Current Hematologic Malignancy Reports

, Volume 2, Issue 1, pp 25–33

Conventional and experimental drug therapy in myelofibrosis with myeloid metaplasia

  • Ruben A. Mesa
  • Alfonso Quintás-Cardama
  • Srdan Verstovsek
Article

Abstract

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (ie, BCR-ABL-negative) myeloproliferative disorder characterized by anemia, multiorgan extramedullary hematopoiesis, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Stem cell transplantation can be curative, but many patients either are not appropriate candidates or do not choose to accept the significant risks associated with transplantation. Current pharmacologic therapy has been beneficial mainly in terms of palliating disease-associated cytopenias, constitutional symptoms, splenomegaly, and other organ damage from excess myeloproliferation. Novel treatment strategies are under investigation, including targeted inhibition of JAK2V617F, the activating tyrosine kinase point mutation present in about half of patients with MMM. In this article, we review both the old and new pharmacologic options for MMM.

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References and Recommended Reading

  1. 1.
    Tefferi A: Myelofibrosis with myeloid metaplasia. N Engl J Med 2000, 342:1255–1265.PubMedCrossRefGoogle Scholar
  2. 2.
    Mesa RA, Silverstein MN, Jacobsen SJ, et al.: 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.
    Cervantes F, Barosi G, Hernandez-Boluda JC, et al.: Myelofibrosis with myeloid metaplasia in adult individuals 30 years old or younger: presenting features, evolution and survival. Eur J Haematol 2001, 66:324–327.PubMedCrossRefGoogle Scholar
  4. 4.
    Tefferi A, Mesa RA, Nagorney DM, et al.: Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood 2000, 95:2226–2233.PubMedGoogle Scholar
  5. 5.
    Koch CA, Li CY, Mesa RA, Tefferi A: Nonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment. Mayo Clin Proc 2003, 78:1223–1233.PubMedCrossRefGoogle Scholar
  6. 6.
    Mesa RA, Li CY, Schroeder G, Tefferi A: Clinical correlates of splenic histopathology and splenic karyotype in myelofibrosis with myeloid metaplasia. Blood 2001, 97:3665–3667.PubMedCrossRefGoogle Scholar
  7. 7.
    Mesa RA, Wadleigh M, Niblack J, et al.: Fatigue, the un-addressed curse of myeloproliferative diseases (MPD): results of an international Internet based QOL survey of 830 MPD patients [abstract]. Blood (ASH Annual Meeting Abstracts) 2005, 106:Abstract 2577.Google Scholar
  8. 8.
    Deeg HJ, Gooley TA, Flowers ME, et al.: Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003, 102:3912–3918.PubMedCrossRefGoogle Scholar
  9. 9.
    Rondelli D, Barosi G, Bacigalupo A, et al.: Allogeneic hematopoietic stem-cell transplantation with reduced intensity conditioning in intermediate-or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 2005, 105:4115–4119.PubMedCrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    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
  12. 12.
    Cervantes F, Hernandez-Boluda JC, Alvarez A, et al.: Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica 2000, 85:595–599.PubMedGoogle Scholar
  13. 13.
    Barosi G, Grossi A, Comotti B, et al.: Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2001, 114:78–83.PubMedCrossRefGoogle Scholar
  14. 14.
    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
  15. 15.
    Mesa RA, Steensma DP, Pardanani A, 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
  16. 16.
    Mesa RA, Stensma DP, Li CY, et al.: Phase II study of the combination of low-dose thalidomide, prednisone, and etanercept (PET regimen) in the treatment of anemia, splenomegaly, and constitutional symptoms associated with myelofibrosis with myeloid metaplasia (MMM) [abstract]. Blood (ASH Annual Meeting Abstracts) 2005, 106:Abstract 2576.Google Scholar
  17. 17.
    Benetatos L, Chaidos A, Alymara V, et al.: Combined treatment with thalidomide, corticosteroids, and erythropoietin in patients with idiopathic myelofibrosis. Eur J Haematol 2005, 74:273–274.PubMedCrossRefGoogle Scholar
  18. 18.
    Battegay EJ, Raines EW, Colbert T, Ross R: TNF-alpha stimulation of fibroblast proliferation. Dependence on platelet-derived growth factor (PDGF) secretion and alteration of PDGF receptor expression. J Immunol 1995, 154:6040–6047.PubMedGoogle Scholar
  19. 19.
    Steensma DP, Mesa RA, Li CY, et al.: Etanercept, a soluble tumor necrosis factor receptor, palliates constitutional symptoms in patients with myelofibrosis with myeloid metaplasia: results of a pilot study. Blood 2002, 99:2252–2254.PubMedCrossRefGoogle Scholar
  20. 20.
    Lofvenberg E, Wahlin A: Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol 1988, 41:375–381.PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    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
  23. 23.
    Huang J, Xu J: Proliferation of human marrow fibroblasts suppressed synergistically by interferon alpha and TGF-β1 in vitro [abstract]. Blood (ASH Annual Meeting Abstracts) 2003, 102:Abstract 5077.Google Scholar
  24. 24.
    Carlo-Stella C, Cazzola M, Gasner A, et al.: Effects of recombinant alpha and gamma interferons on the in vitro growth of circulating hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM) from patients with myelofibrosis with myeloid metaplasia. Blood 1987, 70:1014–1019.PubMedGoogle Scholar
  25. 25.
    Dalla KP, Zeigler ZR, Shadduck RK: Alpha-interferon in myelofibrosis: a case report [see comments]. Br J Haematol 1994, 86:654–656.PubMedGoogle Scholar
  26. 26.
    Tefferi A, Elliot MA, Yoon SY, et al.: Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia [letter]. Blood 2001, 97:1896.PubMedCrossRefGoogle Scholar
  27. 27.
    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
  28. 28.
    Verstovsek S, Lawhorn, K, Giles F, et al.: PEG-Intron for myeloproliferative diseases: an update of ongoing phase II study [abstract]. Blood (ASH Annual Meeting Abstracts) 2004, 104:Abstract 633.Google Scholar
  29. 29.
    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
  30. 30.
    James C, Ugo V, Le Couedic JP, et al.: A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005, 434:1144–1148.PubMedCrossRefGoogle Scholar
  31. 31.
    Tefferi A, Lasho TL, Schwager SM, 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
  32. 32.
    Xu M, Bruno E, Chao J, et al.: The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis. Blood 2005, 105:1699–1705.PubMedCrossRefGoogle Scholar
  33. 33.
    Tefferi A, Cortes J, Verstovsek S, et al.: Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006, 108:1158–1164.PubMedCrossRefGoogle Scholar
  34. 34.
    Muller GW, Chen R, Huang SY, et al.: Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999, 9:1625–1630.PubMedCrossRefGoogle Scholar
  35. 35.
    O’Farrell AM, Abrams TJ, Yuen HA, et al.: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003, 101:3597–3605.PubMedCrossRefGoogle Scholar
  36. 36.
    Fiedler W, Serve H, Dohner H, et al.: A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005, 105:986–993.PubMedCrossRefGoogle Scholar
  37. 37.
    Wood JM, Bold G, Buchdunger E, et al.: PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res 2000, 60:2178–2189.PubMedGoogle Scholar
  38. 38.
    Giles FJ, Cooper MA, Silverman L, et al.: Phase II study of SU5416—a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor—in patients with refractory myeloproliferative diseases. Cancer 2003, 97:1920–1928.PubMedCrossRefGoogle Scholar
  39. 39.
    Hasselbach H: SU6668 in idiopathic myelofibrosis—a rational therapeutic approach targeting several tyrosine kinases of importance for the myeloproliferation and the development of bone marrow fibrosis and angiogenesis. Med Hypotheses 2003, 61:244–247.CrossRefGoogle Scholar
  40. 40.
    Kantarjian H, Sawyers C, Hochhaus A, et al.: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002, 346:645–652.PubMedCrossRefGoogle Scholar
  41. 41.
    Kvasnicka HM, Thiele J: Bone marrow angiogenesis: methods of quantification and changes evolving in chronic myeloproliferative disorders. Histol Histopathol 2004, 19:1245–1260.PubMedGoogle Scholar
  42. 42.
    Tefferi A, Mesa RA, Gray LA, et al.: Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood 2002, 99:3854–3856.PubMedCrossRefGoogle Scholar
  43. 43.
    Cortes J, Ault P, Koller C, et al.: Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 2003, 101:4714–4716.PubMedCrossRefGoogle Scholar
  44. 44.
    LeBousse-Kerdilès MC, Desterke C, Guerton B, et al.: Glivec/STI571 treatment stimulates megakaryopoiesis and normalizes PDGF receptor beta kinase expression in thrombocytopenic patients with myeloid metaplasia with myelofibrosis [abstract]. Blood (ASH Annual Meeting Abstracts) 2005, 106:Abstract 2599.Google Scholar
  45. 45.
    Lombardo LJ, Lee FY, Chen P, et al.: Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004, 47:6658–6661.PubMedCrossRefGoogle Scholar
  46. 46.
    Reilly JT: Pathogenesis of idiopathic myelofibrosis: present status and future directions [review]. Br J Haematol 1994, 88:1–8.PubMedGoogle Scholar
  47. 47.
    Beaupre DM, Kurzrock R: RAS and leukemia: from basic mechanisms to gene-directed therapy. J Clin Oncol 1999, 17:1071–1079.PubMedGoogle Scholar
  48. 48.
    Du W, Lebowitz PF, Prendergast GC: Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999, 19:1831–1840.PubMedGoogle Scholar
  49. 49.
    Cortes J, Albitar M, Thomas D, et al.: Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003, 101:1692–1697.PubMedCrossRefGoogle Scholar
  50. 50.
    Mesa RA, Camoriano JK, Geyer SM, et al.: A Phase 2 Consortium (P2C) trial of R115777 (tipifarnib) in myelofibrosis with myeloid metaplasia [abstract]. Blood (ASH Annual Meeting Abstracts) 2004, 104:Abstract 1509.Google Scholar
  51. 51.
    Yingling JM, Blanchard KL, Sawyer JS: Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004, 3:1011–1022.PubMedCrossRefGoogle Scholar
  52. 52.
    Schlingensiepen K, Bischof A, Egger T, et al.: The TGF-beta1 antisense oligonucleotide AP 11014 for the treatment of non-small cell lung, colorectal and prostate cancer: preclinical studies [abstract]. Proc Am Soc Clin Oncol 2004, 23:Abstract 3132.Google Scholar
  53. 53.
    Sawyer JS, Beight DW, Britt KS, et al.: Synthesis and activity of new aryl-and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett 2004, 14:3581–3584.PubMedCrossRefGoogle Scholar
  54. 54.
    Gellibert F, Woolven J, Fouchet MH, et al.: Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors. J Med Chem 2004, 47:4494–4506.PubMedCrossRefGoogle Scholar
  55. 55.
    Callahan JF, Burgess JL, Fornwald JA, et al.: Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem 2002, 45:999–1001.PubMedCrossRefGoogle Scholar
  56. 56.
    Uhl M, Aulwurm S, Wischhusen J, et al.: SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 2004, 64:7954–7961.PubMedCrossRefGoogle Scholar
  57. 57.
    Mesa RA, Tefferi A, Elliott MA, et al.: A phase II trial of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone), a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia. Br J Haematol 2001, 114:111–113.PubMedCrossRefGoogle Scholar
  58. 58.
    O’Brien S, Kipps TJ, Faderl S, et al.: A phase I trial of the small molecule pan-Bcl-2 family inhibitor GX15-070 administered intravenously (IV) every 3 weeks to patients with previously treated chronic lymphocytic leukemia (CLL) [abstract]. Blood (ASH Annual Meeting Abstracts) 2005, 106:Abstract 446.Google Scholar
  59. 59.
    Baylin SB, Herman JG, Graff JR, et al.: Alterations in DNA methylation: a fundamental aspect of neoplasia [review]. Adv Cancer Res 1998, 72:141–196.PubMedCrossRefGoogle Scholar
  60. 60.
    Martyré MC, Steunou V, LeBousse-Kerdilès MC, Wietzerbin J: Lack of alteration in GATA-1 expression in CD34+ hematopoietic progenitors from patients with idiopathic myelofibrosis [letter]. Blood 2003, 101:5087–5088; response 5088–5089.PubMedCrossRefGoogle Scholar
  61. 61.
    Issa JP, Gharibyan V, Cortes J, et al.: Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 2005, 23:3948–3956.PubMedCrossRefGoogle Scholar
  62. 62.
    Komura E, Tonetti C, Penard-Lacronique V, et al.: Role for the nuclear factor kappaB pathway in transforming growth factor-beta1 production in idiopathic myelofibrosis: possible relationship with FK506 binding protein 51 overexpression. Cancer Res 2005, 65:3281–3289.PubMedGoogle Scholar
  63. 63.
    Rameshwar P, Narayanan R, Qian J, et al.: NF-kappa B as a central mediator in the induction of TGF-beta in monocytes from patients with idiopathic myelofibrosis: an inflammatory response beyond the realm of homeostasis. J Immunol 2000, 165:2271–2277.PubMedGoogle Scholar
  64. 64.
    Wagner-Ballon O, Gastinne T, Tulliez M, et al.: Proteasome inhibitor bortezomib can inhibit bone marrow fibrosis development in a murine model of myelofibrosis [abstract]. Blood (ASH Annual Meeting Abstracts) 2005, 106:Abstract 2582.Google Scholar
  65. 65.
    Visani G, Finelli C, Castelli U, et al.: Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol 1990, 75:4–9.PubMedGoogle Scholar
  66. 66.
    Cervantes F, Barosi G, Demory JL, 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
  67. 67.
    Dupriez B, Morel P, Demory JL, et al.: Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996, 88:1013–1018.PubMedGoogle Scholar
  68. 68.
    Dingli D, Schwager SM, Mesa RA, et al.: Prognosis in transplant-eligible patients with agnogenic myeloid metaplasia: a simple CBC-based scoring system. Cancer 2006, 106:623–630.PubMedCrossRefGoogle Scholar
  69. 69.
    Giovanni B, Michelle E, Letizia C, et al.: Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma 2002, 43:2301–2307.PubMedCrossRefGoogle Scholar
  70. 70.
    Lofvenberg E, Wahlin A: Management of polycythaemia vera, essential thrombocythaemia and myelofibrosis with hydroxyurea. Eur J Haematol 1988, 41:375–381.PubMedCrossRefGoogle Scholar
  71. 71.
    Manoharan A, Pitney WR: Chemotherapy resolves symptoms and reverses marrow fibrosis in myelofibrosis. Scand J Haematol 1984, 33:453–459.PubMedCrossRefGoogle Scholar
  72. 72.
    Najean Y, Rain JD: 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. The French Polycythemia Study Group. Blood 1997, 89:2319–2327.PubMedGoogle Scholar
  73. 73.
    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
  74. 74.
    Schafer PH, Gandhi AK, Loveland MA, et al.: Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther 2003, 305:1222–1232.PubMedCrossRefGoogle Scholar
  75. 75.
    Cardones AR, Banez LL: VEGF inhibitors in cancer therapy. Curr Pharm Des 2006, 12:387–394.PubMedCrossRefGoogle Scholar
  76. 76.
    Issa JP, Kantarjian H: Azacitidine. Nat Rev Drug Discov 2005, Suppl:S6–S7.Google Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  • Ruben A. Mesa
    • 1
  • Alfonso Quintás-Cardama
  • Srdan Verstovsek
  1. 1.Division of HematologyMayo ClinicRochesterUSA

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