Conventional and Investigational Therapy for Primary Myelofibrosis

Part of the Contemporary Hematology book series (CH)


Primary myelofibrosis (PMF), also known as myelofibrosis with myeloid metaplasia or agnogenic myeloid metaplasia, is a clonal myeloproliferative neoplasm that, in patients with fully expressed disease, is characterized by profound remodeling of bone marrow architecture and derangement of hematopoiesis. Bone marrow appears with almost constant expanded population of megakaryocytes and clusters of dystrophic and dysmature elements, deposition of excessive amounts of collagen, and other extracellular matrix proteins resulting in marrow reticulin or collagen fibrosis, increase in microvessel density, and osteosclerosis. Specific hallmarks of hematopoiesis derangement consist in the aberrantly decreased expression of disease-associated surface receptors on hematopoietic stem cell, such as SDF-1 receptor CXCR4, TGF-β (beta) receptor, and TPO receptor MPL, associated with high levels of stromal molecules, like SDF-1, elastase, and metalloproteinases. These stem cell and microenvironmental alterations bring to disruption of bone marrow niches with ensuing mobilization and homing of neoplastic hematopoietic stem cells in new or reinitialized niches in the spleen and liver. These features result in extramedullary hematopoiesis (EMH) with splenomegaly, anemia with a leukoerythroblastic blood picture, and possible neutropenia and thrombocytopenia.


Primary myelofibrosis SDF-1 CXCR4 TGF-β (beta) JAK2V617F MPLW515L/K Androgens Nandrolone Fluoxymesterolone Methandrostenolone Oxymetolone Metenolone Danazol Erythropoietin rHuEpo Darbepoetin Thalidomide Anemia Transfusion-dependent anemia Symptomatic splenomegaly Leukemic transformation Pulmonary ­hypertension Erythropoiesis-stimulating agents EUMNET IWG-MRT Iron overload Deferoxamine Deferiprone Deferasirox Hydroxyurea Busulphan Interferon Pegylated interferon Splenic radiotherapy Splenectomy Portal vein thrombosis Post-splenectomy hepatomegaly 2-chlorodexoxyadenosine Liver radiotherapy Extramedullary hematopoiesis Abdominal radiotherapy Paraspinal extramedullary hematopoiesis Lenalidomide Pomalidomide Tipifarnib Bortezomib Vascular Endothelial Growth Factor Epigenetics Azacitidine Decitabine Vorinostat Givinostat 


  1. 1.
    Di Tucci AA, Matta G, Deplano S, et al. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica. 2008;93:1385–1388.PubMedCrossRefGoogle Scholar
  2. 2.
    Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105:973–977.PubMedCrossRefGoogle Scholar
  3. 3.
    Tefferi A, Barosi G, Mesa RA, et al. IWG for Myelofibrosis Research and Treatment (IWG-MRT). 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;108:1497–1503.PubMedCrossRefGoogle Scholar
  4. 4.
    Barosi G, Bordessoule D, Briere J, et al. Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET). Blood. 2005;106:2849–2853.PubMedCrossRefGoogle Scholar
  5. 5.
    Besa EC, Nowell PC, Geller NL, Gardner FH. Analysis of the androgen response of 23 patients with agnogenic myeloid metaplasia: the value of chromosomal studies in predicting response and survival. Cancer. 1982;49:308–313.PubMedCrossRefGoogle Scholar
  6. 6.
    Shimoda K, Shide K, Kamezaki K, et al. The effect of anabolic steroids on anemia in myelofibrosis with myeloid metaplasia: retrospective analysis of 39 patients in Japan. Int J Hematol. 2007;85:338–343.PubMedCrossRefGoogle Scholar
  7. 7.
    Cervantes F, Alvarez-Larran A, Domingo A, et al. 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
  8. 8.
    Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, et al. 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
  9. 9.
    Tefferi A, Strand JJ, Lasho TL, et al. Respective clustering of unfavorable and favorable cytogenetic clones in myelofibrosis with myeloid metaplasia with homozygosity for JAK2(V617F) and response to erythropoietin therapy. Cancer. 2006;106:1739–1743.PubMedCrossRefGoogle Scholar
  10. 10.
    Tsiara SN, Chaidos A, Bourantas LK, et al. Recombinant Human Erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis. Acta Haematol. 2006;117:156–161.PubMedCrossRefGoogle Scholar
  11. 11.
    Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol. 2009;83:154–155.PubMedCrossRefGoogle Scholar
  12. 12.
    Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol. 2006;134:184–186.PubMedCrossRefGoogle Scholar
  13. 13.
    Merup M, Kutti J, Birgerard G, et al. Negligible clinical effects of thalidomide in patients with myelofibrosis with myeloid metaplasia. Med Oncol. 2002;19:79–86.PubMedCrossRefGoogle Scholar
  14. 14.
    Barosi G, Elliott M, Canepa L, et al. Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from 5 studies. Leuk Lymph. 2002;43:2301–2307.CrossRefGoogle Scholar
  15. 15.
    Mesa RA, Steensma DP, Pardanani A, et al. A phase II trial of combination of low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood. 2003;101:2534–2541.PubMedCrossRefGoogle Scholar
  16. 16.
    Strupp C, Germing U, Scherer A, et al. Thalidomide for the treatment of idiopathic myelofibrosis. Eur J Haematol. 2004;72:52–57.PubMedCrossRefGoogle Scholar
  17. 17.
    Marchetti M, Barosi G, Balestri F, 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
  18. 18.
    Abgrall JF, Guibaud I, Bastie JN, et al. Thalidomide versus placebo in myeloid metaplasia with myelofibrosis: a prospective, randomized, double-blind, multicenter study. Haematologica. 2006;91:1027–1032.PubMedGoogle Scholar
  19. 19.
    Thomas DA, Giles FJ, Albitar M, et al. Thalidomide therapy for myelofibrosis with myeloid metaplasia. Cancer. 2006;106:1974–1984.PubMedCrossRefGoogle Scholar
  20. 20.
    Weinkove R, Reilly JT, McMullin MF, et al. Low-dose thalidomide in myelofibrosis. Haematologica. 2008;93:1100–1101.PubMedCrossRefGoogle Scholar
  21. 21.
    Leitch HA, Chase JM, Goodman TA, et al. Improved survival in red blood cell transfusion dependent patients with primary myelofibrosis (PMF) receiving iron chelation therapy. Hematol Oncol. 2010;28:40–48PubMedGoogle Scholar
  22. 22.
    Tefferi A, Mesa RA, Pardanani A, et al. Red blood cell transfusion need at diagnosis adversely affects survival in primary myelofibrosis-increased serum ferritin or transfusion load does not. Am J Hematol. 2009;84:265–267.PubMedCrossRefGoogle Scholar
  23. 23.
    Di Tucci AA, Murru R, Alberti D, et al. Correction of anemia in a transfusion-dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade, ICL670). Eur J Haematol. 2007;78:540–542.PubMedCrossRefGoogle Scholar
  24. 24.
    Messa E, Cilloni D, Messa F, et al. Deferasirox treatment improved the hemoglobin level and decreased transfusion requirements in four patients with the myelodysplastic syndrome and primary myelofibrosis. Acta Haematol. 2008;120:70–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Sirhan S, Lasho TL, Hanson CA, et al. The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol. 2008;83:363–365.PubMedCrossRefGoogle Scholar
  26. 26.
    Petti MC, Latagliata R, Spadea T, et al. Melphalan treatment in patients with myelofibrosis with myeloid metaplasia. Br J Haematol. 2002;116:576–581.PubMedCrossRefGoogle Scholar
  27. 27.
    Chee L, Kalnins R, Turner P. Low dose melphalan in the treatment of myelofibrosis: a single centre experience. Leuk Lymphoma. 2006;47:1409–1412.PubMedCrossRefGoogle Scholar
  28. 28.
    Kiladjian JJ, Chomienne C, Fenaux P. Interferon-alpha therapy in bcr-abl-negative myeloproliferative neoplasms. Leukemia. 2008;22:1990–1998.PubMedCrossRefGoogle Scholar
  29. 29.
    Gilbert HS. Long term treatment of myeloproliferative disease with interferon-alpha-2b:feasibility and efficacy. Cancer. 1998;83:1205–1213.PubMedCrossRefGoogle Scholar
  30. 30.
    Tefferi A, Elliot MA, Yoon SY, et al. Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia. Blood. 2001;97:1896.PubMedCrossRefGoogle Scholar
  31. 31.
    Heis-Vahidi-Fard N, Forberg E, Eichinger S, et al. Ineffectiveness of interferon-gamma in the treatment of idiopathic myelofibrosis: a pilot study. Ann Hematol. 2001;80:79–82.PubMedCrossRefGoogle Scholar
  32. 32.
    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;98:100–109.PubMedCrossRefGoogle Scholar
  33. 33.
    Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. Cancer. 2007;110:2012–2018.PubMedCrossRefGoogle Scholar
  34. 34.
    Ianotto JC, Kiladjian JJ, Demory JL, et al. PEG-IFN-alpha-2a therapy in patients with myelofibrosis: a study of the French Groupe d’Etudes des Myelofibroses (GEM) and France intergroupe des syndromes Myéloprolifératifs (FIM). Br J Haematol. 2009;146:223–225.PubMedCrossRefGoogle Scholar
  35. 35.
    Buxhofer-Ausch V, Gisslinger H, Berg T, et al. Acquired resistance to interferon alpha therapy associated with homozygous MPL-W515L mutation and chromosome 20q deletion in primary myelofibrosis. Eur J Haematol. 2009;82:161–163.PubMedCrossRefGoogle Scholar
  36. 36.
    Elliott MA, Chen MG, Silverstein MN, Tefferi A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 1998;103:505–511.PubMedCrossRefGoogle Scholar
  37. 37.
    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
  38. 38.
    Barosi G, Ambrosetti A, Buratti A, et al. Splenectomy for patients with myelofibrosis and myeloid metaplasia: Pretreatment variables and outcome prediction. Leukemia. 1993;7:200–206.PubMedGoogle Scholar
  39. 39.
    Faoro LN, Tefferi A, Mesa RA. Long-term analysis of the palliative benefit of 2-chlorodeoxyadenosine for myelofibrosis with myeloid metaplasia. Eur J Haematol. 2005;74:117–120.PubMedCrossRefGoogle Scholar
  40. 40.
    Riesterer O, Gmür J, Lütolf U. Repeated and preemptive palliative radiotherapy of symptomatic hepatomegaly in a patient with advanced myelofibrosis. Onkologie. 2008;31:325–327.PubMedCrossRefGoogle Scholar
  41. 41.
    Barosi G, Ambrosetti A, Centra A, et al. Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia. Blood. 1998;91:3630–3636.PubMedGoogle Scholar
  42. 42.
    Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status ­predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. 2007; 110:4030–4036.PubMedCrossRefGoogle Scholar
  43. 43.
    Tefferi A, Jiménez T, Gray LA, et al. Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia. Eur J Haematol. 2001;66:37–42.PubMedCrossRefGoogle Scholar
  44. 44.
    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
  45. 45.
    Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065–3072.PubMedCrossRefGoogle Scholar
  46. 46.
    Xiong Z, Yan Y, Liu E, et al. Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera. Clin Immunol. 2007;122:279–287.PubMedCrossRefGoogle Scholar
  47. 47.
    Silver RT, Vandris K. Recombinant interferon alpha (rIFN alpha-2b) may retard progression of early primary myelofibrosis. Leukemia. 2009;23:1366–1369.PubMedCrossRefGoogle Scholar
  48. 48.
    Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood. 2006;108:1158–1164.PubMedCrossRefGoogle Scholar
  49. 49.
    Quintás-Cardama A, Kantarjian H, Manshouri T, et al. Lenalidomide plus ­prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol. 2009;27:4760–4766.PubMedCrossRefGoogle Scholar
  50. 50.
    Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol. 2009; 27:4563–4569.PubMedCrossRefGoogle Scholar
  51. 51.
    Mesa RA, Camoriano JK, Geyer SM, et al. A phase II trial of tipifarnib in ­myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia. Leukemia. 2007;21:1964–1970.PubMedCrossRefGoogle Scholar
  52. 52.
    Wagner-Ballon O, Pisani DF, Gastinne T, et al. Proteasome inhibitor bortezomib impairs both myelofibrosis and osteosclerosis induced by high thrombopoietin levels in mice. Blood. 2007;110:345–353.PubMedCrossRefGoogle Scholar
  53. 53.
    Mesa RA, Verstovsek S, Rivera C, et al. Bortezomib therapy in myelofibrosis: a phase II clinical trial. Leukemia. 2008;22:1636–1638.PubMedCrossRefGoogle Scholar
  54. 54.
    Barosi G, Gattoni E, Barbui Tet al., A Phase I study of the proteasome inhibitor bortzomib in patients with myelofibrosis. Blood. 2007;110:1036a.CrossRefGoogle Scholar
  55. 55.
    Giles FJ, List AF, Carroll M, et al. PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor of vascular endothelial growth factor (VEGF), has modest activity in myelofibrosis with myeloid metaplasia. Leuk Res. 2007;7:891–897.CrossRefGoogle Scholar
  56. 56.
    Mesa RA, Verstovsek S, Rivera C, et al. 5-Azacitidine has limited therapeutic activity in myelofibrosis. Leukemia. 2009;23:180–182.PubMedCrossRefGoogle Scholar
  57. 57.
    Danilov AV, Relias V, Feeney DM, et al. Decitabine is an effective treatment of idiopathic myelofibrosis. Br J Haematol. 2009;145:131–132.PubMedCrossRefGoogle Scholar
  58. 58.
    Rambaldi A, Della Casa CM, Salmoiraghi S, et al. A phase 2A study of the ­histone deacetylase inhibitor ITF2357 in patients with Jak2 V617F positive chronic myeloproliferative neoplasms. Blood. 2008;112:100a.CrossRefGoogle Scholar
  59. 59.
    Lee J. Clinical efficacy of vorinostat in a patient with essential thrombocytosis and subsequent myelofibrosis. Ann Hematol. 2009;88:699–700.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Unit of Clinical Epidemiology and Centre for the Study of MyelofibrosisIRCCS Policlinico San Matteo FoundationPaviaItaly

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