Polycythemia vera natural history, complications, and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and acute myeloid leukemia, and these are the most devastating complications of the disease. Myelofibrosis and acute myeloid leukemia are part of the natural history of the disease.

Natural History

The symptoms of polycythemia vera usually develop in the sixth decade of life and start with symptoms such as headache and fatigue. If left untreated, the natural history of polycythemia vera will result in post-polycythemia vera (post-PV) myelofibrosis and acute myeloid leukemla (AML). The median time to development of myelofibrosis is 8-20 years. The natural history of polycythemia vera is that it will evolve into post-PV myelofibrosis.

• The cumulative risk of developing myelofibrosis is 4.9 to 6.0% at 10 years, 6-14% at 15 years, and 26% at 20 years from the initial diagnosis of polycythemia vera. This is in comparison to the risk of post-essential thrombocythemia (post-ET) myelofibrosis, for which the risk is 0.8% to 4.9% at 10 years and 4-11% at 15 years.
• The cumulative risk of developing acute myeloid leukemia is 2.3-14% at 10 years, 5.5-18% at 15 years, and greater than 10% at 20 years from the initial diagnosis of polycythemia vera. This is in comparison to the risk of post-ET acute myeloid leukemia, for which the risk is 0.7-3% at 10 years and 2.1-5.3% at 15 years.

Complications

Polycythemia vera may lead to the following complications:

• Thrombosis: Clot formation occurs in 15% of patients with polycythemia vera, with yearly rates between 2.5% to 4%.

• Deep venous thrombosis: Clots can develop in the deep veins of the lower extremities, such as the popliteal vein or femoral vein.
• Pulmonary embolism: Clots can develop in the segmental or subsegmental arteries of the pulmonary vasculature.
• Myocardial infarction: Clots can develop within the coronary arteries, and this is usually exacerbated by underlying cardiac risk factors.
• Stroke: Clots can develop in the anterior or posterior circulation in the brain.
• Budd-Chiari syndrome: Clots can develop in the hepatic vein.
• Splanchnic vein thrombosis: Clots can develop in mesenteric vasculature like the splenic vein, superior mesenteric vein, inferior mesenteric vein, or portal vein.

• Bleeding

• Epistaxis: Bleeding can occur in the anterior or posterior circulation of the nasal cavity.
• Gingival bleeding: Bleeding gums is typically seen after brushing teeth.
• Menorrhagia: Pelvis bleeding commonly occurs in pre-menopausal females.
• Metrorrhagia: Irregular pelvic bleeding can occur in pre-menopausal females.
• Petechiae: Pinpoint hemorrhages can occur in the skin.

• Splenomegaly: Extramedullary hematopoiesis occurs when the bone marrow is unable to sustain normal cell production.
• Gout
• Peptic ulcer

• Clonal proliferation

• Myelofibrosis: This is a condition in which the bone marrow becomes replaced by collagen and reticulin fibers. When myelofibrosis occurs in the setting of polycythemia vera, it is referred to as post-polycythemia vera (post-PV) myelofibrosis. Myelofibrosis carries an overall poor prognosis given that collagen fibers preclude normal hematopoiesis, resulting in infections, bleeding, and fatigue.
• Acute myeloid leukemia: This is a malignancy of the hematopoietic stem cell (specifically myeloid precursors). It is characterized by clonal proliferation and resultant cytopenias and ineffective hematopoiesis. Patients typically die as a result of infections and/or bleeding.

• Microvascular symptoms

• Hearing impairment
• Visual impairment
• Paresthesia
• Headache

Prognosis

The prognosis of polycythemia vera is generally good with treatment. Without treatment, polycythemia vera will result in death. Once myelofibrosis or acute myeloid leukemia ensues, the prognosis is very poor. Prognosis for post-PV myelofibrosis is adversely affected by older age, presence of leukocytosis, reticulin fibrosis, high JAK2 allele burden, splenomegaly, and history of venous thromboembolic events. Other risk factors for post-PV myelofibrosis include presence of baseline fibrotic change in the bone marrow, platelet count above 550,000/mcl, and masked polycythemia vera (presence of morphologic findings consistent with polycythemia vera on bone marrow biopsy but hemoglobin level below the threshold per WHO 2016 criteria. This is in contrast to adverse prognostic factors in post-ET myelofibrosis, which include absence of JAK2 V617F mutation, use of anagrelide, and presence of ASXL1 mutation. Post-PV acute myeloid leukemia, adverse risk factors include older age, leukocytosis, splenomegaly, reticulin, abnormal and complex karyotype, p53 mutation, and RUNX1 mutation.

Life expectancy

After transformation of polycythemia vera to myelofibrosis, the life expectancy is approximately 5.7 years. The median survival for patients with acute myeloid leukemia that has progressed from polycythemia vera is 5 months. High-risk patients with polycythemia vera have an average survival of 10.9 years. Low-risk patients have an average survival of 29 months. There is a 4.2-fold increase in the risk of death in the presence of any of the following risk factors:

• Hemoglobin < 10 g/dl
• Platelet count < 100,000/mcl
• Leukocyte count > 30,000/mcl

The 5-year survival rate is 17.3% for patients who develop post-PV myelofibrosis and have hemoglobin < 10 g/dl and age above 65 years. In elderly patients compared to younger patients, leukemic transformation contributes to more deaths, suggesting that age of onset of leukemia is an important prognostic risk factor for life expectancy.

Gallery

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  Magnetic resonance imaging of the brain. Diffusion-weighted magnetic resonance image of the brain demonstrating numerous small foci of restricted diffusion scattered within the left frontoparietal cortex, subcortical white matter, and centrum semiovale. These foci are consistent with an acute embolic ischemic infarction shower within the left middle cerebral artery distribution.

References

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