Polycythemia vera: Disease and treatment overview

Polycythemia vera (PV) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). It is indolent when compared with the other MPN disease subtypes, such as essential thrombocythemia and myelofibrosis.¹ PV is characterized by uncontrolled clonal proliferation of myeloid blood cells, specifically of the erythropoietic lineage.² In most patients, this is caused by a Janus kinase 2 (JAK2)  mutation and results in erythrocytosis and bone marrow hypercellularity.³ Here, we provide an overview of the epidemiology, pathophysiology, diagnosis, and management of PV.

Etiology

• Approximately 90% of patients diagnosed with PV harbor a JAK2 mutation.²
  • the most common mutation is  JAK2^V617F
• Around 2% of patients exhibit a mutation at exon 12 of JAK2.²

• In healthy individuals, the JAK2 gene is responsible for the activation of intracellular signaling involved in cell proliferation regulation, DNA damage repair, and cellular apoptosis.⁵
• The presence of a mutation leads to loss of the normal inhibitory function of JAK2, and results in constitutive activation of the JAK/signal transducers and activators of transcription and phosphoinositide 3-kinase/mitogen-activated protein kinase signaling pathways.⁵
• Risk factors for PV include:
  • working in agriculture and petroleum refineries;
  • benzene exposure; and
  • smoking.⁶

Epidemiology

*Data from Tefferi, et al.¹ and Greenfield, et al.⁵

 Pathophysiology

It is widely accepted that a JAK2 mutation, and subsequent changes in downstream signaling, cause the recognized phenotype of increased proliferation of red blood cells, white blood cells, and platelets in PV (Figure 2).⁸ However, uncertainty remains around the specific interactions of erythropoietin, a key component in the development of erythrocytosis, and other associated growth factors and receptors.⁸

• Erythropoietin-dependent apoptosis inhibition is blocked by mutated expression of kinase-deficient dominant-negative forms of JAK2.⁸
  • It is suggested that erythropoietin triggers the JAK/signal transducers and activators of transcription signaling pathway, inducing expression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-xL).⁸
  • BCL-xL and BCL-2 have also been found to be overexpressed on PV cells.⁸
  • Deregulated BCL-xL expression also accounts for the continuously elevated levels of growth factor observed at all stages of the erythroid differentiation pathway.⁸
• PV cells exhibit hypersensitivity to antiapoptotic insulin-like growth factor-1, which in turn stimulates erythroid burst formation and overexpression of BCL-xL.
  • The resulting interactions and downstream signaling lead to cellular accumulation and hypercoagulable blood, which significantly increases the risk of thrombosis.

Epo, erythropoietin; EpoR, erythropoietin receptor; JAK2, Janus kinase 2; SHP1, Src homology region 2 domain containing phosphatase 1; STAT5, signal transducer and activator of transcription 5.
*Adapted from Fernandez-Luna, et al.⁸ Created with BioRender.com.

 Signs and symptoms

• The most common complication of PV is the risk of thrombo-hemorrhagic events and transformation to acute myeloid leukemia or secondary myelofibrosis.⁵
• The most frequent constitutional symptoms reported by patients are fatigue, pruritus, night sweats, and bone pain (Figure 3).²

*Adapted from Khodier and Gadó.² Created with BioRender.com.

 Diagnosis

• The diagnosis of each MPN subtype has historically been defined by the World Health Organization classification of MPN.
• However, the most recent revision has resulted in a new scheme, the International Consensus Classification of MPN, with an emphasis on criteria refinement for easier distinction between subtypes.⁹
• For a confirmed subtype diagnosis, a patient must meet all major criteria defined in the International Consensus Classification, or most of the major criteria together with a minor criterion (Figure 4).⁹

BM, bone marrow; Hb, hemoglobin; ICC, International Consensus Classification; JAK, Janus kinase; PV, polycythemia vera; RBC, red blood cell.
*Adapted from Arber, et al.⁹

•  Once diagnosis is confirmed, conventional risk stratification is primarily based on age (>60 years/<60 years) and history of thrombosis.²
• These factors were confirmed as the most important in the multicenter European Collaboration on Low-Dose Aspirin in PV study.²
• Patients who are high risk have either or both factors present, while low-risk patients have neither factor present.²

Guidance on diagnosis may vary between countries (see key guidelines section).

Management

• Low-risk patients without any contraindications are prescribed low-dose aspirin to reduce the risk of fatal myocardial infarction, stroke, pulmonary embolism, venous thrombosis, or death from other cardiovascular causes.⁴
• Phlebotomy is also commonly recommended for all patients to maintain hematocrit levels of <45% in males and <42% in females.¹⁰
• Patients defined as high risk are recommended cytoreductive treatment, specifically hydroxyurea (HU).²
  • Regularly, phlebotomy should be maintained alongside cytoreductive treatment.²
• Second-line therapy for patients who have become resistant or intolerant to HU is pegylated interferon (IFN) alfa-2a.²
  • Pegylated IFN alfa-2a is also recommended as a first-line treatment option for patients who are pregnant or aged <40 years.²
• Although less routinely used, ruxolitinib has been investigated for use as another second-line treatment option due to the high frequency of JAK2 mutations in PV.²
• Major drug classes/types of therapy and their cellular targets are summarized in Figure 5.

IFN, interferon; JAK2, Janus kinase 2; PV, polycythemia vera; RBC, red blood cell.
*Adapted from Spivak.¹⁰; Arif and Aggarwal.¹¹

 Treatment with aspirin is associated with a greater risk of bleeding.²

• Other more general side effects include gastrointestinal problems, ranging from gastritis to gastrointestinal bleeding.¹¹
• HU treatment is associated with the development of anemia, leukopenia, and thrombocytopenia.²
  • Treatment also increases the propensity for leukemic transformation.²
• General adverse effects associated with IFN treatment include injection-site reactions, hair and weight loss, weakness, myalgia, and severe depression.²

Guidance on management may vary between countries—see key guidelines section below.

Key Guidelines and organizations

• European LeukemiaNet
• Leukemia & Lymphoma Society
• World Health Organization
• MPN Research Foundation
• MPN Hub key updates to the 5th WHO Classification of MPN
• MPN Hub International Consensus Classification 2022