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Polycythemia Vera

(Primary Polycythemia)

by Jane Liesveld, MD, Patrick Reagan, MD

Polycythemia vera (PV) is an idiopathic chronic myeloproliferative disorder characterized by an increase in RBC mass, which often manifests as an increased Hct. There is an increased risk of thrombosis and, rarely, acute leukemia and myelofibrotic transformation. Hepatosplenomegaly may also occur. Diagnosis is made by CBC, testing for JAK2 mutations, and clinical criteria. Treatment involves phlebotomy, low-dose aspirin, myelosuppressive drugs for high-risk patients, and rarely stem cell transplantation.

PV is the most common of the myeloproliferative disorders; incidence in the US is estimated to be 1.9/100,000, with incidence increasing with age. PV may be slightly more common in men. The mean age at diagnosis is around 60 yr. PV is very rare in children.

Pathophysiology

PV involves increased production of all cell lines, including RBCs, WBCs, and platelets. Thus, PV is sometimes called a panmyelosis because of elevations of all 3 peripheral blood components. Increased production confined to the RBC line is termed erythrocytosis; erythrocytosis may occur with PV but is more commonly due to other causes (secondary erythrocytosis—see Secondary Erythrocytosis). In PV, RBC production proceeds independently of erythropoietin levels.

Extramedullary hematopoiesis may occur in the spleen, liver, and other sites that have the potential for blood cell formation. Peripheral blood cell turnover increases. Eventually, progression to a spent-phase may occur, with a phenotype indistinguishable from primary myelofibrosis. Transformation to acute leukemia is rare, although the risk is increased with exposure to alkylating agents, such as chlorambucil, and radioactive phosphorus (mostly of historic significance).

Complications

In PV, blood volume expands and hyperviscosity develops. Patients are prone to develop thrombosis. Thrombosis can occur in most blood vessels, resulting in stroke, transient ischemic attacks, deep venous thrombosis, MI, retinal artery or vein occlusion, splenic infarction (often with a friction rub), or Budd-Chiari syndrome (see Budd-Chiari Syndrome). Previously, most experts believed hyperviscosity was the predisposing factor for thrombosis. Newer studies suggest that risk of thrombosis may be primarily related to the degree of leukocytosis. However, this hypothesis has yet to be confirmed in dedicated, prospective trials.

Platelets may function abnormally, predisposing to increased bleeding. Increased cell turnover may cause hyperuricemia, increasing the risk of gout and urate kidney stones.

Genetic basis

Clonal hematopoiesis is a hallmark of PV, suggesting that a mutation of hematopoietic stem cells is the cause of proliferation. The JAK2 V617F mutation (or one of several other rarer JAK2 mutations) is present in virtually all patients with PV. However, one or more other disease-initiating mutations almost certainly exist. These mutations lead to sustained activation of the JAK2 protein, which causes excess cell production, independent of erythropoietin levels.

Symptoms and Signs

PV itself is often asymptomatic. Occasionally, increased red cell volume and viscosity cause weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath. The face may be red and the retinal veins engorged. The palms and feet may be red, warm, and painful, sometimes with digital ischemia (erythromelalgia). Hepatomegaly is common, and > 75% of patients have splenomegaly (which may be massive).

Thrombosis may cause symptoms in the affected site (eg, neurologic deficits with stroke or transient ischemic attack, leg pain, swelling or both with lower extremity thrombosis, unilateral vision loss with retinal vascular occlusion).

Bleeding (typically GI) occurs in about 10% of patients.

Hypermetabolism can cause low-grade fevers and weight loss and suggests progression to spent-phase polycythemia, which is clinically indistinguishable from primary myelofibrosis.

Diagnosis

  • CBC

  • Testing for JAK2 mutations

  • Sometimes bone marrow examination and serum erythropoietin level

  • Use of WHO criteria

PV is often first suspected because of an abnormal CBC (eg, Hb > 18.5 g/dL in men or > 16.5 g/dL in women), but it must be considered in patients with suggestive symptoms, particularly Budd-Chiari syndrome (however, some patients develop Budd-Chiari syndrome before the Hct increases). Neutrophils and platelets are often, but not invariably, increased; in patients with only elevated Hb, PV may be present, but secondary erythrocytosis, a more common cause of elevated Hb, must first be considered (see Secondary Erythrocytosis). PV should also be considered in the rare patient with a normal Hb level but microcytosis and evidence of iron deficiency; this combination of findings can occur with iron-limited hematopoiesis, which is a hallmark of some cases of PV.

Revised WHO criteria for diagnosis have been established (see Table: Revised WHO Criteria for Diagnosis of Polycythemia Vera*). Thus, patients suspected of having PV typically should have testing for JAK2 mutations; bone marrow examination is not always necessary.

When done, bone marrow examination typically shows panmyelosis, large and clumped megakaryocytes, and sometimes reticulin fibers. However, no bone marrow findings absolutely differentiate PV from other disorders of excessive erythrocytosis, such as congenital familial polycythemia.

Patients with PV typically have low or low-normal serum erythropoietin levels. Elevated levels suggest secondary erythrocytosis.

RBC mass determination with chromium-labeled RBCs can help differentiate between true and relative polycythemia and can also help to differentiate between PV and other myeloproliferative disorders. However, this test is technically difficult and is rarely done due to its limited availability.

Nonspecific laboratory abnormalities that may occur in PV include elevated vitamin B 12 and B 12 -binding capacity, hyperuricemia and hyperuricosuria (present in 30% of patients), increased expression of PRV-1 gene in leukocytes, and decreased expression of C-mpl (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.

Revised WHO Criteria for Diagnosis of Polycythemia Vera*

Level

Specifics

Major criteria

  • Evidence of increased RBC volume, including 1 of the following:

    • Hb >18.5 g/dL in men or > 16.5 g/dL in women

    • Hb or Hct > 99th percentile of method-specific reference range for age, sex, and altitude of residence

    • Hb >17 g/dL in men or 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from the patient's baseline value not accounted for by correction of iron deficiency

    • Elevated RBC mass > 25% above mean normal predicted value

  • Presence of JAK2 617VF or other functionally similar mutation (eg, JAK2 exon 12 mutation)

Minor criteria

  • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) and prominent erythroid, granulocytic, and megakaryocytic proliferation

  • Serum erythropoietin level below the reference range for normal

  • Endogenous erythroid colony formation in vitro

*Diagnosis requires presence of the 2 major criteria and one minor criterion or the presence of the first major criterion plus 2 minor criteria.

This research was originally published in Blood. Adapted from Tefferi A, Thiele J, Orazi A, et al: Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 110:1092, 2007 © the American Society of Hematology.

Prognosis

Generally, PV is associated with a shortened life span. Median survival for all patients is around 8 to 15 yr, although many patients live much longer. Thrombosis is the most common cause of death, followed by complications of myelofibrosis and development of leukemia.

Treatment

  • Possibly aspirin therapy

  • Possibly phlebotomy

  • Possibly myelosuppressive therapy

Because PV is the only form of erythrocytosis for which myelosuppressive therapy may be indicated, accurate diagnosis is critical. Therapy must be individualized according to age, sex, medical status, clinical manifestations, and hematologic findings. Patients are classified as high-risk or low-risk. High-risk patients are > 60 yr and have a history of thrombosis or transient ischemic attacks (TIA) or both.

Aspirin

Aspirin 81 to 100 mg po once/day reduces the incidence of thrombotic complications. Thus, patients undergoing phlebotomy alone or phlebotomy and myelosuppression should be given aspirin unless contraindicated. Higher doses of aspirin may be associated with an increased risk of bleeding.

Phlebotomy

Phlebotomy has been the mainstay of therapy for both high- and low-risk patients. Common thresholds for phlebotomy are Hct > 45% in men and >42% in women. A randomized controlled trial published in 2013 showed that patients randomized to a Hct < 45% had a significantly lower rate of cardiovascular death and thrombosis than did those with a target Hct of 45 to 50%. In a minority of patients with symptomatic rubor and hyperviscosity symptoms, phlebotomy can be therapeutic.

Initially, 300 to 500 mL of blood are removed every other day. Less blood is removed (ie, 200 to 300 mL twice/wk) from elderly patients and from patients with cardiac or cerebrovascular disorders. Once the Hct is below the target value, it is checked monthly and maintained at this level by additional phlebotomies as needed. If necessary, intravascular volume can be maintained with crystalloid or colloid solutions. Platelets may increase with the decline in Hct, and anagrelide or hydroxyurea may be needed.

Myelosuppressive therapy

Myelosuppressive therapy is indicated for high-risk patients.

Hydroxyurea, which inhibits the enzyme ribonucleoside diphosphate reductase, is also used to achieve myelosuppression. It has not been clearly shown to be leukemogenic; however, the possibility of leukemic conversion, although small, does exist. Hydroxyurea is started at a dose of 500 to 1000 mg po once/day. Patients are monitored with a weekly CBC. When a steady state is achieved, the interval between CBCs is lengthened to 2 wk and then to 4 wk. If the WBC count falls to < 4000/μL or the platelet count to < 100,000/μL, hydroxyurea is withheld and reinstituted at 50% of the dose when those values normalize. It is reasonable to titrate the hydroxyurea dose to achieve a near-normal Hct, although there is no evidence that titration is beneficial. It is likely that normalization of the WBC count is more important, but this theory has not been demonstrated prospectively. There is no evidence that normalization of the platelet count is necessary, and some clinicians do not increase the hydroxyurea dose as long as the platelet count is < 1.5 million/μL. Acute toxicity is infrequent; occasionally patients develop a rash, GI symptoms, fever, nail changes, and skin ulcers, which may require stopping hydroxyurea.

Interferon alfa-2b has been used if hydroxyurea does not control blood counts or is not tolerated. However, pegylated interferon alfa-2b is usually well tolerated. This drug affects the disease at the molecular level with relatively low toxicity.

Several inhibitors of the JAK2 pathway are currently in clinical trials, primarily in patients with advanced myelofibrosis, and ruxolitinib is approved for post-PV myelofibrosis.

Radioactive phosphorus ( 32 P) has long been used as a treatment for PV, although its availability is very limited now. It has a success rate of 80 to 90%. Remission may last 6 mo to several years. Radioactive phosphorus is well tolerated and requires fewer follow-up visits once the disorder is controlled. However, radioactive phosphorus is associated with an increased incidence of acute leukemic transformation, and the leukemia that develops after this therapy is often resistant to induction chemotherapy and is never curable. Thus, use of radioactive phosphorus requires careful patient selection (eg, used only for patients who are expected to die of other disorders within 5 yr). It should be used rarely; many clinicians do not use it at all.

Alkylating agents such as chlorambucil are leukemogenic and should be avoided if possible.

Treatment of complications

Hyperuricemia should be treated with allopurinol 300 mg po once/day if it causes symptoms or if patients are receiving simultaneous myelosuppressive therapy. Pruritus may be managed with antihistamines but is often difficult to control; myelosuppression often is most effective. Cholestyramine, cyproheptadine, cimetidine, or paroxetine may be successful. After bathing, the skin should be dried gently. Aspirin relieves symptoms of erythromelalgia; higher doses may be required but clearly increase the risk of hemorrhage.

Key Points

  • Polycythemia vera (PV) is an idiopathic, chronic myeloproliferative disorder that involves increased production of all cell lines, including RBCs, WBCs, and platelets.

  • Cause of PV appears to be a mutation of hematopoietic stem cells that leads to sustained activation of the JAK2 protein, which causes excess cell production.

  • Complications include thrombosis, bleeding, and hyperuricemia; some patients eventually develop myelofibrosis or rarely, transformation to acute leukemia.

  • PV is often first suspected because of an elevated Hb (> 18.5 g/dL in men, > 16.5 g/dL in women); neutrophils and platelets are often, but not invariably, increased.

  • Test for JAK mutations and sometimes bone marrow examination and serum erythropoietin level and apply WHO criteria (see Table: Revised WHO Criteria for Diagnosis of Polycythemia Vera*).

  • Treatment must be individualized, but most patients should take aspirin; phlebotomy to target Hct < 45% is probably helpful; high-risk patients (age > 60 yr, history of thrombosis and/or transient ischemic attack) may benefit from myelosuppressive drugs (eg, hydroxyurea); JAK2 inhibitors are being tested.

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