Polycythemia Vera: Rapid Evidence Review

 

Am Fam Physician. 2021 Jun 1;103(11):680-687.

  Patient information: A handout on this topic is available at https://familydoctor.org/condition/polycythemia-vera/.

Author disclosure: No relevant financial affiliations.

Polycythemia vera is one of three stem-cell–derived myeloid malignancies commonly known as myeloproliferative neoplasms. It is characterized by erythrocytosis, often with associated leukocytosis and thrombocytosis. It has a significant negative impact on overall mortality and morbidity in the form of arterial and venous clots, symptoms of fatigue and pruritus, and conversion to leukemia and myelofibrosis. The World Health Organization's major diagnostic criteria include an elevated hemoglobin or hematocrit level, abnormal results on bone marrow biopsy, and presence of the Janus kinase 2 genetic mutation, which is present in approximately 98% of cases. The only minor criterion is a subnormal erythropoietin level, which helps differentiate polycythemia vera from common causes of secondary erythrocytosis such as smoking, sleep apnea, and testosterone use. First-line treatments, such as low-dose aspirin and goal-directed phlebotomy to a hematocrit level of less than 45% to reduce thrombotic events, improve quality of life and prolong survival. When indicated, cytoreductive therapy, primarily with hydroxyurea, can be added with consideration of second-line agents such as pegylated interferon-alfa, busulfan, and ruxolitinib, depending on the clinical scenario. Smoking cessation and cardiometabolic disease are modifiable risk factors that should be addressed to reduce the risk of thrombosis. Currently, no medications have been shown to cure the disease or to reduce the risk of conversion to leukemia and myelofibrosis.

Polycythemia vera (PV) is one of three common myeloproliferative neoplasms that will likely be encountered during the career of a primary care physician.1 This article summarizes the best, most recent evidence to guide the diagnosis and treatment of PV.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

All people with polycythemia vera should receive phlebotomy with a goal hematocrit level of less than 45%.18,19

B

Consistent, low-quality evidence

All people who have polycythemia vera without contraindications should take daily low-dose aspirin (40 to 100 mg).21

B

Limited-quality randomized controlled trials

Hydroxyurea is considered first-line cytoreductive therapy, if indicated.20,24

B

Systematic review and meta-analysis of lower-quality studies

Patients with polycythemia vera should be counseled to stop smoking to reduce the risk of thrombosis.39

B

Systematic review and meta-analysis of cohort studies


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

All people with polycythemia vera should receive phlebotomy with a goal hematocrit level of less than 45%.18,19

B

Consistent, low-quality evidence

All people who have polycythemia vera without contraindications should take daily low-dose aspirin (40 to 100 mg).21

B

Limited-quality randomized controlled trials

Hydroxyurea is considered first-line cytoreductive therapy, if indicated.20,24

B

Systematic review and meta-analysis of lower-quality studies

Patients with polycythemia vera should be counseled to stop smoking to reduce the risk of thrombosis.39

B

Systematic review and meta-analysis of cohort studies


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Epidemiology

  • The annual incidence of PV is 0.01 to 2.61 per 100,000 people, and the prevalence is 0.49 to 46.88 per 100,000.2,3

  • Median age at diagnosis is 64 years (range = 19 to 95 years), and up to 25% of diagnoses occur before 50 years of age.4,5

  • Nonmodifiable risk factors for PV include older age, male sex, White race, and European descent.2,6,7

  • Modifiable risk factors for PV include smoking, obesity, hypertension, diabetes mellitus, and hyperlipidemia.8,9

Diagnosis

  • Patients who have PV typically present with elevated hemoglobin and hematocrit levels found incidentally or after laboratory evaluation for patients' reported symptoms, physical examination findings, or thrombotic/bleeding events.5,10,11

  • The differential diagnosis of PV includes other myeloproliferative neoplasms and secondary eryt

The Authors

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STEVEN FOX, MD, is an associate professor in the Department of Family Medicine and clerkship director at the University of Tennessee College of Medicine and assistant program director of the University of Tennessee Family Medicine Residency, Chattanooga....

LESLIE GRIFFIN, MD, is the program director of the University of Tennessee Family Medicine Residency and an assistant professor in the Department of Family Medicine at Erlanger Hospital and the University of Tennessee College of Medicine, Chattanooga.

DOMINIQUE ROBINSON HARRIS, MD, is a resident in the Department of Family Medicine at Erlanger Hospital and the University of Tennessee College of Medicine, Chattanooga.

Address correspondence to Steven Fox, MD, University of Tennessee College of Medicine, 1100 E 3rd St., Chattanooga, TN 37403 (email: steven.fox@erlanger.org). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

References

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1. Stuart BJ, Viera AJ. Polycythemia vera. Am Fam Physician. 2004;69(9):2139–2144. Accessed November 20, 2020. https://www.aafp.org/afp/2004/0501/p2139.html...

2. Titmarsh GJ, Duncombe AS, McMullin MF, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis [published correction appears in Am J Hematol. 2015;90(9):850]. Am J Hematol. 2014;89(6):581–587.

3. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 2014;92(4):289–297.

4. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507–2513.

5. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874–1881.

6. Srour SA, Devesa SS, Morton LM, et al. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001–12 [published correction appears in Br J Haematol. 2017;177(2):331]. Br J Haematol. 2016;174(3):382–396.

7. Pedersen KM, Bak M, Sørensen AL, et al. Smoking is associated with increased risk of myeloproliferative neoplasms: a general population-based cohort study. Cancer Med. 2018;7(11):5796–5802.

8. Lindholm Sørensen A, Hasselbalch HC. Smoking and Philadelphia-negative chronic myeloproliferative neoplasms. Eur J Haematol. 2016;97(1):63–69.

9. Accurso V, Santoro M, Mancuso S, et al. Cardiovascular risk in essential thrombocythemia and polycythemia vera. Mediterr J Hematol Infect Dis. 2020;12(1):e2020008.

10. Siegel FP, Tauscher J, Petrides PE. Aquagenic pruritus in polycythemia vera: characteristics and influence on quality of life in 441 patients [published correction appears in Am J Hematol. 2013;88(10):925]. Am J Hematol. 2013;88(8):665–669.

11. Scherber R, Dueck AC, Johansson P, et al. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): international prospective validation and reliability trial in 402 patients. Blood. 2011;118(2):401–408.

12. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2019;94(1):133–143.

13. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15.

14. Essential Evidence Plus, Polycythemia vera. Wiley-Blackwell; 2020. Accessed November 21, 2020. https://www.essentialevidenceplus.com/content/eee/274#accept

15. Mesa R, Jamieson C, Bhatia R, et al. Myeloproliferative neoplasms, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(12):1572–1611.

16. Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm 2018. Blood Cancer J. 2018;8(1):3.

17. Pascale S, Petrucci G, Dragani A, et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood. 2012;119(15):3595–3603.

18. Marchioli R, Finazzi G, Specchia G, et al.; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22–33.

19. Podoltsev NA, Zhu M, Zeidan AM, et al. The impact of phlebotomy and hydroxyurea on survival and risk of thrombosis among older patients with polycythemia vera. Blood Adv. 2018;2(20):2681–2690.

20. Mesa RA, Jamieson C, Bhatia R, et al. NCCN guidelines insights: myeloproliferative neoplasms, version 2.2018. J Natl Compr Canc Netw. 2017;15(10):1193–1207.

21. Landolfi R, Marchioli R, Kutti J, et al.; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350(2):114–124.

22. Michiels JJ, Berneman Z, Schroyens W, et al. Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and coumadin-resistant arterial thrombophilia. Platelets. 2006;17(8):528–544.

23. Barbui T, Vannucchi AM, Finazzi G, et al. A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: a propensity-matched study. Am J Hematol. 2017;92(11):1131–1136.

24. Ferrari A, Carobbio A, Masciulli A, et al. Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis. Haematologica. 2019;104(12):2391–2399.

25. Alvarez-Larrán A, Kerguelen A, Hernández-Boluda JC, et al.; Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN). Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera. Br J Haematol. 2016;172(5):786–793.

26. Barbui T, Barosi G, Birgegard G, et al.; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761–770.

27. Kiladjian J-J, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–3072.

28. Douglas G, Harrison C, Forsyth C, et al. Busulfan is effective second-line therapy for older patients with Philadelphia-negative myeloproliferative neoplasms intolerant of or unresponsive to hydroxyurea. Leuk Lymphoma. 2017;58(1):89–95.

29. Finazzi G, Caruso V, Marchioli R, et al.; ECLAP Investigators. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105(7):2664–2670.

30. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–435.

31. Diehn F, Tefferi A. Pruritus in polycythaemia vera: prevalence, laboratory correlates and management. Br J Haematol. 2001;115(3):619–621.

32. Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood. 2002;99(7):2627.

33. Pardanani A, Vannucchi AM, Passamonti F, et al. JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia. 2011;25(2):218–225.

34. Muller EW, de Wolf JT, Egger R, et al. Long-term treatment with interferon-alpha 2b for severe pruritus in patients with polycythaemia vera. Br J Haematol. 1995;89(2):313–318.

35. Baldo A, Sammarco E, Plaitano R, et al. Narrowband (TL-01) ultraviolet B phototherapy for pruritus in polycythaemia vera. Br J Dermatol. 2002;147(5):979–981.

36. McMullin MFF, Mead AJ, Ali S, et al. A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: a British Society for Haematology Guideline. Br J Haematol. 2019;184(2):161–175.

37. Griesshammer M, Struve S, Barbui T. Management of Philadelphia negative chronic myeloproliferative disorders in pregnancy. Blood Rev. 2008;22(5):235–245.

38. Passamonti F, Rumi E, Pietra D, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;24(9):1574–1579.

39. Wilson K, Gibson N, Willan A, et al. Effect of smoking cessation on mortality after myocardial infarction: meta-analysis of cohort studies. Arch Intern Med. 2000;160(7):939–944.

40. Chievitz E, Thiede T. Complications and causes of death in polycythaemia vera. Acta Med Scand. 1962;172:513–523.

41. Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5(11):e366.

 

 

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