Polycythemia vera medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2] Mohamad Alkateb, MBBCh [3] Shyam Patel [4]

The mainstay of therapy for polycythemia vera is phlebotomy, aspirin, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil. Some of these medications are targeted agents that work specifically in polycythemia vera, while others are non-specific therapies that can have numerous off-target adverse effects. Some of these treatments can modify the course of the disease, while others simply alleviate symptom burden.

Medical therapy for polycythemia vera include:^{[1][2][3][4][5][6][7][8][9][10][11][12]}

• Aspirin
  • It is an irreversible inhibitor of cyclo-oxygenase (prostaglandin endoperoxide synthase) and so inhibits the formation of thromboxane A2 (a prothrombotic molecule).
  • Low-dose aspirin of 81mg has been shown to help prevent thrombosis in patients with polycythemia vera. The combined risk of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes has been shown to be reduced by aspirin.

• Hydroxyurea
  • It is a cytoreductive agent that inhibits ribonucleotide reductase, which is essential is nucleic acid metabolism. The inhibition of ribonucleotide reductase in hematopoetic cells results in a decrease in stem cell proliferation and red blood cell mass reduction.
  • 15mg/kg PO per day is the initial recommended dose of hydroxyurea. This should be adjusted to achieve a platelet count between 100,000 to 400,000microL.
  • It should be given to patients who are considered high-risk, such as those above age 60 and/or with thrombosis history.
  • Adverse effects include cytopenias, skin ulcers, and secondary malignancies.

• Ruxolitinib
  • This is a JAK2 inhibitor that is used in cases of polycythemia that are refractory to interferon therapy. It has been shown to produce splendid hematologic and spleen responses of about 90%. The recommended dose is 20mg PO twice daily. The need for phlebotomy can be reduced with ruxolitinib
  • When measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), which a validated tool for the assessment of disease burden from a subjective standpoint, ruxolitinib was shown to improve the symptoms in polycythemia vera patients. Patients receiving this medication report improvement in spleen symptoms, inflammation, and microvascular abnormalities.
  • Some side effects include non-melanoma skin cancers, weight gain, reactivation of herpes zoster, and cytopenias. Due to the risk of developing skin cancer, active surveillance of the skin is required.

• Interferon-alpha
  • This medication results in a reduction in red blood cell mass. The mechanism of action is not exactly known, but it is thought to induce apoptosis, regulate the immune system, and has a direct inhibitory effect on hematopoetic cells. Those patients considered as high risk can be given this medication, such as those above age 60 and/or with thrombosis history.
  • It can cause infusion reaction and cytopenias. Pegylated interferon-alpha, which is a formulation of the medication is less toxic than the conventional interferon. Interferon alpha is not routinely used in this current era due to its intolerable adverse effect profile. About 20% of patients will discontinue this medication within one year of starting due to the side effects. Approximately 15-20% of patients become resistant to interferon and require alternative therapy.

• Chlorambucil or busulfan
  • These are alkylating agents that inhibit the proliferation of the malignant clone responsible for elevated red blood cell mass.
  • Can be used with intolerance to interferon or hydroxyurea. They are no longer included in the current standard of care for polycythemia vera.
  • They can lead to secondary myelodysplastic syndrome and secondary leukemias, which typically occur 5-7 years after exposure to these medications.

• Phlebotomy

• The goal hematocrit is less than 45%. Because this goal may not be achieved in practice, a goal of 50% is targeted by most clinicians.
• In a normal sized adult, a standard one unit phlebotomy (500ml) should reduce the hematocrit by 3 percentage points.
• In low risk patients (patients under 60 years with no history of thrombosis), phlebotomy alone can be used.
• Some common adverse effects are iron deficiency and pain at the insertion site.

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