Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms

dc.creatorTraina, F
dc.creatorVisconte, V
dc.creatorElson, P
dc.creatorTabarroki, A
dc.creatorJankowska, AM
dc.creatorHasrouni, E
dc.creatorSugimoto, Y
dc.creatorSzpurka, H
dc.creatorMakishima, H
dc.creatorO'Keefe, CL
dc.creatorSekeres, MA
dc.creatorAdvani, AS
dc.creatorKalaycio, M
dc.creatorCopelan, EA
dc.creatorSaunthararajah, Y
dc.creatorSaad, STO
dc.creatorMaciejewski, JP
dc.creatorTiu, RV
dc.date2014
dc.dateJAN
dc.date2014-07-30T18:06:16Z
dc.date2015-11-26T16:53:24Z
dc.date2014-07-30T18:06:16Z
dc.date2015-11-26T16:53:24Z
dc.date.accessioned2018-03-28T23:40:32Z
dc.date.available2018-03-28T23:40:32Z
dc.identifierLeukemia. Nature Publishing Group, v. 28, n. 1, n. 78, n. 87, 2014.
dc.identifier0887-6924
dc.identifier1476-5551
dc.identifierWOS:000329441200008
dc.identifier10.1038/leu.2013.269
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/69995
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/69995
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1276576
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionWe hypothesized that specific molecular mutations are important biomarkers for response to DNA methyltransferase inhibitors (DNMT inhibitors) and may have prognostic value in patients with myelodysplastic syndromes (MDS). Mutational analysis was performed in 92 patients with MDS and related disorders who received 5-azacytidine (n = 55), decitabine (n = 26) or both (n = 11). Mutational status was correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Risk stratification models were created. TET2, DNMT3A, IDH1/IDH2, ASXL1, CBL, RAS and SF3B1 mutations were found in 18, 9, 8, 26, 3, 2 and 13% of patients, respectively. In multivariate analysis, TET2(MUT) and/or DNMT3A(MUT) (P = 0.03), platelets >= 100 x 10(9)/l (P = 0.007) and WBC < 3.0 x 10(9)/l (P = 0.03) were independent predictors of better response. TET2(MUT) and/or DNMT3A(MUT) (P = 0.04) status was also independently prognostic for improved PFS, as were good or intermediate cytogenetic risk (P<0.0001), age<60 (P = 0.0001), treatment with both 5-azacytidine and decitabine (P = 0.02) and hemoglobin >= 10 g/dl (P = 0.01). Better OS was associated with ASXL1(WT) (P = 0.008) and SF3B1(MUT) (P = 0.01), and, similar to PFS, cytogenetic risk (P = 0.0002), age (P = 0.02) and hemoglobin (P = 0.04). These data support the role of molecular mutations as predictive biomarkers for response and survival in MDS patients treated with DNMT inhibitors.
dc.description28
dc.description1
dc.description78
dc.description87
dc.descriptionMDS Foundation YIA grant
dc.descriptionAA & MDS International Foundation YIA
dc.descriptionCleveland Clinic Institutional Seed Support
dc.descriptionScott Hamilton CARES Grant
dc.descriptionCelgene grant
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFAPESP [2011/20750-9, 2012/09982-8]
dc.languageen
dc.publisherNature Publishing Group
dc.publisherLondon
dc.publisherInglaterra
dc.relationLeukemia
dc.relationLeukemia
dc.rightsfechado
dc.sourceWeb of Science
dc.subjectDNMT inhibitors
dc.subjectmolecular mutations
dc.subjectprognostic factors
dc.subjectAcute Myeloid-leukemia
dc.subjectChronic Myelomonocytic Leukemia
dc.subjectInternational Working Group
dc.subjectMyelodysplastic/myeloproliferative Neoplasms
dc.subjectRing Sideroblasts
dc.subjectTet2 Mutations
dc.subjectPhase-iii
dc.subjectAzacitidine
dc.subjectTrial
dc.subjectRisk
dc.titleImpact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms
dc.typeArtículos de revistas


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