Case-Based Review

Polycythemia Vera and Essential Thrombocythemia: Current Management




Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes.1,2 Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML).3 Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other disease-associated symptoms.4 No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF)5,6 has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN.7,8


PV and ET are typically diagnosed in the fifth to seventh decade of life.9 Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population.10–13 Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention.13 The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females.14 Given the long course and low mortality associated with these disorders, the prevalence of PV and ET are significantly higher than the respective incidence: up to 47 and 57 per 100,000, respectively.15–17

Molecular Pathogenesis

In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF.5,6,18,19 JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway.5,6,18,19 More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12.20–22 The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor,23–25 or the calreticulin (CALR) gene,26,27 which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis.28 Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN that are not exclusive of each other (ie, patients may have many at the same time), and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others.29 The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.

Diagnosis and Risk Assessment

Case Presentations

Patient A is a 68-year-old man with a history of gouty arthritis who presents with a 6-month history of recurrent headaches and itching that increases after a hot shower. Over the past 2 months, he has also noticed worsening fatigue and redness of his face. He is a nonsmoker. Physical exam reveals erythromelalgia (ie, erythema, edema, and warmth) of the upper and lower extremities, scattered scratch marks, and splenomegaly 4 cm below the costal margin. Complete blood count (CBC) shows a white blood cell (WBC) count of 8100/µL, hemoglobin 194 g/L, and platelets 582 × 103/µL. Serum erythropoietin level is decreased at 2 mU/mL. Peripheral blood testing reveals a JAK2V617F mutation.

Patient B is a 51-year-old woman with a history of severe depression treated with sertraline and hypertension controlled with lisinopril and amlodipine who presents to her primary care physician for her “50-year-old physical.” She denies symptoms and is a nonsmoker. Physical exam is unrevealing. CBC shows a WBC count of 7400/µL (normal differential), hemoglobin 135 g/L, and platelets 1282 × 103/µL. A bone marrow biopsy shows normal cellularity with clusters of large, hyperlobulated megakaryocytes. Reverse transcriptase-polymerase chain reaction fails to reveal a BCR-ABL fusion product. The patient is diagnosed with ET.


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