title: A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia.
abstract: BACKGROUND
  Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML.
  
  
  METHODS
  We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy. The association of M-score with complete remission (CR) and overall survival (OS) was evaluated. The optimal M-score cut-point for identifying groups with differing survival was used to define a binary M-score classifier. This classifier was validated in an independent cohort of 383 patients from the Eastern Cooperative Oncology Group Trial 1900 (E1900; NCT00049517).
  
  
  RESULTS
  A higher mean M-score was associated with death and failure to achieve CR. Multivariable analysis confirmed that a higher M-score was associated with death (P= 0.011) and failure to achieve CR (P= 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. The ability of the M-score to perform as a classifier was confirmed in patients ≤ 60 years with intermediate cytogenetics and patients who achieved CR, as well as in the E1900 validation cohort.
  
  
  CONCLUSIONS
  The M-score represents a valid binary prognostic classifier for patients with de novo AML. The xMELP assay and associated M-score can be used for prognosis and should be further investigated for clinical decision making in AML patients.
authors.affiliation: Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania (UPENN), Philadelphia, Pennsylvania, USA.
authors.forename: Marlise R
authors.initials: MR
authors.lastname: Luskin
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania (UPENN), Philadelphia, Pennsylvania, USA.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Smith
authors.affiliation: Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania (UPENN), Philadelphia, Pennsylvania, USA.
authors.forename: Alison W
authors.initials: AW
authors.lastname: Loren
authors.affiliation: University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Harrison
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Zhuoxin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Montefiore Medical Center, New York, New York, USA.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Paietta
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Moffit Cancer Center, Tampa, Florida, USA.
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Fernandez
authors.affiliation: Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania (UPENN), Philadelphia, Pennsylvania, USA.
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.affiliation: Division of Hematology and Oncology, Abramson Cancer Center at the University of Pennsylvania (UPENN), Philadelphia, Pennsylvania, USA; Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Master
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gerald B W
authors.initials: GB
authors.lastname: Wertheim