Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia

被引：1535

作者：

Patel, Jay P.

Goenen, Mithat ^{[2
]}

Figueroa, Maria E. ^{[4
]}

Fernandez, Hugo ^{[10
]}

Sun, Zhuoxin ^{[11
]}

Racevskis, Janis ^{[5
]}

Van Vlierberghe, Pieter ^{[6
,7
,8
]}

Dolgalev, Igor

Thomas, Sabrena

Aminova, Olga

Huberman, Kety

Cheng, Janice ^{[3
]}

Viale, Agnes ^{[3
]}

Socci, Nicholas D.

Heguy, Adriana

Cherry, Athena ^{[12
]}

Vance, Gail ^{[13
]}

Higgins, Rodney R. ^{[14
]}

Ketterling, Rhett P. ^{[15
]}

Gallagher, Robert E. ^{[5
]}

Litzow, Mark ^{[16
]}

van den Brink, Marcel R. M. ^{[9
]}

Lazarus, Hillard M. ^{[17
]}

Rowe, Jacob M. ^{[18
,19
]}

Luger, Selina ^{[20
]}

Ferrando, Adolfo ^{[6
,7
,8
]}

Paietta, Elisabeth ^{[5
]}

Tallman, Martin S.

Melnick, Ari ^{[4
]}

Abdel-Wahab, Omar ^{[1
]}

Levine, Ross L. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, Leukemia Serv, Dept Med, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Genom Core Lab, New York, NY 10065 USA

[4] Weill Cornell Med Coll, Dept Med, Div Hematol Oncol, New York, NY USA

[5] Montefiore Med Ctr, New York, NY USA

[6] Columbia Univ, Inst Canc Genet, New York, NY USA

[7] Columbia Univ, Dept Pediat, New York, NY 10027 USA

[8] Columbia Univ, Dept Pathol, New York, NY USA

[9] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA

[10] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Bone Marrow Transplantat, Tampa, FL 33682 USA

[11] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA

[12] Stanford Hosp & Clin, Dept Pathol, Palo Alto, CA USA

[13] Indiana Univ Sch Med, Dept Med & Mol Genet, Bloomington, IN USA

[14] Abbott NW Hosp, Allina Cytogenet Lab, Minneapolis, MN 55407 USA

[15] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA

[16] Mayo Clin, Coll Med, Dept Hematol & Oncol, Rochester, MN USA

[17] Case Western Reserve Univ, Sch Med, Div Hematol Oncol, Cleveland, OH 44106 USA

[18] Technion Israel Inst Technol, Jerusalem, Israel

[19] Shaare Zedek Med Ctr, Jerusalem, Israel

[20] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2012年 / 366卷 / 12期

关键词：

NORMAL CYTOGENETICS; YOUNGER ADULTS; OLDER PATIENTS; MUTATIONS; TET2; IDENTIFY; DNMT3A; AML;

D O I：

10.1056/NEJMoa1112304

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. METHODS We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. RESULTS We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P = 0.001 for FLT3-ITD, P = 0.009 for MLL-PTD, P = 0.05 for ASXL1, and P = 0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P = 0.05 for CEBPA and P = 0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standarddose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P = 0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P = 0.67). CONCLUSIONS We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.)

引用

页码：1079 / 1089

页数：11

共 24 条

[21] Prognostically useful gene-expression profiles in acute myeloid leukemia [J].

Valk, PJM ;

Verhaak, RGW ;

Beijen, MA ;

Erpelinck, CAJ ;

van Doorn-Khosrovani, SBV ;

Boer, JM ;

Beverloo, HB ;

Moorhouse, MJ ;

van der Spek, PJ ;

Löwenberg, B ;

Delwel, R .

NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (16) :1617-1628

[22] PHF6 mutations in adult acute myeloid leukemia [J].

Van Vlierberghe, P. ;

Patel, J. ;

Abdel-Wahab, O. ;

Lobry, C. ;

Hedvat, C. V. ;

Balbin, M. ;

Nicolas, C. ;

Payer, A. R. ;

Fernandez, H. F. ;

Tallman, M. S. ;

Paietta, E. ;

Melnick, A. ;

Vandenberghe, P. ;

Speleman, F. ;

Aifantis, I. ;

Cools, J. ;

Levine, R. ;

Ferrando, A. .

LEUKEMIA, 2011, 25 (01) :130-134

[23] The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate [J].

Ward, Patrick S. ;

Patel, Jay ;

Wise, David R. ;

Abdel-Wahab, Omar ;

Bennett, Bryson D. ;

Coller, Hilary A. ;

Cross, Justin R. ;

Fantin, Valeria R. ;

Hedvat, Cyrus V. ;

Perl, Alexander E. ;

Rabinowitz, Joshua D. ;

Carroll, Martin ;

Su, Shinsan M. ;

Sharp, Kim A. ;

Levine, Ross L. ;

Thompson, Craig B. .

CANCER CELL, 2010, 17 (03) :225-234

[24] Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia [J].

Yan, Xiao-Jing ;

Xu, Jie ;

Gu, Zhao-Hui ;

Pan, Chun-Ming ;

Lu, Gang ;

Shen, Yang ;

Shi, Jing-Yi ;

Zhu, Yong-Mei ;

Tang, Lin ;

Zhang, Xiao-Wei ;

Liang, Wen-Xue ;

Mi, Jian-Qing ;

Song, Huai-Dong ;

Li, Ke-Qin ;

Chen, Zhu ;

Chen, Sai-Juan .

NATURE GENETICS, 2011, 43 (04) :309-U51

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