Signs of Progressive Polycythemia Vera

Transcript:

Harry Erba, MD, PhD: Coming back to the bone marrow, I just want to say, I agree that we should really try to get bone marrow biopsies. A lot of doctors will hang their hats on a JAK2 mutation, and we have to really be careful about that given that about 10% of people over the age of 65 will have a mutation in a number of different genes. The fourth most common to be found is actually JAK2 at a very low allele burden, but we might not even get that information from a panel.

Moshe Talpaz, MD: I would like to speak to this one because I came across this patient very recently. How do you deal with a patient who has some elevated hematocrit but happens to have a very low level of JAK2, a very low quantitative level of JAK2. The end story is he most likely has secondary polycythemia, and the JAK2 is a JAK2; it just depends with age. In a way it’s kind of a double-edged sword. JAK2 mutation is definitive diagnostical for polycythemia vera [PV]. It’s positive in 98% of the patients with polycythemia vera, which is great. It’s very helpful; it’s a blood test.

On the other hand, we absolutely have to create awareness for very low levels of JAK2 and not to rush to a diagnosis that you have MPNs [myeloproliferative neoplasms] just because you have low levels of JAK2. I’m getting those patients. And apparently it’s a recurring problem now.

Harry Erba, MD, PhD: I know. I’ve seen them too.

Robyn Scherber, MD: That really speaks to the importance of the bone marrow to try to help determine if MPNs are present. What is interesting about that literature is that even very low JAK2 allele burden will have increased cardiovascular risk and stroke risk. In those patients, when I see that, I am aggressively managing those factors, even if I don’t think an MPN is present.

Harry Erba, MD, PhD: That’s a critically important point about CHIP [Cardiovascular Health Improvement Project]. Not only the history, the risk of myeloid malignancies, but the risk of cardiovascular disease.

Moshe Talpaz, MD: It’s an emerging, interesting topic in 2 ways. One, to help us a little not to rush into diagnosis. But on the other hand, to calculate risk of patients who have JAK2 positivity. And to start to see clinics for CHIP developing in hospitals. Actually, many hospitals are going up today.

Harry Erba, MD, PhD: Moshe, s long as you have the floor, why don’t you talk us through what are some of the symptoms that patients have that indicated progression of their PV?

Moshe Talpaz, MD: First, we have to be aware that PV is a chronic disease, and that people can live a long time with polycythemia vera. The first prognostic feature of brigatinib that was mentioned, and is not usually accounting for progression, is elevated white count. We should not ignore that it probably is an early sign that the disease is on the move, but it’s something to keep in mind.

The definitive signs of progression are when the disease can evolve at least in 2 definitive patterns: 1 to leukemia and 1 to myelofibrosis. Progression to leukemia is when you start to see blasts or immature myeloid cells, you have to be concerned. I assume that the rate of transformation as well to leukemia is about 10% in 10 years, more or less. It’s still a debatable figure.

The rate of transformation to myeloid fibrosis is higher and may be 20% in 10 years. What we start to see is what has been called classically as the spent phase, where the patients start to develop a change in the pattern of the disease. Instead of having high hemoglobin, they start to have anemia. They start to have change in the blood counts. Immature cells start to show up in the blood. Atypical problems of the red cells show up in the blood, and the patient may have developed a new set of symptoms. At that point you start to be concerned that the disease is switching.

Of course, bone marrow is helpful as well, although I want to make a distinction between bone marrow fibrosis and myelofibrosis. Bone marrow fibrosis, almost all patients with essential thrombocythemia and polycythemia have what pathologists like to call MF1 [reticulin fibers]. Transition to MF2 [initial collagen fibrosis] and further starts to suggest that the patients have low reticulin and begin to have collagen fibrosis, and those are an indication of transition to myelofibrosis.

Harry Erba, MD, PhD: Moshe focused on a lot of the laboratory and clinical features, laboratory and bone marrow features. But how about symptoms?

Robyn Scherber, MD: We have done a new analysis of this as well. When patients have progressive disease, you have to make a distinction first of a progressive disease versus progression. Although they can do the same thing, a lot of times they actually are a little different. There is that increasing white blood cell count. Those early precursors.

Most of all, in my practice I see patients usually with worsening symptoms. A lot of times that can be related back to a thrombotic event or worsening splenomegaly, but sometimes they can’t. Sometimes it’s just worsening constitutional symptoms. Worsening of itching or things like that, and certainly you want to go back and make sure you’re managing the different aspects of PV as best you can.

It also might want to make you go back and say, am I assured that this patient isn’t transforming? Are there elements of this progression that I might be able to treat more aggressively? Especially if I see a patient with unremitting symptoms and increasing their white blood cell count, that is a time when I will consider increasing cytoreduction, essentially trying to change therapies.

Harry Erba, MD, PhD: But even if you use cytoreduction, a lot of times those patients remain symptomatic.

Robyn Scherber, MD: It’s true, and we’ve done those studies where even on hydroxyurea we actually can see increasing symptoms in bone marrow, people on Hydrea versus not on Hydrea. Where phlebotomies over time will see increasing symptoms of iron deficiency. So fatigue, cognitive issues, reckless life symptoms, interferon flu-like effects.

In general I think it is really important that when we’re evaluating patients that we try to a pick a therapy that would be most beneficial for the patients.

Harry Erba, MD, PhD: OK.

Transcript Edited for Clarity