Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) characterized by an increase in the number of platelets in the blood. Of the three main types of MPNs (ET, polycythemia vera, and myelofibrosis), ET is the most common, with an incidence of about 2.2 per 100,000 population yearly, according to the Leukemia and Lymphoma Society.
"It is driven primarily by molecular change in three genes -- JAK2, CALR, or MPL mutation," said Ruben Mesa, MD, director of the UT Health San Antonio MD Anderson Cancer Center. "Clinically, the burden these patients face is a risk of blood clots or bleeding, the potential of elevated counts, as well as the development of disease-related symptoms."
Crucially, there is also a risk of the disease progressing to an advanced stage, Mesa told 乌鸦传媒. "It can progress into myelofibrosis. Typically after patients have had the disease for 10 years or more, scarring develops in the bone marrow, and the disease can become more life threatening, with low blood counts, ineffective functioning of the bone marrow, worsening symptoms, and from there it can progress to acute myeloid leukemia, which can be very life threatening. About 10%-20% of patients progress, the majority of people do not. Many can live close to their normal life expectancy, or live their normal life expectancy."
Diagnosis can be challenging for a number of reasons, said Mesa, including the fact that there are a number of conditions that can cause an increase in platelet counts, including iron deficiency, recent surgery, or any kind of chronic inflammation. A sustained increase in the platelet count suggests something else could potentially be at play.
"ET is also one of several bone marrow diseases that can increase the platelet count and, as we try to diagnose, that involves excluding those bone marrow diseases," Mesa pointed out. One that is particularly important to exclude is chronic myeloid leukemia, he said, "because the drugs we use for that [tyrosine kinase inhibitors] are quite different than what we use for ET."
A bone marrow biopsy can be done to look for classical signs of ET, as well as testing for gene mutations that drive the disease -- JAK2 (occurring in about 50%-60% of patients), CALR (about a quarter of patients), and MPL (about 5%).
According to Mesa, baby aspirin is used to treat most, if not all, patients with ET. "Although it's a simple therapy, it's beneficial," he said. "It helps to decrease the likelihood of blood clots and we use that pretty much across the board."
After that, he said, patients are generally managed on a risk stratification approach with the goal of preventing blood clotting or bleeding. As described in a patient's risk can be stratified into four categories:
- Very low risk: patients 60 years or younger who don't have a JAK2 mutation and no history of thrombosis
- Low risk: patients 60 or younger who have a JAK2 mutation and no history of thrombosis
- Intermediate risk: patients older than 60 who don't have a JAK2 mutation and no history of thrombosis
- High risk: patients older than 60 with a JAK2 mutation or a history of thrombosis
According to these guidelines, initial treatment for the very low-, low-, and intermediate-risk groups include assessments of new blood clots, onset of von Willebrand disease, and major bleeding; management of cardiovascular risk factors; and treatment with aspirin. Initial treatment for high-risk patients adds treatment with hydroxyurea, interferons, or anagrelide.
"These are drugs that have been around for several decades, so their safety has been well established," Naseema Gangat, MBBS, of the division of hematology at the Mayo Clinic in Rochester, Minnesota, told 乌鸦传媒. "But we have to tell patients these drugs are not going to change the natural history of the disease. They may still get myelofibrosis. They may still get acute myeloid leukemia. But they will reduce your risk of clotting and bleeding."
"If you look at the spectrum of MPNs, ET is technically the most benign in the spectrum. So most of the drug discoveries have focused on myelofibrosis," said Gangat. "As of today, even in terms of what has been presented at ASH [the American Society of Hematology annual meeting], there is really no focused drug discovery on ET."
Mesa pointed out there are some agents under investigation. The drug , an oral inhibitor of the epigenetic enzyme lysine-specific demethylase 1 (LSD1), is being tested in patients age 18 and over with ET who have failed at least one standard therapy and require therapy to lower their platelet count. There is also a phase III trial being conducted comparing in ET patients with hydroxyurea resistance or intolerance.
"I think the best trial for essential thrombocythemia that has been conducted recently was on aspirin dosing," Gangat said. This trial, earlier this year, found that twice-daily administration of 100 mg of aspirin could improve antiplatelet response compared to once-daily low-dose aspirin in these patients.
The phase II Aspirin Regimens in Essential Thrombocythemia (ARES) trial randomized patients to receive 100 mg of aspirin either once, twice, or three times daily.
The authors of that study found that both twice- and three times-daily aspirin improved antiplatelet response compared with once-daily aspirin. However, they also found that three times-daily aspirin was associated with a significantly higher gastrointestinal disturbances score compared with once- or twice-daily dosing.
"Based on the trial's results, I think it is reasonable to say that baby aspirin twice a day is safe," said Gangat.
She noted that other studies have examined patients at intermediate risk -- those patients ages 40 to 59 who lack high-risk factors. While cytoreductive therapy has been beneficial in patients with ET at high risk of thrombosis, it is unknown how effective it will be in patients lacking those high-risk features.
In a study in the researchers found that the preemptive addition of hydroxycarbamide to aspirin did not reduce vascular events, myelofibrotic transformation, or leukemic transformation. Thus, they concluded that these intermediate-risk patients should not undergo cytoreductive therapy.
"One area that does deserve more of a focus is young women with ET, particularly in the context of pregnancy," said Gangat. "Pregnancy can be a very challenging scenario. You need a very specific collaboration between the obstetrics and hematology teams, so that these women don't experience miscarriages, postpartum thrombosis, or postpartum hemorrhage."
Disclosures
Mesa has served as an advisor or consultant for Novartis, La Jolla Pharmaceutical, and Sierra Oncology, and has received grants for clinical research from AbbVie, Celgene, CTI, Genentech, and Incyte.
Gangat reported no disclosures.