Polycythemia Vera Treatment & Management

Updated: Dec 02, 2016
  • Author: Srikanth Nagalla, MBBS, MS, FACP; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Treatment

Medical Care

The long-term risks of polycythemia vera (PV) include leukemic and fibrotic transformation, which occurs in fewer than 5% and 10% of patients, respectively, at 10 years. Current treatment modalities do not change these outcomes. Instead, treatment for PV is intended to decrease the risk of arterial and venous thrombotic events, which could be approximately 20%.

Patients can be risk-stratified for their risk of thrombosis according to their age and history of thrombosis. Patients older than 60 years or with a previous history of thrombosis are considered to be high risk. Patients younger than 60 years and with no prior history of thrombosis are considered low risk.

All patients with PV should undergo phlebotomy to keep their hematocrit below 45%. Lower hematocrit targets have been proposed for women with PV, but no empiric evidence supports that recommendation. [1]

All patients with PV should take aspirin, 81 mg daily, unless contraindicated by major bleeding or gastric intolerance. [1] A systematic review concluded that in patients with PV, use of low-dose aspirin is associated with a reduction in the risk of fatal thrombotic events and all-cause mortality; however, the reduction was statisticallly nonsignificant (P = 0.07). The review found no increased risk of major bleeding with low-dose aspirin therapy in PV. [17]

In addition, if a patient is at high risk for thrombosis, cytoreductive therapy is added to the management plan. Hydroxyurea at a starting dose of 500 mg twice daily is the most commonly used cytoreductive agent. It can be titrated on the basis of blood counts. In patients who are refractory to or intolerant of hydroxyurea, interferon-alpha can be used as an alternative. Busulfan is also an option for patients older than 65 years. [18]

The most recent advance in the treatment of PV is the development of JAK inhibitors. [19] The JAK1/2 inhibitor ruxolitinib is approved for treatment of PV in patients who have had an inadequate response to or are intolerant of hydroxyurea.

Alvarez-Larran et al reported resistance or intolerance to hydroxyurea in 137 of 890 (15.4%) patients with polycythemia vera. With a median survival of 19 years, resistance or intolerance had no impact on survival, but patients who developed cytopenia had increased risk of death (hazard ratio [HR] 3.5, P = 0.003) and of myelofibrotic transformation  (HR 5.1, P = 0·001). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukemia (HR 20.3,  P <0.·001). [20]

Leukocytosis may be a risk factor for thrombosis. In a subanalysis of the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial, risk of thrombosis was increased in patients whose WBC exceeded 7000/µL, and reached statistical significance at levels of 11,000/µL and above (HR 3.90, P = 0.02). An association between elevated WBC counts and thrombosis has also been found in studies of patients with essential thrombocythemia. These authors recommend including the WBC count when evaluating response to cytoreductive therapy. [21]

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Phlebotomy

Phlebotomy (bloodletting) has long been the mainstay of therapy for polycythemia vera (PV). The object is to remove excess cellular elements, mainly red blood cells, to improve the circulation of blood by lowering the blood viscosity. Because phlebotomy is the most efficient method of lowering the hemoglobin and hematocrit levels to the reference range, all newly diagnosed patients are initially phlebotomized to decrease the risk of complications.

Patients can be phlebotomized once or twice a week to reduce the hematocrit to less than 45%. A randomized trial demonstrated a significant difference in the rate of thrombotic events and cardiovascular deaths (2.7% vs 9.8%) when the hematocrit goal was 45% versus 50%. [22] 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. The presence of elevated platelet counts, which may be exacerbated by phlebotomy, is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.

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Maintenance therapy

Once the patient's hemoglobin and hematocrit values are reduced to within the reference range, implement a maintenance program either by inducing iron deficiency by continuous phlebotomies (the frequency of the procedure depends on the rate of reaccumulation of the red blood cells) or by 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, chlorambucil) or the type of myelosuppressive agents (eg, hydroxyurea [HU], anagrelide, interferon alfa) and duration of therapy.

The Polycythemia Vera Study Group (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. [23] Increased risk of leukemia was also found with use of phosphorus-32; production of this radionuclide has been discontinued and it is no longer available in the United States or elsewhere.

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 PV since the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation. [24] In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone; the PVSG recommended that HU should be the drug of choice for patients older than 40 years. [25]

The role of HU in leukemic transformation is not clear. Several nonrandomized studies have supported or refuted a significant rise in leukemic conversion with the long-term use of HU in patients with essential thrombocythemia (from 0% to 5.5%) and in patients with 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. Followup for 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.

In an open-label study by Huang and colleagues that included 136 patients with JAK2V617F mutation–positive PV, treatment with interferon alfa 2b (IFN α-2b) did not produce a superior overall hematologic response, compared with HU. However, IFN α-2b provided better 5-year progression-free survival (66.3% versus 46.7%, P< 0.01) and clinical improvement (in vasomotor symptoms, distal paresthesias, and erythromelalgia). No severe hematological adverse events were observed in patients receiving IFN α-2b. [26]

Do not administer alkylating agents to younger patients (<40 y) who need long-term treatment. Alternative nonleukemogenic agents are needed for these patients

Low-dose aspirin suppresses thromboxane biosynthesis by platelets, which is increased in PV and essential thrombocythemia. The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) found that low doses of aspirin (40 mg/d) were effective for preventing thrombosis and controlling microvascular painful symptoms (erythromelalgia), which result from spontaneous platelet aggregation, in patients with PV and essential thrombocythemia, without creating a bleeding diathesis. [27]

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Ruxolitinib

Ruxolitinib (Jakafi), a JAK1/JAK2 inhibitor, was approved by the FDA in December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Approval was based on data from the phase III RESPONSE trial. In this trial, patients treated with ruxolitinib demonstrated superior hematocrit control and reductions in spleen volume compared with best available therapy. A greater proportion of patients on the ruxolitinib treatment arm achieved complete hematologic remission (ie, hematocrit control and lowered platelet count and WBC). Hematologic adverse reactions are prevalent with ruxolitinib (incidence >20%) and include thrombocytopenia and anemia. [28]

Ruxolitinib had initially been approved in the United States in 2011 for patients with intermediate- or high-risk myelofibrosis including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

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Surgical Care

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

Budd-Chiari syndrome occurs in patients with myeloproliferative disease (MPD) and most frequently in young women. Surgical approaches to the management of Budd-Chiari syndrome are, therefore, relevant to patients with polycythemia vera. [29]

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 gastrointestinal bleeding, but 20% of patients are asymptomatic.

The diagnosis is made by using ultrasonography to identify portal vein patency. In addition to the standard computed tomography (CT) scan and magnetic resonance imaging (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 whether 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.

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Consultations

Consultation with a hematologist is recommended in cases of polycythemia vera (PV). Long-term follow-up care of these patients and managing complications of the disease and its treatment can be difficult. [19]

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