Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia

Abstract

Anagrelide (ANA) hydrochloride is an oral imidazoquinazoline registered as an orphan drug in Europe. It is indicated as a second-line agent for the reduction of thrombocytosis in high-risk essential thrombocythemia (ET) in Europe and in any myeloproliferative neoplasmassociated thrombocytosis and for the amelioration of thrombo-hemorrhagic events in the context of myeloproliferative neoplasm in the USA and Japan. The compound has been in clinical use for almost two decades with approval in the European Union (EU) for over a decade. The licensed indication encompasses the apparently specific action of the drug to reduce the platelet count; however, the precise mode of action of ANA remains unclear. Here, we review the current data from two large phase 3 studies, PT-1 and ANAHDRET, and a phase 4 post-approval observational study EXELS. All of these studies were conducted in the EU and therefore pertain to ET as the only licensed indication. Data from these studies suggest that ANA is on the whole as effective as the most commonly used agent hydroxycarbamide (HC). Although ANA, when compared to HC, appears to be slightly less effective in preventing arterial thrombosis and myelofibrotic transformation, it is associated with lower risk of venous thrombosis. Since the initial data from the PT-1 study, a caution has been recommended for the combined use of ANA and aspirin as this may provoke excess hemorrhage. ET is a clinically and biologically heterogeneous condition, and these biological variations may in part explain some of the clinical differences observed in various studies in response to specific treatments. No new toxicities of ANA have emerged in the past decade, which means that clinicians and patients can be reassured about the efficacy and safety of this agent, which is of particular importance in a chronic condition such as ET.

Management of Myeloproliferative Neoplasms (MPNs)

“…Less than 1% of ANA is recovered in the urine, and even in severe renal impairment (CrCl<30 ml/min), it does not appear to have a significant impact on ANA pharmacokinetics. 30…”

“…In patients with mild hepatic impairment, dose reduction is required and careful monitoring for cardiovascular side effects is advised. 30 In patients with known or suspected cardiac disease, the use of ANA must be carefully considered; a baseline electrocardiogram and echocardiogram are recommended. ANA should be used with caution in any patient with known risk factors for prolongation of the QT interval, the use of medicinal products that can prolong QTc interval and cause hypokalaemia should be avoided.…”

“…Substances that have an inhibitory effect on CYP1A2 such as grapefruit juice, fluvoxamine and enoxacin should also be avoided. 30…”

“…Less than 1% of ANA is recovered in the urine, and even in severe renal impairment (CrCl<30 ml/min), it does not appear to have a significant impact on ANA pharmacokinetics. 30 Exposure to ANA in moderate hepatic impairment is around eightfold and its use in patients with moderate to severe hepatic impairment is contradicted. ANA is not recommended in patients with elevated transaminases (>5 times the upper limit of normal).…”

“…Substances that have an inhibitory effect on CYP1A2 such as grapefruit juice, fluvoxamine and enoxacin should also be avoided. 30 Ruxolitinib (RUX), a selective inhibitor of JAK1 and JAK2 is recommended as an option for treating disease-related splenomegaly or symptoms in adults with PMF, Post PV myelofibrosis (MF) or Post ET MF in people with intermediate or high-risk disease. 31 The recommended starting dose of RUX in MF is 15 mg twice daily or 20 mg twice daily dependent on the platelet count.…”