Clinical features of de Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

Sanam Loghavi, Zhuang Zuo, Farhad Ravandi, Hagop M. Kantarjian, Carlos Bueso-Ramos, Liping Zhang, Rajesh R. Singh, Keyur P. Patel, L. Jeffrey Medeiros, Francesco Stingo, Mark Routbort, Jorge Cortes, Rajyalakshmi Luthra, Joseph D. Khoury

Research output: Contribution to journalArticle

Abstract

Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AMLDNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.

Methods. We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AMLDNMT3A/FLT3/NPM1 patients.

Results: Patients with AMLDNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AMLDNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AMLDNMT3A/NPM1 had a significantly shorter OS compared to those with AMLFLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.

Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

Original languageEnglish (US)
Article number74
JournalJournal of Hematology and Oncology
Volume7
Issue number1
DOIs
StatePublished - Oct 4 2014
Externally publishedYes

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Acute Myeloid Leukemia
Mutation
Survival
Cytogenetics
Disease-Free Survival
Bone Marrow

Keywords

  • Acute myeloid leukemia
  • DNMT3A
  • FLT3
  • Next-generation sequencing
  • NPM1

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

Cite this

Loghavi, S., Zuo, Z., Ravandi, F., Kantarjian, H. M., Bueso-Ramos, C., Zhang, L., ... Khoury, J. D. (2014). Clinical features of de Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. Journal of Hematology and Oncology, 7(1), [74]. https://doi.org/10.1186/s13045-014-0074-4

Clinical features of de Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. / Loghavi, Sanam; Zuo, Zhuang; Ravandi, Farhad; Kantarjian, Hagop M.; Bueso-Ramos, Carlos; Zhang, Liping; Singh, Rajesh R.; Patel, Keyur P.; Medeiros, L. Jeffrey; Stingo, Francesco; Routbort, Mark; Cortes, Jorge; Luthra, Rajyalakshmi; Khoury, Joseph D.

In: Journal of Hematology and Oncology, Vol. 7, No. 1, 74, 04.10.2014.

Research output: Contribution to journalArticle

Loghavi, S, Zuo, Z, Ravandi, F, Kantarjian, HM, Bueso-Ramos, C, Zhang, L, Singh, RR, Patel, KP, Medeiros, LJ, Stingo, F, Routbort, M, Cortes, J, Luthra, R & Khoury, JD 2014, 'Clinical features of de Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations', Journal of Hematology and Oncology, vol. 7, no. 1, 74. https://doi.org/10.1186/s13045-014-0074-4
Loghavi, Sanam ; Zuo, Zhuang ; Ravandi, Farhad ; Kantarjian, Hagop M. ; Bueso-Ramos, Carlos ; Zhang, Liping ; Singh, Rajesh R. ; Patel, Keyur P. ; Medeiros, L. Jeffrey ; Stingo, Francesco ; Routbort, Mark ; Cortes, Jorge ; Luthra, Rajyalakshmi ; Khoury, Joseph D. / Clinical features of de Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. In: Journal of Hematology and Oncology. 2014 ; Vol. 7, No. 1.
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abstract = "Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AMLDNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.Methods. We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AMLDNMT3A/FLT3/NPM1 patients.Results: Patients with AMLDNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7{\%} vs. 46.9{\%}; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AMLDNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AMLDNMT3A/NPM1 had a significantly shorter OS compared to those with AMLFLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.",
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T1 - Clinical features of de Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

AU - Loghavi, Sanam

AU - Zuo, Zhuang

AU - Ravandi, Farhad

AU - Kantarjian, Hagop M.

AU - Bueso-Ramos, Carlos

AU - Zhang, Liping

AU - Singh, Rajesh R.

AU - Patel, Keyur P.

AU - Medeiros, L. Jeffrey

AU - Stingo, Francesco

AU - Routbort, Mark

AU - Cortes, Jorge

AU - Luthra, Rajyalakshmi

AU - Khoury, Joseph D.

PY - 2014/10/4

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N2 - Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AMLDNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.Methods. We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AMLDNMT3A/FLT3/NPM1 patients.Results: Patients with AMLDNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AMLDNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AMLDNMT3A/NPM1 had a significantly shorter OS compared to those with AMLFLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

AB - Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AMLDNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.Methods. We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AMLDNMT3A/FLT3/NPM1 patients.Results: Patients with AMLDNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AMLDNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AMLDNMT3A/NPM1 had a significantly shorter OS compared to those with AMLFLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.Conclusions: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.

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KW - Next-generation sequencing

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