Novel Biospecific Agents for the Treatment of Myelodysplastic Syndromes

Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term “biospecific” has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Peter L. Greenberg, MD, Professor of Medicine, Division of Hematology, Stanford University Medical Center, 703 Welch Road, Suite G-1, Stanford, CA 94305-5750. E-mail: peterg@stanford.edu

References

  • 1

    DredgeKMarriottJBDalgleishAG. Immunological effects of thalidomide and its chemical and functional analogs. Crit Rev Immunol.2002;22:425437.

    • Search Google Scholar
    • Export Citation
  • 2

    AndersonKC. Novel biologically based therapies for myeloma. Cancer J.2001;7(Suppl 1):S19S23.

  • 3

    AlviSBorokRZShaherA. Thalidomide significantly modifies bone marrow microenvironment in myelodysplastic syndrome (MDS) patients (Abstr #1454). Blood2002;100(Suppl. 1):375a.

    • Search Google Scholar
    • Export Citation
  • 4

    ShettyVAlviSZoratF. Effect of the anti-angiogenic thalidomide on the biological characteristics of patients with myelodysplastic syndromes (Abstr #4902). Blood2002; 100(Suppl 2):337b.

    • Search Google Scholar
    • Export Citation
  • 5

    AlviSAnthwalSShaikhM. Thalidomide significantly augments proliferation and cytokine secretion in bone marrow cultures established from myelodysplastic syndrome (MDS) patients (Abstr #1484). Blood2001;98(Suppl 1):352a.

    • Search Google Scholar
    • Export Citation
  • 6

    RazaAMeyerPDuttD. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood2001; 98:958965.

    • Search Google Scholar
    • Export Citation
  • 7

    Moreno-AspitiaAGeyerSLiC-Y. N998B: multicenter phase II trial of thalidomide (thal) in adult patients with myelodysplastic syndromes (MDS) (Abstr 354). Blood2002;100(Suppl 1):96a.

    • Search Google Scholar
    • Export Citation
  • 8

    MustoPFalconeASanpaoloG. Thalidomide abolishes transfusion-dependence in selected patients with myelodysplastic syndrome. Haematologica2002;87:884886.

    • Search Google Scholar
    • Export Citation
  • 9

    StruppCGermingUAivadoM. Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia2002;16:16.

  • 10

    RazaALisakLATahirS. Trilineage responses to arsenic trioxide (Trisenox®) and thalidomide in patients with myelodysplastic syndromes (MDS), particularly those with inv(3)(q21q26.2) (Abstr #3142). Blood2002;100(Suppl 1):795a.

    • Search Google Scholar
    • Export Citation
  • 11

    RazaALisakLATahirS. Combination of thalidomide and etanercept (tumor necrosis factor receptor or TNFR) effective in improving the cytopenias of some patients with myelodysplastic syndromes (MDS) (Abstr #4914). Blood2002;100(Suppl 2):340b.

    • Search Google Scholar
    • Export Citation
  • 12

    SteurerMSudmeierIStauderE. Thromboembolic events in patients with myelodysplastic syndrome receiving thalidomide in combination with darbepoetin alfa. Br J Haematol2003;121:101103.

    • Search Google Scholar
    • Export Citation
  • 13

    RichardsonPGSchlossmanRLWellerE. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood2002;100:30633067.

    • Search Google Scholar
    • Export Citation
  • 14

    CorralLGHaslettPAJMullerGW. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J Immunol1999;163:380386.

    • Search Google Scholar
    • Export Citation
  • 15

    MullerGChenRHuangSY. Amino-substituted thalidomide analogs: potent inhibitors of TNF-α production. Bioorg Med Chem Lett1999;9:16251630.

    • Search Google Scholar
    • Export Citation
  • 16

    HideshimaTChauhanDShimaY. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood2000; 96:29432950.

    • Search Google Scholar
    • Export Citation
  • 17

    GuptaDTreonSPShimaY. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia2001;15:19501961.

    • Search Google Scholar
    • Export Citation
  • 18

    DaviesFERajeNHideshimaT. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood2001;98:210216.

    • Search Google Scholar
    • Export Citation
  • 19

    BellamyWTRichterLSirjaniD. Vascular endothelial growth factor is an autocrine promotor of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood2001;97:14271434.

    • Search Google Scholar
    • Export Citation
  • 20

    MahadevanDListAFTateW. The immunomodulatory thalidomide analog CC5013 is a potent receptor tyrosine kinase (RTK) inhibitor that abolishes vascular endothelial growth factor (VEGF) trophic response in malignant myeloid progenitors. Leuk Res2003;27(Suppl 1):S108S109.

    • Search Google Scholar
    • Export Citation
  • 21

    ListAFKurtinSEGlinsmann-GibsonBJ. High erythropoietic remitting activity of the immunomodulatory thalidomide analog, cc5013, in patients with myelodysplastic syndrome (Abstr #353). Blood2002;100(Suppl 1):96a.

    • Search Google Scholar
    • Export Citation
  • 22

    ParkerJMuftiGJ. Ras and myelodysplasia: lesions from the last decade. Semin Hematol1996;33:206224.

  • 23

    CaseyPJSolskiPADerCJ. P21ras is modified by a farnesyl isoprenoid. Proc Natl Acad Sci USA1989; 86:83238327.

  • 24

    EndDWMetsGToddAV. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res2001;61:131137.

    • Search Google Scholar
    • Export Citation
  • 25

    KarpJELancetJEKauffmannSH. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase I clinical-laboratory correlative trial. Blood2001;97: 33613369.

    • Search Google Scholar
    • Export Citation
  • 26

    KurzrockRKantarjianHMCortesJE. Farnesyl protein transferase inhbitor (FTI) ZARNESTRA™ (R115777) in patients with myelodysplastic syndrome (MDS): clinical and biological aspects. Leuk Res2003;27(Suppl 1):S105S106.

    • Search Google Scholar
    • Export Citation
  • 27

    ListABeranADiPersioA. Opportunities for Trisenox® (arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia2003;17:14991507.

    • Search Google Scholar
    • Export Citation
  • 28

    DonelliAChiodinoCPanissidiT. Might arsenic trioxide be useful in the treatment of advanced myelodysplastic syndromes?Haematologica2000;85:10021003.

    • Search Google Scholar
    • Export Citation
  • 29

    MillerWHJrSchipperHMLeeJS. Mechanisms of action of arsenic trioxide. Cancer Res2002;62:38933903.

  • 30

    MillerWHJr. Molecular targets of arsenic trioxide in malignant cells. Oncologist2002;7(Suppl 1):1419.

  • 31

    HuangX-JWiernikPHKleinRS. Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of caspases. Med Oncol1999;16:5864.

    • Search Google Scholar
    • Export Citation
  • 32

    LiYMBroomeJD. Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells. Cancer Res1999;59:776780.

  • 33

    ZhangWOhnishiKShigenoK. The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms. Leukemia1998;12:13831391.

    • Search Google Scholar
    • Export Citation
  • 34

    VeyNDreyfusFGuerciA. Trisenox® (arsenic trioxide) in patients (pts) with myelodysplastic syndromes (MDS): preliminary results of a phase 1/2 study. Leuk Res2003; 27(Suppl 1):S111112.

    • Search Google Scholar
    • Export Citation
  • 35

    ListAFSchillerGJMasonJ. Trisenox® (arsenic trioxide) in patients with myelodysplastic syndromes (MDS): preliminary findings in a phase 2 clinical study. Leuk Res2003;27(Suppl 1):S106.

    • Search Google Scholar
    • Export Citation
  • 36

    GreenbergPL. The myelodysplastic syndromes. In: Hematology: Basic Principles and Practice3rd ed.HoffmanRBenzEShattilSFurieBCohenH eds. New York, NY: Churchill Livingstone; 1999;11061129.

    • Search Google Scholar
    • Export Citation
  • 37

    DeegHJBeckhamCLokenMR. Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. Leuk Lymphoma2000;37:405414.

    • Search Google Scholar
    • Export Citation
  • 38

    RazaAGezerSMundleS: Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood1995; 86:268276.

    • Search Google Scholar
    • Export Citation
  • 39

    RajapaksaRGinztonNRottL: Altered oncogene expression and apoptosis in myelodysplastic syndrome marrow cells. Blood1996;88:42754287.

  • 40

    GreenbergPL: Apoptosis and its role in the myelodysplastic syndromes: implications for disease natural history and treatment. Leuk Res1998;22:11231136.

    • Search Google Scholar
    • Export Citation
  • 41

    ParkerJMuftiGRasoolF. The role of apoptosis, proliferation and the Bcl2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood2000;96:39323938.

    • Search Google Scholar
    • Export Citation
  • 42

    GersukGMLeeJWBeckhamCA. Fas (CD95) receptor and fas-ligand expression in bone marrow cells from patients with myelodysplastic syndrome. Blood1996;88:11221123.

    • Search Google Scholar
    • Export Citation
  • 43

    BouscaryDDe VosJGuesnuM. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia1997;11:839845.

    • Search Google Scholar
    • Export Citation
  • 44

    ShettyVMundleSAlviS. Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes. Leuk Res1996;20:891900.

    • Search Google Scholar
    • Export Citation
  • 45

    ShimazakiKOshimaKSuzimiyaJKawasakiCKikuchiM: Evaluation of apoptosis as a prognostic factor in myelodysplastic syndromes. Br J Haematol2000;110:584590.

    • Search Google Scholar
    • Export Citation
  • 46

    Hellstrom-LindbergESchmidt-MendeJForsblomAM. Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases. Br J Haematol2001;112:714726.

    • Search Google Scholar
    • Export Citation
  • 47

    AliAMundleSDRagasaD. Sequential activation of caspase-1 and caspase-3-like proteases during apoptosis in myelodysplastic syndromes. J Hematother Stem Cell Res1999;8:343356.

    • Search Google Scholar
    • Export Citation
  • 48

    MorelandLBaumgartnerSSchiffM. Treatment of rheumatoid arthritis with the recombinant human TNF receptor (p75)-Fc-fusion protein. N Engl J Med2001; 33:11801187.

    • Search Google Scholar
    • Export Citation
  • 49

    GersukGBeckhamCLokenM. A role for TNF-α, fas and fas ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol.1998;103:176188.

    • Search Google Scholar
    • Export Citation
  • 50

    DeegHJGotlibJBeckhamC. Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: a pilot study. Leukemia2002;16:162164.

    • Search Google Scholar
    • Export Citation
  • 51

    MaciejewskiJPRistianoAMSloandEM. A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndromes. Br J Haematol2002;117:119126.

    • Search Google Scholar
    • Export Citation
  • 52

    SilvermanLRDemakosEPPetersonBL. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the CALGB. J Clin Oncol2002;20:24292440.

    • Search Google Scholar
    • Export Citation
  • 53

    KornblithABHerndonJESilvermanLR. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a CALGB study. J Clin Oncol2002;20:24412452.

    • Search Google Scholar
    • Export Citation
  • 54

    WijermansPLubbertMVerhoefG. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol2000;18:956962.

    • Search Google Scholar
    • Export Citation
  • 55

    LubbertMWijermansPKunzmannR. Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Br J Haematol2001;14:349357.

    • Search Google Scholar
    • Export Citation
  • 56

    DaskalakisMNguyenTTNguyenC. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood2002;100:29572964.

    • Search Google Scholar
    • Export Citation
  • 57

    NajfeldVSilvermanLScaliseLR. Modulation of the cytogenetically abnormal clone in MDS (Abstr # 356). Blood2002;100(Suppl 1):97a.

Article Information

PubMed

Google Scholar

Related Articles

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 30 30 2
PDF Downloads 15 15 1
EPUB Downloads 0 0 0