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Department of
Hematology and
Medical Oncology

Department of
Clinical Pathology

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     Definition

     Prevalence

     Pathophysiology

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Outcomes

     Definition

     Prevalence

     Pathophysiology

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Outcomes

     Definition

     Prevalence

     Pathophysiology

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Outcomes

     Definition

     Prevalence

     Pathophysiology

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Outcomes

     Definition

     Prevalence

     Pathophysiology

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Outcomes

PV is a clonal disorder characterized by the overproduction of mature red blood cells in the bone marrow.¹ Myeloid and megakaryocytic elements are also often increased.

The disorder typically occurs in the sixth or seventh decade of life.³ The prevalence of the disease is approximately 5 per million population, and it occurs more commonly in men and men and women of East European Jewish ancestry.^1,3

No obvious etiology exists.³ Genetic and environmental factors have been implicated in rare cases.³ Familial PV has been associated with mutation of the erythropoietin receptor.⁴ An increased number of cases have been reported in survivors of the atomic bomb explosion in Hiroshima during World War II.³

The primary defect involves a pluripotent stem cell capable of differentiating into red blood cells, granulocytes, and platelets.³ Clonality has been demonstrated through G6PD studies as well as restriction fragment length polymorphism of the active X chromosome.⁴ Erythroid precursors in PV are exquisitely sensitive to erythropoietin, which leads to increased red blood cell production.³ Precursors in PV are also more responsive to cytokines such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and steel factor.⁴ Myeloid and megakaryocytic elements are often increased in the bone marrow.⁴ More than 60% of patients will have endogenous megakaryocyte colony unit formation.³

Increased red blood cell production in PV leads to an increased red cell mass and increased blood viscosity. This in turn can lead to arterial or venous thrombosis and/or bleeding.¹ The hematocrit is directly proportional to the number of thrombotic events.³ Investigators have demonstrated a reduction in cerebral blood flow in patients with hematocrits between 53% and 62%.⁴ An increased platelet count may also contribute to bleeding and thrombosis.³ Although platelet aggregation abnormalities exist in most patients, these abnormalities do not appear to correlate with the risk of bleeding or thrombosis.³ Increased production and breakdown of blood cells can lead to hyperuricemia and hypermetabolism.¹

Patients may be asymptomatic at the time of diagnosis and have only isolated splenomegaly, erythrocytosis, or thrombocytosis.⁴ However, most patients will develop symptoms as the hematocrit and/or platelet count increase. Fifty percent to 60% of patients will have an elevated white blood cell (WBC) count.⁴ Symptoms of hyperviscosity associated with an elevated hematocrit include headache, blurred vision, and plethora.¹ Thrombosis in small blood vessels can lead to cyanosis, erythromelalgia (painful vessel dilation in the extremities), ulceration, or gangrene in the fingers or toes.¹ Thrombosis in larger vessels can lead to myocardial infarction, deep vein thrombosis, transient ischemic attacks, and stroke.¹ A cerebrovascular event may precede the diagnosis in 35% of patients with PV.³ Unusual sites of thromboses also tend to be seen more frequently in PV: splenic, hepatic, portal, and mesenteric.⁴ Ten percent of patients with Budd-Chiari syndrome (hepatic/inferior vena cava obstruction) have coexisting PV.⁴ Abnormalities in platelet function can lead to epistaxis, bruising, and gastrointestinal and gingival bleeding in 2% to 10% of patients.^1,4 Severe bleeding episodes are unusual.¹ Hypermetabolism caused by increased blood cell turnover can lead to hyperuricemia, gout, stomach ulcers, weight loss, and kidney stones.¹ Pruritis is especially common after a warm bath or shower.¹ As the disease progresses, many patients will develop abdominal pain secondary to hepatomegaly and/or splenomegaly.¹

PV should be suspected in men with a hematocrit greater than 50% and in women with a hematocrit greater than 45%.⁴ Confirmation of an elevated hematocrit involves measuring a red blood cell mass,¹ using direct tagging of red blood cells with chromium-51. These studies may not be needed in men with hematocrits greater than 60% or in women with hematocrits greater than 55%.⁴ Secondary causes of polycythemia also need to be ruled out: hypoxia (due to heart/lung disease or smoking) and cysts/tumors in the liver, kidney, or brain (all of which can secrete erythropoietin).¹ Serum erythropoietin levels should be low-normal in patients with PV but high in patients with secondary polycythemia, although there may be some overlap.¹

The Polycythemia Vera Study Group (PVSG) has designed two sets of diagnostic criteria³ that help incorporate the above criteria as well as common laboratory/clinical signs associated with PV:

Category A

Category B

The PVSG has recently changed the definition of elevation of red blood cell mass to be greater than 25% of the mean predicted value of a red blood cell mass for that individual rather than a volume/kg body weight.⁴ A diagnosis of PV is met if a patient has A1 + A2 + A3 or A1 + A2 + any two criteria from B.³ The above criteria may miss patients in the early stages of disease.³ These criteria are not always strictly adhered to clinically (particularly measurement of the red blood cell mass), and new diagnostic algorithms are being developed that incorporate serum erythropoietin levels.

Although not included in the PVSG criteria, other tests may also help establish the diagnosis in the early stages of disease. The bone marrow aspirate and biopsy typically is hypercellular with erythroid, granulocytic, and megakaryocytic hyperplasia in PV (Figure 1).⁴ In addition, the erythroid progenitor cells are typically able to proliferate in the presence of very little erythropoietin (endogenous colony formation).⁴ Cytogenetic abnormalities are found in 8% to 20% of patients at diagnosis,⁴ with the most frequent being trisomy of chromosomes 8 and 9 and partial deletion of the long arm of chromosome 20. Serum erythropoietin levels also are becoming increasingly helpful, as discussed above.

THERAPY

Treatment of PV focuses on decreasing hemoglobin, thereby reducing plasma viscosity and its attendant complications. Therapeutic options include phlebotomy, radioactive phosphorus (³²P), and myelosuppressive agents. The goal of therapy³ is a hematocrit of 45% on the basis of cerebral blood flow studies.³ Multiple clinical trials have tried to address the optimal treatment of PV. In the PVSG-01 study, 431 patients were randomized to phlebotomy, ³²P, or chlorambucil after phlebotomy to a normal hematocrit.³ The minimum follow-up was 11 years.³ Overall survival was equivalent in the phlebotomy and ³²P arms but decreased in the chlorambucil arm.³ Thrombotic events were increased in the phlebotomy arm, particularly in patients with a history of thrombosis, advanced age, or high phlebotomy requirements.³ There was an increased risk of leukemia in the ³²P and chlorambucil arms (2 to 3 times that seen in the phlebotomy arm).³ Because of the increased leukemogenicity associated with chlorambucil, hydroxyurea, which inhibits ribonucleotide reductase, is now the most widely used myelosuppressive agent.³ Side effects of hydroxyurea may include myelosuppression, macrocytosis, leg ulcers, increased creatinine, and jaundice.⁴ There is great controversy regarding the leukemogenic potential of hydroxyurea.³ Until longer follow-up data are available, it should be used with caution in younger patients.³

Based on PVSG-01, investigators have made various treatment recommendations for patients based on their age, phlebotomy requirement, and high risk of thrombosis. For patients older than 70 years, ³²P plus supplemental phlebotomy may be used because of the high risk of thrombosis in these patients.³ For patients less than 70 years of age, phlebotomy alche may be used.³ Hydroxyurea should be added only if the patient has a high phlebotomy requirement or history of thrombosis.³ Myelosuppressive agents should also be used for symptomatic splenomegaly, pruritis intractable to antihistamines, or patients with poor venous access.³ Interferon-alfa may also be used in the place of hydroxyurea for myelosuppression (particularly in younger patients) and intractable pruritis. Side effects of interferon include flulike syndromes, fevers, neuritis, and fatigue.⁴ Patients with PV who are undergoing surgery are at extremely high risk of developing postoperative complications if their erythrocytosis is not controlled before surgery.⁴

Platelet antiaggregating agents should be used in patients with thrombotic events.³ Patients with erythromelalgia experience a rapid relief of their symptoms after low-dose aspirin.³ No studies have demonstrated a decrease in thrombotic events with high-dose aspirin or dipyramidole treatment.³

The median survival is more than 10 years with treatment. The major causes of death in untreated patients are thrombosis and hemorrhage.¹ Less than 10% of patients develop acute myelogenous leukemia.¹ Fifteen percent of patients will develop MF at an average interval of 10 years from diagnosis.³ Once they develop MF, most patients will die within 3 years.³ MF frequently transforms to acute myelogenous leukemia.³

Many symptoms are attributable to the pancytopenia associated with myelofibrosis. Pancytopenia occurs as a result of both decreased hematopoiesis and splenic sequestration. Most patients are anemic and will feel short of breath and fatigued. Thrombocytopenia and neutropenia can lead to hemorrhage and infection.

Other constitutional symptoms include anorexia, weight loss, and night sweats.¹ The WBC count and the platelet count may increase initially but typically decrease as the disease progresses.¹ The blood film displays a characteristic "leukoerythroblastic" picture (teardrop poikilocytosis, nucleated red blood cells, and immature myeloid elements) due to crowding out of normal hematopoietic elements by fibrosis in the bone marrow (Figure 3).⁴

Patients may complain of abdominal discomfort and decreased appetite due to splenic and hepatic enlargement resulting from extramedullary hematopoiesis.¹ Portal hypertension and jaundice may occur as a result of increased hepatic blood flow.⁴ Rarely, extramedullary hematopoiesis can occur at other sites, such as the skin, lung, bladder, genitourinary tract, gastrointestinal tract, and central nervous system.⁴ Severe bone pain typically heralds a poor prognosis and often represents a conversion of MF to acute leukemia.⁴

The blood film demonstrates a characteristic leukoerythroblastic picture.⁴ When performing a bone marrow aspirate and biopsy, a "dry tap" is obtained in many patients when trying to get the aspirate.¹ Special stains of the bone marrow biopsy will demonstrate increased fibrosis. Stains that contain silver can be used to identify reticulin, the glycoprotein coating of stromal cell strands that appears as black fibers.⁶ Trichrome stains identify mature collagen as bluish-green fibers (Figure 4).⁶

The bone marrow biopsy is typically hypercellular, and increased/abnormal megakaryocytes are often present.^1,4 Thirty percent to 75% of patients will have cytogenetic abnormalities at the time of diagnosis,⁴ with the most common abnormalities being del(13q), del(20q), and partial trisomy 1q. Secondary causes of marrow fibrosis (such as metastatic breast cancer, lymphoma, lung cancer, infection, and autoimmune disorders), as well as other hematologic disorders (hairy cell leukemia, CML), need to be excluded since these disorders would be treated differently.⁴ In addition, one needs to rule out panmyelosis with acute myelofibrosis and acute megakaryoblastic leukemia.⁴ These entities will also present with pancytopenia and marrow fibrosis, but patients typically have no splenomegaly, minimal or absent teardrop poikilocytosis, and increased numbers of blasts in acute myelofibrosis and acute megakaryoblastic leukemia.⁴

There are no available treatments to reverse the process of idiopathic myelofibrosis short of bone marrow transplantation.¹ Because of the high median age at diagnosis, most patients are not suitable bone marrow transplant candidates. Patients younger than 55 years old should be considered for allogeneic bone marrow transplantation. A recent study demonstrated a 47% overall survival at 5 years, with regression of fibrosis in 40% of patients.⁶ The role and benefit of using chemotherapeutic agents early in the disease to reverse the fibrosis is highly controversial, and randomized clinical trials are needed to address this issue.⁴ Most care is directed toward symptomatic management with transfusions (red blood cells, platelets) and growth factors (erythropoietin for anemia, granulocyte-colony stimulating factor for neutropenia).¹ Because of the frequency of red blood cell transfusions, patients may require iron chelation therapy to decrease the risk of iron overload.⁴ Androgens (danazol) and, occasionally, low-dose steroids (such as prednisone) may also be helpful in managing the anemia associated with ineffective erythropoiesis.⁴

Splenomegaly may require treatment with myelosuppressive agents, splenectomy, or palliative radiation.¹ Splenic irradiation is typically associated with transient responses and should be considered in patients too ill for splenectomy or chemotherapy.⁴ Splenectomy should be considered for symptomatic splenomegaly, portal hypertension, transfusion-dependent anemia, and severe thrombocytopenia.⁷ In a series of 223 patients at the Mayo Clinic, patients experienced durable remissions in constitutional symptoms (67%), transfusion-dependent anemia (23%), portal hypertension (50%), and thrombocytopenia (0%) after splenectomy.⁷ The operative mortality was 9% and morbidity 31% (including postoperative thrombotic complications).⁷ Sixteen percent of patients developed hepatomegaly, and 22% of patients developed thrombocytosis (which was associated with an increased risk of perioperative thrombosis).⁷ Blastic transformation was 16.3% in this series, and the risk was increased in patients with splenomegaly and preoperative thrombocytopenia, suggesting that pre-splenectomy thrombocytopenia may be a surrogate marker of advanced disease.⁷

In the future, we hope that clinical development of antifibrotic/antiangiogenesis therapies will play an important role in the therapeutic armamentarium.⁶

The proliferation of megakaryocytes is primarily due to a clonal stem cell, as confirmed by enzyme and genetic analysis.⁸ Megakaryocyte progenitor cells in
ET are hypersensitive to the action of several cytokines including IL-3 and IL-6, and possibly thrombopoietin.^4,8 This leads to increased platelet production.⁴ There is
controversy regarding spontaneous megakaryocyte formation in ET.⁴ Thrombopoietin and its associated receptor pathways do not appear to be involved in ET.⁴

Increased platelet counts in ET are associated with increased thrombotic and hemorrhagic complications. Decreasing platelet counts in ET (to less than 600,000/µL)
can decrease thrombotic complications (see below).⁹ High platelet counts (greater than 1 million/mL) are associated with acquired von Willebrand's disease due to adsorption of von Willebrand multimers onto platelet membranes.⁴ A reduction in the platelet count is associated with correction of the defect and cessation of bleeding.⁴ Qualitative abnormalities in the platelets themselves are also likely to contribute to the increased risk of thrombotic and hemorrhagic complications in ET since reactive thrombocytosis is not associated with an increased risk of thrombosis or bleeding, even with high platelet counts.⁹ Platelet aggregation studies in ET are frequently abnormal.⁴

The clinical signs/symptoms are similar to those of PV. Patients may present with splenomegaly, hepatomegaly, or hemorrhagic or thrombotic episodes.⁴ Thirteen percent to 37% of patients will experience a hemorrhagic event, and 22% to 84% of patients will experience a thromboembolic event.⁴ Constitutional symptoms, such as weight loss, fever, and pruritis may also occur.⁴ Other patients may be asymptomatic, with a diagnosis based on an elevated platelet count.

As with PV, thrombotic episodes may occur in the major vessels or microvasculature (see PV: Signs and symptoms).⁴ Thrombotic episodes occur more frequently in older patients and patients with a history of thrombotic events.⁴ This increase in thrombotic risk with age has been attributed to the coexistence of vascular disease in older patients.⁴ Events tend to occur mainly in the microvasculature.⁴

Women of childbearing age may present with a spontaneous abortion (secondary to placental thrombosis).⁴ Hemorrhage is most common in the gastrointestinal tract.⁴

The first step should be examination of the peripheral blood film (Figure 5).⁴ Automated hematology analyzers can erroneously count platelet-sized particles that are red or white cell fragments as platelets (pseudothrombocytosis).⁴

In order to diagnose ET, one must also exclude causes of reactive thrombocytosis as well a clonal thrombocytosis secondary to another myeloproliferative disorder (ie, CML).⁹ Causes of reactive thrombocytosis can include inflammatory states, infection, malignant disease, trauma, blood loss, and the postsplenectomy state.^4,8

In one series of 280 patients with thrombocytosis at a university hospital, 82% of the cases were reactive thrombocytosis.⁴ A number of these patients will have platelet counts above 1 million/µL so the degree of thrombocytosis is not helpful in making a diagnosis.⁴ Reactive thrombocytosis is associated with elevated levels of IL-6 or C-reactive protein in 81% of patients, which may help distinguish it from ET.⁸ Patients with uncomplicated thrombocytosis secondary to a myeloproliferative disorder typically have undetectable IL-6 levels.⁶

A bone marrow aspirate and biopsy with cytogenetics (and reverse transcriptase polymerase chain reaction [RT-PCR] for Bcr-Abl) can be helpful in excluding other myeloproliferative disorders, particularly CML (which has the Bcr-Abl gene).⁹ Two thirds of patients with ET will have bone marrows with marked megakaryocytic hyperplasia, morphologically bizarre megakaryocytes with nuclear pleomorphism, and clustering of megakaryocytes (Figure 6).⁴ Increased myeloid and erythroid precursors, abnormal cytogenetics, reticulin fibrosis, and spontaneous megakaryocyte colony formation may also be present.⁴ These features are not typically present in bone marrows of patients with reactive thrombocytosis.⁴ Clinical features that suggest ET rather than reactive thrombocytosis include a chronically elevated platelet count, splenomegaly, and a history of thrombosis or hemorrhage.⁴ Red cell mass and plasma volume studies may be needed to differentiate ET from PV.⁴

A randomized study⁹ demonstrated that hydroxyurea decreases the risk of thrombosis in high-risk patients who have ET from 24% to less than 4% (P = 0.003), compared with no treatment, when the platelet count is decreased to less than 600,000/µL. In addition, maintaining a platelet count less than 400,000/µL may be associated with a further reduction in thrombosis, although these data have not been confirmed in a randomized trial.⁸ The risk stratification for thrombotic events in ET and PV is the same. Patients older than age 60 or with a history of thrombotic events are considered to be at high risk.⁸ Patients with cardiovascular risk factors or extreme thrombocytosis (platelet counts greater than 1.5 million/µL) are considered to be at intermediate risk.⁸

In low-risk patients, thrombotic events are too infrequent to justify long-term drug therapy, although the use of low-dose aspirin is optional.⁸ Controversy exists regarding the treatment of intermediate-risk patients.⁸

In addition to hydroxyurea, anagrelide can also control thrombocytosis in most patients.⁸ The drug works by interfering with megakaryocyte maturation.⁸ However, no randomized study has demonstrated that the drug actually decreases the risk of thrombotic events.⁸ Therefore, it should be used in patients with ET who do not tolerate hydroxyurea, or in young patients who will need long-term therapy.⁸ The main side effects include headaches, palpitations and, rarely, a nonischemic cardiomyopathy.⁸ The above effects are secondary to the drug's vasodilatory, inotropic actions⁸; therefore, it should be used cautiously in patients with cardiac disease.⁹ Anagrelide can also decrease the hematocrit (but not the WBC count).⁴ Interferon-alfa is another option for patients, but its use in ET is limited primarily to high-risk women of childbearing age.⁸ There are no specific recommendations for ET during pregnancy. Although 45% of women will have spontaneous abortions, abortions cannot be predicted by the course of disease, platelet count, or specific treatment.⁸ Agents such as ³²P or busulfan are rarely used in ET, but can be used in patients whose life expectancy is <10 years.⁸ Low doses of aspirin may decrease the thrombotic risk in ET and PV, but randomized studies are still pending.⁸

Patients with life-threatening hemorrhagic or thrombotic events should be treated with plateletpheresis in combination with myelosuppressive therapy.⁸ Patients with a platelet count greater than 1.5 million/µL and acquired von Willebrand syndrome should be treated with platelet reduction therapy and should avoid aspirin.⁴ These patients also may require treatment with factor VIII and desmopressin in the setting of a bleeding episode.⁴ Finally, patients undergoing surgery have an increased risk of thrombotic and bleeding episodes, and should have their platelet counts normalized before surgery.⁴

Supportive care for CMML includes transfusions and growth factor support.

The active treatment of CMML has been disappointing. Young patients with an HLA- identical sibling should be evaluated for allogeneic bone marrow transplantation.¹¹ However, most patients with CMML are elderly and are not candidates for bone marrow transplantation. Low-dose chemotherapy (cytosine arabinoside) has low response rates, and intensive chemotherapy has been less active than in MDS.¹¹ Hydroxyurea can be used in patients with splenomegaly or high leukocyte counts; however, the responses are often partial, and blood counts may decrease during treatment.¹¹ Investigators have examined other agents such as VP-16 (etoposide). In a randomized trial, hydroxyurea gave higher response rates and better survival than VP-16 in advanced CMML.¹¹ Other agents, such as topotecan, a topoisomerase I inhibitor, look promising in initial trials.¹² However, their long-term impact, and the result of combining them with other agents, is unknown.¹²

A subset of patients with CMML will have a t(5;12)(q33;p13) translocation, encoding a Tel-PDGFR beta fusion protein.¹³ This group of patients may benefit from treatment with STI-571, which inhibits PDGFR as well as the Bcr-Abl kinase.

The prognosis in CMML is highly dependent on the number of blasts in the bone marrow.⁴ The life expectancy can vary from several months to several years.¹⁰ A recent study of 213 patients with CMML was used to define a prognostic scoring system.¹⁰ In a multivariate analysis, hemoglobin less than 12 g/dL , the presence of circulating immature myeloid cells, an absolute lymphocyte count greater than 2.5 x 10⁹/L, and marrow blasts 10% or more were associated with a shorter survival.¹² Based on the number of adverse factors (0 to 4), four subgroups of patients could be defined (low, intermediate-1, intermediate-2, and high-risk), with respective median survivals of 24, 15, 8, and 5 months.¹⁰ This scoring system has subsequently been validated in a separate set of patients.¹⁰

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