Myeloproliferative Neoplasms - Episode 2

Understanding Essential Thrombocythemia And Treatment Options

Stephen Oh, MD, PhD, and Ruben Mesa, MD, explain the fundamentals of essential thrombocythemia (ET) and its treatment options.

Ruben Mesa, MD: So Stephen, why don’t we start with some of that earlier phase of disease? Why don’t you walk us through ET [essential thrombocythemia]? What are some of the key things we need to be aware of in terms of ET?

Stephen Oh, MD, PhD: Sure. So essential thrombocythemia, ET, for many patients the initial presenting time really is the cardinal feature in terms of the blood counts, which is an elevated platelet count or a thrombocytosis. Quite commonly, this may be detected when a patient has a routine CBC [complete blood count], and they actually feel fine and that prompts the workup. Now, on the other hand, patients may initially present with a complication from ET, such as a blood clot, thrombosis, and that’s what prompts the workup. In addition, patients with ET kind of often have a number of nonspecific or microvascular symptoms—headaches, weakness, fatigue. They can also be at risk for bleeding complications.

One challenge in particular with some of these symptoms is distinguishing are they in fact truly related to ET or could they be due to something else or some combination of factors? Coming back to the diagnosis, when you start with an elevated platelet count leading to further workup, quite typically the next step is to proceed with molecular testing. Patients with ET will frequently have mutations in either, JAK2 [Janus kinase 2], CALR [calreticulin], or MPL [myeloproliferative leukemia], the vast majority will. Approximately 50% to 60% of patients are JAK2 mutant, another 20% to 30% are CALR mutant, and then a smaller percentage are mutated from MPL. So that together comprises at least 80% to 85% of patients with ET. It does leave a significant proportion of patients who are so called triple-negative JAK2, CALR, and MPL negative, but the majority will have 1 of these mutations. Just to complete the workup, bone marrow biopsy would be considered part of the standard diagnostic criteria to diagnose ET. In some cases, where the picture is quite clearly consistent with ET, a bone marrow biopsy may not necessarily be performed but it is part of the standard workup. Together those things would be the typical process for making a diagnosis of ET and then proceeding from there in terms of management.

Ruben Mesa, MD: Very helpful. Now Angela, as you’re thinking about your patients with ET, so Stephen has walked us through diagnosis, molecular testing, as you try to pivot and think about who you might be starting on therapy and what sorts of things do you assess in terms of risk or what drives you to start someone on therapy for ET?

Angela Fleischman, MD, PhD: That’s a very interesting question and really it depends on the person in terms you had mentioned risk. So when we’re talking about risk in PV [polycythemia vera] and ET, we’re talking about the risk of thrombosis. It makes sense that if they’d had a blood clot in the past, they’re probably the type of person that’s going to be more likely to have a blood clot in the future so that brings them up to a higher risk. We also do know that people with a JAK2 mutation have a higher risk of thrombosis than somebody without a JAK2 mutation. Also, age plays a role in our risk assessment for starting treatment. Other factors—because a lot of my ET patients do happen to be younger people and may not necessarily qualify for a cytoreductive agent simply based on their classic risk factors in terms of thrombosis but are really interested in doing something proactive about their disease or may be very symptomatic from their MPN. So that’s another discussion that I have with the patients in terms of what their goals are for treatment and whether or not to start treatment with something like interferon if they are really wanting to be very proactive.

Ruben Mesa, MD: As I think about treatment, I know some of you and some other colleagues we were involved with developing the first NCCN [National Comprehensive Cancer Network] guidelines for ET. There was a lot of discussion because there’s been much discussion over the years with this disease. What’s the appropriate aggressiveness of therapy? I think where we stand at the moment is we have 2 therapies. One, that largely individuals probably benefit from aspirin particularly if they’re JAK2 mutated. There certainly is discussion that lower risk folks that are calreticulin mutated may not require aspirin, although I would only avoid aspirin in a really select few that were also quite asymptomatic. Sometimes they have erythromelalgia, headaches, other things that really may require aspirin. Those that require cytoreduction are individuals that have a higher risk of thrombotic events or have difficult symptoms that really are not managed adequately by the disease.

Our current front-line options in the U.S. include hydroxyurea that has good, randomized phase 3 data behind it in terms of its cytoreduction, and pegylated interferon is also considered an option. At the current time, it is off-label. It is used globally in many different settings; I’ve found particularly in younger individuals, women of childbearing potential and others. Then we have other backup therapies, [such as] anagrelide [Agrylin] which can also be a helpful platelet-lowering agent or even JAK inhibitors, again off-label, typically as at least second- or third-line for much more difficult cases maybe with splenomegaly, maybe with difficult symptoms.

There are some important new options being investigated and we’ll get around [to] those as we talk about some of the updates from the 2021 ASH [American Society of Hematology] meeting including new drugs in development, such as ropeginterferon currently in a phase 3 study for ET, as well as the LSD1 [lysine-specific demethylase 1] inhibitor IMG7289. So more coming, but a few options at the current time.

This transcript has been edited for clarity.