Drugs

, Volume 66, Issue 17, pp 2173–2187

Polycythaemia Vera and Essential Thrombocythaemia

Current Treatment Strategies
Therapy In Practice

Abstract

Polycythaemia vera (PV) and essential thrombocythaemia (ET) are classified as Philadelphia-negative chronic myeloproliferative diseases. Both PV and ET are rare diseases, but the prevalence is high. Patients who have not been treated for the diseases are at great risk of morbidity and mortality as a result of thrombohaemorrhagic events. However, if patients have been well treated, their prognosis is good and life-expectancy approaches normal.

This article provides diagnostic tools and flowcharts for treatment of PV and ET. Treatment of PV and ET should be risk-adjusted and individualised. Low-dose aspirin is recommended as an antiaggregative drug in both diseases. For PV, phlebotomy to control a haematocrit at <0.45 is the cornerstone in treatment, and treatment with hydroxycarbamide (hydroxyurea) or interferon (IFN)-α is added to reduce hypermetabolic symptoms or splenomegaly becoming cytoreductive. In ET, hydroxycarbamide and anagrelide are the most used drugs, and anagrelide may also be added in PV to reduce thrombocytosis. IFNα is the only myelosuppressive treatment available during pregnancy. Current controversies regarding treatment illustrate the need for more randomised clinical trials. Demonstration of over expression of the PV-1 gene and in particular the JAK-2 mutation will be novel diagnostic criteria and may have an impact for future therapy of both PV and ET.

References

  1. 1.
    Bench AJ, Cross NCP, Huntly BJP, et al. Myeloproliferative disorders. Clin Haematol 2001; 14: 531–51Google Scholar
  2. 2.
    Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–90PubMedCrossRefGoogle Scholar
  3. 3.
    Temerinac S, Klippel S, Strunck E, et al. Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. Blood 2000; 95: 2569–76PubMedGoogle Scholar
  4. 4.
    Panteli KE, Hatzimichael EC, Bouranta PK, et al. Serum in-terleukin (IL)-l, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases. Br J Haematol 2005; 130: 709–15PubMedCrossRefGoogle Scholar
  5. 5.
    Barbui T, Finazzi G. Treatment indications and choice of a platelet-lowering agent in essential thrombocythemia. Curr Hematol Rep 2003; 2: 248–56PubMedGoogle Scholar
  6. 6.
    Chintagumpala MM, Steuber CP, Mahoney DH, et al. Essential thrombocythemia in a child: management with anagrelide. Am J Pediatr Hematol Oncol 1991; 13: 52–6PubMedCrossRefGoogle Scholar
  7. 7.
    Chintagumpala MM, Kennedy LL, Steuber CP. Treatment of essential thrombocythemia with anagrelide. J Pediatr 1995; 127: 495–8PubMedCrossRefGoogle Scholar
  8. 8.
    Hermann J, Collins MH, D’Angio GJ. Successful treatment of essential thrombocythemia with anagrelide in a child. Med Pediatr Oncol 1998; 30: 367–71PubMedCrossRefGoogle Scholar
  9. 9.
    Lackner H, Urban C, Beham-Schmid C, et al. Treatment of children with anagrelide for thrombocythemia. J Pediatr Hematol Oncol 1998; 20: 469–73PubMedCrossRefGoogle Scholar
  10. 10.
    Tefferi A. Current management of polycythemia vera. Leuk Lymphoma 2002; 43: 1–7PubMedCrossRefGoogle Scholar
  11. 11.
    Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol 2001; 49: 164–6PubMedCrossRefGoogle Scholar
  12. 12.
    Fenaux P, Dimon M, Caulier MT, et al. Clinical course of essential thrombocythemia in 147 cases. Cancer 1990; 66: 549–56PubMedCrossRefGoogle Scholar
  13. 13.
    Jensen MK, de Nully Brown P, Nielsen OJ. Incidence, clinical features and outcome of essential thrombocythemia in a well defined geographical area. Eur J Haematol 2000; 65: 132–9PubMedCrossRefGoogle Scholar
  14. 14.
    Tefferi A, Solberg LA, Silverstein MN. A clinical update in polycytemia vera and essential thrombocythemia. Am J Med 2000; 109: 141–9PubMedCrossRefGoogle Scholar
  15. 15.
    Van Genderen PJJ, Troost MM. Polycythemia vera and essential thrombocythemia in elderly. Drugs Aging 2000; 17: 107–19PubMedCrossRefGoogle Scholar
  16. 16.
    Michiels JJ, Thiele J. Clinical and pathological criteria for the diagnosis of essential thrombocythemia, polycythemia vera and idiopathic myelofibrosis (agnogenic myeloid metaplasia). Int J Hematol 2002; 76: 133–45PubMedCrossRefGoogle Scholar
  17. 17.
    Green AR, Vassiliou GS, Curtin N, et al. Management of the myeloproliferative disorders: distinguishing data from dogma. Hematol J 2004; 5: 126–32CrossRefGoogle Scholar
  18. 18.
    Mesa RA. Clinical and scientific advances in the Philadelphia-chromosome negative chronic myeloproliferative disorders. Int J Hematol 2002; 76 Suppl. 2: 193–203CrossRefGoogle Scholar
  19. 19.
    Pearson TC, Messinezy M, Westwood N, et al. A polycythemia vera update: diagnosis, pathobiology and treatment. In: Hematology 2000, the American Society of Hematology Education Book. Washington, DC: American Society of Hematology, 2000: 51–68Google Scholar
  20. 20.
    Tefferi A. A contemporary approach to the diagnosis and management of polycythemia vera. Curr Hematol Rep 2003; 2: 237–41PubMedGoogle Scholar
  21. 21.
    Spivak JL. Polycythemia vera: myths, mechanisms and management. Blood 2002; 100: 4272–90PubMedCrossRefGoogle Scholar
  22. 22.
    Gilbert HS. Modern treatment strategies in polycythemia vera. Semin Hematol 2003; 40: 26–9PubMedGoogle Scholar
  23. 23.
    McMullin MF, Barefod D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/ erythrocytosis. Br J Haematol 2005; 130: 174–95PubMedCrossRefGoogle Scholar
  24. 24.
    Spivak JL. The optimal management of polycythemia vera. Br J Haematol 2002; 116: 243–54PubMedCrossRefGoogle Scholar
  25. 25.
    Osier W. Chronic cyanosis with polycythemia and enlarged spleen: a new clinical entity. Am J Med Sci 1903; 126: 187–201CrossRefGoogle Scholar
  26. 26.
    Berlin NI. Diagnosis and classification of the polycytemias. Semin Hemattol 1975; 12: 339–51Google Scholar
  27. 27.
    Andreasson B, Lofvenberg E, Westin J. Management of patients with polycythaemia vera: results of a survey among Swedish haematologists. Eur J Haematol 2005; 74: 489–95PubMedCrossRefGoogle Scholar
  28. 28.
    Sirhan S, Fairbanks VF, Tefferi A. Red cell mass and plasma volume measurements in polycytemia vera: evaluation of performance and practical utility. Cancer 2005; 104: 213–5PubMedCrossRefGoogle Scholar
  29. 29.
    Jaffe ES, Harris NL, Stein H. World Health Organization Classification of tumours: pathology and genetics of tumours of haematopoietic and plymphoid tissues. Lyon: IARC Press, 2001Google Scholar
  30. 30.
    Cazzola M, Skoda R. Gain of function, loss of control-a molecular basis for chronic myeloproliferative disorders. Haematologica 2005; 90: 871–4PubMedGoogle Scholar
  31. 31.
    Michiels JJ, de Raeve H, Berneman Z, et al. The 2001 World Health Organization and updated European clinical and pathological criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic meyloproliferative disorders. Semin Thromb Hemost 2006; 32: 307–40PubMedCrossRefGoogle Scholar
  32. 32.
    Tefferi A. The diagnosis of polycythemia vera: new tests and old dictums. Best Pract Res Clin Haematol 2006; 19: 455–69PubMedCrossRefGoogle Scholar
  33. 33.
    Villeval J-L, James C, Pisani DF, et al. New insights into the pathogenesis of JAK2 V617F-positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost 2006; 32: 341–51PubMedCrossRefGoogle Scholar
  34. 34.
    Gilbert HS. Current management in polycythemia vera. Semin Hematol 2001; 38: 25–8PubMedCrossRefGoogle Scholar
  35. 35.
    Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114–24PubMedCrossRefGoogle Scholar
  36. 36.
    Gilbert HS. Historical perspective on the treatment of essential thrombocythemia and polycythemia vera. Semin Hematol 2006; 36 (1 Suppl. 2): 19–22Google Scholar
  37. 37.
    Harrison CN. Essential thrombocythemia: challenges and evidence-based management. Br J Haematol 2005; 130: 153–65PubMedCrossRefGoogle Scholar
  38. 38.
    Van Genderen PJJ, Michiels JJ. Primary thrombocythemia: diagnosis, clinical manifestations and management. Ann Hematol 1993; 67: 57–62PubMedCrossRefGoogle Scholar
  39. 39.
    Briere J, Guilmion F. Management of patients with essential thrombocythemia: current concepts and perspectives. Pathol Biol (Paris) 2001; 49: 178–83CrossRefGoogle Scholar
  40. 40.
    Dugan V, Higginbotham R, Gilbert J, et al. Essential thrombocytosis: diagnostic and treatment dilemmas. J La State Med Soc 2003; 155: 306–13PubMedGoogle Scholar
  41. 41.
    Barbui T, Barosi G, Grossi A, et al. Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004; 89: 215–32PubMedGoogle Scholar
  42. 42.
    McMullin MF, Bareford D, Craig J, et al. The optimal management of polycythemia vera. Br J Haematol 2003; 120: 543–4PubMedCrossRefGoogle Scholar
  43. 43.
    Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and high risk of thrombosis. N Engl J Med 1995; 332: 1132–6PubMedCrossRefGoogle Scholar
  44. 44.
    Löfvenberg E, Wahlin A. Management of polycythemia vera, essential thrombocytosis and myelofibrosis with hydroxyurea. Eur J Haematol 1988; 41: 375–81PubMedCrossRefGoogle Scholar
  45. 45.
    Olesen LH, Pedersen BB. Hydroxyurea-induced leg ulcers in patients with chronic myeloproliferative disorders. Ugeskr Laeger 2001; 163: 6908–11PubMedGoogle Scholar
  46. 46.
    Lengfelder E, Berger U, Hehlmann R. Interferon-alpha in the treatment of polycythemia vera. Ann Hematol 2000; 79: 103–9PubMedCrossRefGoogle Scholar
  47. 47.
    Lengfelder E, Grisshammer M, Hehlmann R. Interferon-alpha in the treatment of essential thrombocythemia. Leuk Lymphoma 1996; 22: 135–42PubMedCrossRefGoogle Scholar
  48. 48.
    Radin AI, Kim HT, Grant BW, et al. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487), a trial of the Eastern Cooperative Oncology Group. Cancer 2003; 98: 100–9PubMedCrossRefGoogle Scholar
  49. 49.
    Samuelsson J, Hasselbalch HC, Bruserud O, et al. A phase II trial of pegylated inteferon alfa-2b therapy for polycythemia vera and essential thrombocythemia. Cancer 2006; 106: 2397–405PubMedCrossRefGoogle Scholar
  50. 50.
    Kiladjian JJ, Cassinat B, Turlure P, et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood 2006 Sep 15; 108(6): 2037–40PubMedCrossRefGoogle Scholar
  51. 51.
    Samuelsson J, Mutschler M, Birgegard G, et al. Limited effects on JAK2 mutational status after pegylated interferon alpha-2b therapy in polycythemia vera and essential thrombocythemia. Haematologica 2006 Sep; 91(9): 1281–2PubMedGoogle Scholar
  52. 52.
    Silver RT. Imatinib mesylate (Gleevec (™) reduces phlebotomy requirements in polycythemia vera. Leukemia 2003; 17: 1186–7PubMedCrossRefGoogle Scholar
  53. 53.
    Tefferi A. Recent progress in the pathogenesis and management of essential thrombocythemia. Leuk Res 2001; 25: 369–77PubMedCrossRefGoogle Scholar
  54. 54.
    Tefferi A, Murphy S. Current opinion in essential thrombocythemia: pathogenesis, diagnosis and management. Blood Rev 2001; 15: 121–31PubMedCrossRefGoogle Scholar
  55. 55.
    Thiele J, Kvasnicka HM. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 2003; 82: 148–52PubMedGoogle Scholar
  56. 56.
    Barbui T, Finazzi G, Dupuy E, et al. Treatment strategies in essential thrombocythemia a critical appraisal of various experiences in different centers. Leuk Lymphoma 1996; 22: 149–60PubMedCrossRefGoogle Scholar
  57. 57.
    Campbell PJ, Scott LM, Wheathley K, et al. Definition of subtypes of essential thrombocythaemia and relation to polycytaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366: 1945–53PubMedCrossRefGoogle Scholar
  58. 58.
    Barbui T. Barbui T. Indications for lowering platelet numbers in essential thrombocythemia. Semin Hematol 2003; 40: 22–5Google Scholar
  59. 59.
    Barbui T. What is the standard treatment in essential thrombocythemia. Int J Hematol 2002; 76 Suppl. 2: 311–7CrossRefGoogle Scholar
  60. 60.
    Gisslinger H. Update on diagnosis and management of essential thrombocythemia. Semin Thromb Hemost 2006; 32: 430–6PubMedCrossRefGoogle Scholar
  61. 61.
    Schafer AI. Thrombocytosis. N Engl J Med 2004; 350: 1211–9PubMedCrossRefGoogle Scholar
  62. 62.
    Michiels JJ, Berneman Z, van Bockstaele D, et al. Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications, and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Semin Thromb Hemost 2006; 32: 174–207PubMedCrossRefGoogle Scholar
  63. 63.
    Penninga EI, Jensen BA, Hansen PB, et al. Anagrelide treatment in 52 patients with chronic myeloproliferative diseases. Clin Lab Haematol 2004; 26: 335–40PubMedCrossRefGoogle Scholar
  64. 64.
    Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 2001; 97: 863–6PubMedCrossRefGoogle Scholar
  65. 65.
    Van Genderen PJJ, Mulder PG, Waleboer M, et al. Prevention and treatment of thrombotic complications in essential thrombocythemia: efficacy and safety of aspirin. Br J Haematol 1997; 97: 179–84PubMedCrossRefGoogle Scholar
  66. 66.
    Nand S, Stock W, Godwin J, et al. Leukemogenic risk of hydroxyurea therapy in polycytemia vera, essential thrombocytosis and myeloid metaplasia with myelofibrosis. Am J Hematol 1996; 52: 42–6PubMedCrossRefGoogle Scholar
  67. 67.
    Sterkers Y, Preudhomme C, Lai JL, et al. Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocytosis treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 1998; 91: 616–22PubMedGoogle Scholar
  68. 68.
    Tatarsky I, Sharon R. Management of polycytemia vera with hydroxyurea. Semin Hematol 1997; 34: 24–8PubMedGoogle Scholar
  69. 69.
    Weinfeld A, Swolin J. Acute leukemia after hydroxyurea treatment in polycytemia vera and allied disorders: prospective study of efficacy and leukemogenicity with therapeutic implications. Eur J Haematol 1994; 52: 134–9PubMedCrossRefGoogle Scholar
  70. 70.
    Lõfvenberg E, Nordenson I, Wahlin A. Cytogenetic abnormalities and leukemic transformation in hydroxyurea treated patients with Philadelphia chromosome negative diseases. Cancer Genet Cytogenet 1990; 49: 57–67PubMedCrossRefGoogle Scholar
  71. 71.
    Haft VN, Fruchtman SM, Pickens CV, et al. DNA mutating associated with in vivo hydroxyurea-exposure. Blood 2000; 95: 3589–93Google Scholar
  72. 72.
    Halsey C, Roberts IA. The role of hydroxyura in sickel cell disease. Br J Haematol 2003; 120: 177–86PubMedCrossRefGoogle Scholar
  73. 73.
    Finazzi G, Ruggeri M, Rodeghiero F, et al. Second malignancies in patients with essential thrombocythemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol 2000; 110: 577–83PubMedCrossRefGoogle Scholar
  74. 74.
    Murphy S, Peterson P, Hand H, et al. Experience of the Polycytemia Vera Study Group with essential thrombocytosis: a final report on diagnostic criteria, survival and leukemic transformation by treatment. Semin Hematol 1997; 34: 29–39PubMedGoogle Scholar
  75. 75.
    Anagrelide Study Group. Anagrelide, a novel therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992; 92: 69–76CrossRefGoogle Scholar
  76. 76.
    Brooks WG, Standley DD, Goode JV. Role of anagrelide in the treatment of thrombocytosis. Ann Pharmacother 1999; 33: 1116–8PubMedCrossRefGoogle Scholar
  77. 77.
    Oertel MD. Anagrelide, a selective thrombocytopenic agent. Am J Health Syst Pharm 1998; 55: 1979–86PubMedGoogle Scholar
  78. 78.
    Petrides PE, Beykirch MK, Trapp OM. Anagrelide, a novel platelet lowering option in essential thrombocythemia: treatment experiences in 48 patientes in Germany. Eur J Haematol 1998; 61: 71–6PubMedCrossRefGoogle Scholar
  79. 79.
    Wagstaff AJ, Keating GM. Anagrelide: a review of its use in the management of essential thrombocythaemia. Drugs 2006; 66: 111–31PubMedCrossRefGoogle Scholar
  80. 80.
    Birgegaard G. Anagrelide treatment in myeloproliferative disorders. Semin Thromb Hemost 2006; 32: 260–6CrossRefGoogle Scholar
  81. 81.
    Petitt RM, Silverstein MN, Petrone ME. Anagrelide for control of thrombocythemia in polycytemia and other myeloproliferative disorders. Semin Hematol 1997; 34: 51–4PubMedGoogle Scholar
  82. 82.
    Silverstein MN, Petitt RM, Solberg LA, et al. Anagrelide: a new drug for treating thrombocytosis. N Engl J Med 1988; 318: 1292–4PubMedCrossRefGoogle Scholar
  83. 83.
    Knutsen H, Hyssing J. Anagrelid ved primær trombocytemi. Tidsskr Nor Laegeforen 2001; 121: 1478–82PubMedGoogle Scholar
  84. 84.
    Silverstein MN, Tefferi A. Treatment of essential thrombocythemia with anagrelide. Semin Hematol 1999; 36 (1 Suppl. 2): 23–5PubMedGoogle Scholar
  85. 85.
    Birgegård G, Björkholm M, Kutti J, et al. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004; 89: 520–7PubMedGoogle Scholar
  86. 86.
    Steurer M, Gastl G, Jedrzejczak W-W, et al. Anagrelide for thrombocytosis in myeloproliferative disorders. Cancer 2004; 101: 2239–46PubMedCrossRefGoogle Scholar
  87. 87.
    Harrison CN, Path MR, Campbell PJ, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353: 33–45PubMedCrossRefGoogle Scholar
  88. 88.
    Barbui T, Finazzi G. When and how to treat essential thrombocythemia. N Engl J Med 2005; 353: 85–6PubMedCrossRefGoogle Scholar
  89. 89.
    Alvarado Y, Cortes J, Verstovsek S, et al. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia. Cancer Chemother Pharmacol 2003; 51: 81–6PubMedCrossRefGoogle Scholar
  90. 90.
    Niittyvuopio R, Juvonen E, Kaaja R, et al. Pregnancy in essential thrombocythemia: experiment with 40 pregnancies. Eur J Haematol 2004; 73: 431–6PubMedCrossRefGoogle Scholar
  91. 91.
    Vantroyen B, Vanstraelen D. Management of essential thrombocythemia during pregnancy with aspirin, interferon alpha-2a and no treatment. Acta Haematol 2002; 107: 158–69PubMedCrossRefGoogle Scholar
  92. 92.
    Harrison C. Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br J Haematol 2005; 129: 293–306PubMedCrossRefGoogle Scholar
  93. 93.
    Griesshammer M, Struve S, Harrison CM. Essential thrombocythemia / Polycythemia vera and pregnancy: the need for an observational study in Europe. Semin Thromb Hemost 2006; 32: 422–9PubMedCrossRefGoogle Scholar
  94. 94.
    Doubek M, Brychtova Y, Doubek R, et al. Anagrelide therapy in pregnancy: report of a case of essential thrombocythemia. Ann Hematol 2004; 83: 726–7PubMedCrossRefGoogle Scholar
  95. 95.
    Byrd DC, Pitts SR, Alexander CK. Hydroxyurea in two pregnant women with sickle cell anemia. Pharmacotherapy 1999; 19: 1459–62PubMedCrossRefGoogle Scholar
  96. 96.
    Pata O, Tok CE, Yazici G, et al. Polycythemia vera and pregnancy: a case report with the use of hydroxyurea in the first trimester. Am J Perinatal 2004; 21: 135–7CrossRefGoogle Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of HaematologyNational University Hospital, RigshospitaletCopenhagenDenmark

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