Case 3: Prediction of Thrombosis in Essential Thrombocythemia

Srdan Verstovsek, MD, PhD: Now, going back to ET [essential thrombocythemia]and prognostication, in patients with polycythemia vera, we traditionally use 2 factors. On the left side of the slide are patients over 60 years of age and those with previous thrombosis that would dissect the patients in 2 groups: the low-risk group without any of these factors and the high-risk group with at least 1 of the 2 factors. The difference here in thrombosis incidence is the key to understand why we say that somebody is low risk for thrombosis and why the other patient with ET is a high risk for thrombosis.

The significance of platelet number, as you can see on this slide, as it relates to the risk of thrombosis, does not really exist in multiple different studies. But there is a correlation between the extreme thrombocytosis when platelets are above a million and a half and the connection with increased risk of bleeding due to acquired von Willebrand factor deficiency. When the patients have such a high number of platelets, a million and a half, 2 million, we would actually test the patient for the presence of a von Willebrand factor deficiency. And if present, we would stop the therapy with aspirin and try to decrease those platelets or consider decreasing the platelets for the risk of bleeding, not for the risk of thrombosis.

Now, the development of the molecular testing that can be done on blood has confirmed the spread of the 3 different driver mutations among the patients with ET as I mentioned before, but it also led us to realize that there is a significant difference in thrombotic risk between the patients with ET who have different driver mutations. What we see here easily on the left side of the slide, that the patients with the calreticulin mutation have a much lower risk of thrombosis than others. The patients with wild-type disease do not have any of the 3 markers (or we cannot find any of them on our testing) also have a lower risk for thrombosis.

The consequence of this particular testing has been introduced into enhancement of our risk assessment. This is endorsed by NCCN [National Comprehensive Cancer Center] guidelines now, not to only account for the age and previous thrombosis but also for the presence or absence of the JAK2 mutation. We did not really see specification in the NCCN guidelines of what mutation the patient should have to contribute to the prognostication for thrombosis, but simply just to say is there a JAK2 V617 mutation—yes or no. With that, then we have 3 factors that would divide patients in 4 groups rather than in 2. For simplicity, in the lower part of the slide, we divided the so-called elderly low-risk patients (again, just based on age and thrombosis) into now a very low-risk group and a low-risk group, where the very low-risk group would have none of the 3 factors. The question is, do they need even aspirin? In the low-risk group (patients younger than 60 years) who never had thrombosis and had the JAK2 mutation … aspirin would be proper therapy. Similarly, for patients in the elderly high-risk group, we now have 2 groups: the intermediate-risk group for patients 60 years and older and that’s the only factor—the question is whether we really need cytoreduction therapy in them—and the high-risk patients of all the other ones that have 1 of the 3 factors in them, where we do provide aspirin and cytoreduction?

Now, this is a very simplified view of the NCCN guidelines. If we want to go in much more detail, then we would come up with this summary on 1 slide of multiple other slides that are available online when you go to the NCCN guidelines on the management of PV [polycythemia vera], ET, and myelofibrosis. This is a summary on ET. Baby aspirin in the very low or low-risk group and perhaps in those that have a very low risk and no cardiovascular risk factors may not be valuable at all. In fact studies suggest that in low-risk patients with the calreticulin mutation in particular, there is no value of taking baby aspirin because there is no high-risk thrombosis in these patients justifiably enough to even give the aspirin. It may even produce the countereffect of increasing risk of bleeding.

But the intermediate group (patients older than 60 years and with no JAK2 mutation and no thrombosis but takes baby aspirin) is good enough without cytoreductive therapy. But in high-risk groups one would prescribe cytoreductive therapy, and here hydroxyurea would be first-line therapy. Interferon is also mentioned as a possibility and an anagrelide, but this is usually second-line therapy. Hydroxyurea has been standard front-line therapy. The twice-a-day aspirin can be sometimes tried in patients who have a consistent problem with symptoms, in particular because of the rapid turnover of the platelets, 1 daily aspirin is not good enough to decrease the thickness and the symptomatology that comes from that.

The patients in the low-risk group may occasionally require cytoreduction therapy for progressive leukocytosis, progressive or worsening of disease-related symptoms, or progressive splenomegaly, but none of this is very common. But it needs to be noted in every practice that even for a low-risk patient, there are exceptions in terms of prescribing cytoreductive therapy.

Now, who are those patients with wild-type disease that don’t have any of the 3 driver mutations? Do they really have a disease? That is the usual question. This elevation in platelets in these particular patients, is it reactive or is it really a disease? Molecular dissection in almost half of the patients would show alternative mutations in 1 of the driver genes, not only in those that we commonly test for. So there is a possibility of having a molecular marker by extensive more detailed genetic testing in those who are usually labeled as having wild-type ET.

Transcript edited for clarity.