Chapter 43: Polycythemia Vera

• Polycythemia vera (PV) is a clonal disorder due to somatic mutations of a multipotential hematopoietic cell, in which blood cell production, notably erythropoiesis, is increased independent of cytokine regulation. This results in exaggerated proliferation and accumulation of erythrocytic, granulocytic, and megakaryocytic cells. PV is one of the chronic myeloproliferative disorders (MPDs): essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML); these disorders are also called myeloproliferative neoplasms (MPN).

• Three myeloproliferative neoplasms (PV, ET, PMF) share a common molecular abnormality/marker, the JAK2 kinase V617F mutation.

• PV arises from the neoplastic transformation of a single hematopoietic multipotential cell, which provides both a selective growth and survival advantage that results in the cells produced in the clone suppressing and replacing normal polyclonal hematopoiesis.

• The JAK2 kinase V617F mutation directly activates erythropoietin (EPO) receptor.

• In vitro erythroid colonies developing in the absence of added EPO are characteristic for PV.

• Karyotypic abnormalities are not specific; develop later in the disease, may portend transformation into myelofibrosis or myelogenous leukemia.

• Familial incidence of PV and/or other MPDs, occurs in about 5 percent of patients.

• Incidence ranges from 1 to 2.5 per 100,000 reported in different countries.

• PV usually has an insidious onset, most commonly during the sixth decade of life, although may occur at any age, including childhood.

• Presenting symptoms and signs: headache, plethora, pruritus, thrombosis (esp. Budd-Chiari syndrome), erythromelalgia, and gastrointestinal bleeding. Many patients diagnosed because of elevated hemoglobin and/or platelets on routine medical examination. Other cases may be uncovered during investigation for blood loss, iron-deficiency anemia (sometimes as a result of prior bleeding), or thrombosis. Symptoms are reported by at least 30 percent of patients with polycythemia at the time of diagnosis.

• Neurologic complaints include vertigo, diplopia, scotomata, and transient ischemic events.

• Associated disorders include peptic ulcer disease and gout.

• Thrombotic and hemorrhagic events are the most significant clinical manifestations of PV; they may occur prior to diagnosis of the disease.

• Thrombotic episodes are the most common and the most important complications, occurring in about one-third of the patients; these may be fatal, and include stroke, myocardial infarction, deep venous thrombosis, hepatic vein thrombosis, and pulmonary embolism.

• Bleeding and bruising are common complications of PV, occurring in about one-quarter of the patients in some series (generally when platelet count over 1000 × 10⁹/L). Whereas such episodes (such as gingival bleeding, nose bleeding, or easy bruising) are usually minor, serious gastrointestinal bleeding (which may mask polycythemia) and other hemorrhagic complications with a fatal outcome also can occur.

• Patients with uncontrolled PV undergoing surgery have a high risk of bleeding and/or thrombosis. Phlebotomy should be used to decrease hematocrit prior to surgery to lessen risk.

• The most consistent is a mutation in exon 14 of JAK2 kinase, present in >95 percent of PV patients. It is a single nucleotide change JAK2 G1849T, referred to as the JAK2 V617F mutation.

• The detection of the JAK2 V617F mutation provides a qualitative diagnostic marker for the identification of PV (as well as ET and PMF) and its differentiation from congenital and acquired reactive polycythemic disorders.

• JAK2 V617F is present in other MPDs. In general, PMF and PV patients have the higher level, and ET patients the lower JAK2 V617F allelic burden. In virtually all PV JAK2 V617F-positive patients, at least some progenitors exist that are homozygous for the JAK2 V617F mutation by uniparental disomy acquired by mitotic recombination.

• The uncommon cases of PV negative for JAK2 V617F often carry one of a number of mutations in the terminus of exon 12.

• Hemoglobin is typically elevated. In patients who have or have had hepatic vein thrombosis, gastrointestinal blood loss, or have been treated with phlebotomy, hemoglobin may be normal. Hypochromia, microcytosis, and other evidence of iron deficiency are often present as a result of prior chronic blood loss usually through the stool.

• Red cell mass is usually elevated, sometimes not in proportion to the level of hemoglobin, implying a concomitant increase in plasma volume.

• Nucleated red cells and teardrops (dacrocytes) are not present in the blood film early in the disease.

• Absolute neutrophilia occurs in about two-thirds of patients, with occasional myelocytes and metamyelocytes. Slight basophilia also occurs in about two-thirds of patients.

• The platelet count is increased in over 50 percent of patients and exceeds 1000 × 10⁹/L in about 10 percent. Acquired von Willebrand disease may be present (see Chap. 80).

• Platelets also may have a characteristic functional defect in the primary wave of aggregation induced by epinephrine while spontaneous platelet aggregation is accelerated.

• Marrow is usually hypercellular, with absent iron stores. A mild degree of marrow reticulin fibrosis may be present, particularly in long-standing disease.

• Prothrombin time and partial thromboplastin time may be spuriously prolonged if the amount of anticoagulant used in the test is not adjusted for the decreased proportion of plasma.

• The most important diagnostic features of polycythemia vera include:

  — The presence of the JAK2 V617F mutation in blood cells.

  — Erythrocytosis (elevated hemoglobin and or red cell mass).

  — Low serum EPO levels.

  — Leukocytosis (specifically neutrophilia).

  — Thrombocytosis.

  — Splenomegaly.

• Other helpful clinical features are:

  — Pruritus, often provoked by a warm bath or shower.

  — Elevated serum vitamin B₁₂ level.

  — Elevated serum uric acid level.

  — Normal or near-normal arterial oxygen saturation.

• Another test of value, if available, is demonstration of erythroid colony growth in vitro in absence of added EPO.

• Some consider the measurement of red cell mass to be the sine qua non for diagnosis of PV, but others believe this study should be reserved for special circumstances, such as in the case of unexplained thrombocytosis, splenomegaly, or a JAK2 mutation and a normal hemoglobin concentration. If the hemoglobin concentration is greater than 16.5 g/dL in a woman or greater than 18.5 g/dL in a man, the probability of an elevated red cell mass is very high.

• The diagnostic task has been facilitated by the discovery of the JAK2 kinase mutation that is present in >95 percent of all PV patients.

• Diagnostic criteria recently established by the World Health Organization are helpful in most cases (see Table 43–1). They are yet to be validated by prospective clinical studies.

• A V617F-negative patient may have PV and require a search for other JAK2 mutations or they may have another type of polycythemia.

• A V617-positive patient may have another MPD.

• The mainstay of therapy for PV remains nonspecific myelosuppression, which many practitioners supplement with phlebotomies. Anagrelide may be added to control thrombocytosis (see Table 43–2).

• Additional measures are medications to prevent thrombotic events (i.e., aspirin) and to relieve symptoms; aspirin should not be used when platelet count is higher than 1000 × 10⁹/L because it increases risk of bleeding.

• Promising therapies are pegylated interferon preparations, which are better-tolerated than non-pegylated preparations, and JAK2 inhibitors, which are being evaluated mainly in the post PV-myelofibrotic stage.

• It is useful to consider treatments in the plethoric and the spent phases separately.

Plethoric Phase

• The treatment of patients in the plethoric phase of the disease is aimed at ameliorating symptoms and decreasing the risk of thrombosis or bleeding by reducing the blood counts. This is accomplished by myelosuppressive drugs and, additionally in some patients, phlebotomies, platelet-reducing agents, or interferon-α therapy.

• Treatment should be individualized according to risk factors:

  — High risk – patients with previous thrombosis and/or transient ischemic attacks.

  — Intermediate risk – patients over 60 years of age.

  — Low risk – the remaining patients.

• High risk and intermediate risk patients require interferon or other myelosuppressive therapy.

• The absolute leukocyte count strongly correlates with thrombotic complications, and this laboratory parameter is now being evaluated in the therapeutic decision-making process as are additional risk factors, including hypertension, smoking, and diabetes.

• Myelosuppression

  — Myelosuppressive therapy decreases blood counts, decreases the risk of vascular events, and ameliorates symptoms, and increases an overall sense of well-being. While there is also a clinical impression that it increases a patient's long-term survival, there are no clinical studies to document this.

  — At present, hydroxyurea at doses of 500 to 2500 mg daily is the preferred drug.

  — Hydroxyurea's suppressive effect is of short duration. Thus, continuous rather than intermittent therapy is required. Because it is short acting, it is relatively safe to use, even when excessive marrow suppression occurs, since the blood counts rise within a few days of decreasing the dose or stopping the drug.

  — Because it is not an alkylating agent, hydroxyurea has less potential for causing leukemic transformation.

  — Busulfan (Myleran) or P³² may be used in selected cases.

• Phlebotomy

  — Is best used in conjunction with myelosuppression; it is also used as the initial treatment by some physicians.

  — Most patients of average size can tolerate initial phlebotomy of 450 to 500 mL about every 4 days until the target hemoglobin level is reached.

  — Contributes to iron deficiency. Iron supplementation is counterproductive and may result in rapid reappearance of polycythemia, but a short course of oral iron therapy is often helpful in amelioration of fatigue.

  — Phlebotomy alone is associated with a higher incidence of thrombotic events, especially in older patients, those with a high phlebotomy requirement, and those with a prior thrombotic event.

• Summary of therapeutic approach for patients not participating in clinical trials:

  — Myelosuppression with hydroxyurea daily, both as initial therapy (1500 mg qd) and long-term treatment (500 to 2000 mg qd), aiming to maintain neutrophil counts at low-normal levels. In addition, some patients require the use of phlebotomies and/or anagrelide to maintain the hemoglobin and platelet levels in normal ranges.

  — Aspirin at a dose 80 to 100 mg qd is given to all patients without histories of major bleeding or gastric intolerance and when platelet count is not over 1000 × 10⁹/L).

  — Allopurinol for elevated uric acid levels and medication to control pruritus is used when required.

  — Judicious phlebotomies with isovolemic replacement in patients with hematocrits >55 percent (others recommend keeping hematocrtit <45 for men and <43 for women) and in patients who report immediate improvement of symptoms after phlebotomy. The symptoms that may be related to hyperviscosity are headaches, difficulty concentrating, and fatigue.

  — Pegylated interferon preparations are being used increasingly with excellent results reported in pilot studies.

  — JAK2 tyrosine kinase inhibitors are also being evaluated.

Spent Phase

• Sometimes after only a few years and usually after 10 or more years (but not in all patients), erythrocytosis in patients with PV gradually abates, phlebotomy requirements decrease and cease, and anemia develops. During this "spent" phase of the disease, marrow fibrosis becomes more marked and the spleen often becomes greatly enlarged. The condition (post-PV PMF) is indistinguishable from PMF (see Chap. 48). Patients typically have teardrops and leukoerythroblastic morphology, may have leukocytosis or leukopenia, thrombocytosis or thrombocytopenia, and immature leukocytes (including blasts) in the blood.

• Nonmyeloablative allogeneic stem cell transplantation should be considered for eligible patients as only a curative therapy.

• For patients not eligible for transplantation, the treatment is symptomatic/supportive only. It consists of any of:

  — JAK2 inhibitors.

  — Gentle myelosuppression with low doses of hydroxyurea.

  — Red cell transfusion and/or erythropoiesis stimulating agents.

  — thalidomide and its derivatives

  — androgens

  — experimental therapies

  — General comfort measures and analgesics.

  — Splenectomy may be considered for significant cytopenias, recurrent infarctions.

• See Table 43–3 for criteria that define a patient's response to therapy.

• Thrombotic complications discussed in the preceding sections are the dominant cause of morbidity and mortality in patients with PV.

• In addition, and in contrast to other polycythemic disorders, PV has an increased risk of evolution to acute leukemia. While several clinical stages of PV are recognized (plethoric or proliferative phase, stable phase, spent phase or post-polycythemic myelofibrosis phase, and acute leukemia), it is not clear that these stages represent a sequential progression of the disease.

• PV is a disease that is compatible with normal or near-normal life for many years and many patients may not need any therapy while most would benefit from aspirin. However, most studies agree that there is excess mortality attributable to thrombotic complications and acute leukemia transformation as a direct consequence of PV.