Chronic myeloproliferative disorders (MPDs) are characterized by the clonal proliferation of one or more hematopoietic cell lineages, predominantly in the bone marrow, but sometimes in the liver and spleen.¹ Traditionally, the chronic myeloproliferative disorders have included polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), chronic myelogenous leukemia (CML), and chronic myelomonocytic leukemia (CMML).¹ The World Health Organization (WHO) has reclassified CMML from the myelodysplastic syndrome (MDS) group into a new group of MDS/MPDs because its clinical and pathologic features overlap those of traditional MDS disorders and MPDs.² Revisions to the WHO classification of PV, CIMF, and ET are anticipated, and reflect a new understanding of the role of Janus kinase 2 (JAK2) mutation as a molecular marker of myeloid neoplasia.³ This chapter reviews the definition, prevalence, pathophysiology, signs and symptoms, diagnosis, treatment, and outcomes of each of these clinical entities. CML is discussed elsewhere in this section (“Chronic Leukemias”).

Polycythemia vera

Definition and Etiology

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. No obvious cause exists.⁴ Genetic and environmental factors have been implicated in rare cases. Familial PV has been associated with mutation of the erythropoietin receptor.⁵ An increased number of cases has been reported in survivors of the atomic bomb explosion in Hiroshima during World War II.

Epidemiology

The disorder typically occurs in the sixth or seventh decade of life. The prevalence of the disease is approximately 5 per million population; it occurs more commonly in men and in men and women of East European Jewish ancestry.^1,4

Pathophysiology

The primary defect involves a pluripotent stem cell capable of differentiating into red blood cells, granulocytes, and platelets.⁴ Clonality has been demonstrated through glucose-6-phosphate dehydrogenase (G6PD) studies as well as restriction fragment length polymorphism of the active X chromosome.⁵ Erythroid precursors in PV are exquisitely sensitive to erythropoietin, which leads to increased red blood cell production. Precursors in PV are also more responsive to cytokines such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and steel factor. Myeloid and megakaryocytic elements are often increased in the bone marrow (Fig. 1). More than 60% of patients have endogenous megakaryocyte colony unit formation.

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, bleeding, or both.¹ The hematocrit is directly proportional to the number of thrombotic events.⁴ Investigators have demonstrated a reduction in cerebral blood flow in patients with hematocrits between 53% and 62%.⁵ An increased platelet count can also contribute to bleeding and thrombosis. Although platelet aggregation abnormalities exist in most patients, these abnormalities do not appear to correlate with the risk of bleeding or thrombosis. Increased production and breakdown of blood cells can lead to hyperuricemia and hypermetabolism.

Signs and Symptoms

Patients may be asymptomatic at the time of diagnosis and have only isolated splenomegaly, erythrocytosis, or thrombocytosis.⁵ However, most patients develop symptoms as the hematocrit, platelet count, or both increase. An elevated white blood cell (WBC) count is found in 50% to 60% of patients. 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. Thrombosis in larger vessels can lead to myocardial infarction, deep venous thrombosis, transient ischemic attacks, and stroke. A cerebrovascular event precedes the diagnosis in 35% of patients with PV.⁴ Unusual sites of thromboses also tend to be seen more frequently in PV—splenic, hepatic, portal, and mesenteric.

Of patients with Budd-Chiari syndrome (hepatic–inferior vena cava obstruction), 10% have coexisting PV. Abnormalities in platelet function lead to epistaxis, bruising, and gastrointestinal and gingival bleeding in 2% to 10% of patients. Severe bleeding episodes are unusual. Hypermetabolism caused by increased blood cell turnover can lead to hyperuricemia, gout, stomach ulcers, weight loss, and kidney stones. Pruritis is especially common after a warm bath or shower. As the disease progresses, many patients develop abdominal pain secondary to hepatomegaly, splenomegaly, or both.

Diagnosis

PV should be suspected in men with a hematocrit higher than 50% and in women with a hematocrit higher than 45%.⁵ Confirmation of an elevated hematocrit involves measuring a red blood cell mass¹ using direct tagging of red blood cells with chromium 51, a test unfortunately not widely available. These studies might not be needed in men with hematocrits higher than 60% or in women with hematocrits higher than 55%.

Secondary causes of polycythemia also need to be ruled out: hypoxia caused by heart or lung disease or smoking and cysts or tumors in the liver, kidneys, or brain, all of which can secrete erythropoietin. Serum erythropoietin levels should be low to normal in patients with PV but high in patients with secondary polycythemia, although there may be some overlap. Molecular testing for the JAK2 V617 or other functionally similar mutation plays a central role in the diagnosis of PV as a way of separating neoplastic from reactive myeloid proliferations.

The initial diagnostic criteria defined by the PVSG (Polycythemia Vera Study Group) have undergone changes over the last several years. The current diagnostic criteria have been published by WHO.⁶ A diagnosis of PV is met if a patient has the first two A criteria together with any other A criterion or two B criteria. New proposed revised WHO criteria for polycythemia vera include major and minor criteria, and diagnosis will require the presence of both major criteria and 1 minor criterion or the presence of the first major criterion together with 2 minor criteria.³

A Criteria

• Elevated red cell mass more than 25% above mean normal predicted value, or hemoglobin higher than 18.5 g/dL in men or 16.5 g/dL in women, or higher than the 99th percentile of method-specific reference range for age, sex, and altitude of residence
• No cause of secondary erythrocytosis, including:
  • Absence of familial erythrocytosis
  • No elevation of erythropoietin caused by:
    1. Hypoxia (arterial Po₂ <92%)
    2. High oxygen affinity hemoglobin
    3. Truncated erythropoietin receptor
    4. Inappropriate erythropoietin production by tumor
• Splenomegaly
• Clonal genetic abnormality other than the Philadelphia chromosome or BCR/ABL1 fusion gene in marrow cells
• Endogenous erythroid colony formation in vitro

B Criteria

• Thrombocytosis higher than 400 × 10⁹/ L
• Leukocytosis higher than 12 × 10⁹/ L
• Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocyte proliferation
• Low serum erythropoietin levels

Major Criteria

• Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume
  1. Hemoglobin or hematocrit greater than the 99th percentile of method-specific reference range for age, sex, altitude of residence or hemoglobin greater than 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from a patient's baseline value that cannot be attributed to correction of iron deficiency, or
  2. Elevated red cell mass greater than 25% above mean normal predicted value
• Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation

Minor Criteria

• Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
• Serum erythropoietin level below the reference range for normal
• Endogenous erythroid colony formation in vitro

Treatment

Treatment of PV focuses on decreasing the hemoglobin level, thereby reducing plasma viscosity and its attendant complications. Therapeutic options include phlebotomy, radioactive phosphorus (³²P), and myelosuppressive agents. The goal of therapy is a hematocrit of 45% on the basis of cerebral blood flow studies.⁴ Several clinical trials have tried to address the optimal treatment of PV.

Treatment for PV should be risk-adapted.⁶ Patients at high risk for thrombosis include patients older than 60 years and those with a prior history of thrombosis. Low-risk patients include those who are younger than 60 years with no history of thrombosis, a platelet count below 1500 × 10⁹/L, and the absence of cardiovascular risk factors (e.g., smoking, hypertension, congestive heart failure). In the PSVG-01 study, thrombotic events were increased in the phlebotomy arm, particularly in patients with a history of thrombosis, advanced age, or high phlebotomy requirement.⁴ Therefore, high-risk patients should be treated with phlebotomy plus hydroxyurea or interferon. Hydroxyurea is typically used as first-line therapy. However, interferon should be used in women of childbearing age and in patients who cannot tolerate hydroxyurea. Low-risk or intermediate-risk patients may be treated with phlebotomy alone.

In the PVSG-01 study, there was an increased risk of leukemia in the ³²P and chlorambucil arms (two or three times that seen in the phlebotomy arm).⁴ Because of the increased leukemogenicity associated with chlorambucil, hydroxyurea, which inhibits ribonucleotide reductase, is now the most widely used myelosuppressive agent. Side effects of hydroxyurea include myelosuppression, macrocytosis, leg ulcers, increased creatinine level, and jaundice.⁵ A recent large study has demonstrated no increased incidence of leukemia in PV patients treated with hydroxyurea.⁶ For older high-risk patients, ³²P can be used to help with issues of compliance and convenience, especially if the patient's life expectancy is less than 10 years.

Myelosuppressive agents should also be used for symptomatic splenomegaly, pruritis intractable to antihistamines, or patients with poor venous access.⁴ Interferon-alfa may also be used in the place of hydroxyurea for myelosuppression, particularly in younger patients and n patients with intractable pruritus. Side effects of interferon include flulike syndromes, fevers, neuritis, and fatigue.⁵ Patients with PV who are undergoing surgery are at extremely high risk of developing postoperative complications if their erythrocytosis is not controlled before surgery.

Patients with PV and no drug contraindications or evidence of acquired von Willebrand syndrome should be treated with low-dose aspirin.⁶ One study has demonstrated an antithrombotic benefit for low-dose aspirin (100 mg/day) in patients already receiving treatment for PV.⁶ Patients with erythromelalgia also experience a rapid relief of their symptoms after low-dose aspirin.⁴

Outcomes

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 develop postpolycythemic myelofibrosis (MF) at an average interval of 10 years from diagnosis.⁴ Once they develop MF, most patients die within 3 years.⁴ MF often transforms to acute myelogenous leukemia.

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Chronic idiopathic myelofibrosis

Definition and Causes

Other common names for CIMF include agnogenic myeloid metaplasia and primary myelofibrosis.^1,7 In CIMF, a clonal hematopoietic stem cell expansion in the bone marrow is accompanied by a reactive nonclonal fibroblastic proliferation and marrow fibrosis. As the bone marrow becomes fibrotic and normal hematopoiesis can no longer occur, extramedullary hematopoiesis (myeloid metaplasia) occurs in the liver and spleen.⁸ The cause is unknown.

Epidemiology

The prevalence of CIMF is 2 per 1,000,000 population.¹ The risk of developing CIMF is increased by exposure to benzene or radiation. It typically occurs in whites, and the median age at diagnosis is 67 years.⁵ Men and women are affected equally. As noted earlier, patients with PV and other myeloproliferative disorders can develop secondary MF late in the course of their disease.⁴

Pathophysiology

Clonal studies have demonstrated a stem cell origin.⁸ The clonal proliferation of hematopoietic stem cells is believed to produce growth factors (platelet-derived growth factor, transforming growth factor-β, epidermal growth factor, and basic fibroblastic growth factor) that lead to fibrosis of the bone marrow.^1,5 Initially, the bone marrow is hypercellular, but normal hematopoiesis is diminished as the bone marrow becomes fibrotic and patients become pancytopenic (Fig. 2).¹ Because of this, the extramedullary hematopoiesis occurring in the liver and spleen causes these organs to enlarge.

Signs and Symptoms

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

Other constitutional symptoms include anorexia, weight loss, and night sweats.¹ The WBC and platelet counts might increase initially but typically decrease as the disease progresses. The blood film displays a characteristic leukoerythroblastic picture (teardrop poikilocytosis, nucleated red blood cells, and immature myeloid elements) caused by crowding out of normal hematopoietic elements by fibrosis in the bone marrow (Fig. 3).⁵

Patients might complain of abdominal discomfort and decreased appetite because of splenic and hepatic enlargement resulting from extramedullary hematopoiesis.¹ Portal hypertension and jaundice can occur as a result of increased hepatic blood flow.⁵ Rarely, extramedullary hematopoiesis can occur at other sites, such as the skin, lungs, bladder, genitourinary tract, gastrointestinal tract, and central nervous system. Severe bone pain typically heralds a poor prognosis and often represents a conversion of CIMF to acute leukemia.

Diagnosis

The blood film demonstrates a characteristic leukoerythroblastic picture.⁵ Attempts to perform a bone marrow aspirate and biopsy are often complicated by a dry tap.¹ Special stains of the bone marrow biopsy 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.⁸ Trichrome stains identify mature collagen as bluish-green fibers, depending on the stain used (Fig. 4).

The bone marrow biopsy is typically hypercellular, and increased numbers of abnormal megakaryocytes with a tendency to form loose to tight clusters are often present.^1,5 Thirty percent to 75% of patients have cytogenetic abnormalities at the time of diagnosis, with the most common abnormalities being del(13q), del(20q), and partial trisomy 1q. Molecular analysis can reveal a JAK2 V617F or MPL W515L/K in as many as 50% of patients. Secondary causes of marrow fibrosis (e.g., metastatic breast cancer, lymphoma, lung cancer, infection, autoimmune disorders), as well as other hematologic disorders (e.g., hairy cell leukemia, CML), need to be excluded. In addition, acute panmyelosis with myelofibrosis and acute megakaryoblastic leukemia need to be ruled out. These entities also manifest with pancytopenia and marrow fibrosis, but patients typically have no splenomegaly, minimal or absent teardrop poikilocytosis, and increased numbers of blasts.

Proposed revised WHO criteria for CIMF have been published³ and emphasize the role of assessing megakaryocyte morphology in bone marrow biopsies and excluding secondary causes for marrow fibrosis when establishing a diagnosis.

Treatment

There are no available treatments to reverse the process of idiopathic myelofibrosis short of bone marrow transplantation.¹ Because of their older median age at diagnosis, most patients are not suitable bone marrow transplant candidates. One transplant study has demonstrated a 47% overall survival at 5 years, with regression of fibrosis in 40% of patients.⁸ Future studies might clarify the role of nonmyeloablative transplants in CIMF and possibly extend this option to an older patient population. The role and benefit of using chemotherapeutic agents early in the disease to reverse the fibrosis are highly controversial, and randomized clinical trials are needed to address this issue.⁵ 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). Because of the frequency of red blood cell transfusions, patients can require iron chelation therapy to decrease the risk of iron overload. Androgens (danazol) and, occasionally, low-dose steroids (e.g., prednisone) may also be helpful in managing the anemia associated with ineffective erythropoiesis.

Thalidomide has antiangiogenic, immunomodulatory, and anti-inflammatory properties, and it has been evaluated in the treatment of myelofibrosis. A pooled analysis of small phase 2 studies published between 2000 and 2002 has demonstrated a response (increase in hemoglobin, or reduction or elimination of blood transfusion requirements) in 29% of patients with moderate or severe anemia receiving thalidomide at a dosage of 200 to 800 mg/day.⁹ However, a large number of patients stopped thalidomide secondary to side effects. More recent studies have combined low-dose thalidomide with prednisone, leading to a better-tolerated and possibly more effective regimen.

The immunomodulatory agent lenalidomide (Revlimid) has also been evaluated in two separate, but similarly designed phase 2 studies.¹⁰ Overall response rates were 22% for improvement of anemia, 33% for reduction of splenomegaly, and 50% for improvement of thrombocytopenia.¹⁰ A subset of patients had an impressive improvement in their anemia or resolution of bone marrow abnormalities (fibrosis, angiogenesis), or both.¹⁰ Treatment with hypomethylating agents is currently under investigation.

Splenomegaly can require treatment with myelosuppressive agents, splenectomy, or palliative radiation.¹ Splenic irradiation is typically associated with transient responses and should be considered for patients too ill for splenectomy or chemotherapy.⁵ Splenectomy may be considered for symptomatic splenomegaly. 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 severe thrombocytopenia (0%) after splenectomy.¹¹ The operative mortality rate was 9% and the morbidity rate was 31%, including postoperative thrombotic complications. Sixteen percent of patients developed hepatomegaly, and 22% of patients developed thrombocytosis, which was associated with an increased risk of perioperative thrombosis. Blastic transformation was 16.3% in this series, and the risk was increased in patients with splenomegaly and preoperative thrombocytopenia, suggesting that presplenectomy thrombocytopenia may be a surrogate marker of advanced disease.

In the future, the clinical development of antifibrotic and antiangiogenesis therapies might play an important role in the therapeutic armamentarium.⁸

Outcomes

Patients asymptomatic at the time of diagnosis can have an indolent clinical course for several years. However, among the myeloproliferative disorders, CIMF has the worst prognosis, with a median survival of 3.5 to 5.5 years.⁸ The most common causes of death include infection, cardiovascular disease, cerebrovascular disease, hemorrhage or thrombosis, and acute leukemia (10% to 25%). Patients with acute leukemia arising from CIMF rarely achieve a remission from induction chemotherapy.⁵ Scoring symptoms have been developed to help determine prognosis for individual patients more definitively and to help identify younger patients who might benefit from bone marrow transplantation. Hoffman and colleagues⁵ have defined a scoring system based on hemoglobin (<10 g/dL) and WBC count (either <4 × 10⁹/L or >30 × 10⁹/L). Patients with none, one, or two of the preceding factors had a median survival of 93, 26, and 13 months, respectively. Bone marrow transplantation might cure a subset of patients, but longer follow-up is needed.

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Essential thrombocythemia

Definition and Etiology

ET⁵ is characterized by a sustained clonal proliferation of megakaryocytes in the bone marrow, with a peripheral blood platelet count greater than 600 × 10⁹/L. Proposed revised criteria suggest lowering the platelet threshold to greater than 450 × 10⁹/L.³ Causes of reactive thrombocytosis must be excluded. The underlying cause is unknown.¹

Epidemiology

The incidence of the disease (2.38/100,000 population per year in Olmsted County, Minn) is the lowest among the chronic myeloproliferative disorders.^1,5 There may be a higher prevalence in younger women. ET occurs equally in men and women, and the average age at diagnosis is 50 to 60 years.

Pathophysiology

The proliferation of megakaryocytes is primarily caused by clonal stem cells, as confirmed by enzyme and genetic analysis.¹² Megakaryocyte progenitor cells in ET are hypersensitive to the action of several cytokines, including IL-3 and IL-6, and possibly thrombopoietin.^5,12 This leads to increased platelet production. There is controversy regarding spontaneous megakaryocyte formation in ET. Thrombopoietin and its associated receptor pathways do not appear to be involved in the development of ET.

Increased platelet counts in ET are associated with increased thrombotic and hemorrhagic complications. Decreasing platelet counts in ET (to <600 × 10⁹/L) can decrease thrombotic complications (see later).¹³ High platelet counts (>1000 × 10⁹/L) are associated with acquired von Willebrand disease resulting from the adsorption of von Willebrand multimers onto platelet membranes.⁵ A reduction in the platelet count is associated with correction of the defect and cessation of bleeding. Qualitative abnormalities in the platelets themselves are also likely to contribute to the increased risk of thrombotic and hemorrhagic complications in ET, because reactive thrombocytosis is not associated with an increased risk of thrombosis or bleeding, even with high platelet counts. Platelet aggregation studies in ET are often abnormal.

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Signs and symptoms

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

As with PV, thrombotic episodes can occur in the major vessels or microvasculature (see earlier, “Polycythemia Vera: Signs and Symptoms”).⁵ Thrombotic episodes occur more often in older patients and in patients with a history of thrombotic events. This increase in thrombotic risk with age has been attributed to the coexistence of vascular disease in older patients. Events tend to occur mainly in the microvasculature.

Women of childbearing age can present with a spontaneous abortion secondary to placental thrombosis.⁵ Hemorrhage is most common in the gastrointestinal tract.

Diagnosis

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

To diagnose ET, causes of reactive thrombocytosis as well as clonal thrombocytosis secondary to another myeloproliferative disorder (e.g., CML) must be excluded. Causes of reactive thrombocytosis can include inflammatory states, infection, malignant disease, trauma, blood loss, and the postsplenectomy state.⁵

In one series of 280 patients with thrombocytosis at a university hospital, 82% of cases were reactive thrombocytosis.⁵ Some of these patients have platelet counts greater than 1000 × 10⁹/L, so the degree of thrombocytosis is not always helpful in making a diagnosis. Reactive thrombocytosis is associated with elevated levels of IL-6 or C-reactive protein in 81% of patients, which can help distinguish it from ET.¹² Patients with uncomplicated thrombocytosis secondary to a myeloproliferative disorder typically have undetectable IL-6 levels.⁸

A bone marrow aspirate and biopsy with cytogenetics (and reverse transcriptase polymerase chain reaction [RT-PCR] for BCR/ABL1 fusion) can be helpful in excluding CML, which is BCR/ABL1 positive. Two thirds of patients with ET have bone marrow with marked megakaryocytic hyperplasia, morphologically bizarre megakaryocytes with nuclear pleomorphism, and clustering of megakaryocytes (Fig. 6).⁵ Increased myeloid and erythroid precursors, abnormal cytogenetics, minimal reticulin fibrosis, and spontaneous megakaryocyte colony formation may also be present. These features are not typically present in the bone marrow of patients with reactive thrombocytosis. Identifying a JAK2 V617F mutation can be useful in excluding a reactive thrombocytosis. Additional clinical features that suggest ET rather than reactive thrombocytosis include a chronically elevated platelet count, splenomegaly, and history of thrombosis or hemorrhage. Red cell mass and plasma volume studies may be needed to differentiate ET from PV. Finding significant dyserythropoiesis or dysgranulopoiesis should prompt consideration of MDS rather than ET.

Treatment

A randomized study¹³ has 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 × 10⁹/L. In addition, maintaining a platelet count less than 400 × 10⁹/L may be associated with a further reduction in thrombosis, although these data have not been confirmed in a randomized trial.¹² The risk stratification for thrombotic events in ET and PV is the same. Patients older than 60 years or with a history of thrombotic events are considered to be at high risk. Patients with cardiovascular risk factors or extreme thrombocytosis (platelet counts >1500 × 10⁹/L ) are considered to be at intermediate risk.

In low-risk patients, thrombotic events are too infrequent to justify long-term drug therapy, although the use of low-dose aspirin is optional.¹² Controversy exists regarding the treatment of intermediate-risk patients.

In addition to hydroxyurea, anagrelide can also control thrombocytosis in most patients.¹² The drug works by interfering with megakaryocyte maturation. However, no randomized study has demonstrated that the drug actually decreases the risk of thrombotic events. Therefore, it should be used in patients with ET who do not tolerate hydroxyurea or in younger patients who will need long-term therapy. The main side effects include headaches, palpitations, and, rarely, a nonischemic cardiomyopathy. These effects are secondary to the drug's vasodilative inotropic actions; therefore, it should be used cautiously in patients with cardiac disease.¹³ Anagrelide can also decrease the hematocrit (but not the WBC count). A randomized study (the P1 study), has demonstrated that hydroxyurea should be considered first-line treatment for patients with high-risk ET.¹⁴ In this study, 809 patients were randomized to receive low-dose aspirin plus either anagrelide or hydroxyurea. The primary composite end point was the actuarial risk of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from hemorrhagic or thrombotic causes. After a median follow-up of 39 months, patients in the anagrelide arm were more likely than those in the hydroxyurea arm to have reached the primary end point (odds ratio, 1.57; P = 0.03).

Interferon-alfa is another option for patients, but its use in ET is limited primarily to high-risk women of childbearing age.¹² There are no specific recommendations for ET during pregnancy. Although 45% of these women have spontaneous abortions, abortions cannot be predicted by the course of disease, platelet count, or specific treatment. Agents such as ³²P or busulfan are rarely used in ET but can be used in patients whose life expectancy is shorter than 10 years. Low-dose aspirin can decrease the thrombotic risk in ET, but randomized studies are still pending.

Patients with life-threatening hemorrhagic or thrombotic events should be treated with plateletpheresis in combination with myelosuppressive therapy.¹² Patients with a platelet count greater than 1500 × 10⁹/L and acquired von Willebrand disease should be treated with platelet-reduction therapy and should avoid aspirin.⁵ These patients also might require treatment with factor VIII concentrates that also contain von Willebrand factor (VWF) and desmopressin in the setting of a bleeding episode. Finally, patients undergoing surgery have an increased risk of thrombotic and bleeding episodes and should have their platelet counts normalized before surgery.

Outcomes

Prognosis is highly dependent on the age and history of thrombosis, because thrombosis can be life-threatening for some patients.¹² One series has demonstrated that most patients with ET die from thrombotic complications.⁵ The 10-year survival rate is 64% to 80% for patients with ET. Less than 10% of patients with ET convert to acute leukemia, and 5% of patients develop myelofibrosis.

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Chronic myelomonocytic leukemia

Definition

Based on the WHO diagnostic criteria for CMML, patients must have a persistent peripheral blood monocytosis exceeding 1 × 10⁹/L (Fig. 7), no Philadelphia chromosome or BCR/ABL1 fusion gene, less than 20% blasts in the blood or bone marrow, and dysplasia in one or more myeloid lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML may still be made if the other requirements are met and an acquired clonal cytogenetic abnormality is present, or if the monocytosis has been persistent for at least 3 months and all other causes of monocytosis have been excluded.¹⁵

Epidemiology

The disease typically occurs in older patients.¹⁵

Pathophysiology

CMML was initially characterized as a myelodysplastic syndrome because of the associated dysplasia and cytopenia observed in some patients; however, some patients display myeloproliferative features (increased myelopoiesis).⁵ High peripheral monocyte counts are often associated with pericardial, pleural, synovial, and ascitic effusions, as well as hepatomegaly and splenomegaly secondary to tissue infiltration by monocytes.

Signs and Symptoms

Patients with the dysplastic or proliferative form of CMML may have shortness of breath, fatigue, bleeding or bruising, or they might have infections as the blood counts decrease secondary to splenic sequestration, dysplasia, crowding out of normal hematopoietic cells by myeloproliferation, or a combination of these factors. As noted earlier, patients with the myeloproliferative form can develop splenomegaly, hepatomegaly, skin lesions, and effusions and can present with abdominal pain or swelling, shortness of breath, or joint swelling.¹⁶

Diagnosis

The diagnosis requires evaluation of peripheral blood monocyte counts, in addition to bone marrow aspirate and biopsy (Fig. 8). Cytogenetics as well as molecular methods including fluorescence in situ hybridization (FISH) or RT-PCR for BCR/ABL1 fusion should be performed to rule out CML.

Treatment

Supportive care for CMML includes transfusions and growth factor therapy. The active treatment of CMML has been disappointing. Younger patients with a human leukocyte antigen (HLA)–identical sibling should be evaluated for allogeneic bone marrow transplantation.¹⁶ However, most patients with CMML are older 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.¹⁶ Hydroxyurea may be used for patients with splenomegaly or high leukocyte counts; however, the responses are often partial, and blood counts can decrease during treatment. Investigators have examined other agents such as etoposide (VP-16). In a randomized trial, hydroxyurea yielded higher response rates and better survival than etoposide in patients with advanced CMML.¹⁶ Other agents, such as topotecan, a topoisomerase I inhibitor, have also been studied. However, their long-term impact, and the result of combining them with other agents, is unknown. Hypomethylating agents and farnesyltransferase inhibitors have also been evaluated.

A subset of patients who have CMML with eosinophilia have a t(5;12)(q33;p13) translocation, encoding a TEL/PDGFRβ fusion protein. This group of patients might benefit from treatment with imatinib, which inhibits PDGFR as well as the BCR/ABL1 kinase.

Outcomes

The prognosis in CMML is highly dependent on the number of blasts in the bone marrow.⁵ The life expectancy can vary from several months to several years. A study of 213 patients with CMML was used to define a prognostic scoring system.¹⁵ In a multivariate analysis, hemoglobin lower than 12 g/dL, the presence of circulating immature myeloid cells, an absolute lymphocyte count higher than 2.5 × 10⁹/L, and 10% or more marrow blasts were associated with a shorter survival.¹⁵ 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. This scoring system has subsequently been validated in a separate set of patients.

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Jak2 and myeloproliferative disorders

Janus kinase 2 is a tyrosine kinase. Constitutive activation of tyrosine kinases can lead to uncontrolled cell growth. Recently, the V617F mutation in JAK2 was found in a significant proportion of myeloproliferative disorders (60%-90% of PV and 50%-60% of ET and CIMF).¹⁷ Other JAK2 mutations have now been identified (i.e., exon 12). The presence of this mutation is determined by PCR assays and may be helpful in differentiating a myeloproliferative disorder from a reactive cause for elevated counts. JAK2 allele burden might also be important in identifying high-risk patients with PV or ET (i.e. those at risk for requiring treatment with chemotherapy or those at risk for developing major cardiovascular complications).¹⁸ Incorporation of this information may lead to a risk-adapted treatment approach in the future. Clinical trials with small molecule inhibitors of JAK2 are currently enrolling patients, and these drugs will likely become an important part of the therapeutic armamentarium.

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Summary

• The myeloproliferative disorders include polycythemia vera, chronic idiopathic myelofibrosis, essential thrombocythemia, and chronic myelogenous leukemia. Chronic myelomonocytic leukemia has features that overlap traditional myelodysplastic and myeloproliferative disorders.
• Myeloproliferative disorders are characterized by the clonal proliferation of one or more hematopoietic cell lineages.
• Review of the peripheral blood film and a bone marrow aspirate or biopsy is needed to make a definitive diagnosis.
• Reverse transcriptase polymerase chain reaction (RT-PCR) or fluorescence in-situ hybridization (FISH) for the BCR/ABL1gene fusion should be performed to rule out chronic myelogenous leukemia.
• Janus kinase 2, a tyrosine kinase, is mutated in a significant proportion of myeloproliferative disorders, and may represent a therapeutic target.

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Suggested Readings

• Barosi G, Hoffman R. Idiopathic myelofibrosis. Semin Hematol. 2005, 42: 248-258.
• Bilgrami S, Greenberg BR. Polycythemia rubra vera. Semin Oncol. 1995, 22: 307-326.
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