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

doi:10.1186/s13045-014-0074-4

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 journal › Article › peer-review

104 Scopus citations

Abstract

Background: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML^{DNMT3A/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 AML^{DNMT3A/FLT3/NPM1} patients.

Results: Patients with AML^{DNMT3A/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 AML^{DNMT3A/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 AML^DNMT3A/NPM1 had a significantly shorter OS compared to those with AML^{FLT3-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 language	English (US)
Article number	74
Journal	Journal of Hematology and Oncology
Volume	7
Issue number	1
DOIs	https://doi.org/10.1186/s13045-014-0074-4
State	Published - Oct 4 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Acute myeloid leukemia
DNMT3A
FLT3
NPM1
Next-generation sequencing

ASJC Scopus subject areas

Hematology
Molecular Biology
Oncology
Cancer Research

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10.1186/s13045-014-0074-4

Cite this

Loghavi, S., Zuo, Z., Ravandi, F., Kantarjian, H. M., Bueso-Ramos, C., Zhang, L., Singh, R. R., Patel, K. P., Medeiros, L. J., Stingo, F., Routbort, M., Cortes, J., Luthra, R., & 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), Article 74. https://doi.org/10.1186/s13045-014-0074-4

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

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

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.",

keywords = "Acute myeloid leukemia, DNMT3A, FLT3, NPM1, Next-generation sequencing",

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

note = "Publisher Copyright: {\textcopyright} 2014 Loghavi et al.; licensee BioMed Central Ltd.",

year = "2014",

month = oct,

day = "4",

doi = "10.1186/s13045-014-0074-4",

language = "English (US)",

volume = "7",

journal = "Journal of Hematology and Oncology",

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TY - JOUR

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

Y1 - 2014/10/4

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.

KW - Acute myeloid leukemia

KW - DNMT3A

KW - FLT3

KW - NPM1

KW - Next-generation sequencing

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U2 - 10.1186/s13045-014-0074-4

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M3 - Article

C2 - 25281355

AN - SCOPUS:84907942640

SN - 1756-8722

VL - 7

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

IS - 1

M1 - 74

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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