Harry Erba, MD, PhD: Let’s turn to the first of the diseases we’re going to talk about, the ones with the highest prevalence, and that is polycythemia vera [PV]. Robin, why don’t you guide us through some of the initial steps in your clinical evaluation of these patients and challenges in making the diagnosis.

Robyn Scherber, MD: The most typical referral we’ll get is for erythrocytosis. The question is, is it primary or is it secondary? Getting an erythrocytosis level really can help with that, and especially if I see that EPO level being low really clues me in that something might be going on with bone marrow.

It is notable that some MPN [myeloproliferative neoplasm] patients actually will have a normal or even a high EPO level. Mary Frances, I think your group has actually characterized that. The other thing I really think about is, what are blood counts over time? I want to see a history of what the blood counts are as best as I can. There is, in the WHO [World Health Organization] 2016 criteria, a little bit of a loophole. For some patients, if their blood counts are high enough, they said that you may not need the bone marrow. I agree with Moshe, though. I really do like to see the bone marrow biopsy in all the patients who are willing to get one.

From there, especially specific in my practice, I ask a lot about symptom burden. A lot of patients will be having things like itching and headaches. Especially in polycythemia vera, I think it’s really been a problem. I look for erythromelalgia-type symptoms. Otherwise, spleen-related symptoms, especially splenomegaly present—abdominal discomfort, early satiety. There also can be constitutional symptoms, things like night sweats, fevers, and generalized fatigue.

When I first approach the patient I also really want to see what their thrombotic risk has been. Do they have a history of thrombosis? I’m looking at factors as well as their age, smoking status, and cardiovascular risk factors like hypertension and hyperlipidemia. All really go into my initial prognosis of a PV patient. I’m also looking at blood counts. More than ever, we know that a white blood cell count, even with a well-controlled hematocrit, may or may not play a role in thrombotic risk.

Harry Erba, MD, PhD: What I heard you say is that you use more than just some arbitrary age cutoff in the United States—I think it’s 60 or 65 in Europe—and our history of thromboses but all the other cardiovascular risk factors, and you threw in white count as well.

Robyn Scherber, MD: I am interested in that. Along with John’s group, and then our groups as well, we’ve been looking at this to better understand what the role of the white blood cell count is. We did a specific analysis in the VA [Veterans Administration] database, and even with well-controlled hematocrit, it did seem to play a role. But then we also recently looked at another cohort of PV patients for whom it didn’t play as much of a role.

The real question is, in a prospective study, what happens if you control the white blood cell count? And that’s really what the critical issue is going to be in the future.

Harry Erba, MD, PhD: John, let’s say you have a patient who doesn’t have splenomegaly or symptoms but has a high hematocrit. You can control them with phlebotomy and put them on aspirin, but their white count is just consistently above normal. Is that a patient you give cytoreductive therapy [CYTO] to?

John Mascarenhas, MD: Although thrombosis has increased over the last few decades, we still don’t totally understand the mechanisms that really promote it. They’re varied. It’s probably leukocyte activation. It’s the right milieu of endothelial cell activation in the right person with stages from high hematocrit, with cardiovascular comorbidities added in. I don’t think there’s anything magical about a white count of 13,000 versus 16,000 versus 9000.

The problem I have is that many of the guidelines talk about uncontrolled polycythemia vera with high white counts and controlling the white counts. There are very little data available, prospective data, that would suggest that controlling the white count affords the patient a risk reduction in thrombosis or progressive disease.

As Robyn mentioned, we did a retrospective study that was presented at the American Society of Hematology 2019 Annual Meeting & Exposition of over 11 centers throughout the United States, over 500 patients in total. Using a trajectory-based model, we really found no association with elevation of the white count and thrombotic risk. With progressive disease, which makes sense, but not thrombotic risk. The same holds for thrombocytosis. There’s really no literature that supports that bringing the platelet counts to a specific number really affords the patient a platelet risk.

One of the most challenging, sometimes frustrating, aspects in MPNs is that we have guidelines that a lot of use, but they’re not terribly evidence based. That becomes challenging. To your answer, to your question, if I have a low-risk patient who is young and does not have thrombosis, and their white count is 13,000, I do not push the white count down for the sake of beautifying the CDC [Centers for Disease Control and Prevention] report. I have hematocrit controlling their 45% by the CYTO-PV study, low-dose aspirin, and cardiovascular modifiable risk factors.

Harry Erba, MD, PhD: Let me push you just a little. You picked a single point in time, a certain number, 13,000. None of us are really upset about that. But how about over time if you see 11,000, 13,000, 15,000? Does the trend, the kinetics, change your decision making?

John Mascarenhas, MD: We did this study that would suggest that even the trends, even up to 35,000, don’t predict thrombotic risk. It’s still unclear. If one has a more overarching goal of disease-course modification, one can make the argument that employing drugs, perhaps like interferon alfa-2a, may have a more overarching benefit, both thrombotic and disease-course modifying. We don’t have great evidence that reducing that platelet, that white count, to any specific number has any immediate benefit.

Transcript Edited for Clarity