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Blastic Transformation of Classic Myeloproliferative Neoplasms

  • Ruben A. MesaEmail author
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Part of the Contemporary Hematology book series (CH)

Abstract

The BCR-ABL negative myeloproliferative neoplasms (MPNs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis have an increasing predisposition over the course of a patient’s illness to transform to overt acute leukemia what is referred to as MPN-Blast Phase (MPN-BP). Current therapies for the MPNs are limited, and no therapy other than allogeneic stem cell transplant has clearly altered the natural history of these neoplasms. Pathogenetic mechanisms which lead to an MPN progressing to MPN-BP are incompletely understood, but seem to correlate with accumulation of additional karyotypic abnormalities as opposed to increases in MPN-associated molecular lesion burden (such as JAK2V617F). The development of MPN-BP is heralded by worsening cytopenias, constitutional symptoms, and a very poor survival despite therapeutic intervention. Risk factors for developing MPN-BP include both features at diagnosis (such as increased peripheral blood blasts, karyotypic abnormalities, and thrombocytopenia), as well as exposure to established agents which enhance leukemogenesis (i.e., P-32 and alkylators). Salvage of MPN-BP by induction chemotherapy followed by allogeneic stem cell transplant is possible, but a successful option in a small minority of patients. Multiple avenues of therapeutic investigation are ongoing to treat, or prevent, MPN-BP including early allogeneic stem cell transplantation, hypomethylating agents, and JAK2 inhibition. An improved understanding of the pathogenetic underpinings of MPN-BP are necessary if more effective targeted therapies are to be developed.

Keywords

Myeloproliferative disorder Blast phase Acute myeloid leukemia Leukemic transformation 

References

  1. 1.
    Damashek W. Some speculations on the myeloproliferative syndrome. Blood. 1951;6:372–5.Google Scholar
  2. 2.
    Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.PubMedGoogle Scholar
  3. 3.
    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(17):1779–90.PubMedCrossRefGoogle Scholar
  4. 4.
    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(7037):1144–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Levine RL, Wadleigh M, Cools J. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. Cancer Cell. 2005;7:387–97.PubMedCrossRefGoogle Scholar
  6. 6.
    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(10):3472–6.PubMedCrossRefGoogle Scholar
  7. 7.
    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(5):459–68.PubMedCrossRefGoogle Scholar
  8. 8.
    Mesa RA, Verstovsek S, Cervantes F, Barosi G, Reilly JT, Dupriez B, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res. 2007;31(6):737–40.PubMedCrossRefGoogle Scholar
  9. 9.
    Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105(3):973–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C, et al. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105(7):2664–70.PubMedCrossRefGoogle Scholar
  11. 11.
    Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7(9):673–83.PubMedCrossRefGoogle Scholar
  12. 12.
    Mesa RA, Powell H, Lasho T, Dewald G, McClure R, Tefferi A. JAK2(V617F) and leukemic transformation in myelofibrosis with myeloid metaplasia. Leuk Res. 2006;30:1457–60.PubMedCrossRefGoogle Scholar
  13. 13.
    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. 2008;22(4):756–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood. 2007;110(1):375–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Swierczek SI, Yoon D, Prchal JT. Blast transformation in a patient with primary myelofibrosis initiated from JAK2 V617F progenitor. ASH Annual Meeting Abstracts. 2007;110(11):a4665.Google Scholar
  16. 16.
    Tam CS, Nussenzveig RM, Popat U, Bueso-Ramos CE, Thomas DA, Cortes JA, et al. The natural history and treatment outcome of blast phase BCR-ABL-myeloproliferative neoplasms. Blood. 2008;112(5):1628–37.PubMedCrossRefGoogle Scholar
  17. 17.
    Beer P, Delhommeau F, LeCouédic J, Bareford D, Kušec R, McMullin M, et al. Two routes to leukemic transformation following a jak2 mutation positive myeloproliferative neoplasm. 14th European Hematology Association Meeting. 2009.Google Scholar
  18. 18.
    Vardiman JW, Brunning RD, Harris NL. WHO histological classification of chronic myeloproliferative diseases. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World Health Organization classification of tumors: Tumours of the haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer (IARC) Press; 2001; p. 17–44.Google Scholar
  19. 19.
    Mesa RA, Cervantes F, Verstovsek S, Tam C, Dupriez B, Reilly J, et al. Clinical evolution to primary myelofibrosis – blast phase: an International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) collaborative retrospective analysis. ASH Annual Meeting Abstracts. 2007;110(11):682.Google Scholar
  20. 20.
    Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Cervantes F. Myelofibrosis: biology and treatment options. Eur J Haematol Suppl. 2007 (68):13–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Cervantes F, Mesa R, Barosi G. New and old treatment modalities in primary myelofibrosis. Cancer J. 2007;13(6):377–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Barosi G, Viarengo G, Pecci A, Rosti V, Piaggio G, Marchetti M, et al. Diagnostic and clinical relevance of the number of circulating CD34(+) cells in myelofibrosis with myeloid metaplasia. Blood. 2001;98(12):3249–55.PubMedCrossRefGoogle Scholar
  24. 24.
    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(3):635–40.PubMedCrossRefGoogle Scholar
  25. 25.
    Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108(5):1497–503.PubMedCrossRefGoogle Scholar
  26. 26.
    Kroger N, Zabelina T, Schieder H, Panse J, Ayuk F, Stute N, et al. Pilot study of reduced-intensity conditioning followed by allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. Br J Haematol. 2005;128(5):690–7.PubMedCrossRefGoogle Scholar
  27. 27.
    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(2):159–66.PubMedCrossRefGoogle Scholar
  28. 28.
    Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. A new prognostic scoring system for primary myelofibrosis based on a Study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2008;112(11):657.Google Scholar
  29. 29.
    Huang J, Li CY, Mesa RA, Wu W, Hanson CA, Pardanani A, et al. Risk factors for leukemic transformation in patients with primary myelofibrosis. Cancer. 2008;112(12):2726–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Tefferi A, Gangat N, Wolanskyj AP, Schwager S, Pardanani A, Lasho TL, et al. 20+ yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis. Eur J Haematol. 2008;80(5):386–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Osgood EE. Contrasting incidence of acute monocytic and granulocytic leukemias in P32-treated patients with polycythemia vera and chronic lymphocytic leukemia. J Lab Clin Med. 1964;64:560–73.PubMedGoogle Scholar
  32. 32.
    Parmentier C. Use and risks of phosphorus-32 in the treatment of polycythaemia vera. Eur J Nucl Med Mol Imaging. 2003;30(10):1413–7.PubMedCrossRefGoogle Scholar
  33. 33.
    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(3):576–81.PubMedCrossRefGoogle Scholar
  34. 34.
    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(9):3370–7.PubMedGoogle Scholar
  35. 35.
    Kiladjian JJ, Rain JD, Bernard JF, Briere J, Chomienne C, Fenaux P. Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia. Semin Thromb Hemost. 2006;32(4 Pt 2):417–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289(13):1645–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Barosi G, Ambrosetti A, Centra A, Falcone A, Finelli C, Foa P, et al. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia. Blood. 1998;91(10):3630–6.PubMedGoogle Scholar
  38. 38.
    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(2):361–70.PubMedCrossRefGoogle Scholar
  39. 39.
    van Besien K, Deeg HJ. Hematopoietic stem cell transplantation for myelofibrosis. Semin Oncol. 2005;32(4):414–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Verstovsek S, Kantarjian HM, Pardanani AD, Thomas D, Cortes J, Mesa RA, et al. The JAK inhibitor, INCB018424, demonstrates durable and marked clinical responses in primary myelofibrosis (PMF) and post-polycythemia/essential thrombocythemia myelofibrosis (Post PV/ETMF). Blood. 2008;112(11):abstract 1762.Google Scholar
  41. 41.
    Pardanani AD, Gotlib J, Jamieson C, Cortes J, Talpaz M, Stone RM, et al. A phase I study of TG101348, an orally bioavailable JAK2-selective inhibitor, in patients with myelofibrosis. Blood. 2008;112(11):97.Google Scholar
  42. 42.
    Shah NP, Olszynski P, Sokol L, Verstovsek S, Hoffman R, List AF, et al. A phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. ASH Annual Meeting Abstracts. 2008;112(11):98.Google Scholar
  43. 43.
    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(11):3543.Google Scholar
  44. 44.
    Rambaldi A, Dellacasa CM, Salmoiraghi S, Spinelli O, Ferrari ML, Gattoni E, et al. A phase 2A study of the histone-deacetylase inhibitor ITF2357 in patients with Jak2V617F positive chronic myeloproliferative neoplasms. Blood. 2008;112(11):100.Google Scholar
  45. 45.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia ­chromosome. N Engl J Med. 2001;344(14):1038–42.PubMedCrossRefGoogle Scholar
  46. 46.
    Mesa RA, Verstovsek S, Rivera C, Pardanani A, Hussein K, Lasho T, et al. 5-Azacitidine has limited therapeutic activity in myelofibrosis. Leukemia. 2009;23(1):180–2.PubMedCrossRefGoogle Scholar
  47. 47.
    Quintas-Cardama A, Tong W, Kantarjian H, Thomas D, Ravandi F, Kornblau S, et al. A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. Leukemia. 2008;22(5):965–70.PubMedCrossRefGoogle Scholar
  48. 48.
    Odenike OM, Godwin JE, van Besien K, Huo D, Stiff PJ, Sher D, et al. Phase II study of decitabine in myelofibrosis with myeloid metaplasia. ASH Annual Meeting Abstracts. 2006;108(11):a4923.Google Scholar
  49. 49.
    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet oncol. 2009;10(3):223–32.PubMedCrossRefGoogle Scholar
  50. 50.
    Blum WG, Klisovic R, Liu S, Kefauver C, Grever MR, Schaaf L, et al. Efficacy of a novel schedule of decitabine in previously untreated AML, age 60 or older. J Clin Oncol (Meeting Abstracts). 2009;27(15S):7010.Google Scholar
  51. 51.
    Mesa RA, Camoriano JK, Geyer SM, Wu W, Kaufmann SH, Rivera CE, et al. A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia. 2007;21(9):1964–70.PubMedCrossRefGoogle Scholar
  52. 52.
    Lancet JE, Gojo I, Gotlib J, Feldman EJ, Greer J, Liesveld JL, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007;109(4):1387–94.PubMedCrossRefGoogle Scholar
  53. 53.
    Faderl S, Verstovsek S, Cortes J, Ravandi F, Beran M, Garcia-Manero G, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood. 2006;108(1):45–51.PubMedCrossRefGoogle Scholar
  54. 54.
    Mesa RA, Loegering D, Powell HL, Flatten K, Arlander SJ, Dai NT, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Blood. 2005;106(1):318–27.PubMedCrossRefGoogle Scholar
  55. 55.
    Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I, et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood. 1996;88(3):1013–8.PubMedGoogle Scholar
  56. 56.
    Cervantes F. Prognostic factors and current practice in treatment of myelofibrosis with myeloid metaplasia: an update anno 2000. Pathol Biol (Paris). 2001;49(2):148–52.CrossRefGoogle Scholar
  57. 57.
    Dingli D, Schwager SM, Mesa RA, Li CY, Tefferi A. Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer. 2006;106(3):623–30.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Consultant of Hematology & OncologyMayo ClinicScottsdaleUSA

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