title: Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms.
abstract: We 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 > or = 100 × 10(9)/l (P=0.007) and WBC<3.0 × 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 > or = 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.
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Hematology and Hemotherapy Center - INCT do Sangue, University of Campinas - UNICAMP, Campinas, SP, Brazil [3] Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Traina
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: V
authors.initials: V
authors.lastname: Visconte
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: P
authors.initials: P
authors.lastname: Elson
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tabarroki
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Jankowska
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hasrouni
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Szpurka
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: O'Keefe
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Sekeres
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Advani
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kalaycio
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Copelan
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Hematology and Hemotherapy Center - INCT do Sangue, University of Campinas - UNICAMP, Campinas, SP, Brazil.
authors.forename: S T
authors.initials: ST
authors.lastname: Olalla Saad
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
authors.affiliation: 1] Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [2] Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: R V
authors.initials: RV
authors.lastname: Tiu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000473:pathology*; D012189:Retrospective Studies
chemical_list: D004791:Enzyme Inhibitors; D015254:DNA Modification Methylases
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