POLYCYTHEMIA VERA: UPDATE ON PATHOGENESIS, DIAGNOSIS AND MANAGEMENT

Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by increased red blood cell mass and usually overproduction of granulocytes and platelets and increased spleen size. JAK2V617F mutation is present in more than 95% of PV patients. Bone marrow examination reveals excessive proliferation of erythroid, myeloid, and megakaryocytic elements. The prognosis of PV depends on the severity of the complications occurring during the clinical course. Thrombotic complications are the main cause of morbidity and mortality in PV. Survival is affected whether appropriate therapy is applied during the erythrocytotic phase of the disease. Uncontrolled erythrocytosis poses very high risk for development of thrombosis. Some studies suggest that PV patients have a normal or near-normal lifeexpectancy. Most studies, however, report excess mortality caused by thrombotic complications and acute leukemia transformation during course of PV. This review aims to highlight the pathogenesis, diagnosis and current management in PV

Keywords

• Acute leukemia transformation
• Myeloproliferative neoplasm
• Polycythemia vera
• Thrombotic complications

POLİSİTEMİA VERA: PATOGENEZ, TEŞHİS VE TEDAVİDE GÜNCEL BİLGİLER

Abstract

Polisitemia vera (PV), eritrosit kitlesinde mutlak artış ile karakterize, sıklıkla granülosit ve trombositlerin aşırı üretiminin ve splenomegalinin eşlik ettiği bir miyeloproliferatif neoplazidir. JAK2V617F mutasyonu, PV tanılı olguların %95’inden fazlasında görülmektedir. Kemik iliği incelemesinde eritroid, miyeloid ve megakaryositik seride proliferasyon görülür. PV’nın prognozu, klinik seyir sırasında ortaya çıkan komplikasyonların ciddiyetine bağlıdır. PV’da morbidite ve mortalitenin ana nedeni trombotik komplikasyonlardır. Yaşam, hastalığın pletorik fazında uygun tedavinin başlanıp başlanmamasından etkilenmektedir. Kontrol edilemeyen eritrositoz varlığında tromboz riski belirgin şekilde artış gösterir. Bazı çalışmalarda PV’nın normal veya normale yakın yaşam süresi ile ilişkisi gösterilmiştir. Fakat, birçok çalışmada PV’da trombotik komplikasyonlar ve akut lösemiye dönüşüm sonucunda artmış mortalite olduğu bildirilmiştir. Bu derlemenin amacı, PV tanılı olgularda patogenez, tanı yöntemleri ve güncel tedaviyi vurgulamaktır.

Keywords

• Akut lösemiye dönüşüm
• Miyeloproliferatif neoplazi
• Polisitemia vera
• Trombotik komplikasyonlar

References

1. Anger B, Haug U, Seidler R, Heimpel H.Polycythemia vera. A clinical study of 141 patients. Blut. 1989;59(6):493-500.
2. Balan KK, Critchley M. Outcome of 259 patients with primary proliferative polycythaemia (PPP) and idiopathic thrombocythaemia (IT) treated in a regional phosphorus-32--a 15 year review. Br J Radiol. 1997;70(839):1169-73. department with
3. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR; Cancer Genome Project. Acquired mutation of the myeloproliferative 2005;365(9464):1054-61. JAK2 disorders. Lancet.
4. Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR. Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol. 1986;23(2):132-43.
5. Buchanan JG, Ameratunga RV, Hawkins RC. Polycythemia vera and water-induced pruritus: evidence against mast cell involvement. Pathology. 1994;26(1):43-5.
6. Budde U, Scharf RE, Franke P, Hartmann-Budde K, Dent J, Ruggeri ZM. Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma. Blood. 1993;82(6):1749-57.
7. Bittencourt RI, Vassallo J, Chauffaille Mde L, Xavier SG, Pagnano KB, Nascimento AC, De Souza CA, Chiattone CS. Philadelphia-negative chronic myeloproliferative neoplasms. Rev Bras Hematol Hemoter. 2012;34(2):140-9.
8. Camós M, Cervantes F, Montoto S, Hernández- Boluda JC, Villamor N, Montserrat E. Acute lymphoid leukemia following polycythemia vera. Leuk Lymphoma. 1999;32(3-4):395-8.

9. Campbell PJ, Griesshammer M, Döhner K, Döhner H, Kusec R, Hasselbalch HC, Larsen TS, Pallisgaard N, Giraudier S, Le Bousse-Kerdilès MC, Desterke C, Guerton B, Dupriez B, Bordessoule D, Fenaux P, Kiladjian JJ, Viallard JF, Brière J, Harrison CN, Green AR, Reilly JT. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood 2006;107:2098–100.
10. Caramazza D, Caracciolo C, Barone R, Malato A, Saccullo G, Cigna V, Berretta S, Schinocca L, Quintini G, Abbadessa V, Di Raimondo F, Siragusa S. Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms. Ann Hematol. 2009;88(10):967-71.
11. Carobbio A, Finazzi G, Antonioli E, Guglielmelli P, Vannucchi AM, Dellacasa CM, Salmoiraghi S, Delaini F, Rambaldi A, Barbui T. JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol. 2009;37(9):1016-21.
12. Crisà E, Venturino E, Passera R, Prina M, Schinco P, Borchiellini A, Giai V, Ciocca Vasino MA, Bazzan M, Vaccarino A, Boccadoro M, Ferrero D. A retrospective study on 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and non-alkylating drugs. Ann Hematol. 2010;89(7):691-9.
13. Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 2002;16(7):1207-12. Review.
14. Di Nisio M, Barbui T, Di Gennaro L, Borrelli G, Finazzi G, Landolfi R, Leone G, Marfisi R, Porreca E, Ruggeri M, Rutjes AW, Tognoni G, Vannucchi AM, Marchioli R; European Collaboration on Low- dose Aspirin in Polycythemia Vera (ECLAP) Investigators. The haematocrit and platelet target in polycythemia vera. Br J Haematol. 2007;136(2):249- 59.
15. Finazzi G, Barbui T. How I treat patients with polycythemia vera. Blood 2007;109:5104–5111.
16. Gangat N, Wolanskyj AP, McClure RF, Li CY, Schwager S, Wu W, Tefferi A. Risk stratification for survival and leukemic transformation in essential thrombocythemia: A single institutional study of 605 patients. Leukemia 2007;21:270–276.
17. Gruppo Italiano Studio Policitemia. Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med. 1995;123(9):656-64.
18. Gutman AB, Kupfer S, Sharney L, Weissmann B, Yu TF. On the biosynthesis of uric acid from glycine-N15 polycythemia. Am J Med. 1956;21(6):901-17. and secondary
19. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR; United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353(1):33-45.
20. Heller PG, Lev PR, Salim JP, Kornblihtt LI, Goette NP, Chazarreta CD, Glembotsky AC, Vassallu PS, Marta RF, Molinas FC. JAK2V617F mutation in platelets from essential thrombocythemia patients: correlation with clinical features and analysis of STAT5 phosphorylation status. Eur J Haematol, 2006; 77: 210–216.
21. James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144-8.
22. Johansson P, Kutti J, Andréasson B, Safai-Kutti S, Vilén L, Wedel H, Ridell B. Trends in the incidence of chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders in the city of Göteborg, Sweden, 2004;256(2):161-5. J Intern Med.
23. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-90. of JAK2 in
24. Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T; 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):114-24.
25. complications in polycythemia vera. Semin Thromb
26. Hemost. 1997;23(5):441-54. and vascular
27. Mirza AM, Ezzat S, Axelrad AA. Insulin-like growth factor binding protein-1 is elevated in patients with polycythemia vera and stimulates erythroid 1997;89(6):1862-9. in vitro. Blood. 31. Moliterno AR, Spivak JL. Posttranslational
28. processing of the thrombopoietin receptor is impaired
29. 1999;94(8):2555-61. vera. Blood.
30. Nand S, Messmore H, Fisher SG, Bird ML, Schulz W, Fisher RI. Leukemic transformation in polycythemia vera: analysis of risk factors. Am J Hematol. 1990;34(1):32-6.
31. Parker RG. Occlusion of the hepatic veins in man. Medicine (Baltimore). 1959;38:369-402.
32. Passamonti F, Malabarba L, Orlandi E, Baratè C, Canevari A, Brusamolino E, Bonfichi M, Arcaini L, Caberlon S, Pascutto C, Lazzarino M. Polycythemia vera in young patients: a study on the long-term risk of Haematologica. 2003;88(1):13-8. and leukemia.
33. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative 1978;2(8102):1219-22. J, Lancet. 36. Perkins Israuels MC, Wilkinson JF. Polycythaemia vera: clincical studies on a series of 127 patients managed without radiation therapy. Q J Med. 1964;33:499-518.
34. Petitt RM, Silverstein MN, Petrone ME. Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders. Semin Hematol. 1997;34(1):51-4.
35. Prchal JF, Axelrad AA. Letter: Bone-marrow responses in polycythemia vera. N Engl J Med. 1974;290(24):1382.
36. Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P, Gattoni E, Salmoiraghi S, Finazzi MC, Di Tollo S, D'Urzo C, Vannucchi AM, Barosi G, Barbui T. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with myeloproliferative neoplasms. Br J Haematol. 2010;150(4):446-55. positive chronic
37. Rosenbaum DL, Murphy GW, Swisher SN. Hemodynamic studies of the portal circulation in myeloid metaplasia. Am J Med. 1966;41(3):360-8.
38. Röder S, Steimle C, Meinhardt G, Pahl HL. STAT3 is constitutively active in some patients with Polycythemia 2001;29(6):694-702. vera. Exp Hematol.
39. Salem HH, Van der Weyden MB, Young IF, Wiley JS. Pruritus and severe iron deficiency in polycythaemia vera. Br Med J (Clin Res Ed). 1982;285(6335):91-2.
40. Silver RT. Interferon alfa: effects of long-term treatment for polycythemia vera. Semin Hematol. 1997;34(1):40-50.
41. Solar GP, Kerr WG, Zeigler FC, Hess D, Donahue C, de Sauvage FJ, Eaton DL. Role of c-mpl in early hematopoiesis. Blood. 1998;92(1):4-10.
42. Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100(13):4272-90.
43. Steinman HK, Greaves MW. Aquagenic pruritus. J Am Acad Dermatol. 1985;13(1):91-6.
44. Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood. 2001;97(4):863-6.
45. Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS, Sekeres MA, Maciejewski JP. Refractory associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 2006;108:2173– 2181. ringed sideroblasts
46. Tefferi A, Spivak JL. Polycythemia vera: scientific advances and current practice. Semin Hematol 2005;42:206-220.
47. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point- of-care diagnostic algorithms. Leukemia. 2008; 22(1):14-22. 2008;22(11):2118-9. in: Leukemia.
48. Towell BL, Levine SP. Massive hepatomegaly following splenectomy for myeloid metaplasia. Case report and review of the literature. Am J Med. 1987;82(2):371-5. 52. Treatment of polycythaemia vera by radiophosphorus or busulphan: a randomized trial. "Leukemia and
49. Hematosarcoma" Cooperative Group, European Organization for Research on Treatment of Cancer (E.O.R.T.C.). Br J Cancer. 1981;44(1):75-80.
50. Ugo V, Marzac C, Teyssandier I, Larbret F, Lécluse Y, Debili N, Vainchenker W, Casadevall N. Multiple signaling pathways are involved in erythropoietin-independent erythroid progenitors in polycythemia vera. Exp Hematol. 2004;32(2):179-87. differentiation of
51. Valla D, Casadevall N, Lacombe C, Varet B, Goldwasser E, Franco D, Maillard JN, Pariente EA, Leporrier myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med. 1985;103(3):329-34.
52. Wehmeier A, Daum I, Jamin H, Schneider W. Incidence and clinical risk factors for bleeding and thrombotic complications in myeloproliferative disorders. A retrospective analysis of 260 patients. Ann Hematol. 1991;63(2):101-6.
53. Westin J, Granerus G, Weinfeld A, Wetterquist H. Histamine metabolism in polycythaemia vera. Scand J Haematol. 1975;15(1):45-57.