Mesa Provides Perspective on Diagnosis and Treatment in Essential Thrombocythemia

Ruben Mesa, MD

The diagnosis and treatment of patients with essential thrombocythemia (ET) can be complex and should include thoughtful discussions with patients, explained Ruben A. Mesa, MD, who added that ongoing research will help augment the advances that have been made to date.

"The science is evolving to allow us to try to understand and predict which patients are likely to progress," said Mesa. "Are there any markers of progression early on? Then, does that give us any insight as to which therapies we should be using or developing to try to prevent progression in the majority of patients with ET?"

Importantly, patients who achieve stable disease are unlikely to develop complications from ET, unless they progress, explained Mesa.

"If we keep patients from progressing, they will live out their normal lifespan," Mesa said. "The avoidance of progression is a key goal because we still have a scientific gap in terms of having enough information to develop rationally designed drugs to block disease progression. However, I think the future is indeed bright."

In an interview with OncLive, which was part of our OncLive on Air podcast episode, Mesa, director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, discussed the current state of ET treatment, the challenges of diagnosing the disease, and available educational resources for healthcare providers and patients.

OncLive: What is the natural history of ET?

Mesa: Patients with ET have a disease that, in the short-term, can lead to elevated blood counts, a risk of blood clots or bleeding, and, more rarely, enlargement of the spleen. How ET affects an individual can be very different from how it affects another on the basis of whether there is a significant risk of blood clots or bleeding, whether that’s how we found the disease to begin with, and what the individual's risk is in the future.

Second, there is a risk of the disease progressing to an advanced phase, which we call myelofibrosis, or rarely, to acute leukemia. Fortunately, the majority of patients with ET will live out their normal lifespan. The minority of individuals have progressive disease. However, even in those patients who do live a normal lifespan, we need to be mindful of controlling their disease to help minimize the symptom burden and decrease the risk of blood clots or bleeding.

How do you approach the conversation on diagnosis with your patients?

The discussion we have around ET is a complex one because ET is technically a cancer; it is technically a leukemia. It is a clonal neoplasm, but its behavior is quite different than what people associate with [a cancer diagnosis].

First, I try to frame [ET] as a chronic disease. There are many other chronic diseases that patients are more familiar with such as diabetes, rheumatoid arthritis, lupus, and high blood pressure. These are different diseases, but they are chronic conditions that we don't typically have a cure for. While there is a subset of patients who pass away from complications from those diseases, the majority of patients will live out their normal lifespan. [Those chronic diseases are] a fairly good analogy for ET.

A lot of education needs to occur [when a patient is diagnosed with ET]. Perhaps it can all be done within the first visit, but the patient might be overwhelmed, or lack sufficient insight into the disease that to be able to cover all the points in the first visit. It is important to be mindful of what we know and what we do not know.

[Historically], patients with ET may have been told that their life expectancy was 15 years. While that is probably true, it is a little misleading because the average age at which we diagnose ET is in the mid-60s. That average life expectancy of 15 years is the average life expectancy in the United States. Therefore, while the number is true, that doesn't mean that patients are passing away from ET.

It is important to realize that when you are visiting with a patient, this is likely the first time they have heard anything about a disease like this. They don't have a frame of reference, so you need to be cautious and clear in terms of trying to explain it in a way the patient is likely to understand.

Then, I revisit the key parts of that discussion every time I visit with my patients because sometimes it takes a few visits for them to become familiar with the disease, and to frame some of the online reading that they may be doing in parallel with our discussions.

What are some of the challenges of diagnosing myeloproliferative neoplasms (MPNs) and, specifically, ET?

The diagnosis of an MPN begins with a suspicion that is based sometimes on a blood clot that occurred in an unexpected location. We know that [patients who have] blood clots in the portal venous system [or] various unexplained thrombotic events have a much higher rate of having an MPN.

Most commonly, [our suspicion is based on] a finding in the peripheral blood, [such as] clear erythrocytosis, elevated red blood cell count, unexplained elevated platelet count, or more rarely, an unexplained elevated white blood cell count, or splenomegaly.

Over time, we have had a greater level of diagnostic certainly with the discovery of the JAK2 V617F mutation that can now be easily tested for by peripheral blood, as well as the less common but important calreticulin or MPL [driver mutations].

One of the challenges that remains in 2020 is that there is still reluctance to obtain a bone marrow biopsy from individuals who have been found to have an increased blood count and a JAK2 mutation.

In particular, this relates to ET because the majority of individuals who have a JAK2 mutation and thrombocytosis will have ET, but not everyone. These individuals might have associated MPN or myelodysplastic/myeloproliferative overlap syndromes, such as refractory anemia with ring sideroblasts or chronic myelomonocytic leukemia (CML), or they may have early myelofibrosis.

Even more rarely, there have been individuals who have CML and have a small incidental JAK2 mutation that was present as well. I do find the diagnostic work-up for ET is sometimes incomplete. There may be individuals who we assume have ET who really have a [related] disorder, which may have important implications in terms of choice of therapy and/or prognosis.

What is the standard course of treatment for patients with ET?

In ET, the key treatment goals are to try to control the patient's symptoms, get their platelet count below 400,000, decrease the risk of blood clots and bleeding, and have the therapy be well-tolerated. We also want to avoid disease progression, but that can be difficult to quantify.

Typically, the first therapy for patients begins with a baby aspirin; almost everyone receives it. After, our current National Comprehensive Cancer Network guidelines list hydroxyurea, interferon alfa-2b, or pegylated interferon, as available options for the frontline treatment of patients with ET. These treatments are not technically approved by the FDA, but they are available and efficacious. They have not been compared head-to-head in randomized clinical trials.

In ET, they appear to be relatively equivalent with some differences in toxicity. There may be a slight advantage with interferon in terms of avoiding disease progression.

In polycythemia vera, where there have been further randomized studies, it is probably clearer that interferon is slightly better than hydroxyurea, but I wouldn't say it is dramatically better.

In some cases, [the amount of these] medications [that is needed] to fully control the counts can lead to unacceptable adverse events. There are individuals who will feel better with a little bit of 2 agents as opposed to a lot of 1 agent. All of these agents have a dose-associated toxicity profile. Sometimes a lower dose is better tolerated.

It is all part of trying to personalize therapy to an individual to decrease their symptoms, control their blood counts, and manage the toxicity.

What resources are available to physicians and patients to gain more knowledge of MPNs?

There is good educational information out there online and at in-person events such as national meetings.

Online, there is great content from Patient Power, OncLive, Physician's Education Resource, and TotalCME. There are many robust platforms. [We should be discussing] updates [with our patients], [as well as having] case-based discussions regarding new options, how they are applied, and how to balance challenging situations [with them].

Medicine is art and science—–that has been well-recognized. The science is knowing what the options are. We know for ET that includes hydroxyurea, pegylated interferon, perhaps a JAK inhibitor like ruxolitinib (Jakafi), or even other chemotherapeutic drugs. We know drugs like trastuzumab (Herceptin) or pembrolizumab (Keytruda) [are not part of] our arsenal.

The art of medicine is knowing what [therapy] to use in which patient, adjusting it in the appropriate way, knowing how long it takes to see a response, and asking the right questions of the patient to understand whether they are tolerating the therapy.

In a disease like ET, [we should] strive to get to a plateau where the patient feels reasonably well. Then you watch them and adjust therapy if needed. Once an individual reaches that plateau, they may remain in it for many years. [That’s important because we know] achieving stable disease state is important in a disease like ET.

Where should ongoing research efforts be focused in the space?

Without question, we know there are clear unmet needs in ET. There are still patients who progress or those on our available therapies who have unacceptable toxicities or little response.

There are several therapies in development. Ruxolitinib has been in phase III trials for patients with refractory ET in an attempt to define the role of ruxolitinib in patients who have more difficult symptoms like splenomegaly and who have progressed on hydroxyurea. Second, pegylated interferon alfa-2a, which is commonly used in the United States, is not FDA approved. I’m co-leading an international phase III trial with a new interferon—ropeginterferon alfa-2b—which is evaluating the benefit of that agent as second-line therapy compared with anagrelide (Agrylin) in high-risk patients who progressed on hydroxyurea.

Third, there may be benefit from LSD1 inhibition. There is a clinical trial that will be tested at [UT Health San Antonio MD Anderson Cancer Center], as well as another company-sponsored study for patients who have refractory ET.