Polycythemia Vera Treatment & Management

Phlebotomy or bloodletting has been the mainstay of therapy for the polycythemia vera (PV) disease process for a long time. The object is to remove excess cellular elements, mainly red blood cells, to improve the circulation of blood by lowering the blood viscosity.

Patients with hematocrit values of less than 70% may be bled twice a week to reduce the hematocrit to the range of less than 45%. Patients with severe plethora who have altered mentation or associated vascular compromise can be bled more vigorously, with daily removal of 500 mL of whole blood.

• Elderly patients with some cardiovascular compromise or cerebral vascular complications should have the volume replaced with saline solution after each procedure to avoid postural hypotension.

  • Because phlebotomy is the most efficient method of lowering the hemoglobin and hematocrit levels to the reference range, all new patients are initially phlebotomized to decrease the risk of complications. The presence of elevated platelet counts that may be exacerbated by the phlebotomy is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.
  • Once the patient's hemoglobin and hematocrit values are reduced to within the reference range (ie, < 45%), implement a maintenance program either by inducing iron deficiency by continuous phlebotomies (frequency of the procedure depends on the rate of reaccumulation of the red blood cells) or using a myelosuppressive agent. The choice depends on the risks of secondary leukemias and the rate of thrombosis or bleeding. Patients must be cautioned to not take iron supplements.
• The risks for secondary leukemia depend on the type of therapy (eg, phlebotomy, radioactive phosphorus-32 [³² P], chlorambucil) or the type of myelosuppressive agents (eg, hydroxyurea [HU], anagrelide, interferon alfa) and duration of therapy.

  • The PVSG demonstrated a decreased survival rate and increased mortality rate from acute leukemia in the first 5 years, and a total of 17% of patients had leukemia after 15 years with chlorambucil and with³² P.^[11] An increased incidence of thrombotic complications occurred in the phlebotomy arm. This indicates that phlebotomy is not ideal for patients with elevated platelet counts and previous thrombosis, as are observed in patients who are older. In this situation, using HU has decreased these complications.
• Hydroxyurea has been the mainstay therapy for polycythemia vera (PV) after the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation.^[12] In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone and should be the drug of choice for patients older than 40 years.^[13]

  • The role of HU in leukemic transformation is not clear, but several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with the long-term use of HU in persons with ET (from 0% to 5.5%) and in persons with polycythemia vera (PV) (from 2.1% to 10%).
  • The PVSG closed the chlorambucil arm because of increased rates of acute leukemia after 7 years. However, in the 15-year follow-up of the HU arm compared with the phlebotomy-alone arm, the trend for leukemic transformation was greater in the HU arm but the differences did not meet statistical significance. PVSG data after a follow-up examination of a median of 8.6 years and a maximum of 795 weeks showed that 5.4% of patients developed leukemia in the HU arm compared with 1.5% of patients treated with phlebotomy alone.
  • Other case series have reported secondary leukemia in 3-4% of patients, which is relatively low compared with the benefits of preventing thrombotic complications.
• Anagrelide (Agrylin) is a cyclic adenosine monophosphate phosphodiesterase inhibitor that prevents platelet aggregation and inhibits megakaryocyte maturation, thereby decreasing platelet counts. The total response rate for controlling platelet counts with anagrelide is greater than 70% in patients with MPDs (ie, PV, ET). Acute side effects include headaches, palpitations, and fluid retention.

  • The most frequent adverse effect was headache (44%), followed by palpitation (26%) and diarrhea (26%) due to lactose deficiency and intolerance.^[14] Approximately 17% of patients withdrew from therapy because of intolerance or adverse effects.^[14]
  • Long-term treatment with anagrelide in 3660 patients with polycythemia vera (PV) or ET, with a maximum follow-up of 7 years, was efficacious and safe with respect to leukemic transformation.^{[15, 16]} To date, this agent does not appear to increase the risk of acute leukemia in patients with PV and ET over time.
• Interferon alfa has been demonstrated in small anecdotal studies to possibly be useful in patients who have relapsed or progressed into AMM or large hepatosplenomegaly. However, only low doses are tolerated and significant adverse effects from long-term use may limit its usefulness.^[17]
• Do not administer alkylating agents to younger patients (< 40 y) who need long-term treatment. Alternative nonleukemogenic agents are needed for these patients.

  • Although HU has been considered safe for long-term maintenance, a study assessed the use of low doses of aspirin (40 mg/d). Therapy with low-dose aspirin in patients with thrombocytosis suppresses thromboxane biosynthesis by platelets, which is increased in polycythemia vera (PV) and ET.
  • The Italian study, European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP), found aspirin efficacious for preventing thrombosis and controlling microvascular painful symptoms (erythromelalgia), which result from spontaneous platelet aggregation, in patients with polycythemia vera (PV) and ET without a bleeding diathesis.^[18]
• In November 2011, the JAK1/JAK2 inhibitor, ruxolitinib (Jakafi), became the first US Food and Drug Administration (FDA)–approved drug for patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Approval was expedited in accordance with the US Orphan Drug Act and based on US and international data from the COMFORT-1 and COMFORT-2 trials. Results from the COMFORT-1 trial showed patients (n=309) who received ruxolitinib had a significant reduction in spleen volume (at least 35%) at 24 weeks when assessed by MRI or CT compared with placebo (41.9% vs 0.7%).

Consider splenectomy in patients with painful splenomegaly or repeated episodes of thrombosis causing splenic infarction.

• Budd-Chiari syndrome occurs in patients with MPD and most frequently in young women. Surgical approaches to the management of Budd-Chiari syndrome are, therefore, relevant to patients with MPD.^[19]

  • Budd-Chiari syndrome is a liver-related condition associated with large vessel thromboses and outflow obstruction with inferior vena cava or portal vein thrombosis. This is associated with the development of ascites, hepatosplenomegaly, abdominal pain, and GI bleeding, but 20% of patients are asymptomatic.
  • The diagnosis is made by using ultrasonography to identify portal vein patency. In addition to the standard CT scan and MRI, patients with Budd-Chiari syndrome may need invasive angiographic imaging to determine the hemodynamics of the liver and the intrahepatic and vena caval gradients to determine the best surgical procedure. The histology of the liver helps determine the acuteness of the problem, the presence of chronic changes, and the degree of cirrhosis. This determines if a patient requires a shunt or a liver transplant.
  • The following procedures have been used in patients with Budd-Chiari syndrome:
    • Transjugular intrahepatic portosystemic shunt (TIPS)
    • Side-to-side portocaval shunt or mesocaval shunt, portocaval/cavoatrial shunt, or mesoatrial shunt.
  • These procedures have been reported to be successful in 38-100% of patients, with follow-up ranging from 9-98 months.

A consultation with a hematologist is recommended in cases of polycythemia vera (PV) because experience in long-term follow-up care of these patients and managing complications of the disease and their treatment can be difficult.^[20]