S18 EXABS-116-MPN Current and Emergent Therapies for ET Kristen Pettit, MD1,* 1University of Michigan Rogel Cancer Center, Ann Arbor, MI 48109, USA *Corresponding author: krpettit@med.umich.edu Keywords Myeloproliferative neoplasm, thrombosis, JAK2, CALR, targeted therapy Introduction Essential thrombocytosis (ET) is a clonal stem cell disorder characterized by excess JAK/STAT pathway signaling as a result of activating mutations in JAK2, CALR, or MPL.1–3 Clinically, an ET diagnosis carries an increased risk of thrombosis and/or bleeding, potential for bothersome constitutional or vasomotor symptoms, and risk for progression to myelofibrosis or acute myeloid leukemia. Among the myeloproliferative neoplasms (MPN), ET is associated with the lowest risk for progression and longest life expectancy, but many patients still experience significant disease-related symptoms and impaired QOL.4 Current management strategies largely focus on preventing hematologic complications of the disease, with modest impact on the natural history of the disease itself. Treatments that better address ET pathophysiology in order to mitigate symptoms and prevent progression remain significant areas of unmet need. Current Management Treatment strategies for patients with ET currently aim to decrease risk of thrombotic events, therefore treatment is decided based on the individual’s risk of these events. The International Prognostic Score for Thrombosis in ET (IPSET-thrombosis) revised score uses clinical information and JAK2 mutation status to stratify patients into 4 risk groups: very low risk (no prior thrombosis, age ≤60 years, and JAK2 unmutated), low risk (no prior thrombosis, age ≤60 years, and JAK2-mutated), intermediate risk (no prior thrombosis, age >60 years, and JAK2 unmutated), and high risk (history of thrombosis, or age >60 years plus JAK2-mutated).5 Low-dose aspirin is recommended for the vast majority of patients, perhaps with rare exceptions among select patients with very low risk disease as well as those with acquired von Willebrand disease.6 For those with intermediate or high risk ET, cytoreductive therapy is generally recommended.6 The cytoreductive agent of choice for an individual with ET should take into account the toxicity profile in relation to the patient’s comorbidities, differences in administration, future family planning, and patient preferences. First-line cytoreductive treatment options include hydroxyurea (HU) and pegylated interferon alfa (Peg-IFN). HU and Peg-IFN were compared in a phase 3 study (MPD-RC 112) in patients with ET and polycythemia vera (PV), which resulted in similar rates of complete response and thrombotic events at 12 months.7 With longer treatment, Peg-IFN has demonstrated improved molecular responses in both ET and PV, though the clinical implications of molecular response in these settings are not yet clear.7–10 A longeracting interferon, ropeginterferon alfa-2b, is under investigation for patients with ET (NCT04285086) and has been approved for those with PV.11 Anagrelide is a potential later-line option to help control platelet counts and prevent thromboses. Two studies have compared anagrelide to HU in patients with ET; first a large (n=809) study demonstrated that HU was superior to anagrelide at preventing thrombotic or hemorrhagic events, and second the ANAHYDRET study showed that anagrelide was non-inferior to HU in preventing such events.12,13 Anagrelide commonly causes vasodilation-related toxicities including headaches, dizziness, palpitations, and fluid retention, which significantly limit its clinical utility for patients with ET. Emergent Therapies As the molecular drivers of MPN pathophysiology have become better understood, several novel therapeutic directions have emerged. Promising therapies in development for ET including JAK inhibitors, epigenetic agents, and mutation-specific biologic/ immunologic therapies. Ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis and second-line treatment of PV, is an agent of understandable interest in the setting of ET. In a randomized study of ruxolitinib versus best available therapy (BAT) for patients with ET after hydroxyurea resistance or intolerance (MAJIC-ET), both treatments demonstrated similar rates of hematologic response, thrombosis, and hemorrhage, but ruxolitinib improved some disease-related symptoms to a greater extent than BAT suggesting a potential role in select cases.14 Another randomized trial of ruxolitinib in ET, RUXO-BEAT, is ongoing (NCT02577926). Several epigenetic regulators including bromodomain and extraterminal motif (BET) and lysine-specific demethylase 1 (LSD1) have arisen as possible therapeutic targets for ET. BET inhibition has been shown to down-regulate NF-kB signaling and decrease cytokine production in MPN settings.15 The BET inhibitor pelabresib is being developed for patients with myelofibrosis and is also under investigation for those with ET (NCT02158858). Similarly, LSD1 inhibition can modulate aberrant gene transcription in myeloid malignancies, resulting in decreased
RkJQdWJsaXNoZXIy MTk3NTQxMg==