Diagnosis and Therapy of Polycythemia Vera

ABSTRACT

Polycythemia vera (PV) is a hematopoietic stem cell disorder characterized by a predominant proliferation of the erythroid cell line. The diagnosis is commonly based on the WHO criteria. The acquired V617F mutation in the tyrosine kinase gene JAK2 represents a new molecular marker proving clonality in PV and other chronic myeloproliferative disorders. Phlebotomy is still the treatment of choice to reduce the red cell mass. Low-dose acetylsalicylic acid is successful in the primary prophylaxis of vascular complications. However, the majority of patients require myelosuppressive therapy during the course of their disease due to progressive myeloproliferation. Hydroxyurea still plays a role in patients of all age groups. Interferon α represents an alternative, particularly for younger patients. Apart from sporadic cases of bone marrow transplantation, there is no known curative treatment in PV. To date, the diagnosis of PV was based mainly on clinical criteria. The identification of the JAK2 mutation enables new approaches to the diagnosis, classification, and treatment of PV and of the other myeloproliferative disorders.

Polycythemia vera - diagnosis - therapy - leukemia - myelofibrosis - thrombosis

REFERENCES

• 1 Dameshek W. Some speculations on the myeloproliferative syndromes.  Blood. 1951;  6 372-375
• 2 Pierre R, Imbert M, Thiele J, Vardiman J, Brunning R, Flandrin G. Polycythemia vera. In: Jaffe E, Harris N, Stein H, Vardiman J Pathology and Genetics. Tumors of Haematopoietic and Lymphoid Tissues. Lyon, France; IARC Press 2001: 32-34
• 3 Thiele J, Kvasnicka H M, Fischer R, Diehl V. Histochemistry and morphometry on bone marrow specimens in chronic myeloproliferative disorders - aids to diagnosis and classification.  Ann Hematol. 1999;  78 495-506
• 4 Silva M, Richard C, Benito A, Sanz C, Olalla I, Fernandez-Luna L. Expression of Bcl-x in erythroid precursors from patients with polycythemia vera.  N Engl J Med. 1998;  338 564-571
• 5 Moliterno A, Hankins D, Spivak J. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera.  N Engl J Med. 1998;  338 572-580
• 6 Klippel S, Strunck S, Temerinac S et al.. Quantification of PRV-1 mRNA distinguishes polycythemia vera from secondary erythrocytosis.  Blood. 2003;  102 3569-3574
• 7 Teofili L, Martini M, Luongo M et al.. Overexpression of the polycythemia rubra vera-1 gene in essential thrombocythemia.  J Clin Oncol. 2002;  20 4249-4254
• 8 Palmqvist L, Goerttler P, Wasslavik C et al.. Comparison of methods for polycythemia rubra vera-1 mRNA quantification in whole-blood leukocytes and purified granulocytes.  Clin Chem. 2004;  50 644-647
• 9 Emig M, Ernst T, Schenk T et al.. Relationship of PRV1 expression and JAK2 V617F mutations in chronic myeloproliferative disorders.  Onkologie. 2005;  28(suppl 3) 136 (abst 409)
• 10 Kralovics R, Passamonti F, Buser A et al.. A gain-of-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
• 11 Baxter E, Scott L, Campbell P et al.. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.  Lancet. 2005;  365 1054-1061
• 12 James C, Ugo V, Couédic J et al.. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.  Nature. 2005;  434 1144-1148
• 13 Levine R, Wadleigh M, Cools J et al.. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.  Cancer Cell. 2005;  7 387-397
• 14 Jones A, Kreil S, Zoi K et al.. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.  Blood. 2005;  106 2162-2168
• 15 Gruppo Italiano Studio Polycythemia vera. The natural history of 1213 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
• 16 Najean Y, Dresch C, Rain J D. The very-long-term course of polycythemia: a complement to the previously published data of the polycythemia vera study group.  Br J Haematol. 1994;  86 233-235
• 17 Rozman C, Giralt M, Feliu E, Rubio D, Cortés M T. Life expectancy of patients with chronic nonleukemic myeloproliferative disorders.  Cancer. 1991;  67 2658-2663
• 18 Passamonti F, Malabarba L, Orlandi E et al.. Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia.  Haematologica. 2003;  88 13-18
• 19 Najean Y, Mugnier P, Dresch C, Rain J. Polycythemia vera in young people. An analysis of 58 cases diagnosed before 40 years.  Br J Haematol. 1987;  67 285-291
• 20 Berk P D, Goldberg J D, Silverstein M N et al.. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy.  N Engl J Med. 1981;  304 441-447
• 21 Berk P D, Goldberg J D, Donovan P D, Fruchtman S M, Berlin N I, Wasserman L R. Therapeutic recommendations in polycythemia vera based on polycythemia vera study group protocols.  Semin Hematol. 1986;  23 132-143
• 22 Messinezy M, Pearson T C. Incidence of myelofibrosis following treatment of primary polycythaemia by venesection.  Br J Haematol. 1995;  89 228-229
• 23 Haanen C, Mathé G, Hayat M. Treatment of polycythemia vera by radiophosphorus or busulfan: a randomized trial.  Br J Cancer. 1981;  44 75-80
• 24 Najean Y, Rain J D. for the French Polycythemia Study Group . Treatment of polycythemia vera: use of ³²P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age.  Blood. 1997;  89 2319-2327
• 25 Fruchtman S M, Mack K, Kaplan M E, Peterson P, Berk P D, Wasserman L R. From efficacy to safety: a polycythemia vera study group report on hydroxyurea in patients with polycythemia vera.  Semin Hematol. 1997;  34 17-23
• 26 Tatarsky I, Sharon R. Management of polycythemia vera with hydroxyurea.  Semin Hematol. 1997;  34 24-28
• 27 Najean Y, Rain J D. for the French Polycythemia Study Group . Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years.  Blood. 1997;  90 3370-3377
• 28 Finazzi G, Ruggeri M, Rodheghiero F, Barbui T. Second malignancies in patients with essential thrombocythemia treated with busulphan and hydroxyurea: long-term follow up of a randomized trial.  Br J Haematol. 2000;  110 577-583
• 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 2664-2670
• 30 Brusamolino E, Salvaneschi L, Canevari A, Bernasconi C. Efficacy trial of pipobroman in polycythemia vera and incidence of acute leukemia.  J Clin Oncol. 1984;  2 558-561
• 31 Petti M C, Spadea A, Avvisati G et al.. Polycythemia vera treated with pipobroman as single agent: low incidence of secondary leukemia in a cohort of patients observed during 20 years (1971-1991).  Leukemia. 1998;  12 869-874
• 32 Passamonti F, Brusalimo E, Lazzarino M et al.. Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.  Haematologica. 2000;  85 1011-1018
• 33 Kiladjian J J, Gardin C, Renoux M, Bruno F, Bernard J F. Long-term outcomes of polycythemia vera patients treated with pipobroman as initial therapy.  Hematol J. 2003;  4 198-207
• 34 Lengfelder E, Berger U, Hehlmann R. Interferon α in the treatment of polycythemia vera.  Ann Hematol. 2000;  79 103-109
• 35 Gilbert H S. Long term treatment of myeloproliferative disease with interferon-α-2b.  Cancer. 1998;  83 1205-1213
• 36 Merx K, Fabarius A, Pahl H et al.. Pegylated interferon alpha (PegIntron) in patients with polycythemia vera. A prospective multicenter phase II Study.  Onkologie. 2004;  27(suppl 3) 74 (abst O 363)
• 37 Anagrelide study group . Anagrelide, a therapy for thrombocythemic states: experience in 577 patients.  Am J Med. 1992;  92 69-76
• 38 Fruchtman S M. Treatment paradigms in the management of myeloproliferative disorders.  Semin Hematol. 2004;  42(suppl 3) 18-22
• 39 Storen E, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia.  Blood. 2001;  97 863-866
• 40 Harrison C N, Campbell P J, Buck G et al.. United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.  N Engl J Med. 2005;  353 33-45
• 41 Silver R T. Imatinib mesylate (Gleevec^TM) reduces phlebotomy requirements in polycythemia vera.  Leukemia. 2003;  17 1186-1187
• 42 Silver R T, Fruchtman S M, Feldman E J, Spivak J L, Salvado A J. Imatinib mesylate (GLEEVEC) is effective in the treatment of polycythemia vera: a multi-institutional clinical trial.  Blood. 2004;  104 (abst 656)
• 43 Hasselbalch H C, Pedersen M, Bostrom H. Imatinib mesylate therapy reduces phlebotomy requirements in polycythemia vera.  Blood. 2003;  102 (abst 5087)
• 44 Borthakur G, Kantarjian H, Vesrtovsek S et al.. Imatinib mesylate therapy for patients with polycythemia vera.  Blood. 2004;  104 (abst 1527)
• 45 Hasselbalch H C, Larsen T S, Henriksen A S et al.. Imatinib mesylate in polycythemia vera. A Heterogeneous Response pattern but a consistent reduction in phlebotomy requirements.  Blood. 2004;  104 (abst 4747)
• 46 Kuriakose P, Shurafa M S. A phase II trial of imatinib mesylate (Gleevec) in myeloproliferative disorders.  Blood. 2004;  104 (abst 4765)
• 47 Jones C M, Dickinson T M. Polycythemia vera responds to imatinib mesylate.  Am J Med Sci. 2003;  325 149-152
• 48 Merx K, Maywald O, Fabarius A et al.. Imatinib (Glivec^®) therapy in patients with polycythemia vera. Interim analyses of an open label phase II trial.  Onkologie. 2005;  27(suppl 3) 80 (abst 235)
• 49 Tartaglia A, Goldberg J D, Berk P D, Wasserman L R. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera.  Semin Hematol. 1986;  23 172-176
• 50 Gruppo Italiano Studio Polycythemia vera. Low dose aspirin in polycythemia vera: a pilot study.  Br J Haematol. 1997;  97 453-456
• 51 Landolfi R, Marchioli R, Kutti J et al.. Efficacy and safety of low dose aspirin in polycythemia vera.  N Engl J Med. 2004;  350 114-124