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Polycythemia Vera

(Primary Polycythemia)

By Jane Liesveld, MD, University of Rochester ; Patrick Reagan, MD, University of Rochester Medical Center

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Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an increase in morphologically normal red cells, white cells and platelets; erythrocytosis is typical. Ten to 30 % of patients eventually develop myelofibrosis and marrow failure; acute leukemia occurs spontaneously in 1.0 to 2.5 %. There is an increased risk of bleeding and arterial or venous thrombosis. Common manifestations include splenomegaly, microvascular events (eg, transient ischemic attacks, erythromelalgia, ocular migraine), and aquagenic pruritus (itching triggered by exposure to hot water). Diagnosis is made by CBC, testing for JAK2or CALR mutations, and clinical criteria. Treatment involves phlebotomy, low-dose aspirin, ruxolitinib, interferon, and rarely stem cell transplantation.

Polycythemia vera 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. The mean age at diagnosis is about 60 yr.

Pathophysiology

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

Extramedullary hematopoiesis may occur in the spleen, liver, and other sites that have the potential for blood cell formation. In PV, in contrast to the secondary erythrocytoses, the red cell mass increase is often initially masked by an increase in the plasma volume that leaves the hematocrit in the normal range. This is particularly the case in women, who most commonly present with hepatic vein thrombosis and a normal Hct.

Iron deficiency may eventually occur because of the increased need for iron to produce RBCs. In the presence of iron deficiency of any kind, RBCs become increasingly smaller (microcytic erythrocytosis) because the red cell hemoglobin concentration (MCHC) is defended at the expense of red cell volume (MCV). Although patients with iron deficiency from other causes become anemic, patients with PV have increased RBC production and thus even when iron-deficient initially have a normal Hct level but microcytic RBC indices ; this combination of findings (iron-limited hematopoiesis) is a hallmark of PV.

Eventually, progression leads to a spent phase, 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, radioactive phosphorus (mostly of historic significance), and possibly hydroxyurea.

Genetic basis

Polycythemia vera is caused by clonal hematopoiesis due to a mutation in an hematopoietic stem cell..

Mutations of the Janus kinase 2(JAK2 ) gene are responsible in a high proportion of cases of polycythemia vera. JAK2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and G-CSF among other entities. Specifically, the JAK2V617F mutation or the JAK2exon12 mutation is present in most patients with PV. However, recently calreticulin (CALR) mutations have been found in PV patients lacking a JAK2 mutation, and lymphocytic adaptor protein (LNK) mutations have been found in patients with isolated erythrocytosis. These mutations lead to sustained activation of the JAK2 kinase, which causes excess blood cell production independent of erythropoietin.

Complications

Complications of polycythemia vera include

  • Thrombosis

  • Bleeding

In polycythemia vera, blood volume expands and the increased number of RBCs can cause hyperviscosity. Hyperviscosity predisposes to macrovascular thrombosis, resulting in stroke, deep venous thrombosis, MI, retinal artery or vein occlusion, splenic infarction (often with a friction rub), or, particularly in women, the Budd-Chiari syndrome, Microvascular events (eg, transient ischemic attack, erythromelalgia, ocular migraine) also may occur. There is no evidence that the increase in other cell lines (leukocytosis, thrombocytosis) increases risk of thrombosis.

Platelets may function abnormally if the platelet count is about 1,500,000/μL due to acquired deficiency of von Willebrand factor because the platelets adsorb and proteolyze high molecular weight von Willebrand multimers. This acquired von Willebrand disease predisposes to increased bleeding.

Increased cell turnover may cause hyperuricemia, increasing the risk of gout and urate kidney stones. PV patients are prone to acid-peptic disease due to H. pylori infection.

Symptoms and Signs

PV itself is often asymptomatic, but eventually the increased red cell volume and viscosity cause weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath or shower (aquagenic pruritus) and may be the earliest symptom. 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). Over 30 % 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 secondary myelofibrosis, which is clinically indistinguishable from primary myelofibrosis but has a better prognosis.

Diagnosis

  • CBC

  • Testing forJAK2, CALR, or LNK mutations (done sequentially)

  • Sometimes bone marrow examination and serum erythropoietinlevel

  • Sometimes RBC mass determination

Polycythemia vera 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 or thrombotic events in unusual sites, particularly the Budd-Chiari syndrome (women) or portal vein thrombosis (men). Neutrophils and platelets are often, but not invariably, increased; in patients with only elevated Hct, PV may be present, but secondary erythrocytosis, a more common cause of elevated Hct, must be considered first. PV should also be considered in patients with a normal Hct level but microcytic erythrocytosis and evidence of iron deficiency; this combination of findings can occur with iron-limited hematopoiesis, which is a hallmark of PV.

The challenge in diagnosing PV is that several other myeloproliferative disorders can cause the same genetic mutations and bone marrow findings and because some patients with PV do not initially manifest an elevated Hb level. Thus, multiple findings must be integrated.

Patients suspected of having PV typically should have testing for JAK2V617F and JAK2 exon12 mutations. If these are negative,do testing for CALR and LNK mutations. The presence of a known causative mutation in a patient with clear erythrocytosis is strongly suggestive of the diagnosis. If erythrocytosis is not clearly present, do a direct measure of red cell mass and plasma volume (eg, with chromium-labeled RBCs, although this test is usually available only at specialized centers) to help differentiate between true and relative polycythemia and between PV and other myeloproliferative disorders (which do not have increased red cell mass). If erythrocytosis is present but secondary causes have not been excluded, serum erythropoietin level may be done; patients with PV typically have low or low-normal serum erythropoietin levels; elevated levels suggest secondary erythrocytosis.

Bone marrow examination is not diagnostic of polycythemia vera. When done, bone marrow examination typically shows panmyelosis, large and clumped megakaryocytes, and sometimes an increase in reticulin fibers. However, no bone marrow findings absolutely differentiate PV from other disorders of excessive erythrocytosis, such as congenital familial polycythemia, or from other myeloprolierative disorders, which is important because PV is the most common myeloproliferative neoplasm.

Acquired von Willebrand disease (as a cause of bleeding) may be diagnosed by showing decreased plasma von Willebrand factor antigen using the ristocetin cofactor test.

Nonspecific laboratory abnormalities that may occur in PV include elevated vitamin B12 and B12-binding capacity, hyperuricemia and hyperuricosuria (present in 30% of patients), and decreased expression of C-mpl (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not needed for diagnosis.

Prognosis

Generally, PV is associated with a shortened life span. In a recent retrospective study, median survival was 27 yr but this is anticipated to improve as new therapies become more widely used.

Thrombosis is the most common cause of morbidity and death, followed by the complications of myelofibrosis and development of leukemia. In the future, gene expression profiling or other characteristics may aid in the identification of prognostic subgroups.

Treatment

  • Phlebotomy

  • Possibly aspirin therapy

  • Possibly targeted therapy with ruxolitinib or pegylated interferon. Currently, ruxolitinib is approved in the US only for patients who have not responded to or are intolerant of hydroxyurea.

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. However, previous criteria used to stratify treatment by high- or low-risk classification have not been prospectively validated and are not recommended.

Phlebotomy

Phlebotomy is the mainstay of therapy. The targets for phlebotomy are a 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%. Indeed, phlebotomy to a Hct < 45 % in men and < 42% in women eliminates the risk of thrombosis.

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 phlebotomy, but this is transient, and a gradual increase in the platelet count as well as the leukocyte count is a feature of PV and requires no therapy in asymptomatic patients.

In some patients treated only with phlebotomy, the phlebotomy requirement may eventually markedly diminish. This is not a sign of marrow failure (ie, the so-called spent phase) but rather is due to an expansion of plasma volume.

Aspirin

Aspirin alleviates symptoms of microvascular events. Thus, patients with symptoms of erythromelalgia, ocular migraine, or transient ischemic attacks should be given aspirin 81 to 100 mg po once/day unless contraindicated (eg, because of acquired von Willebrand disease); higher doses may be required but clearly increase the risk of hemorrhage. Aspirin does not reduce the incidence of microvascular events and thus is not indicated in asymptomatic PV patients (in the absence of other indications).

Myelosuppressive therapy

Numerous studies have shown that many previously used myelosuppressive treatments, including hydroxyurea, radioactive phosphorus, and alkylating agents such as busulfan and chlorambucil, do not reduce incidence of thrombosis, and fail to improve survival over appropriate phlebotomy. The alkylating agents such as chlorambucil and hydroxyurea also increase the incidence of acute leukemia and solid tumors; these agents are no longer recommended.

If intervention other than phlebotomy is necessary (eg, because of symptoms or thrombotic events), interferon or ruxolitinib are preferred. Anagrelide has been used to control the platelet count but has both cardiac and renal toxicity and can cause anemia.

Interferon alfa-2b or alfa-2a specifically targets the affected cell and not normal stem cells in PV. Its pegylated versions are usually well tolerated and are effective in controlling pruritus and excessive blood production as well as reducing spleen size. About 20 % of patients achieve a complete molecular remission.

Ruxolitinib, a nonspecific JAK inhibitor, is approved for use in polycythemia vera with inadequate response to or intolerance to hydroxyurea and in post-PV myelofibrosis. In PV, it is usually given at 10 mg po twice/day continued as long as response is occurring without undue toxicity.

Hydroxyurea is in widespread use in polycythemia vera, but its role is evolving with the advent of JAK inhibitors such as ruxolitinib. Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring. If JAK inhibitor drugs are not available and cytoreduction is needed, hydroxyurea is started at a dose of 500 to 1000 mg po once/day. Patients are monitored with a weekly CBC. If the WBC count falls to <4000/μL or the platelet count is <100,000/μL, hydroxyurea is withheld and reinstituted at 50% of the dose when the value normalizes. When a steady state is achieved, the interval between CBCs is lengthened to 2 wk and then to 4 wk.

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; ruxolitinib and interferon are effective. Cholestyramine, cyproheptadine, cimetidine, paroxetine, or PUVA light therapy may also be successful. After bathing, the skin should be dried gently.

Key Points

  • Polycythemia vera (PV) is a chronic myeloproliferative disorder that involves increased production of RBCs, WBCs, and platelets.

  • PV is due to mutations involving JAK2, CALR or rarely, LNK in hematopoietic stem cells that lead to sustained activation of the JAK2 kinase, which causes excess blood 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 JAK2, CALR, or LNK mutations and sometimes obtain bone marrow examination and serum erythropoietin level.

  • Phlebotomy to target Hct < 45% in men or <42% in women is essential; ruxolitinib and interferon are the preferred myelosuppressants. Cytotoxic agents should be avoided if possible and then used only temporarily.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • LEUKERAN
  • PAXIL
  • No US brand name
  • ZYLOPRIM
  • AGRYLIN
  • TAGAMET
  • MYLERAN
  • HYDREA

* This is the Professional Version. *