Polycythemia Vera

Etiology

The etiology of the disease process appears to be neoplastic proliferation. There is a signaling defect leading to an abnormal response to growth factors, and the abnormal clonal line interferes with normal lineage proliferation. The Janus kinase-2 (JAK2) gene involved with intracellular signaling is mutated in 90% of cases of polycythemia vera (PV).[1] Cytogenetic studies show the presence of an abnormal karyotype in the hematopoietic progenitor cells in approximately 34% of patients with PV. At the time of diagnosis, 20% of patients have cytogenetic abnormalities, increasing to more than 80% for those with more than 10 years of follow-up care.

Epidemiology

Polycythemia vera (PV) can affect all ethnic groups with no sex predilection, although there are slightly more cases in men than women.[2] It can occur in all age groups, but the median age of diagnosis is 60.[3] PV affects 0.6 to 1.6 per million people in the United States. There are fewer incidences in Japan than in the United States or Europe.[4]

Pathophysiology

The bone marrow of patients with polycythemia vera (PV) contains normal stem cells and contains abnormal clonal stem cells that suppress normal stem cell growth and maturation. The cause of panmyelosis is unregulated neoplastic proliferation. JAK2 kinase mutation likely leads to the signaling derangements resulting in PV. A valine to phenylalanine substitution at position 617 of the JAK2 gene, or JAK2V617F, leads to constitutively active cytokine receptors.[5] This mutation is observed in over 90% of patients with PV and 50% to 60% of primary myelofibrosis, and 50% of essential thrombocythemia.[1][6] This process leads to increased production of red blood cells and platelets with associated complications of thrombosis and bleeding.

Histopathology

Peripheral blood smear findings can be different based on the stage of the disease. In pre-polycythemia and overt polycythemia, normochromic and normocytic red blood cells are seen. A hypochromic and microcytic pattern can accompany concomitant iron deficiency. Platelets and white blood cells can also be elevated. Leukocytosis, predominantly with neutrophils, can be seen without blast activity. Myelofibrosis develops with teardrop red blood cells, poikilocytosis, and circulating nucleated red cells in the post-polycythemic stage.

Bone marrow sampling typically shows hypercellularity with panproliferation. Again, histopathology is dependent on the stage of the disease. Erythrocytosis is seen with pre-polycythemia, increased red cell mass in overt polycythemia, and increased reticulin deposition in post-polycythemia with fibrosis, ineffective production, and extramedullary hematopoiesis.[7]

History and Physical

Symptoms of polycythemia vera (PV) are related to hyperviscosity and thrombosis, impairing oxygen delivery. Physical complaints can include fatigue, headache, dizziness, tinnitus, vision changes, insomnia, claudication, pruritus, gastritis, and early satiety. Aquagenic pruritus, which occurs during or after a hot shower, is a complaint in 40% of patients.[8][9] The mechanism is likely from mast cell and basophil degranulation, causing a histamine surge. In a 2013 study with 1545 patients, pruritis was associated with better survival.[10] Erythromelalgia is a burning pain in the hands and feet with erythema or pallor. This can be seen in PV or essential thrombocythemia and responds well to low-dose aspirin.[11] Bleeding and thrombotic complications are each observed in 1% of patients. Bleeding events can include epistaxis, gum bleeding, and gastrointestinal (GI) bleeding. Thrombotic events can include deep venous thrombosis (DVT), pulmonary embolism (PE), Budd-Chiari syndrome, splanchnic vein thrombosis, stroke, and arterial thrombosis.[12] Early satiety occurs from impaired gastric filling due to splenomegaly. GI discomfort and peptic ulcer disease are common, likely from increased histamine release from basophils and increased viscosity in gastrointestinal blood supply.[13]

Patients can display a plethora and flushing of the face and palms, conjunctival injection, and skin excoriation from pruritus on physical exam. Splenomegaly and hepatomegaly are also often observed.[14]

Evaluation

In the 1970s, the polycythemia vera study group (PVSG) set the first diagnostic criteria for polycythemia vera (PV). The diagnosis can be made if all three category A criteria are met, or if A1, A2, and two from category B are met.[15]

Category A

• Total red blood cell mass more than or equal to 36 mL/kg in males or more than or equal to 32 mL/kg in females
• Arterial oxygen saturation more than or equal to 92%
• Splenomegaly

Category B

• Platelets of more than 400,000/microliter
• White blood cell count more than 12,000/microliter
• Leukocyte alkaline phosphatase (ALP) more than 100 U/L
• Serum vitamin B12 more than 900 pg/mL or binding capacity more than 2200 pg/mL

Measuring the red blood cell mass requires labeling with the 51Cr isotope, which is no longer readily available. Therefore, the PVSG guidelines have fallen out of favor, and the World Health Organization (WHO) published revised guidelines for diagnosing PV in 2016. These criteria are composed of three major and one minor criterion. Diagnosis can be made if all three major or two major and minor criteria are met.[16]

Major

• Hemoglobin (Hgb) more than 16.5 g/dL or hematocrit (Hct) more than 49% in men, Hgb more than 16 g/dL or Hct more than 48% in women; or red blood cell mass more than 25% above mean normal predicted
• Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
• JAK2 V617For JAK2 exon 12 mutation

Minor

• Serum erythropoietin level below the reference range for normal

These criteria should only be applied for diagnosis after secondary causes of polycythemia have been ruled out.

Treatment / Management

There is no cure for polycythemia vera (PV); treatment goals are aimed at symptom relief and reducing the risk of disease complications, including thrombosis, bleeding, and hematologic transformation. There are currently no means for preventing transformation into myelofibrosis or acute leukemia/myelodysplastic syndrome, but there are known agents to avoid that can increase this risk.[17]

Medical Treatment

  Patients under the age of 60 without a history of thrombotic events are considered low risk, and treatment recommendations include:

• Phlebotomy: Target hematocrit to less than 45%. Each unit of phlebotomized blood (500 mL) should drop the hematocrit by 3% in an average-sized adult. Men may tolerate up to the removal of 1.5 to 2 units a week. Whereas women, the elderly, those who weigh less than 50 kg, or those with cardiovascular disease may only tolerate removal of 0.5 units a week. The goal of phlebotomy is to deliberately induce an iron-deficient state, which will, to some degree, limit the marrow's capacity for erythropoiesis; therefore, patients should not take iron supplements. Patients with hematocrits maintained at less than 45% have significantly fewer cardiovascular and thrombotic events compared to when the goal hematocrit is 50%.[18]
• Low dose aspirin (40 mg to 100 mg) once or twice daily should be given, if no contraindications, to lower thrombotic risk.[19] Patients with platelets greater than 1 million/microliter can have increased bleeding risk due to acquired von Willebrand disease and, therefore, should not be placed on aspirin.[20]
• Treat aspirin refractory symptoms.
• Optimizing cardiovascular health such as weight loss, exercise, tobacco cessation, blood pressure control.
(A1)

 Patients 60 years of age or older and/or who have a history of thrombosis are considered high risk. In high-risk patients, cytoreductive therapy is recommended in addition to phlebotomy and aspirin. The first-line agent is hydroxyurea (HU) due to its safety profile, cost, and efficacy.[21] Initial dosing is 15 mg/kg of actual body weight per day divided into twice-daily dosing. The goal is to reduce platelets to 100,000 to 400,000/microliter without excessive neutropenia and anemia. Dosing should not be adjusted more frequently than once weekly because it takes three to five days for a dose modification to achieve the therapeutic effect. Patients failing hydroxyurea therapy or who are intolerant may try pegylated interferon or busulfan. Other alternatives include ruxolitinib, anagrelide, pipobroman, and radioactive phosphorus.[17][20]

The FDA approved a JAK inhibitor (ruxolitinib) in 2014 to treat patients with PV who have an inadequate response or are intolerant of hydroxyurea. A great proportion of patients on ruxolitinib achieved complete hematological remission.

To manage pruritus, initial treatment should include antihistamines and selective serotonin reuptake inhibitors (SSRIs). If ineffective, INF-a can be attempted, followed by JAK2 inhibitors for highly resistant cases.[17]

Surgical Treatment

Splenectomy may be appropriate in the setting of painful splenomegaly or recurrent splenic infarcts.

Budd-Chiari syndrome, or hepatic venous outflow thrombosis, is a potential complication requiring surgical intervention such as transjugular intrahepatic portosystemic shunt (TIPS), portocaval shunt, mesocaval shunt, portocaval/cavoatrial shunt, or mesoatrial shunt.[22](B2)

Differential Diagnosis

Primary polycythemia vera (PV) must demonstrate increased production in all three cell lines to make the diagnosis. Increased red blood cell mass alone is not enough for diagnosis because other conditions such as chronic hypoxia and erythropoietin-secreting tumors can lead to polycythemia. Secondary polycythemia (from hypoxia or smoking) is much more common than primary PV and must be ruled out before the diagnosis of primary PV can be made.[3] A rare mutation of the erythropoietin (EPO) receptor can mimic the basic presentation of PV, including increased red cell mass and decreased EPO. However, the mechanism is an over-sensitive receptor to EPO rather than EPO independence.[23][24] Isolated granulocytosis can occur from infections or leukemoid reactions. Thrombocytosis alone can result from bleeding or iron deficiency.

Differential diagnoses to consider include:

• Essential thrombocythemia
• Chronic myelogenous leukemia
• Agnogenic myeloid metaplasia
• Chronic myelogenous leukemia
• Primary myelofibrosis
• Secondary polycythemia

Toxicity and Adverse Effect Management

Older patients and those with cardiovascular disease should have a smaller volume of blood removed during phlebotomy sessions to minimize orthostatic effects. Normal saline may be given post phlebotomy to replace the volume lost. Patients need to stay well-hydrated and limit aggressive physical activity within the first 24 hours of phlebotomy.

Higher dose aspirin (more than 100 mg/day) is associated with an increased risk of bleeding, and 900 mg daily is associated with a high rate of gastrointestinal bleeding.[25][19][26]

Adverse effects of hydroxyurea include cytopenias, oral ulcers, GI upset, peripheral neuropathy, and rare but severe pulmonary toxicity. If HU is not tolerated, cytoreductive therapy should be changed to other agents listed above.

Prognosis

The average survival of untreated polycythemia vera (PV) is 18 months, whereas median survival is 14 years overall and 24 years if younger than 60 for those undergoing treatment.[17][20][27] According to one study, mortality in PV is higher than in age and sex-matched populations. Five-year survival in the overall cohort was 79.5%, but patients are at a high risk of second primary malignancies and leukemic transformation, which may compromise long-term survival.[28]

Complications

Polycythemia vera-related complications and mortality are related to thrombosis, hemorrhage, peptic ulcer disease, myelofibrosis, acute leukemia, or myelodysplastic syndrome (MDS).

Thrombosis is a major complication of polycythemia vera (PV), and current treatment recommendations aim to minimize these risks. In the setting of a first thrombotic event, an appropriate dose and length of anticoagulation are recommended. There is currently no difference in treatment recommendations for patients with underlying PV.[29]

Bleeding is another common complication of the disease process, but major bleeding is rare. The risk for bleeding increases with severe thrombocytosis and high-dose aspirin (more than 100 mg/day) or anticoagulation.[25]

Myelofibrosis worsens with the progression of the disease. Recommended treatment for secondary myelofibrosis is the same as primary myelofibrosis. Transformation to myelodysplasia and acute leukemia yields a poor prognosis. Treatment is the same as primary MDS and acute myeloid leukemia (AML).