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Suspecting Polycythemia Vera: Challenges in Diagnosis

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; Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center
Published: Thursday, Jul 19, 2018



Transcript: 

Ruben A. Mesa, MD, FACP: I think that pretest probability is such a crucial point. In addition to those points that Srdan raised, which I think are excellent, what is it that raises the suspicion? Because it can overlap with a normal hemoglobin when all those other things are factors. Other factors we clearly have found that really should raise the suspicion amongst treating physicians are in that unexpected area of thrombosis. It’s not only thrombosis, but particular areas of thrombosis. Portal vein thrombosis is a big one, certainly a thrombosis in the skull.

Harry P. Erba, MD, PhD: Or Budd–Chiari syndrome.

Ruben A. Mesa, MD, FACP: Or Budd–Chiari syndrome, and why these areas are biologically more common than others, there is certainly interesting research looking into those reasons. But there is an important scientific clue. Why those areas of circulation? It can be anywhere. It can be arterial, it can be an MI, it can be a stroke, but some of these areas are really peculiar. Certainly, in Budd–Chiari syndrome, certain studies would suggest if you assess for the JAK2 mutation, at least a third of patients will be JAK2 mutated, many of them without overt erythrocytosis. In fact, sometimes their counts are even a bit suppressed because of the acute reaction that they’ve had to the thrombotic event.

Rami Komrokji, MD: But the rationale to lower the threshold is that there were cases that were missed. We used to talk about masked polycythemia vera. In the setting of thrombosis, you could not call it that before also having clonal marker. I think the rationale for lowering that is really to allow making the proper diagnosis in those cases. I think in my experience, as we said, common is common: Patients would still present with DVT and could have polycythemia. The other thing I would like to highlight is basically that this is the only myeloproliferative disease that one could check for the exon 12 mutation of JAK2, not just V617F. It’s probably not needed in any other disease, but there’s a small subset. I am seeing a lot of patients challenging that everything looks like polycythemia vera, but they are still negative for all the mutations. In this day and age, how do you make that diagnosis? Is it true polycythemia vera in absence of mutations?

Harry P. Erba, MD, PhD: That was going to be one of my next questions. When I go and lecture and talk about this disease, everyone has a patient or 2 who has been through the entire workup for erythrocytosis, including all of this that we talked about, and nothing is obvious. The question is, How do you manage those patients? What I tell them to do is maintain patients, keep them well hydrated, put and them on an aspirin. I typically don’t recommend cytoreductive therapy there because you don’t have a diagnosis of cancer.

Jamile M. Shammo, MD, FASCP, FACP: I tend to think that if you have someone who you’re probably talking about, that 1% that doesn’t have clonal hematopoiesis, you should see something on the bone marrow biopsy. If there’s nothing in the bone marrow biopsy that supports myeloproliferative neoplasm, then I would like to try and find some other cause. Oftentimes, patients are taking testosterone and if you don’t ask, they won’t tell you. Or they’re taking something over the counter that may cause a very similar effect. And so, I suppose the real question is what happens if you have someone who is taking testosterone causing erythrocytosis, and what is their thrombotic risk? I’m not sure that we have enough data in the literature to support what we should be doing. It’s a problem.

Harry P. Erba, MD, PhD: Srdan?

Srdan Verstovsek, MD, PhD: The presence of the JAK2 mutation, either the V617F or exon 12, is not mandatory for diagnosis.

Harry P. Erba, MD, PhD: That’s right.

Srdan Verstovsek, MD, PhD: We have to recognize that, and there is a link mutation that we know can happen in occasional patients. There is a possibility of—at least in Italy, they reported a couple of cases—calreticulin-positive PV. Nevertheless, one practical point here is that testing needs to be sensitive as well as specific. Many times in the community setting, the sensitivity of the test for JAK2 V617F is not good enough. They come with 10% sensitivity or 20% sensitivity. I’ve seen it in consultations all the time. They say it’s PV, everything is PV, but it’s JAK2-negative. They may have a low JAK2 V617F allele burden. It doesn’t have to be 50%: it can be 10% and the sensitivity is 20%, so you’re not going to catch it. It’s false negative. The proper test or proper sensitivity of the test is sometimes an issue in making a diagnosis.

Harry P. Erba, MD, PhD: But let me push back on that a little bit. The other side of the coin is that you brought up clonal hematopoiesis of indeterminate prognosis. You have a patient with a hemoglobin that’s running 17 gm/dL and they’re 65 years old, so you do a myeloid gene panel or just check for JAK2. You do have a sensitive assay and it’s positive, but that doesn’t mean that the patient necessarily has PV . It could be true and unrelated. It could just be clonal hematopoiesis.

Srdan Verstovsek, MD, PhD: Absolutely.

Harry P. Erba, MD, PhD: That’s probably the reason why the allelic burden isn’t actually included in the diagnostic criteria.

Rami Komrokji, MD: I think JAK2 was one of the top 5 mutations you would see in the CHIP (clonal hematopoiesis of indeterminate potential) patients.

Srdan Verstovsek, MD, PhD: In all the people that don’t have any disease, yes.

Transcript Edited for Clarity 

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Transcript: 

Ruben A. Mesa, MD, FACP: I think that pretest probability is such a crucial point. In addition to those points that Srdan raised, which I think are excellent, what is it that raises the suspicion? Because it can overlap with a normal hemoglobin when all those other things are factors. Other factors we clearly have found that really should raise the suspicion amongst treating physicians are in that unexpected area of thrombosis. It’s not only thrombosis, but particular areas of thrombosis. Portal vein thrombosis is a big one, certainly a thrombosis in the skull.

Harry P. Erba, MD, PhD: Or Budd–Chiari syndrome.

Ruben A. Mesa, MD, FACP: Or Budd–Chiari syndrome, and why these areas are biologically more common than others, there is certainly interesting research looking into those reasons. But there is an important scientific clue. Why those areas of circulation? It can be anywhere. It can be arterial, it can be an MI, it can be a stroke, but some of these areas are really peculiar. Certainly, in Budd–Chiari syndrome, certain studies would suggest if you assess for the JAK2 mutation, at least a third of patients will be JAK2 mutated, many of them without overt erythrocytosis. In fact, sometimes their counts are even a bit suppressed because of the acute reaction that they’ve had to the thrombotic event.

Rami Komrokji, MD: But the rationale to lower the threshold is that there were cases that were missed. We used to talk about masked polycythemia vera. In the setting of thrombosis, you could not call it that before also having clonal marker. I think the rationale for lowering that is really to allow making the proper diagnosis in those cases. I think in my experience, as we said, common is common: Patients would still present with DVT and could have polycythemia. The other thing I would like to highlight is basically that this is the only myeloproliferative disease that one could check for the exon 12 mutation of JAK2, not just V617F. It’s probably not needed in any other disease, but there’s a small subset. I am seeing a lot of patients challenging that everything looks like polycythemia vera, but they are still negative for all the mutations. In this day and age, how do you make that diagnosis? Is it true polycythemia vera in absence of mutations?

Harry P. Erba, MD, PhD: That was going to be one of my next questions. When I go and lecture and talk about this disease, everyone has a patient or 2 who has been through the entire workup for erythrocytosis, including all of this that we talked about, and nothing is obvious. The question is, How do you manage those patients? What I tell them to do is maintain patients, keep them well hydrated, put and them on an aspirin. I typically don’t recommend cytoreductive therapy there because you don’t have a diagnosis of cancer.

Jamile M. Shammo, MD, FASCP, FACP: I tend to think that if you have someone who you’re probably talking about, that 1% that doesn’t have clonal hematopoiesis, you should see something on the bone marrow biopsy. If there’s nothing in the bone marrow biopsy that supports myeloproliferative neoplasm, then I would like to try and find some other cause. Oftentimes, patients are taking testosterone and if you don’t ask, they won’t tell you. Or they’re taking something over the counter that may cause a very similar effect. And so, I suppose the real question is what happens if you have someone who is taking testosterone causing erythrocytosis, and what is their thrombotic risk? I’m not sure that we have enough data in the literature to support what we should be doing. It’s a problem.

Harry P. Erba, MD, PhD: Srdan?

Srdan Verstovsek, MD, PhD: The presence of the JAK2 mutation, either the V617F or exon 12, is not mandatory for diagnosis.

Harry P. Erba, MD, PhD: That’s right.

Srdan Verstovsek, MD, PhD: We have to recognize that, and there is a link mutation that we know can happen in occasional patients. There is a possibility of—at least in Italy, they reported a couple of cases—calreticulin-positive PV. Nevertheless, one practical point here is that testing needs to be sensitive as well as specific. Many times in the community setting, the sensitivity of the test for JAK2 V617F is not good enough. They come with 10% sensitivity or 20% sensitivity. I’ve seen it in consultations all the time. They say it’s PV, everything is PV, but it’s JAK2-negative. They may have a low JAK2 V617F allele burden. It doesn’t have to be 50%: it can be 10% and the sensitivity is 20%, so you’re not going to catch it. It’s false negative. The proper test or proper sensitivity of the test is sometimes an issue in making a diagnosis.

Harry P. Erba, MD, PhD: But let me push back on that a little bit. The other side of the coin is that you brought up clonal hematopoiesis of indeterminate prognosis. You have a patient with a hemoglobin that’s running 17 gm/dL and they’re 65 years old, so you do a myeloid gene panel or just check for JAK2. You do have a sensitive assay and it’s positive, but that doesn’t mean that the patient necessarily has PV . It could be true and unrelated. It could just be clonal hematopoiesis.

Srdan Verstovsek, MD, PhD: Absolutely.

Harry P. Erba, MD, PhD: That’s probably the reason why the allelic burden isn’t actually included in the diagnostic criteria.

Rami Komrokji, MD: I think JAK2 was one of the top 5 mutations you would see in the CHIP (clonal hematopoiesis of indeterminate potential) patients.

Srdan Verstovsek, MD, PhD: In all the people that don’t have any disease, yes.

Transcript Edited for Clarity 
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