Management of Myeloproliferative Neoplasms: A Focus on Polycythemia Vera and Myelofibrosis - Episode 3

Diagnosing Polycythemia Vera


Harry P. Erba, MD, PhD: Let’s now turn and get into PV [polycythemia vera]. Rami, I’m going to turn to you to talk about some of the signs and symptoms these patients present with and the initial clinical work-up that we should be doing.

Rami Komrokji, MD: With polycythemia vera particularly, the initial presentation can be very valuable. I have to say nowadays, probably half of the patients are found to have erythrocytosis on routine CBC [complete blood count] checkup by the primary care doctors, and they get referred to us based on that. There are symptoms related to the erythrocytosis that patients can present with, such as headache, aches, and double vision. They are really nonspecific symptoms—pruritus, some of the constitutional symptoms we see with myeloproliferative diseases. Unfortunately, there is still a subset of patients whose initial presentation is a thrombotic event, whether it’s an arterial or venous event with polycythemia vera.

The initial work-up had become a little bit easier, in a way, with all this molecular testing, but it’s always the task of distinguishing a primary polycythemia vera from secondary erythrocytosis causes. We still see some challenging cases where all the molecular testing is negative for those patients, and we don’t know if we can label them as PV. With the availability of testing for the JAK2 mutation, I think 95% of the patients or more would have the mutation. That’s an objective way to tell us that this is a primary polycythemia.

When we see those patients, obviously the work-up would include their blood counts and looking at the mutations again, like for the JAK2 mutation. I still do bone marrow biopsies on those patients as a baseline, personally, partly because I think down the road, if there are clinical changes, one would like to have a baseline. For diseases such as ET [essential thrombocythemia] and myelofibrosis [MF], it’s important to try to distinguish a prefibrotic MF from ET. Even in polycythemia vera, there is a subset of patients who could have some fibrosis in their bone marrow at the beginning, and those patients are probably more likely progress to myelofibrosis. It may not be needed for diagnosis, as you mentioned, because if you have erythrocytosis and JAK2 mutation in the peripheral blood, you could make the diagnosis, but I think there is still value in doing the bone marrow.

In terms of the risk assessment, for many years, we’ve looked at the risk assessment in terms of risk of thrombotic events. We look at traditional risk factors such as age and presence of prior event—whether the patients had a stroke, MI [myocardial infarction], or DVT [deep vein thrombosis]. Those patients who are above age 60 or had an event, we consider a higher risk, and we tailor the treatment based on that. We’ve learned a little bit more in terms of risk assessment, that there are other variables that are important. For example, leukocytosis could be predictive of outcome in those patients, whether it’s the risk of thrombotic events, prognosis in general, or progression of the disease.

Based on the mutations we see, for example, the variant and frequency of the JAK2 mutation in patients with PV, those who have a homozygotic mutation were maybe at higher risk of progression to myelofibrosis. Certain mutations, such as IDH1/2, can predict progression to leukemias. We are becoming a little bit more sophisticated. Tailoring the treatment is still based on the traditional risk factors for clotting, but I think there are several other factors that we have to consider when we assess the risk for those patients.

Harry P. Erba, MD, PhD: So, Rami, 95% of patients with PV will have a JAK2 V617F, and most of the remaining patients, an exon 12. We also know that the fourth most common mutation in clonal hematopoiesis of indeterminate prognosis [CHIP] can be a JAK2 mutation. Does allelic frequency help you in distinguishing CHIP from true PV? Do we use those at all?

Rami Komrokji, MD: I think it does, because in most of the patients with PV, the variant allele frequency [VAF] will be at a higher level than what you expect to see with CHIP. Typically with CHIP, the VAF is usually in the 10% to 20% range and also absent of other mutations. In CHIP, you are not supposed to see, for example, a JAK2 and TET2 mutation, right? If there are a couple of mutations, those will tell you more that this is probably not CHIP. But I think the VAF could be helpful.

Transcript Edited for Clarity