Polycythemia vera, thromboembolies D45

Patients with myeloproliferative neoplasms have an increased risk of thrombosis compared to the general population. In polycythaemia vera, the occurrence of thromboembolic events is also increased compared to other myeloproliferative neoplasms and are observed in approximately 39-41% of patients (Barbui T et al. 2013). Approximately one third of MPN patients are affected by a vascular event. According to a Swedish study, PV patients have a 3-fold increased risk of arterial thrombosis and a 13-fold increased risk of venous thrombosis in the first 3 months of therapy after diagnosis compared to the control group of the same sex and age (Griesshammer M et al. (2019). Other risk factors such as immobile lifestyle, D. mellitus and nicotine abuse further increase the risk of thrombosis in the course of polycythaemia vera (Cerquozzi S et al. 2017). In this context, thromboembolism (TE) occurs in atypical vessels in more than 55% of cases and thus may be detected late:

• Splanchnic venous thrombosis
• Cerebrovascular arterial thrombosis
• Sinus-sagittalis-superior thrombosis

In addition, deep vein thrombosis in the extremities and pulmonary embolism also occur. Thus, the occurrence of cardiovascular complications often leads to the diagnosis of myeloproliferative neoplasia in the first place, as is the case with PV: in almost 40% of patients, thromboembolism occurs shortly before or during the period of diagnosis.

Thromboembolism contributes significantly to the morbidity and mortality of polycythemia vera (PV) and is the cause of death in over 60% of cases of untreated PV (Griesshammer M et al. (2019). Depending on the risk group, different therapeutic options can be considered:

To adjust hematocrit < 45%, the guideline recommends regular phlebotomies and administration of acetylsalicylic acid (Barbui T et al (2013). In case of inadequate response or intolerance, conversion to drug cytoreduction should be considered.

Alternative: Rusfertide, a hepcidin mimetic, may provide a novel method to achieve this goal. This is shown by results from the randomized section of the phase II REVIVE trial, In PV, phlebotomies result in iron deficiency, which adds to the nonhematologic symptoms of the disease. Hepcidin is produced in the liver and regulates iron metabolism. Therefore, clinical trials are testing whether rusfertide, a synthetic molecule similar to hepcidin, can lower HCT elevated in PV due to erythrocytosis and reduce the need for phlebotomy. Rusfertide was well tolerated in a larger study. Adverse events (AEs) mostly reached only grade 1 or 2 (grade 3: 17%, no AEs grade 4 and 5). Most commonly reported were injection site reactions, which decreased over the course of the study (Kremyanskaya M 2023).

High-risk patients: ≥ 60 years and/or previous thromboembolism: If thromboembolism occurs in PV patients, phlebotomy alone is no longer sufficient to control hematocrit. Patients who have had TE are considered high-risk. They should be treated cytoreductively with hydroxycarbamide. This also generally applies to patients > 60 years of age. 34% of patients develop hydroxycarbamide resistance during the course of therapy. In these cases, patients should be switched to an effective second-line therapy with the JAK1/JAK2 inhibitor ruxolitinib (^Jakavi®) (DGHO 2019).

1. Barbui T et al (2013) Myeloproliferative neoplasms and thrombosis. Blood 122: 2176-2284.
2. Cerquozzi S et al. (2017) Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer Journal 7: 662.
3. DGHO (2019) Onkopedia Guideline: Polycythaemia vera, available at: https://www.onkopedia.com/de/onkopedia/guidelines/polycythaemia-vera-pv/@@view/html/index.html (accessed 9/13/2021).
4. Griesshammer M et al (2019) Thromboembolic events in polycythemia vera. Annals of Hematology 2019; 98(5): 1071-1082.
5. Hultcrantz M et al (2018) Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms. A Population-Based Cohort Study. Annals of Internal Medicine 2018; 168: 317-325.
6. Jentsch-Ullrich K et al. (2016) Characteristics and treatment of polycythemia vera patients in clinical practice: a multicenter chart review on 1476 individuals in Germany. Journal of Cancer Research and Clinical Oncology 142: 2041-2049.
7. Kremyanskaya M (2023) Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rustfertide. Bilnded randomized withdrwal results of the revive study. EHA Library; https://library.ehaweb.org/eha/2023/eha2023-.