A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia

被引:18
作者
Luskin, Marlise R. [1 ]
Gimotty, Phyllis A. [2 ]
Smith, Catherine [3 ]
Loren, Alison W. [1 ]
Figueroa, Maria E. [4 ]
Harrison, Jenna [3 ]
Sun, Zhuoxin [5 ]
Tallman, Martin S. [6 ]
Paietta, Elisabeth M. [7 ]
Litzow, Mark R. [8 ]
Melnick, Ari M. [9 ]
Levine, Ross L. [6 ]
Fernandez, Hugo F. [10 ]
Luger, Selina M. [1 ]
Carroll, Martin [1 ,11 ]
Master, Stephen R. [12 ]
Wertheim, Gerald B. W. [3 ,13 ]
机构
[1] Univ Penn UPENN, Abramson Canc Ctr, Div Hematol & Oncol, Philadelphia, PA USA
[2] Univ Penn UPENN, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA USA
[3] Childrens Hosp Philadelphia, Dept Pathol, 5199b Main Bldg,324 S 34th St, Philadelphia, PA 19104 USA
[4] Univ Michigan, Sch Med, Ann Arbor, MI USA
[5] Dana Farber Canc Inst, Boston, MA 02115 USA
[6] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA
[7] Montefiore Med Ctr, New York, NY USA
[8] Mayo Clin, Rochester, MN USA
[9] Weill Cornell Med Coll, Div Hematol & Oncol, 525 E 68th St,Suite F-715,Box 79, New York, NY 10065 USA
[10] Moffit Canc Ctr, Tampa, FL USA
[11] Philadelphia Vet Adm Med Ctr, Philadelphia, PA USA
[12] Weill Cornell Med Coll, Dept Pathol & Lab Med, 525 E 68th St,Suite F-715,Box 79, New York, NY 10065 USA
[13] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
关键词
INTENSIVE CHEMOTHERAPY; MUTATIONS RESULT; TET2; FUNCTION; HYPERMETHYLATION; EPIGENETICS; RESISTANCE; SURVIVAL; IMPACT; OLDER;
D O I
10.1172/jci.insight.87323
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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. CONCLUSION. 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.
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页数:9
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