Seminars in Hematology
Volume 45, Issue 1 , Pages 31-38 , January 2008

Targeted Therapies in Myelodysplastic Syndrome

  • Magda Melchert

      Affiliations

    • Corresponding Author InformationAddress correspondence to Magda Melchert, MD, Moffitt Cancer Center, 12902 Magnolia Dr, SRB-4, Tampa, FL 33611.
    • ,
  • Alan List

References 

  1. Molldrem J, Jiang Y, Stetler-Stevenson M, Mavroudis D, Hensel N, Barrett J. Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haemtol. 1998;102:1314–1322
  2. Kochenderfer J, Kobayashi S, Wieder E, Su C, Molldrem J. Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppressive. Blood. 2002;100:3639–3645
  3. Steensma D, Dispenzieri A, Moore S, Schroeder G, Tefferi A. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood. 2003;101:2156–2158
  4. Molldrem J, Caples M, Mavroudis D, Plante M, Young N, Barrett A. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997;99:699–705
  5. Molldrem J, Leifer E, Bahceci E, Saunthararajah Y, Rivera M, Dunbar C, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002;137:156–163
  6. Jonasova A, Neuwirtova R, Cermak J, Vozobulova V, Mocikova K, Siskova M, et al. Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 1998;100:304–309
  7. Yazji S, Giles F, Tsimberidou A, Estey E, Kantarjian H, O’Brien S, et al. Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia. 2003;17:2101–2106
  8. Killick S, Mufti G, Cavenagh J, Mijovic A, Peacock J, Gordon-Smith E, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with ‘low-risk’ myelodysplasia. Br J Haematol. 2003;120:679–684
  9. Broliden P, Dahl I, Hast R, Johansson B, Juvonen E, Kjeldsen L, et al. Antithymocyte globulin and cyclosporin A as combination therapy for low-risk non-sideroblastic myelodysplastic syndromes. Haematologica. 2006;91:667–670
  10. Stadler M, Germing U, Kliche K, Kuse R, Hofmann W, Schrezenmeier H, et al. A prospective, randomized, phase II study of horse antithymocyte globulin vs. rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004;18:460–465
  11. Sloand E, Wu C, Greenberg P, Young N, Barrett J: Prolonged survival in patients with myelodysplasia responding to immunosuppressive therapy. Cancer (in press)
  12. Saunthararajah Y, Nakamura R, Wesley R, Wang Q, Barrett J. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003;102:3025–3027
  13. Saunthararajah Y, Nakamura R, Nam J, Robyn J, Loberiza F, Maciejewski J, et al. HLA-DR15(DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100:1570–1574
  14. Bartlett J, Dredge K, Dalgleish A. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4:314–322
  15. Raza A, Meyer P, Dutt D, Zorat F, Lisak L, Nascimben F, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001;98:958–965
  16. Thomas D, Estey E, Giles F, Faderl S, Cortes J, Keating M, et al. Single agent thalidomide in patients with relapsed or refractory acute myeloid leukemia. Br J Haematol. 2003;123:436–441
  17. Zorat F, Shetty V, Dutt D, Lisak L, Nascimben F, Allampallam K, et al. The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes. Br J Haematol. 2001;115:881–894
  18. Moreno-Aspitia A, Colon-Otero G, Hoering A, Tefferi A, Niedringhaus RD, Vukov A, et al. Thalidomide therapy in adult patients with myelodypslastic syndrome (A North Central Cancer Treatment Group phase II trial). Cancer. 2006;107:767
  19. List A, Kurtin S, Roe D, Buresh A, Mahadevan D, Fuchs D, et al. Efficacy of lenalidomide in myelodypslastic syndromes. N Engl J Med. 2005;352:549–557
  20. Raza A, Reeves J, Feldman E, Deeg HJ, Dreisbach L, Schiffer C, et al. Long term clinical benefit of lenalidomide (revlimid) treatment in patients with myelodyplastic syndrome without del 5q cytogenetic abnormalities. Blood. 2006;108:250;(abstr)
  21. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–1465
  22. Pedersen-Bjergaard J, Andersen M, Christiansen H, Nerlov C. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood. 2002;99:1909–1912
  23. List A, Wride K, Dewald G, Bennett J, Giagounidis A, Kurtin S, et al. Cytogenetic response to lenalidomide is associated with improved survival in patients with chromosome 5q deletion. Leuk Res. 2007;31(suppl 1):S38
  24. Sekeres M, Maciejewski JP, Giagounidis A, Wride K, Knight R, List A. Cytopenias correlate with response to lenalidomide in del 5q MDS patients. Leuk Res. 2007;31(suppl 1):S37–S38
  25. List A, Baker A, Green S, Bellamy W. Lenalidomide: Targeted anemia therapy for myelodysplastic syndrome. Cancer Control. 2006;13(suppl):4–11
  26. List A, Vardiman J, Issa JP, DeWitte T. Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program). 2004;297–317
  27. Mangi M, Mufti G. Primary myelodysplastic syndromes: Diagnostic and prognostic significance of immunohistochemical assessment of bone marrow biopsies. Blood. 1992;79:198–205
  28. Bellamy W, Richter L, Sirjani D, Roxas C, Glinsmann-Gibson B, Frutiger Y, et al. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood. 2001;97:1427–1434
  29. Roboz G, Dias S, Lam G, Lane WJ, Soignet SL, Warrell R, et al. Arsenic trioxide induces dose-and time dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood. 2000;96:1525–1530
  30. Vey N, Bosly A, Guerci A, Feremans W, Dombret H, Dreyfus F, et al. Arsenic trioxide in patients with myelodysplastic syndromes: A phase II multicenter study. J Clin Oncol. 2006;24:1–7
  31. Schiller G, Slack J, Hainsworth J, Mason J, Mansoor S, Rizzieri D, et al. Phase II multicenter trial of arsenic trioxide in patients with myelodysplastic syndrome. J Clin Oncol. 2006;24:1–9
  32. Raza A, Buonamici S, Lisak L, Tahir S, Li D, Imran M, et al. Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression. Leuk Res. 2004;28:791–803
  33. Wetzler M, Brady M, Tracy E, Li Z, Donohue K, O’Loughlin K, et al. Arsenic trioxide affects signal transducer and activator of transcription proteins through alteration of protein tyrosine kinase phosphorylation. Clin Cancer Res. 2006;12:6817–6825
  34. Shetty V, Sanoy A, Payne G, et al. High degree of TNF-α may be responsible for extensive apoptosis of bone marrow cells in MDS. Cell Prolif. 1994;27:411;(abstr)
  35. Gotlib J, Jamieson C, List AF, Cortes J, Albitar M, Sridhar K, et al. Phase II study of bevacizumab (anti-VEGF humanized monoclonal antibody) in patients with myelodysplastic syndrome (MDS): Preliminary results. Blood. 2003;102:425;(abstr)
  36. Stasi R, Amadori S. Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes. Br J Haematol. 2002;116:334–337
  37. Giles FJ, Stopeck AT, Silverman LR, Lancet JE, Cooper MA, Hannah AL, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood. 2003;102:795–801
  38. List AF, Glinsmann-Gibson B, Stadheim C, Meuillet EJ, Bellamy W, Powis G. Vascular endothelial growth factor receptor-1 and receptor-2 initiate a phosphatidylinositide 3-kinase-dependent clonogenic response in acute myeloid leukemia cells. Exp Hematol. 2004;32:526–535
  39. Foran J, Paquette R, Cooper M, et al. A Phase I study of repeated oral dosing with SU11248 for the treatment of patients with acute myeloid leukemia who have failed, or are not eligible for, conventional chemotherapy. Blood. 2002;100:558;(abstr)
  40. Roboz GJ, Giles FJ, List AF, Cortes JE, Carlin R, Kowalski M, et al. Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2006;20:952–957
  41. List AF, Kurtin S, Callander N, et al. Randomized, double-blind phase II study of the matrix metalloprotease (MMP) inhibitor, AG3340 (Prinomastat) in patients with myelodysplastic syndrome. Blood. 2002;100:789;(abstr)
  42. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002;347:481–487
  43. Nikas SN, Drosos AA. SFCIO-469 Scios Inc. Curr Opin Investig Drugs. 2004;5:1205–1212
  44. Navas TA, Mohindru M, Estes M, Ma JY, Sokol L, Pahanish P, et al. Inhibition of over-activated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood. 2006;108:4170–4177
  45. Sokol L, Cripe L, Kantarjian H, Sekeres M, Simrit P, Greenberg P, et al. Phase I/II, randomized, multicenter, dose-ascension study of the p38MAPK inhibitor SCIO-469 in patients with myelodysplastic syndrome (MDS). Blood. 2006;108:2657;(abstr)
  46. Paquette RL, Landaw EM, Pierre RV, Kahan J, Lubbert M, Lazcano O, et al. N-ras mutations are associated with poor prognosis and increased risk o fleukemia in myelodysplastic syndrome. Blood. 1993;82:590–599
  47. Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemais: A phase I clinical-laboratory correlative trial. Blood. 2001;97:3361–3369
  48. Kuzrock R, Kantarjian HM, Cortes JE, Singhania N, Thomas DA, Wilson EF, et al. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting. Blood. 2003;102:4527–4534
  49. Kuzrock R, Albitar M, Cortes JE, Estey EH, Faderl SH, Garcia-Manero G, et al. Phase II study of R115777, a farnesyltransferase inhibitor, in myelodysplastic syndrome. J Clin Oncol. 2004;22:1287–1292
  50. Fenaux P, Raza A, Mufti GH, Aul C, Germing U, Kantarjian H, et al. A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate-t o high-risk myelodysplastic syndrome. Blood. 2007;109:4158–4163
  51. Feldman EJ, Cortes J, Holyoake T, Simonsson B, De Angelo D, Lipton J, et al. Continuous oral lonafarnib (Sarasar) for the treatment of patients with myelodysplastic syndrome. Blood. 2003;102:176;(abstr)
  52. Cortes J, Holyoake T, Silver R. Continuous oral lonafarnib (Sarasar) for the treatment of patients with advanced hematologic malignancies: A phase II study. Blood. 2002;100:3132;(abstr)
  53. Buresh A, Perentesis J, Rimsza L, Kurtin S, Heaton R, Sugrue M, et al. Hyperleukocytosis complicating lonafarnib treatment in patients with chronic myelomonocytic leukemia. Leukemia. 2005;19:308–310
  54. Stofega M, Cheng M, Ma H, Sambucetti L, Keck J, Brown G, et al. Telintra (TLK199) enhances granulocyte colony-stimulating factor production. Blood. 2006;108:1161;(abstr)
  55. Raza A, Callander N, Ochoa L, Piro L, Emanuel P, Guba S, et al. Hematologic Improvement (HI) by TLK199 (Telintra), a novel glutathione analog, in myelodysplastic syndrome: Phase 2 results. Blood. 2005;106:2520;(abstr)
  56. Kantarjian H, Giles F, List A, Lyons R, Sekeres M, Pierce S, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:1705–1714
  57. Kurzock R, Cortes J, Thomas D, Jeha S, Pilat S, Talpaz M. Pilot study of low-dose interleukin-11 in patients with bone marrow failure. J Clin Oncol. 2001;19:4165–4172
  58. Tsimberidou A, Giles F, Khouri I, Bueso-Ramos C, Pilat S, Thomas D, 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
  59. Kuter D. New thrombopoietic growth factors. Blood. 2007;109:4607–4616
  60. Jenkins J, Williams D, Deng Y, Uhl J, Kitchen V, Collins D, et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood. 2007;109:4739–4741
  61. Desjardins R, Tempel D, Lucek R, Kuter D. Single and multiple oral doses of AKR-501 (YM477) increase the platelet count in healthy volunteers. Blood. 2006;108:477;(abstr)
  62. Bussel J, Kuter D, Phil D, George J, McMillan R, Aledort L, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006;355:1672–1681
  63. Kantarjian H, Giles F, Fenaux P, Becker P, Bouruchov A, Bowen D, et al. Evaluating the safety and efficacy of AMG 531 for the treatment of thrombocytopenic patients with myelodysplastic syndrome (MDS): Preliminary results of a phase 1/2 study. J Clin Oncol. 2007;25(suppl):7032

PII: S0037-1963(07)00152-7

doi: 10.1053/j.seminhematol.2007.10.001

Seminars in Hematology
Volume 45, Issue 1 , Pages 31-38 , January 2008

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