Prognostic relevance of integrated genetic profiling in acute myeloid leukemia

Jay P. Patel, Mithat Gönen, Maria E. Figueroa, Hugo Fernandez, Zhuoxin Sun, Janis Racevskis, Pieter Van Vlierberghe, Igor Dolgalev, Sabrena Thomas, Olga Aminova, Kety Huberman, Janice Cheng, Agnes Viale, Nicholas D. Socci, Adriana Heguy, Athena Cherry, Gail Vance, Rodney R. Higgins, Rhett P. Ketterling, Robert E. GallagherMark Litzow, Marcel R M Van Den Brink, Hillard M. Lazarus, Jacob M. Rowe, Selina Luger, Adolfo Ferrando, Elisabeth M. Paietta, Martin S. Tallman, Ari Melnick, Omar Abdel-Wahab, Ross L. Levine

Research output: Contribution to journalArticle

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Abstract

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.)

Original languageEnglish (US)
Pages (from-to)1079-1089
Number of pages11
JournalNew England Journal of Medicine
Volume366
Issue number12
DOIs
StatePublished - Mar 22 2012

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Acute Myeloid Leukemia
Mutation
Daunorubicin
Induction Chemotherapy
Survival
National Cancer Institute (U.S.)
Therapeutics
Survival Rate
Cell Count
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H., Sun, Z., Racevskis, J., ... Levine, R. L. (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. New England Journal of Medicine, 366(12), 1079-1089. https://doi.org/10.1056/NEJMoa1112304

Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. / Patel, Jay P.; Gönen, Mithat; Figueroa, Maria E.; Fernandez, Hugo; Sun, Zhuoxin; Racevskis, Janis; Van Vlierberghe, Pieter; Dolgalev, Igor; Thomas, Sabrena; Aminova, Olga; Huberman, Kety; Cheng, Janice; Viale, Agnes; Socci, Nicholas D.; Heguy, Adriana; Cherry, Athena; Vance, Gail; Higgins, Rodney R.; Ketterling, Rhett P.; Gallagher, Robert E.; Litzow, Mark; Van Den Brink, Marcel R M; Lazarus, Hillard M.; Rowe, Jacob M.; Luger, Selina; Ferrando, Adolfo; Paietta, Elisabeth M.; Tallman, Martin S.; Melnick, Ari; Abdel-Wahab, Omar; Levine, Ross L.

In: New England Journal of Medicine, Vol. 366, No. 12, 22.03.2012, p. 1079-1089.

Research output: Contribution to journalArticle

Patel, JP, Gönen, M, Figueroa, ME, Fernandez, H, Sun, Z, Racevskis, J, Van Vlierberghe, P, Dolgalev, I, Thomas, S, Aminova, O, Huberman, K, Cheng, J, Viale, A, Socci, ND, Heguy, A, Cherry, A, Vance, G, Higgins, RR, Ketterling, RP, Gallagher, RE, Litzow, M, Van Den Brink, MRM, Lazarus, HM, Rowe, JM, Luger, S, Ferrando, A, Paietta, EM, Tallman, MS, Melnick, A, Abdel-Wahab, O & Levine, RL 2012, 'Prognostic relevance of integrated genetic profiling in acute myeloid leukemia', New England Journal of Medicine, vol. 366, no. 12, pp. 1079-1089. https://doi.org/10.1056/NEJMoa1112304
Patel, Jay P. ; Gönen, Mithat ; Figueroa, Maria E. ; Fernandez, Hugo ; Sun, Zhuoxin ; Racevskis, Janis ; Van Vlierberghe, Pieter ; Dolgalev, Igor ; Thomas, Sabrena ; Aminova, Olga ; Huberman, Kety ; Cheng, Janice ; Viale, Agnes ; Socci, Nicholas D. ; Heguy, Adriana ; Cherry, Athena ; Vance, Gail ; Higgins, Rodney R. ; Ketterling, Rhett P. ; Gallagher, Robert E. ; Litzow, Mark ; Van Den Brink, Marcel R M ; Lazarus, Hillard M. ; Rowe, Jacob M. ; Luger, Selina ; Ferrando, Adolfo ; Paietta, Elisabeth M. ; Tallman, Martin S. ; Melnick, Ari ; Abdel-Wahab, Omar ; Levine, Ross L. / Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 12. pp. 1079-1089.
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abstract = "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.)",
author = "Patel, {Jay P.} and Mithat G{\"o}nen and Figueroa, {Maria E.} and Hugo Fernandez and Zhuoxin Sun and Janis Racevskis and {Van Vlierberghe}, Pieter and Igor Dolgalev and Sabrena Thomas and Olga Aminova and Kety Huberman and Janice Cheng and Agnes Viale and Socci, {Nicholas D.} and Adriana Heguy and Athena Cherry and Gail Vance and Higgins, {Rodney R.} and Ketterling, {Rhett P.} and Gallagher, {Robert E.} and Mark Litzow and {Van Den Brink}, {Marcel R M} and Lazarus, {Hillard M.} and Rowe, {Jacob M.} and Selina Luger and Adolfo Ferrando and Paietta, {Elisabeth M.} and Tallman, {Martin S.} and Ari Melnick and Omar Abdel-Wahab and Levine, {Ross L.}",
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T1 - Prognostic relevance of integrated genetic profiling in acute myeloid leukemia

AU - Patel, Jay P.

AU - Gönen, Mithat

AU - Figueroa, Maria E.

AU - Fernandez, Hugo

AU - Sun, Zhuoxin

AU - Racevskis, Janis

AU - Van Vlierberghe, Pieter

AU - Dolgalev, Igor

AU - Thomas, Sabrena

AU - Aminova, Olga

AU - Huberman, Kety

AU - Cheng, Janice

AU - Viale, Agnes

AU - Socci, Nicholas D.

AU - Heguy, Adriana

AU - Cherry, Athena

AU - Vance, Gail

AU - Higgins, Rodney R.

AU - Ketterling, Rhett P.

AU - Gallagher, Robert E.

AU - Litzow, Mark

AU - Van Den Brink, Marcel R M

AU - Lazarus, Hillard M.

AU - Rowe, Jacob M.

AU - Luger, Selina

AU - Ferrando, Adolfo

AU - Paietta, Elisabeth M.

AU - Tallman, Martin S.

AU - Melnick, Ari

AU - Abdel-Wahab, Omar

AU - Levine, Ross L.

PY - 2012/3/22

Y1 - 2012/3/22

N2 - 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.)

AB - 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.)

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