Seminars in Hematology
Volume 46 , Pages S37-S43 , January 2009

Thrombocytopenia in Myelodysplastic Syndromes and Myelofibrosis

  • Adam M. Boruchov

      Affiliations

    • Corresponding Author InformationAddress correspondence to Adam M. Boruchov, MD, University of Connecticut School of Medicine and the Saint Francis Regional Cancer Center, 114 Woodland St, Hartford, CT 06105

References 

  1. Layton DM, Mufti GJ. Myelodysplastic syndromes: their history, evolution and relation to acute myeloid leukaemia. Blut. 1986;53:423–436
  2. Kantarjian H, Giles F, List A, Lyons R, Sekeres MA, Pierce S, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:1705–1714
  3. Tefferi A. The forgotten myeloproliferative disorder: myeloid metaplasia. Oncologist. 2003;8:225–231
  4. Xu M, Bruno E, Chao J, Huang S, Finazzi G, Fruchtman SM, et al. Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases. Blood. 2005;105:4508–4515
  5. Kimura A, Kawaishi K, Nakata Y, Hyodo H, Kuramoto A, Satow Y. Leukemic transformation of primary myelofibrosis: immunophenotype, genotype and growth characteristics of blast cells. Leuk Lymphoma. 1995;19:493–498
  6. Mesa RA, Barosi G, Cervantes F, Reilly JT, Tefferi A. Myelofibrosis with myeloid metaplasia: disease overview and non-transplant treatment options. Best Pract Res Clin Haematol. 2006;19:495–517
  7. Nolte F, Hofmann WK. Myelodysplastic syndromes: molecular pathogenesis and genomic changes. Ann Hematol. 2008;87:777–795
  8. Aul C, Bowen DT, Yoshida Y. Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica. 1998;83:71–86
  9. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088
  10. Voulgarelis M, Giannouli S, Ritis K, Tzioufas AG. Myelodysplasia-associated autoimmunity: clinical and pathophysiologic concepts. Eur J Clin Invest. 2004;34:690–700
  11. Epperson DE, Nakamura R, Saunthararajah Y, Melenhorst J, Barrett AJ. Oligoclonal T cell expansion in myelodysplastic syndrome: evidence for an autoimmune process. Leuk Res. 2001;25:1075–1083
  12. Giannouli S, Voulgarelis M, Zintzaras E, Tzioufas AG, Moutsopoulos HM. Autoimmune phenomena in myelodysplastic syndromes: a 4-yr prospective study. Rheumatology (Oxford). 2004;43:626–632
  13. Billstrom R, Johansson H, Johansson B, Mitelman F. Immune-mediated complications in patients with myelodysplastic syndromes—clinical and cytogenetic features. Eur J Haematol. 1995;55:42–48
  14. Konstantopoulos K, Lauren L, Hast R, Reizenstein P. Survival, hospitalization and cause of death in 99 patients with the myelodysplastic syndrome. Anticancer Res. 1989;9:893–896
  15. Girtovitis FI, Ntaios G, Papadopoulos A, Ioannidis G, Makris PE. Defective platelet aggregation in myelodysplastic syndromes. Acta Haematol. 2007;118:117–122
  16. Thomas-Kaskel AK, Mattern D, Kohler G, Finke J, Behringer D. Reticulated platelet counts correlate with treatment response in patients with idiopathic thrombocytopenic purpura and help identify the complex causes of thrombocytopenia in patients after allogeneic hematopoietic stem cell transplantation. Cytometry B Clin Cytom. 2007;72:241–248
  17. Houwerzijl EJ, Blom NR, van der Want JJ, Louwes H, Esselink MT, Smit JW, et al. Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients. Blood. 2005;105:3472–3479
  18. Gupta R, Soupir CP, Johari V, Hasserjian RP. Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation. Br J Haematol. 2007;139:265–268
  19. Menke DM, Colon-Otero G, Cockerill KJ, Jenkins RB, Noel P, Pierre RV. Refractory thrombocytopenia (A myelodysplastic syndrome that may mimic immune thrombocytopenic purpura). Am J Clin Pathol. 1992;98:502–510
  20. Sashida G, Takaku TI, Shoji N, Nishimaki J, Ito Y, Miyazawa K, et al. Clinico-hematologic features of myelodysplastic syndrome presenting as isolated thrombocytopenia: an entity with a relatively favorable prognosis. Leuk Lymphoma. 2003;44:653–658
  21. Kuroda J, Kimura S, Kobayashi Y, Wada K, Uoshima N, Yoshikawa T. Unusual myelodysplastic syndrome with the initial presentation mimicking idiopathic thrombocytopenic purpura. Acta Haematol. 2002;108:139–143
  22. Hebbar M, Kaplan C, Caulier MT, Wattel E, Morel P, Wetterwald M, et al. Low incidence of specific anti-platelet antibodies detected by the MAIPA assay in the serum of thrombocytopenic MDS patients and lack of correlation between platelet autoantibodies, platelet lifespan and response to danazol therapy. Br J Haematol. 1996;94:112–115
  23. Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, et al. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol. 2003;120:187–200
  24. Newland AC. Treatment of adults with autoimmune thrombocytopenic purpura. Lancet. 2002;359:4–5
  25. Bourgeois E, Caulier MT, Rose C, Dupriez B, Bauters F, Fenaux P. Role of splenectomy in the treatment of myelodysplastic syndromes with peripheral thrombocytopenia: a report on six cases. Leukemia. 2001;15:950–953
  26. Uchida R, Nakano S, Namura K, Yamada N, Fuchida S, Okano A, et al. Is splenectomy a contraindication for patients with myelodysplastic syndromes complicated by splenomegaly?. Ann Hematol. 2006;85:198–199
  27. Ozyurek E, Cetin M, Tuncer M, Hicsonmez G. The role of splenectomy in children with juvenile myelomonocytic leukemia. Turk J Pediatr. 2007;49:154–157
  28. Berman RS, Feig BW, Hunt KK, Mansfield PF, Pollock RE. Platelet kinetics and decreased transfusion requirements after splenectomy for hematologic malignancy. Ann Surg. 2004;240:852–857
  29. Kraemer D, Rudiger T, Reimer P, Muller-Hermelink HK, Wilhelm M. Splenectomy in patients with mixed myelodysplastic/myeloproliferative disease. Ann Hematol. 2002;81:308–311
  30. Molldrem JJ, Clave E, Jiang YZ, Mavroudis D, Raptis A, Hensel N, et al. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units. Blood. 1997;90:2529–2534
  31. Cermak J, Belickova M, Michalova K. Combined immunosuppressive treatment in patients with early myelodysplasia [abstract 903]. Haematologica. 2005;90:357
  32. Deeg HJ, Jiang PY, Holmberg LA, Scott B, Petersdorf EW, Appelbaum FR. Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells. Leuk Res. 2004;28:1177–1180
  33. Arber C, Buser A, Heim D, Gratwohl A, Tichelli A, Passweg JR. Cyclosporine-responsive thrombocytopenia in a patient with chloramphenicol-associated myelodysplastic syndrome. Eur J Haematol. 2006;76:255–257
  34. Park SJ, Han CW, Lee JH, Eom HS, Lee SH, Jeong DC, et al. Cyclosporine A in the treatment of a patient with immune thrombocytopenia accompanied by myelodysplastic syndrome and nephrotic syndrome. Acta Haematol. 2003;110:36–40
  35. Larsen MS, Hasselbalch HC. [Immunosuppressive treatment of the myelodysplastic syndrome]. Ugeskr Laeger. 2003;165:2654–2657
  36. Crane E, List A. Immunomodulatory drugs. Cancer Invest. 2005;23:625–634
  37. Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol. 2005;32:S24–S30
  38. Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86–93
  39. Muller-Thomas C, Schuster T, Peschel C, Gotze KS. A limited number of 5-azacitidine cycles can be effective treatment in MDS. Ann Hematol. 2008;
  40. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803
  41. Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005;11:3604–3608
  42. Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–3903
  43. Tsimberidou AM, Giles FJ, Khouri I, Bueso-Ramos C, Pilat S, Thomas DA, et al. Low-dose interleukin-11 in patients with bone marrow failure: update of the M.D. Anderson Cancer Center experience. Ann Oncol. 2005;16:139–145
  44. Montero AJ, Estrov Z, Freireich EJ, Khouri IF, Koller CA, Kurzrock R. Phase II study of low-dose interleukin-11 in patients with myelodysplastic syndrome. Leuk Lymphoma. 2006;47:2049–2054
  45. Nimer SD, Paquette RL, Ireland P, Resta D, Young D, Golde DW. A phase I/II study of interleukin-3 in patients with aplastic anemia and myelodysplasia. Exp Hematol. 1994;22:875–880
  46. Gordon MS, Nemunaitis J, Hoffman R, Paquette RL, Rosenfeld C, Manfreda S, et al. A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. Blood. 1995;85:3066–3076
  47. Liu Yin JA, Adams JA, Brereton ML, Hann A, Harrison BD, Briggs M. Megakaryopoiesis in vitro in myelodysplastic syndromes and acute myeloid leukaemia: effect of pegylated recombinant human megakaryocyte growth and development factor in combination with other growth factors. Br J Haematol. 2000;108:743–746
  48. Fontenay-Roupie M, Dupont JM, Picard F, Fichelson S, Botella A, Melle J, et al. Analysis of megakaryocyte growth and development factor (thrombopoietin) effects on blast cell and megakaryocyte growth in myelodysplasia. Leuk Res. 1998;22:527–535
  49. Kuter DJ, Begley CG. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood. 2002;100:3457–3469
  50. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–3248
  51. Basser RL, O'Flaherty E, Green M, Edmonds M, Nichol J, Menchaca DM, et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood. 2002;99:2599–2602
  52. Andemariam B, Psaila B, Bussel JB. Novel thrombopoietic agents. Hematology Am Soc Hematol Educ Program. 2007;106–113
  53. Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109:4607–4616
  54. Broudy VC, Lin NL. AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl. Cytokine. 2004;25:52–60
  55. Alessandrino EP, Amadori S, Barosi G, Cazzola M, Grossi A, Liberato LN, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes (A statement from the Italian Society of Hematology). Haematologica. 2002;87:1286–1306
  56. Kantarjian H, Fenaux P, Sekeres MA, Becker P, Boruchov A, Bowen D, et al. Phase 1/2 study of AMG 531 in thrombocytopenic patients (pts) with low-risk myelodysplastic syndrome (MDS): update including extended treatment [abstract 250]. Blood. 2007;110:81a
  57. Hoffman R, Rondelli D. Biology and treatment of primary myelofibrosis. Hematology Am Soc Hematol Educ Program. 2007;346–354
  58. Thiele J, Kvasnicka HM. Myelofibrosis in chronic myeloproliferative disorders—dynamics and clinical impact. Histol Histopathol. 2006;21:1367–1378
  59. Thiele J, Kvasnicka HM. Grade of bone marrow fibrosis is associated with relevant hematological findings—a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis. Ann Hematol. 2006;85:226–232
  60. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342:1255–1265
  61. Koppikar P, Levine RL. JAK2 and MPL mutations in myeloproliferative neoplasms. Acta Haematol. 2008;119:218–225
  62. Cappio FC, Vigliani R, Novarino A, Camussi G, Campana D, Gavosto F. Idiopathic myelofibrosis: a possible role for immune-complexes in the pathogenesis of bone marrow fibrosis. Br J Haematol. 1981;49:17–21
  63. Hasselbalch H, Berild D, Paaske Hansen O. Platelet-associated IgG and IgM in myelofibrosis. Scand J Haematol. 1984;32:488–492
  64. Hasselbalch H, Nielsen H, Berild D, Kappelgaard E. Circulating immune complexes in myelofibrosis. Scand J Haematol. 1985;34:177–180
  65. Le Bousse-Kerdiles MC, Martyre MC, Samson M. Cellular and molecular mechanisms underlying bone marrow and liver fibrosis: a review. Eur Cytokine Netw. 2008;19:69–80
  66. Kuter DJ, Bain B, Mufti G, Bagg A, Hasserjian RP. Bone marrow fibrosis: pathophysiology and clinical significance of increased bone marrow stromal fibres. Br J Haematol. 2007;139:351–362
  67. Tefferi A. JAK and MPL mutations in myeloid malignancies. Leuk Lymphoma. 2008;49:388–397
  68. Hasselbalch H, Jensen BA. Prognostic factors in idiopathic myelofibrosis: a simple scoring system with prognostic significance. Eur J Haematol. 1990;44:172–178
  69. Varki A, Lottenberg R, Griffith R, Reinhard E. The syndrome of idiopathic myelofibrosis (A clinicopathologic review with emphasis on the prognostic variables predicting survival). Medicine (Baltimore). 1983;62:353–371
  70. Reilly JT, Snowden JA, Spearing RL, Fitzgerald PM, Jones N, Watmore A, et al. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. Br J Haematol. 1997;98:96–102
  71. 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;112:2726–2732
  72. Mesa RA, Tefferi A. Palliative splenectomy in myelofibrosis with myeloid metaplasia. Leuk Lymphoma. 2001;42:901–911
  73. Akiyama T, Matsunaga T, Terui T, Miyanishi K, Tanaka I, Sato T, et al. Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis. Leukemia. 2005;19:1558–1566
  74. Weinkove R, Reilly JT, McMullin MF, Curtin NJ, Radia D, Harrison CN. Low-dose thalidomide in myelofibrosis. Haematologica. 2008;93:1100–1101
  75. 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
  76. 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
  77. 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
  78. Levine RL, Wernig G. Role of JAK-STAT signaling in the pathogenesis of myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2006;510:233–239
  79. Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia. 2007;21:1658–1668
  80. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270
  81. Lipka DB, Hoffmann LS, Heidel F, Markova B, Blum MC, Breitenbuecher F, et al. LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells. Mol Cancer Ther. 2008;7:1176–1184
  82. 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. 2008;111:5663–5671
  83. Verstovsek S, Tefferi AK, Kornblau S, Thomas D, Cortes J, Ravandi-Kashni 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 [abstract 3543]. Blood. 2007;110:1037a
  84. Wernig G, Kharas MG, Okabe R, Moore SA, Leeman DS, Cullen DE, et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell. 2008;13:311–320
  85. Silver RT, Tefferi A. JAK-2 abnormalities in the myeloproliferative diseases and their treatment with JAK-2 inhibitors. Paper presented at: Chemotherapy Foundation Symposium XXVI Innovative Cancer Therapy for Tomorrow 2008;New York, NY

 STATEMENT OF CONFLICT OF INTEREST: Adam M. Boruchov, MD, discloses the following: Consultant: Novartis.

PII: S0037-1963(08)00200-X

doi: 10.1053/j.seminhematol.2008.12.001

Seminars in Hematology
Volume 46 , Pages S37-S43 , January 2009

Article Tools