Predicting outcome in higher-risk myelodysplastic syndrome patients treated with azacitidine

References

• Pfeilstocker M , TuechlerH , SanzGet al. Time-dependent changes in mortality and transformation risk in MDS. Blood128(7), 902–910 (2016).
   PubMed Web of Science ®Google Scholar
• Silverman LR , DemakosEP , PetersonBLet al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol.20(10), 2429–2440 (2002).
   PubMed Web of Science ®Google Scholar
• Fenaux P , MuftiGJ , Hellstrom-LindbergEet al. 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 Oncol.10(3), 223–232 (2009).
   PubMed Web of Science ®Google Scholar
• Vardiman JW , ThieleJ , ArberDAet al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood114(5), 937–951 (2009).
   PubMed Web of Science ®Google Scholar
• Itzykson R , ThepotS , QuesnelBet al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood117(2), 403–411 (2011).
   PubMed Web of Science ®Google Scholar
• Garcia-Delgado R , DeMiguel D , BailenAet al. Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia. Leuk. Res.38(7), 744–750 (2014).
   PubMed Web of Science ®Google Scholar
• Papageorgiou SG , VasilatouD , KontosCKet al. Treatment with 5-Azacytidine improves clinical outcome in high-risk MDS patients in the ‘real life’ setting: a single center observational study. Hematology21(1), 34–41 (2016).
   PubMed Web of Science ®Google Scholar
• Van Der Helm LH , AlhanC , WijermansPWet al. Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme. Br. J. Haematol.155(5), 599–606 (2011).
   PubMed Web of Science ®Google Scholar
• Mozessohn L , CheungMC , FallahpourSet al. Azacitidine in the ‘real-world’: an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada. Br. J. Haematol.181(6), 803–815 (2018).
   PubMed Web of Science ®Google Scholar
• Bernal T , Martinez-CamblorP , Sanchez-GarciaJet al. Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: results from the Spanish registry. Leukemia29(9), 1875–1881 (2015).
   PubMed Web of Science ®Google Scholar
• Gore SD , FenauxP , SantiniVet al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica98(7), 1067–1072 (2013).
   PubMed Web of Science ®Google Scholar
• Sebert M , KomrokjiRS , SekeresMAet al. Impact of baseline cytogenetic findings and cytogenetic response on outcome of high-risk myelodysplastic syndromes and low blast count AML treated with azacitidine. Leuk. Res.63, 72–77 (2017).
   PubMed Web of Science ®Google Scholar
• Scalzulli E , MolicaM , AlunniFegatelli Det al. Identification of predictive factors for overall survival at baseline and during azacitidine treatment in high-risk myelodysplastic syndrome patients treated in the clinical practice. Ann. Hematol.98(8), 1919–1925 (2019).
   PubMed Web of Science ®Google Scholar
• Reda G , RivaM , FattizzoBet al. Bone marrow fibrosis and early hematological response as predictors of poor outcome in azacitidine treated high risk-patients with myelodysplastic syndromes or acute myeloid leukemia. Semin. Hematol.55(4), 202–208 (2018).
   PubMed Web of Science ®Google Scholar
• Dinmohamed AG , Van NordenY , VisserOet al. Effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes in daily practice: results from the Dutch population-based PHAROS MDS registry. Leukemia29(12), 2449–2451 (2015).
   PubMed Web of Science ®Google Scholar
• Nazha A , SekeresMA , Garcia-ManeroGet al. Outcomes of patients with myelodysplastic syndromes who achieve stable disease after treatment with hypomethylating agents. Leuk. Res.41, 43–47 (2016).
   PubMed Web of Science ®Google Scholar
• Papageorgiou SG , KontosCK , KotsianidisIet al. The outcome of patients with high-risk MDS achieving stable disease after treatment with 5-azacytidine: a retrospective analysis of the Hellenic (Greek) MDS Study Group. Hematol. Oncol.36(4), 693–700 (2018).
   PubMed Web of Science ®Google Scholar
• Cabrero M , JabbourE , RavandiFet al. Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up. Leuk. Res.39(5), 520–524 (2015).
   PubMed Web of Science ®Google Scholar
• Greenberg P , CoxC , LebeauMMet al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood89(6), 2079–2088 (1997).
   PubMed Web of Science ®Google Scholar
• Greenberg PL , TuechlerH , SchanzJet al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood120(12), 2454–2465 (2012).
   PubMed Web of Science ®Google Scholar
• Molteni A , RivaM , BorinLet al. The influence of disease and comorbidity risk assessments on the survival of MDS and oligoblastic AML patients treated with 5-azacitidine: a retrospective analysis in ten centers of the “Rete Ematologica Lombarda”. Leuk. Res.42, 21–27 (2016).
   PubMed Web of Science ®Google Scholar
• Papageorgiou SG , KotsianidisI , BouchlaAet al. Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes. Ther. Adv. Hematol.11, doi:2040620720966121 (2020).
   PubMed Web of Science ®Google Scholar
• Kuendgen A , Muller-ThomasC , LausekerMet al. Efficacy of azacitidine is independent of molecular and clinical characteristics - an analysis of 128 patients with myelodysplastic syndromes or acute myeloid leukemia and a review of the literature. Oncotarget.9(45), 27882–27894 (2018).
   PubMedGoogle Scholar
• Bally C , ThepotS , QuesnelBet al. Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk. Res.37(6), 637–640 (2013).
   PubMed Web of Science ®Google Scholar
• Wehmeyer J , ZaissM , LosemCet al. Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Eur. J. Haematol.101(6), 766–773 (2018).
   PubMed Web of Science ®Google Scholar
• Pepe S , ScalzulliE , ColafigliGet al. Predictive factors for response and survival in elderly acute myeloid leukemia patients treated with hypomethylating agents: a real-life experience. Ann. Hematol.99(10), 2405–2416 (2020).
   PubMed Web of Science ®Google Scholar
• Laribi K , BolleD , AlaniMet al. Prognostic impact of elevated pretreatment serum ferritin in patients with high-risk MDS treated with azacitidine. Exp. Hematol.65, 34–37 (2018).
   PubMed Web of Science ®Google Scholar
• Zeidan AM , LeeJW , PrebetTet al. Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS. Br. J. Haematol.167(1), 62–68 (2014).
   PubMed Web of Science ®Google Scholar
• Della Porta MG , MalcovatiL , StruppCet al. Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome. Haematologica96(3), 441–449 (2011).
   PubMed Web of Science ®Google Scholar
• Breccia M , SalaroliA , LoglisciG , FinsingerP , SerraoA , AlimenaG. MDS-specific comorbidity index is useful to identify myelodysplastic patients who can have better outcome with 5-azacitidine. Haematologica97(2), e2 (2012).
   PubMed Web of Science ®Google Scholar
• Molga A , WallM , ChhetriRet al. Comprehensive geriatric assessment predicts azacitidine treatment duration and survival in older patients with myelodysplastic syndromes. J. Geriatr. Oncol.11(1), 114–120 (2020).
   PubMed Web of Science ®Google Scholar
• Garcia Delgado R , de MiguelD , BailenAet al. Multivariate analysis of the impact of pre-treatment serum ferritin level on response and overall survival in patients with myelodysplastic syndromes treated with azacitidine. Blood120(21), 1710 (2012).
   Web of Science ®Google Scholar
• Blunt DN , WellsRA , ChodirkerLet al. Predictive factors of overall survival and the completion of four cycles of azacitidine: an MDS-CAN study. Blood130(Suppl. 1), 4253 (2017).
   Google Scholar
• Cluzeau T , MounierN , KarsentiJMet al. Monosomal karyotype improves IPSS-R stratification in MDS and AML patients treated with Azacitidine. Am. J. Hematol.88(9), 780–783 (2013).
   PubMed Web of Science ®Google Scholar
• Hwang KL , SongMK , ShinHJet al. Monosomal and complex karyotypes as prognostic parameters in patients with International Prognostic Scoring System higher risk myelodysplastic syndrome treated with azacitidine. Blood Res.49(4), 234–240 (2014).
   PubMedGoogle Scholar
• Stengel A , KernW , HaferlachT , MeggendorferM , FasanA , HaferlachC. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. Leukemia31(3), 705–711 (2017).
   PubMed Web of Science ®Google Scholar
• Wu P , WengJ , LiMet al. Co-occurrence of RUNX1 and ASXL1 mutations underlie poor response and outcome for MDS patients treated with HMAs. Am. J. Transl. Res.11(6), 3651–3658 (2019).
   PubMed Web of Science ®Google Scholar
• Bories P , PradeN , LagardeSet al. Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine. PLoS ONE15(10), e0238795 (2020).
   PubMed Web of Science ®Google Scholar
• Takahashi K , PatelK , Bueso-RamosCet al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. Oncotarget7(12), 14172–14187 (2016).
   PubMedGoogle Scholar
• Muller-Thomas C , RudeliusM , RondakICet al. Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica99(10), e179–e181 (2014).
   PubMed Web of Science ®Google Scholar
• Nishiwaki S , ItoM , WataraiRet al. A new prognostic index to make short-term prognoses in MDS patients treated with azacitidine: a combination of p53 expression and cytogenetics. Leuk. Res.41, 21–26 (2016).
   PubMed Web of Science ®Google Scholar
• Bernard E , NannyaY , HasserjianRPet al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat. Med. doi:10.1038/s41591-020-1008-z (2020) ( Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Itzykson R , KosmiderO , CluzeauTet al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia25(7), 1147–1152 (2011).
   PubMed Web of Science ®Google Scholar
• Voso MT , FabianiE , PiciocchiAet al. Role of BCL2L10 methylation and TET2 mutations in higher risk myelodysplastic syndromes treated with 5-azacytidine. Leukemia25(12), 1910–1913 (2011).
   PubMed Web of Science ®Google Scholar
• Malcovati L , GermingU , KuendgenAet al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J. Clin. Oncol.25(23), 3503–3510 (2007).
   PubMed Web of Science ®Google Scholar
• Lamarque M , RaynaudS , ItzyksonRet al. The revised IPSS is a powerful tool to evaluate the outcome of MDS patients treated with azacitidine: the GFM experience. Blood120(25), 5084–5085 (2012).
   PubMed Web of Science ®Google Scholar
• Zeidan AM , LeeJW , PrebetTet al. Comparison of the prognostic utility of the revised International Prognostic Scoring System and the French Prognostic Scoring System in azacitidine-treated patients with myelodysplastic syndromes. Br. J. Haematol.166(3), 352–359 (2014).
   PubMed Web of Science ®Google Scholar
• Papageorgiou SG , VasilatouD , KontosCKet al. The prognostic value of monosomal karyotype (MK) in higher-risk patients with myelodysplastic syndromes treated with 5-Azacitidine: a retrospective analysis of the Hellenic (Greek) Myelodysplastic syndromes Study Group. Am. J. Hematol.93(7), 895–901 (2018).
   PubMed Web of Science ®Google Scholar
• Mishra A , Corrales-YepezM , AliNAet al. Validation of the revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Am. J. Hematol.88(7), 566–570 (2013).
   PubMed Web of Science ®Google Scholar
• Voso MT , NiscolaP , PiciocchiAet al. Standard dose and prolonged administration of azacitidine are associated with improved efficacy in a real-world group of patients with myelodysplastic syndrome or low blast count acute myeloid leukemia. Eur. J. Haematol.96(4), 344–351 (2016).
   PubMed Web of Science ®Google Scholar
• Breccia M , LoglisciG , CannellaLet al. Application of French prognostic score to patients with International Prognostic Scoring System intermediate-2 or high risk myelodysplastic syndromes treated with 5-azacitidine is able to predict overall survival and rate of response. Leuk. Lymphoma53(5), 985–986 (2012).
   PubMed Web of Science ®Google Scholar
• Ravandi F , IssaJP , Garcia-ManeroGet al. Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer115(24), 5746–5751 (2009).
   PubMed Web of Science ®Google Scholar
• Diez-Campelo M , LorenzoJI , ItzyksonRet al. Azacitidine improves outcome in higher-risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries. Br. J. Haematol.181(3), 350–359 (2018).
   PubMed Web of Science ®Google Scholar
• Mcgraw KL , NguyenJ , KomrokjiRSet al. Immunohistochemical pattern of p53 is a measure of TP53 mutation burden and adverse clinical outcome in myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica101(8), e320–323 (2016).
   PubMed Web of Science ®Google Scholar
• Diamantopoulos P , KoumbiD , KotsianidisIet al. The prognostic significance of chromosome 17 abnormalities in patients with myelodysplastic syndrome treated with 5-azacytidine: Results from the Hellenic 5-azacytidine registry. Cancer Med.8(5), 2056–2063 (2019).
   PubMed Web of Science ®Google Scholar
• Della Porta MG , MalcovatiL , BoveriEet al. Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J. Clin. Oncol.27(5), 754–762 (2009).
   PubMed Web of Science ®Google Scholar
• Buesche G , TeomanH , WilczakWet al. Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia22(2), 313–322 (2008).
   PubMed Web of Science ®Google Scholar
• Agarwal A , MorroneK , BartensteinM , ZhaoZJ , VermaA , GoelS. Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-beta. Stem Cell Investig.3, 5 (2016).
   PubMedGoogle Scholar
• Pleyer L , ValentP , GreilR. Mesenchymal stem and progenitor cells in normal and dysplastic hematopoiesis-masters of survival and clonality?Int. J. Mol. Sci.17(7), 1009 (2016).
   PubMed Web of Science ®Google Scholar
• Arber DA , OraziA , HasserjianRet al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood128(3), 462–463 (2016).
   PubMed Web of Science ®Google Scholar
• Zeidan AM , AlAli N , BarnardJet al. Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium. Leukemia31(6), 1391–1397 (2017).
   PubMed Web of Science ®Google Scholar
• Prebet T , SunZ , KetterlingRPet al. Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. Br. J. Haematol.172(3), 384–391 (2016).
   PubMed Web of Science ®Google Scholar
• Fianchi L , CriscuoloM , LunghiMet al. Outcome of therapy-related myeloid neoplasms treated with azacitidine. J. Hematol. Oncol.5, 44 (2012).
   PubMed Web of Science ®Google Scholar
• Wong TN , RamsinghG , YoungALet al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature518(7540), 552–555 (2015).
   PubMed Web of Science ®Google Scholar
• Zipperer E , PostJG , HerkertMet al. Serum hepcidin measured with an improved ELISA correlates with parameters of iron metabolism in patients with myelodysplastic syndrome. Ann. Hematol.92(12), 1617–1623 (2013).
   PubMed Web of Science ®Google Scholar
• Cui R , GaleRP , ZhuGet al. Serum iron metabolism and erythropoiesis in patients with myelodysplastic syndrome not receiving RBC transfusions. Leuk. Res.38(5), 545–550 (2014).
   PubMed Web of Science ®Google Scholar
• Kawabata H , UsukiK , Shindo-UedaMet al. Serum ferritin levels at diagnosis predict prognosis in patients with low blast count myelodysplastic syndromes. Int. J. Hematol.110(5), 533–542 (2019).
   PubMed Web of Science ®Google Scholar
• Kikuchi S , KobuneM , IyamaSet al. Prognostic significance of serum ferritin level at diagnosis in myelodysplastic syndrome. Int. J. Hematol.95(5), 527–534 (2012).
   PubMed Web of Science ®Google Scholar
• Sperr WR , KundiM , WimazalFet al. Proposed score for survival of patients with myelodysplastic syndromes. Eur. J. Clin. Invest.43(11), 1120–1128 (2013).
   PubMed Web of Science ®Google Scholar
• Jin X , HeX , CaoXet al. Iron overload impairs normal hematopoietic stem and progenitor cells through reactive oxygen species and shortens survival in myelodysplastic syndrome mice. Haematologica103(10), 1627–1634 (2018).
   PubMed Web of Science ®Google Scholar
• Alhan C , WestersTM , VanDer Helm LHet al. Absence of aberrant myeloid progenitors by flow cytometry is associated with favorable response to azacitidine in higher risk myelodysplastic syndromes. Cytometry B. Clin. Cytom.86(3), 207–215 (2014).
   PubMed Web of Science ®Google Scholar
• Oka S , OnoK , NohgawaM. Clinical effects of the CD13/CD33 ratio on the prognosis of myelodysplastic syndrome treated with azacitidine. Leuk. Lymphoma61(5), 1250–1253 (2020).
   PubMed Web of Science ®Google Scholar
• Miltiades P , LamprianidouE , VassilakopoulosTPet al. Expression of CD25 antigen on CD34+ cells is an independent predictor of outcome in late-stage MDS patients treated with azacitidine. Blood Cancer J.4, e187 (2014).
   PubMed Web of Science ®Google Scholar
• Cheson BD , GreenbergPL , BennettJMet al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood108(2), 419–425 (2006).
   PubMed Web of Science ®Google Scholar
• Craddock C , QuekL , GoardonNet al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia27(5), 1028–1036 (2013).
   PubMed Web of Science ®Google Scholar
• Unnikrishnan A , PapaemmanuilE , BeckDet al. Integrative genomics identifies the molecular basis of resistance to azacitidine therapy in myelodysplastic syndromes. Cell Rep.20(3), 572–585 (2017).
   PubMed Web of Science ®Google Scholar
• Peterlin P , CluzeauT , JullienMet al. Azacitidine in patients older than 80 years with acute myeloid leukaemia or myelodysplastic syndromes: a report on 115 patients. Br. J. Haematol.190(3), 461–464 (2020).
   PubMed Web of Science ®Google Scholar
• Nakaya A , FujitaS , SatakeAet al. Evaluation of azacitidine in patients with transplant-ineligible myelodysplastic syndromes and acute myeloid leukemia with myelodysplasia-related changes in a Japanese clinical setting. Oncol. Lett.19(2), 1317–1321 (2020).
   PubMed Web of Science ®Google Scholar
• Mahfouz RZ , JankowskaA , EbrahemQet al. Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin. Cancer. Res.19(4), 938–948 (2013).
   PubMed Web of Science ®Google Scholar
• Papageorgiou SG , KontosCK , KotsianidisIet al. Effectiveness of 5-Azacytidine in older patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a retrospective analysis of the Hellenic (Greek) MDS Study Group. J. Geriatr. Oncol.11(1), 121–124 (2020).
   PubMed Web of Science ®Google Scholar
• Howlader N , NooneAM , KrapchoMet al. SEER Cancer Statistics Review. In: Cancer Statistics 1975–2017. National Cancer Institute, MD, USA (2020). https://seer.cancer.gov/archive/csr/1975_2017/
   Google Scholar
• Papadopoulos V , DiamantopoulosPT , PapageorgiouSGet al. Estimated glomerular filtration rate independently predicts outcome of azacitidine therapy in higher-risk Myelodysplastic syndromes. Results from 536 patients of the Hellenic National Registry of Myelodysplastic and Hypoplastic syndromes. Hematol. Oncol. doi:10.1002/hon.2756 (2020) ( Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Gribben JG . Chronic lymphocytic leukemia: planning for an aging population. Expert Rev. Anticancer. Ther.10(9), 1389–1394 (2010).
   PubMed Web of Science ®Google Scholar
• Chen X , MaoG , LengSX. Frailty syndrome: an overview. Clin. Interv. Aging.9, 433–441 (2014).
   PubMed Web of Science ®Google Scholar
• Nishiyama-Fujita Y , NakazatoT , KamiyaTet al. The geriatric nutritional risk index predicts the early death and survival in patients with myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes treated with azacitidine. Hematol. Oncol.38(4), 611–613 (2020).
   PubMed Web of Science ®Google Scholar
• El-Osta A . DNMT cooperativity–the developing links between methylation, chromatin structure and cancer. BioEssays25(11), 1071–1084 (2003).
   PubMed Web of Science ®Google Scholar
• Ko M , HuangY , JankowskaAMet al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature468(7325), 839–843 (2010).
   PubMed Web of Science ®Google Scholar
• Bejar R , LordA , StevensonKet al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood124(17), 2705–2712 (2014).
   PubMed Web of Science ®Google Scholar
• Tobiasson M , MclornanDP , KarimiMet al. Mutations in histone modulators are associated with prolonged survival during azacitidine therapy. Oncotarget7(16), 22103–22115 (2016).
   PubMedGoogle Scholar
• Lin Y , LinZ , ChengKet al. Prognostic role of TET2 deficiency in myelodysplastic syndromes: a meta-analysis. Oncotarget8(26), 43295–43305 (2017).
   PubMedGoogle Scholar
• Du M , ZhouF , JinR , HuY , MeiH. Mutations in the DNA methylation pathway predict clinical efficacy to hypomethylating agents in myelodysplastic syndromes: a meta-analysis. Leuk. Res.80, 11–18 (2019).
   PubMed Web of Science ®Google Scholar
• Solly F , KoeringC , MohamedAMet al. An miRNA-DNMT1 axis is involved in azacitidine resistance and predicts survival in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia. Clin. Cancer. Res.23(12), 3025–3034 (2017).
   PubMed Web of Science ®Google Scholar
• Tobiasson M , AbdulkadirH , LennartssonAet al. Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease. Oncotarget8(17), 28812–28825 (2017).
   PubMedGoogle Scholar
• Vire E , BrennerC , DeplusRet al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature439(7078), 871–874 (2006).
   PubMed Web of Science ®Google Scholar
• Wu X , Bekker-JensenIH , ChristensenJet al. Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals. Cell. Res.25(11), 1205–1218 (2015).
   PubMed Web of Science ®Google Scholar
• Lubbert M . Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes?Leukemia17(9), 1762–1764 (2003).
   PubMed Web of Science ®Google Scholar
• Grovdal M , KarimiM , TobiassonMet al. Azacitidine induces profound genome-wide hypomethylation in primary myelodysplastic bone marrow cultures but may also reduce histone acetylation. Leukemia28(2), 411–413 (2014).
   PubMed Web of Science ®Google Scholar
• Gawlitza AL , SpeithJ , RinkeJet al. 5-Azacytidine modulates CpG methylation levels of EZH2 and NOTCH1 in myelodysplastic syndromes. J. Cancer Res. Clin. Oncol.145(11), 2835–2843 (2019).
   PubMed Web of Science ®Google Scholar
• Valencia A , MasalaE , RossiAet al. Expression of nucleoside-metabolizing enzymes in myelodysplastic syndromes and modulation of response to azacitidine. Leukemia28(3), 621–628 (2014).
   PubMed Web of Science ®Google Scholar
• Gagnon-Kugler T , LangloisF , StefanovskyV , LessardF , MossT. Loss of human ribosomal gene CpG methylation enhances cryptic RNA polymerase II transcription and disrupts ribosomal RNA processing. Mol. Cell.35(4), 414–425 (2009).
   PubMed Web of Science ®Google Scholar
• Monika Belickova M , MerkerovaMD , VotavovaHet al. Up-regulation of ribosomal genes is associated with a poor response to azacitidine in myelodysplasia and related neoplasms. Int. J. Hematol.104(5), 566–573 (2016).
   PubMed Web of Science ®Google Scholar
• Cheng JX , ChenL , LiYet al. RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia. Nat. Commun.9(1), 1163 (2018).
   PubMedGoogle Scholar
• Palii SS , Van EmburghBO , SankpalUT , BrownKD , RobertsonKD. DNA methylation inhibitor 5-Aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol. Cell. Biol.28(2), 752–771 (2008).
   PubMed Web of Science ®Google Scholar
• Cluzeau T , RobertG , MounierNet al. BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients. Oncotarget3(4), 490–501 (2012).
   PubMedGoogle Scholar
• Asano M , OhyashikiJH , Kobayashi-KawanaCet al. A novel non-invasive monitoring assay of 5-azacitidine efficacy using global DNA methylation of peripheral blood in myelodysplastic syndrome. Drug. Des. Devel. Ther.13, 1821–1833 (2019).
   PubMed Web of Science ®Google Scholar
• Prebet T , SunZ , FigueroaMEet al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905. J. Clin. Oncol.32(12), 1242–1248 (2014).
   PubMed Web of Science ®Google Scholar
• Voso MT , SantiniV , FabianiEet al. Why methylation is not a marker predictive of response to hypomethylating agents. Haematologica99(4), 613–619 (2014).
   PubMed Web of Science ®Google Scholar
• Yan P , FrankhouserD , MurphyMet al. Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia. Blood120(12), 2466–2474 (2012).
   PubMed Web of Science ®Google Scholar
• Abaigar M , RamosF , BenitoRet al. Prognostic impact of the number of methylated genes in myelodysplastic syndromes and acute myeloid leukemias treated with azacytidine. Ann. Hematol.92(11), 1543–1552 (2013).
   PubMed Web of Science ®Google Scholar
• Raj K , JohnA , HoAet al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia21(9), 1937–1944 (2007).
   PubMed Web of Science ®Google Scholar
• Hayashi Y , ZhangY , YokotaAet al. Pathobiological pseudohypoxia as a putative mechanism underlying myelodysplastic syndromes. Cancer discovery8(11), 1438–1457 (2018).
   PubMed Web of Science ®Google Scholar
• Mpakou V , SpathisA , BouchlaAet al. Upregulated Hif-1alpha signaling pathway in high risk myelodysplastic syndrome and acute myeloid leukemia patients is associated with better response to 5-azacytidine - Data from the Hellenic MDS study group. Hematol. Oncol. doi:10.1002/hon.2834 (2020) ( Epub ahead of print).
   Web of Science ®Google Scholar
• Martin I , NavarroB , SerranoAet al. Impact of clinical features, cytogenetics, genetic mutations, and methylation dynamics of CDKN2B and DLC-1 promoters on treatment response to azacitidine. Ann. Hematol.99(3), 527–537 (2020).
   PubMed Web of Science ®Google Scholar
• Ettou S , AudureauE , HumbrechtCet al. Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML. Leukemia26(10), 2297–2299 (2012).
   PubMed Web of Science ®Google Scholar
• Fan R , ZhangLY , WangHet al. Methylation of the CpG island near SOX7 gene promoter is correlated with the poor prognosis of patients with myelodysplastic syndrome. Tohoku. J. Exp. Med.227(2), 119–128 (2012).
   PubMed Web of Science ®Google Scholar
• Cocco L , FinelliC , MongiorgiSet al. An increased expression of PI-PLCbeta1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes. J. Leukoc. Biol.98(5), 769–780 (2015).
   PubMed Web of Science ®Google Scholar
• Falantes JF , TrujilloP , PiruatJIet al. Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia. Clin. Lymphoma. Myeloma. Leuk.15(4), 236–244 (2015).
   PubMed Web of Science ®Google Scholar
• Costantini B , KordastiSY , KulasekararajAGet al. The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica98(8), 1196–1205 (2013).
   PubMed Web of Science ®Google Scholar
• Jia X , YangW , ZhouX , HanL , ShiJ. Influence of demethylation on regulatory T and Th17 cells in myelodysplastic syndrome. Oncol. Lett.19(1), 442–448 (2020).
   PubMed Web of Science ®Google Scholar
• Kordasti SY , IngramW , HaydenJet al. CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood110(3), 847–850 (2007).
   PubMed Web of Science ®Google Scholar
• Bouchliou I , MiltiadesP , NakouEet al. Th17 and Foxp3(+) T regulatory cell dynamics and distribution in myelodysplastic syndromes. Clin. Immunol.139(3), 350–359 (2011).
   PubMed Web of Science ®Google Scholar
• Chiappinelli KB , StrisselPL , DesrichardAet al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell162(5), 974–986 (2015).
   PubMed Web of Science ®Google Scholar
• Fraison JB , MekinianA , GrignanoEet al. Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk. Res.43, 13–17 (2016).
   PubMed Web of Science ®Google Scholar
• Dubois A , FurstossN , CallejaAet al. LAMP2 expression dictates azacytidine response and prognosis in MDS/AML. Leukemia33(6), 1501–1513 (2019).
   PubMed Web of Science ®Google Scholar
• Diamantopoulos PT , KontandreopoulouCN , SymeonidisAet al. Bone marrow PARP1 mRNA levels predict response to treatment with 5-azacytidine in patients with myelodysplastic syndrome. Ann. Hematol.98(6), 1383–1392 (2019).
   PubMed Web of Science ®Google Scholar
• Muller-Thomas C , HeiderM , PiontekGet al. Prognostic value of indoleamine 2,3 dioxygenase in patients with higher-risk myelodysplastic syndromes treated with azacytidine. Br. J. Haematol.190(3), doi:10.1111/bjh.16652 (2020) ( Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Santaliestra M , GarridoA , CarricondoMet al. Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5-azacytidine: identification of responding patients. Eur. J. Haematol.103(3), 208–214 (2019).
   PubMed Web of Science ®Google Scholar
• Boasman K , SimmondsMJ , GrahamC , SaunthararajahY , RinaldiCR. Using PU.1 and Jun dimerization protein 2 transcription factor expression in myelodysplastic syndromes to predict treatment response and leukaemia transformation. Ann. Hematol.98(6), 1529–1531 (2019).
   PubMed Web of Science ®Google Scholar
• Miltiades P , LamprianidouE , VassilakopoulosTPet al. The Stat3/5 signaling biosignature in hematopoietic stem/progenitor cells predicts response and outcome in myelodysplastic syndrome patients treated with azacitidine. Clin. Cancer. Res.22(8), 1958–1968 (2016).
   PubMed Web of Science ®Google Scholar
• Hrustincova A , KrejcikZ , KundratDet al. Circulating small noncoding RNAs have specific expression patterns in plasma and extracellular vesicles in myelodysplastic syndromes and are predictive of patient outcome. Cells9(4), 794 (2020).
   PubMed Web of Science ®Google Scholar
• Krejcik Z , BelickovaM , HrustincovaAet al. MicroRNA profiles as predictive markers of response to azacitidine therapy in myelodysplastic syndromes and acute myeloid leukemia. Cancer Biomark22(1), 101–110 (2018).
   PubMed Web of Science ®Google Scholar
• Kim K , ParkS , ChoiHet al. Gene expression signatures associated with sensitivity to azacitidine in myelodysplastic syndromes. Sci. Rep.10(1), 19555 (2020).
   PubMed Web of Science ®Google Scholar
• Blunt DN , WellsRA , ChodirkerLet al. Predictive Factors of Overall Survival and the Completion of Four Cycles of Azacitidine: An MDS-CAN Study. Blood130(Suppl. 1), 4253 (2017).
   Google Scholar