Myeloproliferative Neoplasms

Introduction

The myeloproliferative neoplasms (MPNs), previously termed the myeloproliferative disorders, 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 In contrast to myelodysplastic syndromes (MDS), MPNs demonstrate terminal myeloid cell expansion into the peripheral blood. In the 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms, MPNs include chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia, mastocytosis, and unclassifiable MPNs.2 MDS/MPN overlap disorders are those chronic myeloid disorders unable to be classified as “classic” MPN or MDS. These include chronic myelomonocytic leukemia, atypical CML, juvenile myelomonocytic leukemia, and unclassifiable MDS/MPN.

Chronic myelogenous leukemia is the only MPN that is characterized by the presence of the BCR-ABL fusion gene, which is formed by translocation of the ABL gene from chromosome 9 joining to the BCR gene on chromosome 22. The altered chromosome 22 with the fusion gene is the Philadelphia chromosome. With a unique pathogenesis and treatment, CML is often considered separately from the rest of the MPNs. The most commonly recognized mutation in the remainder of the Philadelphia chromosome-negative MPNs is Janus kinase 2 (JAK2) V617F, which is present in more than 90% of patients with PV and approximately half of those with PMF or ET (Table 1).3 This mutation substitutes phenylalanine for valine at position 617 in the JH2 domain (Val617Phe, V617F) of exon 14, leading to constitutive activation of the JAK-STAT and other pathways resulting in uncontrolled cell growth.4 Subsequent to this, additional mutations within exon 12 of JAK2 have been identified in PV.5 Mutant JAK2 allele burden might be important in identifying high-risk patients with PV or ET (ie, those at risk for requiring treatment with chemotherapy or those at risk for developing major cardiovascular complications).6

Mutations within the thrombopoietin receptor gene (MPL) also have been identified in ET and PMF.7 The presence of these mutations is determined by polymerase chain reaction (PCR) assays and may be helpful in differentiating a MPN from a reactive cause for elevated counts. More recently, mutations in the gene that encodes calreticulin (CALR), have been identified in a large proportion of patient with MPN who did not have a JAK2 or MPL mutation.8,9 These three “driver mutations” are often mutually exclusive, meaning that if one is present the others are absent. Nonetheless, roughly 10% of patients with ET or PMF lack JAK2, CALR, or MPL gene mutations and have been referred to as being “triple-negative.”

This chapter reviews the definition, epidemiology, pathophysiology, signs and symptoms, diagnosis, treatment, and outcomes of the Philadelphia chromosome-negative MPNs—PV, PMF, and ET. Chronic myelogenous leukemia and chronic myelomonocytic leukemia are discussed in the Chronic Leukemia section.
Table 1: Percentage of gene mutations among patients with Philadelphia chromosome-negative myeolproliferative neoplasms
Gene Polycythemia Vera Essential Thrombocythemia Primary Myelofibrosis
JAK2 97% 50 - 60% 50 - 60%
CALR 3 - 10% 3 - 10%
MPL 33% 33%
Unmutated JAK2, CALR, MPL 10 - 15% 10 - 15%

Data from Nangalia J, Green TR. The evolving genomic landscape of myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2014; 2014:287–296.

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Polycythemia Vera
Definition and Etiology

Polycythemia vera is a clonal disorder characterized by the overproduction of mature red blood cells. Myeloid and megakaryocytic elements are also often increased. No obvious cause exists. Genetic and environmental factors have been implicated in rare cases. Familial PV has been associated with mutation of the erythropoietin (EPO) receptor.10 An increased number of cases were reported in survivors of the atomic bomb explosion in Hiroshima during World War II.
Epidemiology

Polycythemia vera typically occurs in the 6th or 7th decade of life and occurs more commonly in men and in both men and women of East European Jewish ancestry.5,11 In the United States, the estimated prevalence of PV ranges from 44 to 57 cases per 100,000 people.12
Pathophysiology
Bone marrow biopsy in polycythemia vera
Figure 1: Click to Enlarge

The primary defect involves a pluripotent stem cell capable of differentiating into red blood cells, granulocytes, and platelets.13 Clonality has been demonstrated through glucose-6-phosphate dehydrogenase studies as well as restriction fragment length polymorphism of the active X chromosome.10 Erythroid precursors in PV are exquisitely sensitive to erythropoietin, which leads to increased red blood cell production. Precursors in PV also are 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 (Figure 1). The abnormal proliferation of PV is due to constitutive activation of the JAK-STAT pathway, with the majority of patients (>95%) harboring the V617F mutation.2 A similar JAK2 exon 12 mutation is found in the few patients lacking the V617F mutation.2

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.11 Hematocrit is directly proportional to the number of thrombotic events. Investigators have demonstrated a reduction in cerebral blood flow in patients with hematocrits between 53% and 62%.10 An increased platelet count also can 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. However, most patients develop symptoms as the hematocrit and/or platelet count increase. Elevated white blood cell (WBC) counts have been found in 50% of patients.14 Elevated hematocrit has been associated with symptoms of hyperviscosity including headache, blurred vision, and plethora.

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.13 Unusual sites of thrombosis (splenic, hepatic, portal, and mesenteric) also tend to be seen more frequently in PV.

Of patients with Budd-Chiari syndrome (hepatic-inferior vena cava obstruction), 10% to 13% have coexisting PV; therefore, testing for the presence of JAK2 V617F mutation is part of the routine workup for unexplained liver thrombosis. Abnormalities in platelet function lead to bleeding complications that include epistaxis, bruising, and gastrointestinal and gingival bleeding in 5% to 10% of patients.15 Severe bleeding episodes are unusual. Hypermetabolism caused by increased blood cell turnover can lead to hyperuricemia, gout, stomach ulcers, weight loss, and kidney stones. A classic symptom is pruritus, especially after a warm bath or shower. As the disease progresses, many patients develop abdominal pain secondary to organomegaly.
Diagnosis

Polycythemia vera should be suspected in men with hemoglobin greater than 18.5 g/dL and in women with hemoglobin greater than 16.5 g/dL.2 An elevated red cell mass, measured using direct tagging of red blood cells with chromium 51, was previously important in making the diagnosis but is rarely used in current practice. The presence of the JAK2 mutation is now a major criterion for diagnosis.2

Secondary causes of polycythemia must be ruled out. Many conditions can physiologically increase the production of EPO. Overproduction occurs in hypoxia (eg, pulmonary disease, high altitude, smoking-related carboxyhemoglobin, cyanotic cardiac disease, and methemoglobinemia), tumors (eg, kidney, brain, hepatoma, uterine fibroid, and pheochromocytoma), renal artery stenosis, and renal cysts. Other causes include androgen therapy, congenital erythrocytosis, EPO-receptor hypersensitivity, autotransfusion (blood doping), and self-injection of EPO. Serum EPO 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 V617F or other functionally similar mutation currently plays a central role in the diagnosis of PV as a way of separating neoplastic from reactive myeloid proliferations.

The diagnostic criteria for PV have undergone changes as new research discoveries are published; however, elevated red cell mass, hemoglobin, or hematocrit levels remain the cornerstones of diagnosis. The current (2008) WHO criteria require the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria to make a diagnosis of PV.2 However, the diagnostic threshold of PV is set to be lowered in the next iteration (Table 2), as the hemoglobin threshold for diagnosis will be below that of the current schema. The proposed revision to the WHO criteria requires the presence of all three major criteria, or the first two major criteria and the minor criterion to make the diagnosis of PV.16