Polycythemia Vera

Background

• Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with increased risk of thrombosis and bleeding, and disease progression to either myelofibrosis and/or acute leukemia.
• PV is caused by somatic mutations in JAK2 (Janus kinase), specifically V617F (in about 96% of patients) and mutations in exon 12 (in about 3% of patients), resulting in erythrocytosis often accompanied by leukocytosis and/or thrombocytosis.
• PV may be diagnosed incidentally following complete blood count in an asymptomatic patient. Alternatively, patients may present with clinical symptoms including vasomotor disturbances, constitutional symptoms such as pruritus, night sweats, fatigue, symptoms of iron deficiency, or history of thrombosis or bleeding.

Evaluation

• Diagnosis is based on World Health Organization (WHO) 2022 diagnostic criteria, requiring either all 3 major criteria, or first 2 major criteria and the minor criterion.
  • Major criteria:
    • Evidence of increased red cell volume as indicated by
      • hemoglobin > 16.5 g/dL (male patients), > 16 g/dL (female patients)
      • hematocrit > 49% (male patients), > 48% (female patients)
    • Bone marrow biopsy with hypercellularity for age with panmyelosis with prominent erythroid, granulocytic, and megakaryocytic proliferation.
    • Presence of JAK2 V617F or other mutation of similar function (for example, JAK2 exon 12 mutation).
  • Minor criterion: Serum erythropoietin level below normal reference range
  • In patients with JAK2 V617 or mutation of similar function and the minor criterion is present, bone marrow biopsy may not be need for diagnosis if presenting with sustained absolute erythrocytosis (Hb > 18.5 g/dL or Hct > 55.5% in male adults or Hb 16.5 g/dL or Hct 49.5% in female adults).
  • Consider possible causes of secondary polycythemia in patients presenting with isolated erythrocytosis and other myeloproliferative neoplasms.

Management

• Treatment goals include reducing the risk of thrombosis and hemorrhage, the risk of transformation to myelofibrosis or acute leukemia, and controlling disease-related symptoms and manifestations including splenomegaly when present.
• Current treatment has not been shown to reduce the risk of transformation to myelofibrosis or acute leukemia.
• Current therapy is based on the risk stratification for thrombotic complications:
  • Low risk - age < 60 years old and no prior thrombosis or disease-associated bleeding event
  • High risk - age ≥ 60 years old and/or prior thrombosis or disease-associated bleeding event
• For all patients with PV
  • Offer low-dose aspirin unless there are contraindications (for example, acquired von Willebrand syndrome) (Strong recommendation).
  • Offer phlebotomy and maintain hematocrit at < 45% (Strong recommendation).
  • Use targeted intervention to reduce cardiovascular risk factors (Strong recommendation).
• In low-risk patients, presence of factors such as disease-related symptoms, may warrant cytoreductive therapy.
• In high-risk patients, offer either hydroxyurea or interferon-alfa or pegylated interferon-alfa (Strong recommendation).
• In patients who fail first-line therapy or develop intolerance to hydroxyurea, offer ruxolitinib (Strong recommendation), or consider an alkylating agent such as busulfan or pipobroman (Weak recommendation).
• Monitor treatment response for remission. Complete remission defined as all of the following for ≥ 12 weeks:
  • resolution of disease-related signs including palpable hepatosplenomegaly and large symptom improvement
  • peripheral blood count remission, which is defined as hematocrit < 45% without phlebotomy, platelet count ≤ 400 × 10⁹/L, and white blood cell count < 10 × 10⁹/L
  • bone marrow histological remission, which is defined as presence of age-adjusted normal cellularity, disappearance of trilinear hyperplasia, and absence of > grade 1 reticulin fibrosis absence of progressive disease and hemorrhagic and thrombotic events
  • absence of progressive disease and hemorrhagic and thrombotic events
• Management of PV during pregnancy and perioperatively requires special attention and optimized disease management.
• Management of complications may include treatment for venous thromboembolism, hemorrhage, or pruritus.