Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor updated 5/2021
Knowledge is power. Are you facing a new diagnosis, recurrence, living with advanced disease, or supporting a loved one with a diagnosis of polycythemia vera? The Cancer Connect Polycythemia Vera Information Center has current, evidence-based information and a community of individuals sharing and supporting each other. Join the polycythemia community, and get the facts about a polycythemia vera diagnosis, treatment options, and survivorship, and stay up to date with ongoing polycythemia research that could impact your treatment decisions through our daily cancer news.1,2
Polycythemia vera is a type of blood cancer known as a myeloproliferative neoplasm. It involves the abnormal development and function of bone marrow cells that produce blood cells, and leads to the overproduction of red blood cells. White blood cells and platelets may also be overproduced.
The JAK2 V617F genetic mutation is an acquired, somatic mutation found in the JAK2 gene in blood forming cells and is present in nearly 100% of patients with polycythemia vera. Mutations lead to dysregulation of the JAK pathway resulting in over production of many blood cells.
There is currently no cure for polycythemia vera, but the condition can often be managed for many years and the recent FDA approval of Jakafi® is expanding treatment options. In rare cases, polycythemia vera may progress to myelofibrosis (scarring of the bone marrow) or acute myeloid leukemia (AML).
Symptoms of Polycythemia Vera
At its early stages, polycythemia vera may not cause any symptoms. Symptoms that may develop as the condition progresses include the following:1,2
- A feeling of pressure or fullness below the ribs on the left side.
- Double vision or seeing dark or blind spots that come and go.
- Itching all over the body, especially after being in warm or hot water.
- Reddened face that looks like a blush or sunburn.
- Weight loss for no known reason.
Overproduction of blood cells and changes to blood flow increase the risk of serious blood clots in people with polycythemia vera. This can lead to life-threatening conditions such as heart attack, stroke, or pulmonary embolism. Treatment can reduce this risk while also helping to manage bothersome symptoms. Polycythemia vera can also cause pregnancy complications, and women who are pregnant or considering becoming pregnant may wish to talk with their doctor about how to manage their health.
Diagnosis of Polycythemia Vera
Blood tests provide the primary information necessary to diagnosis polycythemia vera. Patients may also undergo a bone marrow examination. Polycythemia vera typically involves a high concentration of red blood cells and the presence of certain gene mutations in blood cells.3
PV is characterized by three mutually-exclusive “driver” mutations: JAK2, CALR, and MPL. The diagnosis of PV often requires the presence of a JAK2 mutation, in addition to documentation of increased hemoglobin/hematocrit, to a threshold level established by the 2016 World Health Organization, (>16.5 g/dL/49% for males and >16 g/dL/48% for females).2
These gene mutations, which involve the Janus kinase 2 (JAK2) gene, are identified in almost all people with polycythemia vera. JAK2 mutations are thought to contribute to the growth of polycythemia vera and some other myeloproliferative neoplasms, but the exact role of this gene continues to be studied.
Bone marrow assessment is encouraged, in order to distinguish PV from JAK2-mutated ET and obtain cytogenetic information, which is also prognostically relevant.
Another common characteristic of polycythemia vera is lower-than-normal blood levels of a protein known as erythropoietin. People with polycythemia may also have elevated levels of platelets and/or white blood cells.
Treatment of Polycythemia Vera
Treatment of polycythemia vera can improve symptoms, reduce the risk of complications and prolong survival. Individuals with PV under current treatment survive on average 14-15 years. Choice of treatment depends in part on a patient’s risk of blood clots and the discomfort of symptoms.2,3,4 Patients who are older or who have history of blood clots are considered high-risk and may require more extensive treatment than patients who are low-risk. Treatment of low-risk patients often involves phlebotomy (removal of some blood) and low-dose aspirin.
- Phlebotomy The periodic removal of blood from a vein is referred to as phlebotomy (using the same technique as blood donation) and this can reduce the concentration of red blood cells.
- Low-dose aspirin. Reduces the risk of blood clots.
- Hydroxyurea (HU) May be used for the treatment of high-risk patients or patients who have not responded adequately to phlebotomy and low-dose aspirin. Hydroxyurea suppresses blood cell production in the bone marrow.
- Interferon Belongs to a group of biologic substances called cytokines. Interferon alpha produces its anti-cancer effects by stimulating the immune system to help fight PV and other cancers. Interferon is in use in Europe and the United States - it has the potential advantage of "reversing the disease biology", it is however associated with more side effects than other treatments and has not been shown to be superior to HU. Update of Ongoing Interferon Trials
- JAK inhibitors JAK inhibitors target abnormal cell signaling that is through to contribute to the growth of cells in Polycythemia Vera and other myeloproliferative neoplasms. The JAK1 and JAK2 inhibitor Jakafi® (ruxolitinib) is the first new drug approved for the treatment of Polycythemia Vera.
A Phase III trial published in the New England Journal of Medicine has determined that Jakafi® is more effective treatment of polycythemia vera than standard therapy. Researchers compared Jakafi with standard therapies in patients who did not respond well to Hydroxyurea. Patients receiving Jakafi had significantly better disease control: 21% compared to only 1% for standard therapy, had better hematocrit control (60% versus 20%) and had a greater reduction in spleen size: 38% of Jakafi treated patients had at least a 35% reduction in spleen volume compared with only 1% on standard therapy. More patients on Jakafi experienced remission: 24% versus 9% and 49% experienced a 50% reduction in symptoms compared to only 5% with standard therapy.(5)
Symptom & Complication Management
PV associated symptoms are common and the inability to effectively control them is a source of great frustration for many PV patients. In addition to itching, and fatigue which negatively impact quality of life, there also major life-threatening complications from PV which include transformation to acute leukemia, fibrotic progression in the bone marrow and thrombosis (blood clotting).
Thrombosis and Bleeding
Approximately 23% to 39% of individuals diagnosed with PV have a history of thrombosis. Arterial thrombosis is more common than venous and and long term studies suggest this risk continues to increase in the absence of treatment. A history of bleeding is less common occurring in less than 10%. Advanced age is an independent risk factor for thrombosis.2
Individuals with either a thrombosis history or advanced age are currently classified as having “high-risk” disease, while the absence of both risk factors is required for “low-risk” disease.
Low Risk PV
Prior to the introduction of phlebotomy as a treatment for PV the average duration of survival was 2 years with mortality mainly occurring due to thrombotic complications. Research has shown that maintaining the hematocrit below 45% and the use of anti-thrombotic low-dose aspirin reduce the risk of thrombosis and prolong survival.2
High Risk PV
High risk and refractory disease is treated with Hydrea, Jakafi, pegylated IFN- α, or busulfan.2
Monitoring of Symptoms More Important Than Blood Counts in Polycythemia Vera
A recent study supports what individuals with polycythemia vera (PV) have known for years. PV associated symptoms are under appreciated by doctors and don't necessarily correlate with blood counts levels. All too often physicians don't appreciate the severity and troublesome nature of these symptoms especially in individuals whose disease seems to be “controlled” as evidenced by their blood counts. Market research in fact with PV patients suggests they often feel their doctor underestimates the severity of their symptoms.
A new research support further confirms the observation that physicians can under appreciate the severity of patient’s symptoms, especially if they overly rely on blood counts to tailor their treatment. This research demonstrated that achieving blood count control does not necessarily result in symptom control.
Patients should work with their physician to create a program for regular monitoring of symptom burden as well as their blood counts as a measurement of disease control. Both patients and their physicians need to better appreciate that making treatment adjustments that reduce blood counts below the recommended targets may be necessary to achieve optimal symptom control.6,7
Itching & Skin Side Effects
Itching and skin side effects are a common and troublesome symptom of PV. Itching has been reported in up to 85% of patients and is very troublesome after bathing in particular.
Treatment with hydroxyurea can exacerbate skin side effects. Researchers have reported a hydroxyurea-associated skin toxicity rate of 55.2%, which included ulcers (15.6%), precancerous lesions (10.4%), skin cancer (4.2%), and various other nonmalignant side effects. (32.3%). In contrast, the incidence of skin toxicity for those treated with Jakaifi (ruxolitinib), anagrelide, or interferon alpha during the study was 3.0%, 0%, and 12.5%, respectively, with an overall non-hydroxyurea cutaneous AE rate of 4.3%.9
Management of PV that Progresses to Myelofibrosis or Acute Myeloid Leukemia
In rare cases, polycythemia vera progresses to myelofibrosis (scarring of the bone marrow) or acute myeloid leukemia (AML). Among people with PV, the 10-year risk of myelofibrosis is less than 10% and the 10-year risk of AML is less than 5%.2 For information about the management of these conditions, click on one of the following:
Management during pregnancy
Although there appears to be increased miscarriage rates with PV most pregnancies are uneventful and have a successful outcome. Experts do not consider pregnancy to be contraindicated in women with PV and they currently advise conservative management with once-daily aspirin therapy and phlebotomy to be adequate in “low risk” women, and recommend the use of pegylated IFN- α for high-risk disease.
Mortality Rates in Polycythemia Vera
The REVEAL clinical study is an observational study of 2510 patients with PV treated at 227 US clinical practices. In January 2021 study authors reported that the median survival for a PV diagnosis is estimated to be about 2 decades. This is the first contemporary report evaluating life expectancy and causes of mortality. Overall 244 patients (9.7%) have died during the study, and at last follow-up 90% were alive. The 4-year mortality rate for PV was estimated to be more than 10%. The average age at death was 77.1 years with a mean disease duration of 8.6 years. Patients who died were significantly older at diagnosis and were more likely to have high-risk disease compared with patients who survived. A history of thrombotic events was associated with reduced survival. in fact thrombotic complications (33.1%) were the most common cause of death followed by hematologic malignancy (15.4%), respiratory failure (13.1%), infection (10.3%), and bleeding (6.3%).8
Strategies to Improve Treatment
Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Areas of active investigation aimed at improving the treatment of polycythemia vera include the following:
JAK inhibitors: Targeted drugs known as JAK inhibitors have changed the way in which polycythemia vera is treated. These drugs target abnormal cell signaling that is through to contribute to the growth of myeloproliferative neoplasms. The JAK1 and JAK2 inhibitor Jakafi® has been approved for the treatment of myelofibrosis and polycythemia vera and researchers are working to determine when best to use Jakafi® and at what dose and schedule.
Interferon vs Jakafi: There is considerable debate among researchers and PV patients alike regarding the role of Interferon and Jakafi. Clinical trials are currently ongoing to determine which might be superior.
Other targeted drugs that are being evaluated for PV include histone deacetylase (HDAC) inhibitors. These drugs—which include givinostat, vorinistat, pabinostat, and others—interfere with enzymes that may contribute to cancer growth.
Are you facing a new diagnosis, recurrence, living with advanced disease, or supporting a loved one with a diagnosis of polycythemia vera? The Cancer Connect Polycythemia Vera Information Center has current, evidence-based information and a community of individuals sharing and supporting each other. Join the polycythemia community, and get the facts about a polycythemia vera diagnosis, treatment options, and survivorship, and stay up to date with ongoing polycythemia research that could impact your treatment decisions through our daily cancer news.
- National Cancer Institute: PDQ® Chronic Myeloproliferative Disorders Treatment. Bethesda, MD: National Cancer Institute. Date last modified 08/07/2013. Available here. Accessed 10/11/2013.
- Polycythemia vera treatment algorithm 2018
- Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. American Journal of Hematology. 2013;88:508-516.
- Hensley B, Geyer H, Mesa R. Polycythemia vera: current pharmacotherapy and future directions. Expert Opinion in Pharmacotherapy. 2013;14:609-617.
- Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. New England Journal of Medicine. 2015 Jan 29;372(5):426-35.
- Clin Lymphoma Myeloma Leuk. 2019;19:579-584.
- [Symptom Burden and Blood Counts in Patients With Polycythemia Vera in the United States: An Analysis From the REVEAL Study](https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(19%2930312-X/fulltext)
- Stein BL, Patel K, Scherber RM, Yu J, Paranagama D, Miller CB. Mortality and causes of death of patients with polycythemia vera: analysis of the reveal prospective, observational study. Presented at: American Society of Hematology (ASH) 62nd Annual Meeting and Exposition; December 5-8, 2020. Abstract 484.
- Stegelmann F, Wille K, Busen H, et al. Significant association of cutaneous adverse events with hydroxyurea: results from a prospective non-interventional study in BCR-ABL1-negative myeloproliferative neoplasms (MPN) – on behalf of the German Study Group-MPN [published online July 3, 2020]. Leukemia. doi: 10.1038/s41375-020-0945-3