Myeloproliferative Neoplasms: Thrombophilic Clonal Stem Cell Diseases

Part of the Cancer Treatment and Research book series (CTAR, volume 148)

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are currently classified as BCR-ABL-negative classic myeloproliferative neoplasms (MPN). According to the revised 2008 World Health Organization (WHO) classification system, adult chronic myeloid neoplasms are now divided into four broad categories; myelodysplastic syndrome (MDS), MPN, “MDS/MPN overlap” and “myeloid or lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1” [1]. The WHO MPN category includes the four classic MPN: chronic myelogenous leukemia (CML; BCR-ABL-positive), PV, ET, and PMF. All three BCR-ABL-negative MPN are uncommon and incidence figures are estimated at 0.2–2.5/100,000 for ET [2–4], 0.4 to 1.5/100,000 for PMF [2, 3] and 0.8–2.6/100,000 for PV [5, 6]. The median age at diagnosis for all these three MPN is approximately 60 years [7].


Acute Myeloid Leukemia Polycythemia Vera Essential Thrombocythemia JAK2 Inhibitor Reduced Intensity Conditioning 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14–22.PubMedCrossRefGoogle Scholar
  2. 2.
    Mesa RA, Silverstein MN, Jacobsen SJ, Wollan PC, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County study, 1976–1995. Am J Hematol. 1999;61:10–15.PubMedCrossRefGoogle Scholar
  3. 3.
    Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol (Paris). 2001;49:164–166.CrossRefGoogle Scholar
  4. 4.
    Jensen MK, de Nully Brown P, Nielsen OJ, Hasselbalch HC. Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol. 2000;65:132–139.PubMedCrossRefGoogle Scholar
  5. 5.
    Ania BJ, Suman VJ, Sobell JL, Codd MB, Silverstein MN, Melton LJ III. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935–1989. Am J Hematol. 1994;47:89–93.Google Scholar
  6. 6.
    Najean Y, Rain JD, Billotey C. Epidemiological data in polycythaemia vera: a study of 842 cases. Hematol Cell Ther. 1998;40:159–165.PubMedGoogle Scholar
  7. 7.
    Chaiter Y, Brenner B, Aghai E, Tatarsky I. High incidence of myeloproliferative disorders in Ashkenazi Jews in northern Israel. Leukemia Lymphoma. 1992;7:251–255.PubMedCrossRefGoogle Scholar
  8. 8.
    Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L. Polycythemia vera: stem-cell and probable clonal origin of the disease. N Engl J Med. 1976;295:913–916.PubMedCrossRefGoogle Scholar
  9. 9.
    Jacobson RJ, Salo A, Fialkow PJ. Agnogenic myeloid metaplasia: a clonal proliferation of hematopoietic stem cells with secondary myelofibrosis. Blood. 1978;51:189–194.PubMedGoogle Scholar
  10. 10.
    Fialkow PJ, Faguet GB, Jacobson RJ, Vaidya K, Murphy S. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood. 1981;58:916–919.PubMedGoogle Scholar
  11. 11.
    Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, 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.PubMedCrossRefGoogle Scholar
  12. 12.
    James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–1148.PubMedCrossRefGoogle Scholar
  13. 13.
    Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–1790.PubMedCrossRefGoogle Scholar
  14. 14.
    Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–1061.PubMedGoogle Scholar
  15. 15.
    Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007;356:459–468.PubMedCrossRefGoogle Scholar
  16. 16.
    Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.PubMedCrossRefGoogle Scholar
  17. 17.
    Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007;21:1960–1963.PubMedCrossRefGoogle Scholar
  18. 18.
    Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108:3472–3476.PubMedCrossRefGoogle Scholar
  19. 19.
    Schnittger S, Haferlach C, Beelen DW, Bojko P, Dengler R, Diestelrath A, et al. Detection of three different MPLW515 mutations in 10.1% of all JAK2 V617 unmutated ET and 9.3% of all JAK2 V617F unmutated OMF: a study of 387 patients. ASH Annual Meeting Abstracts. 2007;110:2546.Google Scholar
  20. 20.
    Beer P, Campbell P, Erber W, Scott L, Bench A, Bareford D, et al. Clinical significance of MPL mutations in essential thrombocythemia: analysis of the PT-1 cohort. ASH Annual Meeting Abstracts. 2007;110:677.Google Scholar
  21. 21.
    Vannucchi AM, Antonioli E, Pancrazzi A, Guglielmelli P, Di Lollo S, Alterini R, et al. The clinical phenotype of patients with essential thrombocythemia harboring MPL 515 W>L/K mutation. ASH Annual Meeting Abstracts. 2007;110:678.Google Scholar
  22. 22.
    Guglielmelli P, Pancrazzi A, Bergamaschi G, Rosti V, Villani L, Antonioli E, et al. Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol. 2007;137:244–247.PubMedCrossRefGoogle Scholar
  23. 23.
    Tefferi A, Lasho TL, Schwager SM, Strand JS, Elliott M, Mesa R, et al. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer. 2006;106:631–635.PubMedCrossRefGoogle Scholar
  24. 24.
    Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617 V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110:840–846.PubMedCrossRefGoogle Scholar
  25. 25.
    Vannucchi AM, Antonioli E, Guglielmelli P, Longo G, Pancrazzi A, Ponziani V, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia. 2007;21:1952–1959.PubMedCrossRefGoogle Scholar
  26. 26.
    Dupont S, Masse A, James C, Teyssandier I, Lecluse Y, Larbret F, et al. The JAK2 617 V>F mutation triggers erythropoietin hypersensitivity and terminal erythroid amplification in primary cells from patients with polycythemia vera. Blood. 2007;110:1013–1021.PubMedCrossRefGoogle Scholar
  27. 27.
    Tefferi A, Strand JJ, Lasho TL, Knudson RA, Finke CM, Gangat N, et al. Bone marrow JAK2V617F allele burden and clinical correlates in polycythemia vera. Leukemia. 2007;21:2074–2075.PubMedCrossRefGoogle Scholar
  28. 28.
    Kittur J, Knudson RA, Lasho TL, Finke CM, Gangat N, Wolanskyj AP, et al. Clinical correlates of JAK2V617F allele burden in essential thrombocythemia. Cancer. 2007;109:2279–2284.PubMedCrossRefGoogle Scholar
  29. 29.
    Wolanskyj AP, Lasho TL, Schwager SM, McClure RF, Wadleigh M, Lee SJ, et al. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005;131:208–213.PubMedCrossRefGoogle Scholar
  30. 30.
    Antonioli E, Guglielmelli P, Pancrazzi A, Bogani C, Verrucci M, Ponziani V, et al. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia. 2005;19:1847–1849.PubMedCrossRefGoogle Scholar
  31. 31.
    Campbell PJ, Scott LM, Buck G, Wheatley K, East CL, Marsden JT, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet. 2005;366:1945–1953.PubMedCrossRefGoogle Scholar
  32. 32.
    Tefferi A, Lasho TL, Schwager SM, Steensma DP, Mesa RA, Li CY, et al. The JAK2 tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates. Br J Haematol. 2005;131:320–328.PubMedCrossRefGoogle Scholar
  33. 33.
    Barosi G, Bergamaschi G, Marchetti M, Vannucchi AM, Guglielmelli P, Antonioli E, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. 2007;110:4030–4036.PubMedCrossRefGoogle Scholar
  34. 34.
    Wolanskyj AP, Schwager SM, McClure RF, Larson DR, Tefferi A. Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006;81:159–166.Google Scholar
  35. 35.
    Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors and Jak2 mutation status 10.1182/blood-2006-09-046342. Blood. 2006:blood-2006-2009-046342.Google Scholar
  36. 36.
    Landolfi R, Di Gennaro L, Barbui T, De Stefano V, Finazzi G, Marfisi R, et al. Leukocytosis as a major thrombotic risk factor in patients with Polycythemia Vera 10.1182/blood-2006-08-042515. Blood. 2006:blood-2006-2008-042515.Google Scholar
  37. 37.
    Maugeri N, Giordano G, Petrilli MP, Fraticelli V, de Gaetano G, Cerletti C, et al. Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug? J Thromb Haemost. 2006.Google Scholar
  38. 38.
    Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol. 2005;33:523–530.PubMedCrossRefGoogle Scholar
  39. 39.
    Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, Villamor N, Colomer D, Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica. 2006;91:169–175.PubMedGoogle Scholar
  40. 40.
    Falanga A, Marchetti M, Evangelista V, Vignoli A, Licini M, Balicco M, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96:4261–4266.PubMedGoogle Scholar
  41. 41.
    Alvarez-Larran A, Garcia-Pagan JC, Abraldes JG, Arellano E, Reverter JC, Bosch J, et al. Increased CD11b neutrophil expression in Budd-Chiari syndrome or portal vein thrombosis secondary to polycythaemia vera. Br J Haematol. 2004;124:329–335.PubMedCrossRefGoogle Scholar
  42. 42.
    Maugeri N, Brambilla M, Camera M, Carbone A, Tremoli E, Donati MB, et al. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J Thromb Haemost. 2006;4:1323–1330.PubMedCrossRefGoogle Scholar
  43. 43.
    Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350:114–124.PubMedCrossRefGoogle Scholar
  44. 44.
    Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33–45.PubMedCrossRefGoogle Scholar
  45. 45.
    Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. New England Journal of Medicine. 1995;332:1132–1136.PubMedCrossRefGoogle Scholar
  46. 46.
    Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood. 2007;110:1092–1097.PubMedCrossRefGoogle Scholar
  47. 47.
    Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7:673–683.PubMedCrossRefGoogle Scholar
  48. 48.
    Tefferi A, Gilliland DG. The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc. 2005;80:947–958.Google Scholar
  49. 49.
    Gattenlohner S, Peter C, Bonengel M, Einsele H, Bargou R, Muller-Hermelink HK, et al. Detecting the JAK2 V617F mutation in fresh and ‘historic' blood and bone marrow. Leukemia. 2007;21:1559–1602.CrossRefGoogle Scholar
  50. 50.
    Hermouet S, Dobo I, Lippert E, Boursier MC, Ergand L, Perrault-Hu F, et al. Comparison of whole blood vs purified blood granulocytes for the detection and quantitation of JAK2(V617F). Leukemia. 2007;21:1128–1130.PubMedGoogle Scholar
  51. 51.
    James C, Delhommeau F, Marzac C, Teyssandier I, Couedic JP, Giraudier S, et al. Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis. Leukemia. 2006;20:350–353.PubMedCrossRefGoogle Scholar
  52. 52.
    McClure R, Mai M, Lasho T. Validation of two clinically useful assays for evaluation of JAK2 V617F mutation in chronic myeloproliferative disorders. Leukemia. 2006;20:168–171.PubMedCrossRefGoogle Scholar
  53. 53.
    Tefferi A. JAK2 mutations in polycythemia vera – molecular mechanisms and clinical applications. N Engl J Med. 2007;356:444–445.PubMedCrossRefGoogle Scholar
  54. 54.
    Remacha AF, Montserrat I, Santamaria A, Oliver A, Barcelo MJ, Parellada M. Serum erythropoietin in the diagnosis of polycythemia vera – a follow-up study. Haematologica. 1997;82:406–410.PubMedGoogle Scholar
  55. 55.
    Messinezy M, Westwood NB, El-Hemaidi I, Marsden JT, Sherwood RS, Pearson TC. Serum erythropoietin values in erythrocytoses and in primary thrombocythaemia. Br J Haematol. 2002;117:47–53.PubMedCrossRefGoogle Scholar
  56. 56.
    Mossuz P, Girodon F, Donnard M, Latger-Cannard V, Dobo I, Boiret N, et al. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. Haematologica. 2004;89:1194–1198.PubMedGoogle Scholar
  57. 57.
    Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia advance online publication 28 June 2007; doi: 101038/sjleu2404810. 2007.Google Scholar
  58. 58.
    Sidon P, El Housni H, Dessars B, Heimann P. The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors. Leukemia. 2006;20:1622.PubMedCrossRefGoogle Scholar
  59. 59.
    Vizmanos JL, Ormazabal C, Larrayoz MJ, Cross NC, Calasanz MJ. JAK2 V617F mutation in classic chronic myeloproliferative diseases: a report on a series of 349 patients. Leukemia. 2006;20:534–535.PubMedCrossRefGoogle Scholar
  60. 60.
    Michiels JJ, Abels J, Steketee J, van Vliet HH, Vuzevski VD. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia. Ann Intern Med. 1985;102:466–471.PubMedGoogle Scholar
  61. 61.
    van Genderen PJ, Michiels JJ. Erythromelalgia: a pathognomonic microvascular thrombotic complication in essential thrombocythemia and polycythemia vera. [Review] [23 refs]. Semin Thromb Hemost. 1997;23:357–363.PubMedCrossRefGoogle Scholar
  62. 62.
    Fenaux P, Simon M, Caulier MT, Lai JL, Goudemand J, Bauters F. Clinical course of essential thrombocythemia in 147 cases. Cancer. 1990;66:549–556.PubMedCrossRefGoogle Scholar
  63. 63.
    Cortelazzo S, Viero P, Finazzi G, A DE, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol. 1990;8:556–562.PubMedGoogle Scholar
  64. 64.
    Colombi M, Radaelli F, Zocchi L, Maiolo AT. Thrombotic and hemorrhagic complications in essential thrombocythemia. A retrospective study of 103 patients. Cancer. 1991;67:2926–2930.PubMedCrossRefGoogle Scholar
  65. 65.
    Besses C, Cervantes F, Pereira A, Florensa L, Sole F, Hernandez-Boluda JC, et al. Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia. 1999;13:150–154.PubMedCrossRefGoogle Scholar
  66. 66.
    Chim CS, Kwong YL, Lie AK, Ma SK, Chan CC, Wong LG, et al. Long-term outcome of 231 patients with essential thrombocythemia: prognostic factors for thrombosis, bleeding, myelofibrosis, and leukemia. Arch Intern Med. 2005;165:2651–2658.PubMedCrossRefGoogle Scholar
  67. 67.
    Polycythemia vera: the natural history of 1213 patients followed for 20 years. Gruppo Italiano Studio Policitemia. Ann Intern Med. 1995;123:656–664.Google Scholar
  68. 68.
    Passamonti F, Brusamolino E, Lazzarino M, Barate C, Klersy C, Orlandi E, et al. Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients. Haematologica. 2000;85:1011–1018.PubMedGoogle Scholar
  69. 69.
    Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224–2232.PubMedCrossRefGoogle Scholar
  70. 70.
    Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, Valentini M, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am J Med. 2004;117:755–761.PubMedCrossRefGoogle Scholar
  71. 71.
    Bounameaux H, Reber-Wasem MA. Superficial thrombophlebitis and deep vein thrombosis. A controversial association. Arch Intern Med. 1997;157:1822–1824.PubMedCrossRefGoogle Scholar
  72. 72.
    Gangat N, Wolanskyj AP, Tefferi A. Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications. Eur J Haematol. 2006;77:327–333.PubMedCrossRefGoogle Scholar
  73. 73.
    Tefferi A, Fonseca R, Pereira DL, Hoagland HC. A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc. 2001;76:22–28.Google Scholar
  74. 74.
    Berlin NI. Diagnosis and classification of the polycythemias. Seminars in Hematology. 1975;12:339–351.PubMedGoogle Scholar
  75. 75.
    Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood. 2002;99:2627.PubMedCrossRefGoogle Scholar
  76. 76.
    Gilbert HS, Warner RR, Wasserman LR. A study of histamine in myeloproliferative disease. Blood. 1966;28:795–806.PubMedGoogle Scholar
  77. 77.
    Jaroch MT, Broughan TA, Hermann RE. The natural history of splenic infarction. Surgery. 1986;100:743–750.PubMedGoogle Scholar
  78. 78.
    Price F, Bell H. Spinal cord compression due to extramedullary hematopoiesis. Successful treatment in a patient with long-standing myelofibrosis. Jama. 1985;253:2876–2877.PubMedCrossRefGoogle Scholar
  79. 79.
    Cervantes F, Barosi G, Demory JL, Reilly J, Guarnone R, Dupriez B, et al. Myelofibrosis with myeloid metaplasia in young individuals: disease characteristics, prognostic factors and identification of risk groups. Br J Haematol. 1998;102:684–690.PubMedCrossRefGoogle Scholar
  80. 80.
    Gangat N, Wolanskyj AP, McClure RF, Li CY, Schwager S, Wu W, et al. Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients. Leukemia. 2007;21:270–276.PubMedCrossRefGoogle Scholar
  81. 81.
    Gangat N, Strand J, Li CY, Wu W, Pardanani A, Tefferi A. Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation. Br J Haematol. 2007;138:354–358.PubMedCrossRefGoogle Scholar
  82. 82.
    Huang J, Li CY, Mesa RA, Wu W, Hanson CA, Pardanani AD, et al. Erythropoiesis stimulating agents and the risk of leukemic transformation in primary myelofibrosis. Blood. 2007;110:Abstract #554.Google Scholar
  83. 83.
    Cervantes F, Pereira A, Esteve J, Rafel M, Cobo F, Rozman C, et al. Identification of ‘short-lived' and ‘long-lived' patients at presentation of idiopathic myelofibrosis. Br J Haematol. 1997;97:635–640.PubMedCrossRefGoogle Scholar
  84. 84.
    Berk PD, Wasserman LR, Fruchtman SM, Goldberg JD. Treatment of polycythemia vera: a summary of clinical trials conducted by the polycythemia vera study group. In: Wasserman LR, Berk PD, Berlin NI, eds. Polycythemia vera and the myeloproliferative disorders. Philadelphia: W.B. Saunders; 1995:166–194.Google Scholar
  85. 85.
    Tefferi A. Polycythemia vera: a comprehensive review and clinical recommendations. Mayo Clin Proc. 2003;78:174–194.Google Scholar
  86. 86.
    Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood. 2007;109:2310–2313.PubMedCrossRefGoogle Scholar
  87. 87.
    De Stefano V, Za T, Rossi E, Vannucchi AM, Ruggeri M, Elli E, et al. Recurrent thrombosis in patients with polycythemia vera or essential thrombocythemia: efficacy of treatment in preventing rethrombosis in different clinical settings. Blood. 2006;108:Abstract # 119.Google Scholar
  88. 88.
    Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol. 2005;128:275–290.PubMedCrossRefGoogle Scholar
  89. 89.
    Harrison CN, Gale RE, Machin SJ, Linch DC. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications. Blood. 1999;93:417–424.PubMedGoogle Scholar
  90. 90.
    Vannucchi AM, Grossi A, Pancrazzi A, Antonioli E, Guglielmelli P, Balestri F, et al. PRV-1, erythroid colonies and platelet Mpl are unrelated to thrombosis in essential thrombocythaemia. Br J Haematol. 2004;127:214–219.PubMedCrossRefGoogle Scholar
  91. 91.
    Chiusolo P, La Barbera EO, Laurenti L, Piccirillo N, Sora F, Giordano G, et al. Clonal hemopoiesis and risk of thrombosis in young female patients with essential thrombocythemia. Exp Hematol. 2001;29:670–676.PubMedCrossRefGoogle Scholar
  92. 92.
    Zamora L, Espinet B, Florensa L, Besses C, Bellosillo B, Sole F. Clonality analysis by HUMARA assay in Spanish females with essential thrombocythemia and polycythemia vera. Haematologica. 2005;90:259–261.PubMedGoogle Scholar
  93. 93.
    Patel RK, Lea NC, Heneghan MA, Westwood NB, Milojkovic D, Thanigaikumar M, et al. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology. 2006;130:2031–2038.PubMedCrossRefGoogle Scholar
  94. 94.
    Campbell PJ, Griesshammer M, Dohner K, Dohner H, Kusec R, Hasselbalch HC, et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood. 2006;107:2098–2100.PubMedCrossRefGoogle Scholar
  95. 95.
    Tefferi A, Lasho TL, Huang J, Finke C, Mesa RA, Li CY, et al. Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival. Leukemia advance online publication 24 January 2008; doi: 101038/sjleu2405097. 2008.Google Scholar
  96. 96.
    Chievitz E, Thiede T. Complications and causes of death in polycythemia vera. Acta Med Scand. 1962;172:513–523.PubMedCrossRefGoogle Scholar
  97. 97.
    Finazzi G, Barbui T. How I treat patients with polycythemia vera. Blood. 2007;109:5104–5111.PubMedCrossRefGoogle Scholar
  98. 98.
    Di Nisio M, Barbui T, Di Gennaro L, Borrelli G, Finazzi G, Landolfi R, et al. The haematocrit and platelet target in polycythemia vera. Br J Haematol. 2007;136: 249–259.PubMedCrossRefGoogle Scholar
  99. 99.
    Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M, 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;89:215–232.PubMedGoogle Scholar
  100. 100.
    Barbui T, Finazzi G. When and how to treat essential thrombocythemia. N Engl J Med. 2005;353:85–86.PubMedCrossRefGoogle Scholar
  101. 101.
    van Genderen PJ, Mulder PG, Waleboer M, van de Moesdijk D, Michiels JJ. Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin. Br J Haematol. 1997;97:179–184.PubMedCrossRefGoogle Scholar
  102. 102.
    Finazzi G, Ruggeri M, Rodeghiero F, Barbui T. Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol. 2000;110:577–583.PubMedCrossRefGoogle Scholar
  103. 103.
    Finazzi G, Ruggeri M, Rodeghiero F, Barbui T. Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis. Blood. 2003;101:3749.PubMedCrossRefGoogle Scholar
  104. 104.
    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;82:1749–1757.PubMedGoogle Scholar
  105. 105.
    Tefferi A, Gangat N, Wolanskyj AP. Management of extreme thrombocytosis in otherwise low-risk essential thrombocythemia; does number matter? Blood. 2006;108:2493–2494.PubMedCrossRefGoogle Scholar
  106. 106.
    Fabris F, Casonato A, Grazia del Ben M, De Marco L, Girolami A. Abnormalities of von Willebrand factor in myeloproliferative disease: a relationship with bleeding diathesis. Br J Haematol. 1986;63:75–83.PubMedCrossRefGoogle Scholar
  107. 107.
    Najean Y, Rain JD. Treatment of polycythemia vera – the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood. 1997;90:3370–3377.PubMedGoogle Scholar
  108. 108.
    De Sanctis V, Mazzucconi MG, Spadea A, Alfo M, Mancini M, Bizzoni L, et al. Long-term evaluation of 164 patients with essential thrombocythaemia treated with pipobroman: occurrence of leukaemic evolution. Br J Haematol. 2003;123:517–521.PubMedCrossRefGoogle Scholar
  109. 109.
    Kiladjian JJ, Gardin C, Renoux M, Bruno F, Bernard JF. Long-term outcomes of polycythemia vera patients treated with pipobroman as initial therapy. Hematol J. 2003;4:198–207.PubMedCrossRefGoogle Scholar
  110. 110.
    Passamonti F, Malabarba L, Orlandi E, Pascutto C, Brusamolino E, Astori C, et al. Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis. Br J Haematol. 2002;116:855–861.PubMedCrossRefGoogle Scholar
  111. 111.
    Messinezy M, Pearson TC, Prochazka A, Wetherley-Mein G. Treatment of primary proliferative polycythaemia by venesection and low dose busulphan: retrospective study from one centre. Br J Haematol. 1985;61:657–666.PubMedCrossRefGoogle Scholar
  112. 112.
    D'Emilio A, Battista R, Dini E. Treatment of primary proliferative polycythaemia by venesection and busulphan. Br J Haematol. 1987;65:121–122.PubMedCrossRefGoogle Scholar
  113. 113.
    Shvidel L, Sigler E, Haran M, Klepfish A, Duek A, Berrebi A, et al. Busulphan is safe and efficient treatment in elderly patients with essential thrombocythemia. Leukemia. 2007;21:2071–2072.PubMedCrossRefGoogle Scholar
  114. 114.
    Silver RT. Interferon alfa: effects of long-term treatment for polycythemia vera. Semin Hematol. 1997;34:40–50.PubMedGoogle Scholar
  115. 115.
    Elliott MA, Tefferi A. Interferon-alpha therapy in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost. 1997;23:463–472.PubMedCrossRefGoogle Scholar
  116. 116.
    Silver RT. Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer. 2006;107:451–458.PubMedCrossRefGoogle Scholar
  117. 117.
    Samuelsson J, Hasselbalch H, Bruserud O, Temerinac S, Brandberg Y, Merup M, et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer. 2006;106:2397–2405.PubMedCrossRefGoogle Scholar
  118. 118.
    Kiladjian JJ, Cassinat B, Turlure P, Cambier N, Roussel M, Bellucci S, et al. High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood. 2006;108:2037–2040.PubMedCrossRefGoogle Scholar
  119. 119.
    Jones AV, Silver RT, Waghorn K, Curtis C, Kreil S, Zoi K, et al. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood. 2006;107:3339–3341.PubMedCrossRefGoogle Scholar
  120. 120.
    Wright CA, Tefferi A. A single institutional experience with 43 pregnancies in essential thrombocythemia. Eur J Haematol. 2001;66:152–159.PubMedCrossRefGoogle Scholar
  121. 121.
    Passamonti F, Randi ML, Rumi E, Pungolino E, Elena C, Pietra D, et al. Increased risk of pregnancy complications in patients with essential thrombocythemia carrying the JAK2 (617 V>F) mutation. Blood. 2007;110:485–489.PubMedCrossRefGoogle Scholar
  122. 122.
    Griesshammer M, Struve S, Harrison CM. Essential thrombocythemia/polycythemia vera and pregnancy: the need for an observational study in Europe. Semin Thromb Hemost. 2006;32:422–429.PubMedCrossRefGoogle Scholar
  123. 123.
    Elliott MA, Tefferi A. Thrombocythaemia and pregnancy. Best Pract Res Clin Haematol. 2003;16:227–242.PubMedCrossRefGoogle Scholar
  124. 124.
    Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V, Arcese W, et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European group for blood and marrow transplantation, Societe Francaise de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center collaborative study. Blood. 1999;93:2831–2838.PubMedGoogle Scholar
  125. 125.
    Guardiola P, Anderson JE, Gluckman E. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;343:659; discussion 659–660.PubMedCrossRefGoogle Scholar
  126. 126.
    Deeg HJ, Gooley TA, Flowers ME, Sale GE, Slattery JT, Anasetti C, et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood. 2003;102:3912–3918.PubMedCrossRefGoogle Scholar
  127. 127.
    Kroeger N, Holler E, Kobbe G, Bornhaeuser M, Schwerdtfeger R, Nagler A, et al. Dose-reduced conditioning followed by allogeneic stem cell transplantation in patients with myelofibrosis. Results from a Multicenter Prospective Trial of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). ASH Annual Meeting Abstracts. 2007;110:683.Google Scholar
  128. 128.
    Silverstein MN. Agnogenic myeloid metaplasia. Acton Mass, Publishing Science Group. 1975:126.Google Scholar
  129. 129.
    Rodriguez JN, Martino ML, Dieguez JC, Prados D. rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach. Haematologica. 1998;83:616–621.PubMedGoogle Scholar
  130. 130.
    Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Granell M, Vallansot R, et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol. 2006;134:184–186.PubMedCrossRefGoogle Scholar
  131. 131.
    Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, Sureda A, Torrebadell M, Montserrat E. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol. 2004;127:399–403.PubMedCrossRefGoogle Scholar
  132. 132.
    Cervantes F, Hernandez-Boluda JC, Alvarez A, Nadal E, Montserrat E. Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica. 2000;85:595–599.PubMedGoogle Scholar
  133. 133.
    Cervantes F, Alvarez-Larran A, Domingo A, Arellano-Rodrigo E, Montserrat E. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol. 2005;129:771–775.PubMedCrossRefGoogle Scholar
  134. 134.
    Tefferi A, Elliot MA. Serious myeloproliferative reactions associated with the use of thalidomide in myelofibrosis with myeloid metaplasia. Blood. 2000;96:4007.PubMedGoogle Scholar
  135. 135.
    Elliott MA, Mesa RA, Li CY, Hook CC, Ansell SM, Levitt RM, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;117: 288–296.PubMedCrossRefGoogle Scholar
  136. 136.
    Marchetti M, Barosi G, Balestri F, Viarengo G, Gentili S, Barulli S, et al. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol. 2004;22:424–431.PubMedCrossRefGoogle Scholar
  137. 137.
    Mesa RA, Elliott MA, Schroeder G, Tefferi A. Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc. 2004;79:883–889.Google Scholar
  138. 138.
    Mesa RA, Steensma DP, Pardanani A, Li CY, Elliott M, Kaufmann SH, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood. 2003;101:2534–2541.PubMedCrossRefGoogle Scholar
  139. 139.
    Tefferi A, Cortes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood. 2006;108:1158–1164.PubMedCrossRefGoogle Scholar
  140. 140.
    Tefferi A, Lasho TL, Mesa RA, Pardanani A, Ketterling RP, Hanson CA. Lenalidomide therapy in del(5)(q31)-associated myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia. 2007;21:1827–1828.PubMedCrossRefGoogle Scholar
  141. 141.
    Lofvenberg E, Wahlin A. Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol. 1988;41:375–381.PubMedCrossRefGoogle Scholar
  142. 142.
    Naqvi T, Baumann MA. Myelofibrosis: response to busulfan after hydroxyurea failure. Int J Clin Pract. 2002;56:312–313.PubMedGoogle Scholar
  143. 143.
    Petti MC, Latagliata R, Spadea T, Spadea A, Montefusco E, Aloe Spiriti MA, et al. Melphalan treatment in patients with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;116:576–581.PubMedCrossRefGoogle Scholar
  144. 144.
    Tefferi A, Silverstein MN, Li CY. 2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia. Br J Haematol. 1997;99:352–357.PubMedCrossRefGoogle Scholar
  145. 145.
    Tefferi A, Elliot MA, Yoon SY, Li CY, Mesa RA, Call TG, et al. Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia. Blood. 2001;97:1896.PubMedCrossRefGoogle Scholar
  146. 146.
    Tefferi A, Mesa RA, Nagorney DM, Schroeder G, Silverstein MN. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood. 2000;95:2226–2233.PubMedGoogle Scholar
  147. 147.
    Mesa RA, Nagorney DS, Schwager S, Allred J, Tefferi A. Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. 2006;107:361–370.PubMedCrossRefGoogle Scholar
  148. 148.
    Houck WA, Mesa RA, Tefferi A. Antemortem presentation and management of non-hepatosplenic extramedullary hematopoiesis in myelofibrosis with myeloid metaplasia. Blood. 2000;96:747a.Google Scholar
  149. 149.
    Dingli D, Utz JP, Krowka MJ, Oberg AL, Tefferi A. Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Chest. 2001;120:801–808.PubMedCrossRefGoogle Scholar
  150. 150.
    Steensma DP, Hook CC, Stafford SL, Tefferi A. Low-dose, single-fraction, whole-lung radiotherapy for pulmonary hypertension associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;118:813–816.PubMedCrossRefGoogle Scholar
  151. 151.
    Bartlett RP, Greipp PR, Tefferi A, Cupps RE, Mullan BP, Trastek VF. Extramedullary hematopoiesis manifesting as a symptomatic pleural effusion. Mayo Clinic Proc. 1995;70:1161–1164.Google Scholar
  152. 152.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–566.PubMedCrossRefGoogle Scholar
  153. 153.
    Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–2417.PubMedCrossRefGoogle Scholar
  154. 154.
    Kantarjian HM, Talpaz M, O'Brien S, Jones D, Giles F, Garcia-Manero G, et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood. 2006;108: 1835–1840.PubMedCrossRefGoogle Scholar
  155. 155.
    Pardanani A. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia. 2008;22:23–30.PubMedCrossRefGoogle Scholar
  156. 156.
    Verstovsek S, Kantarjian H, Pardanani A, Thomas D, Cortes J, Mesa R, et al. INCB018424, an oral, selective JAK2 inhibitor, shows significant clinical activity in a Phase I/II study in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF). ASH Annual Meeting Abstracts. 2007;110:558.Google Scholar
  157. 157.
    Verstovsek S, Pardanani AD, Shah NP, Sokol L, Wadleigh M, Gilliland DG, et al. A Phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis and post-polycythemia vera/essential thrombocythemia myelofibrosis. ASH Annual Meeting Abstracts. 2007;110:553.Google Scholar
  158. 158.
    Verstovsek S, Tefferi A, Kornblau S, Thomas D, Cortes J, Ravandi-Kashani F, et al. Phase II Study of CEP701, an orally available JAK2 inhibitor, in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis. ASH Annual Meeting Abstracts. 2007;110:3543.Google Scholar
  159. 159.
    Hexner EO, Serdikoff C, Jan M, Swider CR, Robinson C, Yang S, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood %R 101182/blood-2007-04-083402. 2007:blood-2007-2004-083402.Google Scholar
  160. 160.
    Tefferi A, Elliott M. Thrombosis in myeloproliferative disorders: prevalence, prognostic factors, and the role of leukocytes and JAK2V617F. Semin Thromb Hemost. 2007;33:313–320.PubMedCrossRefGoogle Scholar
  161. 161.
    Tefferi A, Huang J, Schwager S, Li CY, Wu W, Pardanani A, et al. Validation and comparison of contemporary prognostic models in primary myelofibrosis: analysis based on 334 patients from a single institution. Cancer. 2007;109:2083–2088.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Hematology, Mayo ClinicRochesterUS

Personalised recommendations