination of tests that needs to be combined for a diagnosis to be made. In myelofibrosis, for example, it is the bone marrow biopsy, it is genetics, it is a physical exam looking at the spleen, it is a CBC looking at the left shift in anemia, and it is the chemistry looking at LDH. It is really a team effort or an experienced clinician who will pull all this information together from different laboratories or test sites to make a diagnosis.

Harry P. Erba, MD, PhD: It sounds simple, but I’m going to say something that I’m a little afraid to say with this panel: Sometimes, I’m challenged. Sometimes the pathologists have a bone marrow biopsy and they say it is ET, yet this young patient keeps having a hemoglobin that goes high, a low EPO level, or JAK2 positivity. I feel obliged to treat him like a PV patient even though it’s being called ET. Am I alone here, or do these things change? Does a patient shift from one diagnosis to another?

Ruben A. Mesa, MD, FACP: I think the point you raise is an excellent one. I think we’re clearly evolving from the era of phenotypes to being much more precise in our diagnoses. Indeed, you started the conversation regarding Dameshek’s observation. It’s interesting. Over time, he also had included in that list of myeloproliferative neoplasms things like PMH (personal medical history), but now we know the molecular biology is dramatically distinct. Some are similar, some are distinct. I do think between these 3 entities, ET, PV, and MF, there clearly is a spectrum of overlap. We try to have very clear subgrouping because of trials conducted through criteria, and all of these criteria are very helpful the majority of the time, but they’re not perfect. They’re consensus criteria, but they don’t truly get at the issue of biology itself. The case you raise is probably the one that overlaps the most. Is the JAK2-mutated ET truly a very distinct entity from polycythemia vera? Probably enough to cause a fist fight at any MPN meeting, but you’re right: the JAK2-mutated ET patient who has erythrocytosis, functionally, I’m treating like polycythemia vera.

Harry P. Erba, MD, PhD: I agree.

Ruben A. Mesa, MD, FACP: I’m not sure there’s really any proof to say that’s incorrect.

Srdan Verstovsek, MD, PhD: Over time, it will be more and more obvious that the patient is evolving to PV. And then, you get a situation where the patient comes and says, “My doctor tells me I have 2 diseases; I have ET and PV,” and my answer is, “No, you have 1 disease that is changing like any other living tissue with acquisition of new mutations.” Something else happened in the body of the patient leading to a disease with 2 different characteristics.

Harry P. Erba, MD, PhD: I think what this introduction has done is shown a couple of things. First, it shows that clinicians have to be aware of what the goals of management are in each of these diseases because sometimes patients may have manifestations of a couple, like ET and PV. Second, as we learn more about the biology, hopefully we’re going to move more towards targeted agents that will be directed at the biology. At the end of this discussion, we’ll get to some of those agents.

Transcript Edited for Clarity 

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Transcript: 

Harry P. Erba, MD, PhD: It does bring up this question: if they all have these things in common, how do we distinguish the major MPNs from each other, specifically essential thrombocythemia, polycythemia vera, and myelofibrosis? Jamile, would you like to talk about that?

Jamile M. Shammo, MD, FASCP, FACP: I think that we’ve all had patients who have a classical presentation for ET with isolated thrombocytosis and JAK2 positivity; or, you’ve had a patient who has erythrocytosis with very high hematocrit and JAK2 positivity. I think some cases are certainly very easy to make a diagnosis with, but obviously when it comes to the MPNs, there’s a great deal of overlap among all entities. I think to some respect, that’s why the WHO 2016 classification emphasized the role of a bone marrow biopsy and placed a little bit more pressure on pathologists, so that they can actually make the distinction among the 3 entities. In a way, it makes sense.

As you had said, a JAK2 mutation puts all 3 entities together, but I think we need to separate them out. Obviously, you may end up with a patient who has PV but who is iron deficient, so they’re not going to manifest with a very high hematocrit or hemoglobin and hence, the diagnosis may be in question. I think that’s where the bone marrow biopsy may come in handy. Obviously, if you see panmyelosis, you can maybe see a karyocytic clustering, plus granulocytic proliferation. Then you’d be more inclined to call this PV as opposed to just seeing clusters of megakaryocytes and thrombosis, in which case you may favor ET.

On the other hand, there’s this new entity of prefibrotic myelofibrosis, which also needs to be distinguished from ET because those patients will not have fibrosis on their bone marrow biopsy. That is typically the case in cases of primary myelofibrosis, for both PV and ET myelofibrosis as well. I think that’s an important entity to distinguish from ET because it has a worse prognosis.

Rami Komrokji, MD: If I may add to that. I think nowadays, what we are learning is that this is a spectrum of myeloid diseases referring to what we call chronic diseases. We have MDS, myeloproliferative neoplasms, and the MDS MPNs. The hallmark of myeloproliferative diseases is probably that activation of the JAK/STAT pathway. We know that there are phenotypic driver mutations that drive the clinical features we see such as the JAK2 mutation, the calreticulin mutation, and the MPL mutation. Probably what distinguishes those diseases, or what makes something look like ET or polycythemia-vera sometimes, is the sequence and combination of those somatic mutations that we see that would lead to a certain clinical phenotype. Back to your point, I think now we are understanding much more about the biology that leads to those different presentations or manifestations. But the common thing is really the overactivation of the JAK/STAT pathway.

Harry P. Erba, MD, PhD: Srdan?

Srdan Verstovsek, MD, PhD: We now know much more about biology, and we all agree that activation of JAK/STAT pathway is the underlying biological problem of all 3 classic Philadelphia chromosome-negative MPNs. But when we talk about diagnosis, emphasis is about and should be about the bone marrow biopsy. The diagnostic criteria still exist. That means we don’t have 1 test. The bone marrow is not the 1 test. There is no molecular test. It’s a combination of tests that needs to be combined for a diagnosis to be made. In myelofibrosis, for example, it is the bone marrow biopsy, it is genetics, it is a physical exam looking at the spleen, it is a CBC looking at the left shift in anemia, and it is the chemistry looking at LDH. It is really a team effort or an experienced clinician who will pull all this information together from different laboratories or test sites to make a diagnosis.

Harry P. Erba, MD, PhD: It sounds simple, but I’m going to say something that I’m a little afraid to say with this panel: Sometimes, I’m challenged. Sometimes the pathologists have a bone marrow biopsy and they say it is ET, yet this young patient keeps having a hemoglobin that goes high, a low EPO level, or JAK2 positivity. I feel obliged to treat him like a PV patient even though it’s being called ET. Am I alone here, or do these things change? Does a patient shift from one diagnosis to another?

Ruben A. Mesa, MD, FACP: I think the point you raise is an excellent one. I think we’re clearly evolving from the era of phenotypes to being much more precise in our diagnoses. Indeed, you started the conversation regarding Dameshek’s observation. It’s interesting. Over time, he also had included in that list of myeloproliferative neoplasms things like PMH (personal medical history), but now we know the molecular biology is dramatically distinct. Some are similar, some are distinct. I do think between these 3 entities, ET, PV, and MF, there clearly is a spectrum of overlap. We try to have very clear subgrouping because of trials conducted through criteria, and all of these criteria are very helpful the majority of the time, but they’re not perfect. They’re consensus criteria, but they don’t truly get at the issue of biology itself. The case you raise is probably the one that overlaps the most. Is the JAK2-mutated ET truly a very distinct entity from polycythemia vera? Probably enough to cause a fist fight at any MPN meeting, but you’re right: the JAK2-mutated ET patient who has erythrocytosis, functionally, I’m treating like polycythemia vera.

Harry P. Erba, MD, PhD: I agree.

Ruben A. Mesa, MD, FACP: I’m not sure there’s really any proof to say that’s incorrect.

Srdan Verstovsek, MD, PhD: Over time, it will be more and more obvious that the patient is evolving to PV. And then, you get a situation where the patient comes and says, “My doctor tells me I have 2 diseases; I have ET and PV,” and my answer is, “No, you have 1 disease that is changing like any other living tissue with acquisition of new mutations.” Something else happened in the body of the patient leading to a disease with 2 different characteristics.

Harry P. Erba, MD, PhD: I think what this introduction has done is shown a couple of things. First, it shows that clinicians have to be aware of what the goals of management are in each of these diseases because sometimes patients may have manifestations of a couple, like ET and PV. Second, as we learn more about the biology, hopefully we’re going to move more towards targeted agents that will be directed at the biology. At the end of this discussion, we’ll get to some of those agents.

Transcript Edited for Clarity 
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