Myelodysplastic syndromes (MDS) are clonal disorders of the hematopoietic system with resultant cytopenias and shortened survival. Better recognition of MDS and an aging population, some of whom have been treated with chemotherapy and radiation therapy for other cancers, is largely responsible for the growing incidence of this malignancy, which is divided into lower- and higher-risk subtypes. Erythropoiesis-stimulating agents are the first-line treatment options for patients with lower-risk MDS and symptomatic anemia or for those requiring transfusion support. Lenalidomide has been successfully used for patients with the del(5q) chromosomal abnormality who are also transfusion dependent. Hypomethylating agents, such as azacitidine and decitabine, are indicated for patients with higher-risk disease, with azacitidine demonstrating a survival advantage. Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic approach available to less than 5% of patients with MDS. Combination therapies and newer single agents targeting the important cellular pathways are being explored for treatment of MDS with promising results.
AlessandrinoE.P.Della PortaM.G.BacigalupoA.MalcovatiL.AngelucciE.Van LintM.T. (2010) Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: A GITMO study. Haematologica95: 476–484.
2.
Arber, A., Brunning, R.D., Orazi, A., Bain, B.J., Porwit, A., Vardiman, J.W. et al. (2008) Acute myeloid leukaemia with myelodysplasia-related changes, In: Swerdlow, S.H., Campo, E., Harris, N.L. et al. (eds), WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer: Lyon, France, pp. 124–126.
3.
BeranM.ShenY.KantarjianH.O'BrienS.KollerC.A.GilesF.J. (2001) High-dose chemotherapy in high-risk myelodysplastic syndrome: Covariate-adjusted comparison of five regimens. Cancer92: 1999–2015.
4.
CasadevallN.DurieuxP.DuboisS.HemeryF.LepageE.QuarreM.C. (2004) Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: A randomized, controlled trial. Blood104: 321–327.
CutlerC.S.LeeS.J.GreenbergP.DeegH.J.PerezW.S.AnasettiC. (2004) A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood104: 579–585.
7.
De RoosA.J.DeegH.J.OnstadL.KopeckyK.J.BowlesE.J.YongM. (2010) Incidence of myelodysplastic syndromes within a nonprofit healthcare system in western Washington State, 2005–2006. Am J Hematol85: 765–770.
8.
EbertB.L.PretzJ.BoscoJ.ChangC.Y.TamayoP.GaliliN. (2008) Identification of Rps14 as a 5q-syndrome gene by RNA interference screen. Nature451: 335–339.
9.
EsteyE. (2007) Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol25: 1908–1915.
10.
FabreC.GrosjeanJ.TaillerM.BoehrerS.AdesL.PerfettiniJ.L. (2008) A novel effect of DNA methyltransferase and histone deacetylase inhibitors: NFkappab inhibition in malignant myeloblasts. Cell Cycle7: 2139–2145.
11.
FaderlS.RavandiF.HuangX.Garcia-ManeroG.FerrajoliA.EstrovZ. (2008) A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood112: 1638–1645.
12.
FenauxP.MuftiG.J.Hellstrom-LindbergE.SantiniV.FinelliC.GiagounidisA. (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol10: 223–232.
13.
Gabrilove, J., Paquette, R., Lyons, R.M., Mushtaq, C., Sekeres, M.A., Tomita, D. et al. (2008) Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol 142(3): 379–393.
14.
Gafter-GviliA.FraserA.PaulM.LeiboviciL. (2005) Meta-analysis: Antibiotic prophylaxis reduces mortality in neutropenic patients. Ann Int Med142: 979–995.
15.
GaliliN.CernyJ.RazaA. (2007) Current treatment options: Impact of cytogenetics on the course of myelodysplasia. Curr Treat Options Oncol8: 117–128.
16.
Garcia-ManeroG.AssoulineS.CortesJ.EstrovZ.KantarjianH.YangH. (2008) Phase 1 study of the oral isotype specific histone deacetylase inhibitor Mgcd0103 in leukemia. Blood112: 981–989.
17.
GolshayanA.R.JinT.MaciejewskiJ.FuA.Z.BershadskyB.KattanM.W. (2007) Efficacy of growth factors compared to other therapies for low-risk myelodysplastic syndromes. Br J Haematol137: 125–132.
18.
GreenbergP.CoxC.LebeauM.M.FenauxP.MorelP.SanzG. (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood89: 2079–2088.
19.
GreenbergP.L. (1998) NCCN practice guidelines for myelodyplastic syndromes. Oncology12: 53–80.
20.
GreenbergP.L. (2010) Current therapeutic approaches for patients with myelodysplastic syndromes. Br J Haematol150: 131–143.
21.
GreenbergP.L.SunZ.MillerK.B.BennettJ.M.TallmanM.S.DewaldG. (2009) Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: Results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood114: 2393–2400.
22.
GoldbergS.L.ChenE.CorralM.GuoA.Mody-PatelN.PecoraA.L. (2010) Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol28: 2847–2852.
23.
Hellstrom-LindbergE.GulbrandsenN.LindbergG.AhlgrenT.DahlI.M.DybedalI. (2003) A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: Significant effects on quality of life. Br J Haematol120: 1037–1046.
24.
Hellstrom-LindbergE.NegrinR.SteinR.KrantzS.LindbergG.VardimanJ. (1997) Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: Proposal for a predictive model. Br J Haematol99: 344–351.
25.
JaderstenM.MalcovatiL.DybedalI.Della PortaM.G.InvernizziR.MontgomeryS.M. (2008) Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol26: 3607–3613.
26.
JiangY.DunbarA.GondekL.P.MohanS.RataulM.O'KeefeC. (2009) Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood113: 1315–1325.
27.
KantarjianH.FenauxP.SekeresM.A.BeckerP.S.BoruchovA.BowenD. (2010) Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol28: 437–444.
28.
KantarjianH.IssaJ.P.RosenfeldC.S.BennettJ.M.AlbitarM.DipersioJ. (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer106: 1794–1803.
29.
KantarjianH.M.O'BrienS.HuangX.Garcia-ManeroG.RavandiF.CortesJ. (2007) Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: Comparison with historical experience. Cancer109: 1133–1137.
30.
KantarjianH.O'BrienS.RavandiF.CortesJ.ShanJ.BennettJ.M. (2008) Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original international prognostic scoring system. Cancer113: 1351–1361.
31.
KantarjianH.M.O'BrienS.ShanJ.AribiA.Garcia-ManeroG.JabbourE. (2007) Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer109: 265–273.
32.
LimZ.Y.KillickS.GermingU.CavenaghJ.CulliganD.BacigalupoA. (2007) Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia21: 1436–1441.
33.
ListA.DewaldG.BennettJ.GiagounidisA.RazaA.FeldmanE. (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med355: 1456–1465.
34.
List, A., Fenaux, P., Mufti, G., Hellström-Lindberg, E., Gore, S., Bennett, J. et al. (2008) Effect of azacitidine (AZA) on overall survival in higher-risk myelodysplastic syndromes (MDS) without complete remission. ASCO Meeting Abstracts Aug 18: 7006.
35.
MalcovatiL.PortaM.G.PascuttoC.InvernizziR.BoniM.TravaglinoE. (2005) Prognostic factors and life expectancy in myelodysplastic syndromes classified according to who criteria: A basis for clinical decision making. J Clin Oncol23: 7594–7603.
36.
Mohan, S., Fu, A., Tiu, R., Copelan, E., Saunthararajah, Y., Advani, A. et al. (2010) Prior therapy with DNA methyltransferase inhibitors (DNMTI) predicts for lower remission rates and worse survival in secondary acute myeloid leukemia patients (sAML) receiving remission induction therapy. ASH 2010, Poster Board III-812.
37.
NegrinR.S.SteinR.DohertyK.CornwellJ.VardimanJ.KrantzS. (1996) Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood87: 4076–4081.
38.
NegrinR.S.SteinR.VardimanJ.DohertyK.CornwellJ.KrantzS. (1993) Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. Blood82: 737–743.
39.
OlianskyD.M.AntinJ.H.BennettJ.M.DeegH.J.EngelhardtC.HeptinstallK.V. (2009) The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: An evidence-based review. Biol Blood Marrow Transplant15: 137–172.
ParkS.GrabarS.KelaidiC.Beyne-RauzyO.PicardF.BardetV. (2008) Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: The GFM experience. Blood111: 574–582.
42.
PigaA.GalanelloR.ForniG.L.CappelliniM.D.OrigaR.ZappuA. (2006) Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica91: 873–880.
43.
RazaA.GaliliN.SmithS.GodwinJ.LancetJ.MelchertM. (2009) Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood113: 6533–6540.
44.
RazaA.ReevesJ.A.FeldmanE.J.DewaldG.W.BennettJ.M.DeegH.J. (2008) Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood111: 86–93.
45.
ReuterS.KernW.SiggeA.DöhnerH.MarreR.KernP. (2005) Impact of fluoroquinolone prophylaxis on reduced infection-related mortality among patients with neutropenia and hematologic malignancies. Clin Infect Dis40: 1087–1093.
46.
RollisonD.E.HowladerN.SmithM.T.StromS.S.MerrittW.D.RiesL.A. (2008) Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood112: 45–52.
47.
SaunthararajahY.NakamuraR.NamJ.M.RobynJ.LoberizaF.MaciejewskiJ.P. (2002) Hla-Dr15 (Dr2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood100: 1570–1574.
48.
ScottB.L.SandmaierB.M.StorerB.MarisM.B.SorrorM.L.MaloneyD.G. (2006) Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: A retrospective analysis. Leukemia20: 128–135.
49.
SekeresM.A. (2010) The epidemiology of myelodysplastic syndromes. Hematol Oncol Clin North Am24: 287–294.
50.
SekeresM.A.FuA.Z.MaciejewskiJ.P.GolshayanA.R.KalaycioM.E.KattanM.W. (2007) A decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes. Cancer109: 1125–1132.
51.
SekeresM.A.KantarjianH.FenauxP. (2010a) Subcutaneous or intravenous administration of romiplostim in thrombocytopenic patients with lower-risk myelodysplastic syndromes. Cancer [Epub Ahead of Print].
52.
SekeresM.A.ListA.F.CuthbertsonD.PaquetteR.GanetzkyR.LathamD. (2010b) Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol28: 2253–2258.
53.
SekeresM.A.MaciejewskiJ.P.DoneleyD.W.GrinblattD.L.NarangM.MaloneJ.M. (2009) A study comparing dosing regimens and efficacy of subcutaneous to intravenous azacitidine (AZA) for the treatment of myelodysplastic syndromes (MDS). Blood114: 1460–1460.
54.
SekeresM.A.MaciejewskiJ.P.GiagounidisA.A.WrideK.KnightR.RazaA. (2008b) Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol26: 5943–5949.
55.
Sekeres, M., Narang, M., Komrokji, R., Maciejewski, J., List, A., Street, T. et al., (2010c) Therapeutic response to azacitidine (AZA) in patients with secondary myelodysplastic syndromes (sMDS) enrolled in the AVIDA registry. ASH 2010, Poster Board II-811.
56.
SekeresM.A.SchoonenW.M.KantarjianH.ListA.FryzekJ.PaquetteR. (2008a) Characteristics of US patients with myelodysplastic syndromes: Results of six cross-sectional physician surveys. J Natl Cancer Inst100: 1542–1551.
57.
SierraJ.PerezW.S.RozmanC.CarrerasE.KleinJ.P.RizzoJ.D. (2002) Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood100: 1997–2004.
58.
SilvermanL.R. (2009) Hypomethylating agents in myelodysplastic syndromes changing the inevitable: The value of azacitidine as maintenance therapy, effects on transfusion and combination with other agents. Leuk Res33(Suppl 2): S18–S21.
59.
SilvermanL.R.DemakosE.P.PetersonB.L.KornblithA.B.HollandJ.C.Odchimar-ReissigR. (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol20: 2429–2440.
60.
SloandE.M.MainwaringL.FuhrerM.RamkissoonS.RisitanoA.M.KeyvanafarK. (2005) Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood106: 841–851.
61.
SteensmaD.P.BaerM.R.SlackJ.L.BucksteinR.GodleyL.A.Garcia-ManeroG. (2009) Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: The alternative dosing for outpatient treatment (Adopt) trial. J Clin Oncol27: 3842–3848.
62.
WeiS.ChenX.RochaK.Epling-BurnetteP.K.DjeuJ.Y.LiuQ. (2009) A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci U S A106: 12974–12979.
63.
WijermansP.SuciuS.Liliana BailaL.PlatzbeckerU.GiagounidisA.SelleslagD. (2008) Low dose decitabine versus best supportive care in elderly patients with intermediate or high risk MDS not eligible for intensive chemotherapy: Final results of the randomized phase III study (06011) of the EORTC Leukemia and German MDS study groups. Blood112(Suppl.): abstr–abstr.
