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

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 - J Hematol Oncol (2014)

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

View Article: PubMed Central - PubMed

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.

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EstimatedDNMT3A, FLT3, andNPM1variant (allelic) frequencies in a subset ofde novoacute myeloid leukemia samples harboring all three mutations.
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Fig3: EstimatedDNMT3A, FLT3, andNPM1variant (allelic) frequencies in a subset ofde novoacute myeloid leukemia samples harboring all three mutations.

Mentions: To assess the relative dominance of mutations in individual cases within the AMLDNMT3A/FLT3/NPM1 group, we estimated the variant frequency of each of the mutant DNMT3A, FLT3, and NPM1 alleles in a subset MDACC samples and found them to be generally commensurate, suggesting that they commonly co-occur within a dominant clone (Figure 3). In addition, the estimated variant frequency suggested that these mutations are heterozygous.Figure 3


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

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 - J Hematol Oncol (2014)

EstimatedDNMT3A, FLT3, andNPM1variant (allelic) frequencies in a subset ofde novoacute myeloid leukemia samples harboring all three mutations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197326&req=5

Fig3: EstimatedDNMT3A, FLT3, andNPM1variant (allelic) frequencies in a subset ofde novoacute myeloid leukemia samples harboring all three mutations.
Mentions: To assess the relative dominance of mutations in individual cases within the AMLDNMT3A/FLT3/NPM1 group, we estimated the variant frequency of each of the mutant DNMT3A, FLT3, and NPM1 alleles in a subset MDACC samples and found them to be generally commensurate, suggesting that they commonly co-occur within a dominant clone (Figure 3). In addition, the estimated variant frequency suggested that these mutations are heterozygous.Figure 3

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

View Article: PubMed Central - PubMed

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.

Show MeSH
Related in: MedlinePlus