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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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Survival analysis by mutation status. Overall survival (a) and event-free survival (b) of de novo acute myeloid leukemia patients younger than 60 years of age with concomitant mutations in DNMT3A, FLT3, and NPM1 (AMLDNMT3A/FLT3/NPM1) in comparison to those within other mutation subgroups in this study. Overall survival (c) and event-free survival (d) of patients with AML harboring NPM1 mutation in conjunction with wild-type DNMT3A (NPM1 group) or mutant DNMT3A (NPM1/DNMT3A group). Overall survival (e) of patients with CN-AML harboring NPM1 mutations with concomitant FLT3 (NPM1/FLT3 group) or DNMT3A (NPM1/DNMT3A group).
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Fig4: Survival analysis by mutation status. Overall survival (a) and event-free survival (b) of de novo acute myeloid leukemia patients younger than 60 years of age with concomitant mutations in DNMT3A, FLT3, and NPM1 (AMLDNMT3A/FLT3/NPM1) in comparison to those within other mutation subgroups in this study. Overall survival (c) and event-free survival (d) of patients with AML harboring NPM1 mutation in conjunction with wild-type DNMT3A (NPM1 group) or mutant DNMT3A (NPM1/DNMT3A group). Overall survival (e) of patients with CN-AML harboring NPM1 mutations with concomitant FLT3 (NPM1/FLT3 group) or DNMT3A (NPM1/DNMT3A group).

Mentions: Younger (<60 years) patients with AMLDNMT3A/FLT3/NPM1 had a significantly shorter EFS (p = 0.047) and a tendency towards shorter OS (p = 0.095) compared to those in the other mutation groups (Figure 4a-b). Although patients with AMLDNMT3A/FLT3/NPM1 tended to have shorter OS compared to those in the other mutation groups, the difference was not significant in the entire group as well as within the CN-AML group (p = 0.211 and p = 0.209, respectively). Importantly, there was no significant difference in OS among AMLDNMT3A/FLT3/NPM1 patients with FLT3-ITD and FLT3-TKD mutations types (p = 0.822).Figure 4


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)

Survival analysis by mutation status. Overall survival (a) and event-free survival (b) of de novo acute myeloid leukemia patients younger than 60 years of age with concomitant mutations in DNMT3A, FLT3, and NPM1 (AMLDNMT3A/FLT3/NPM1) in comparison to those within other mutation subgroups in this study. Overall survival (c) and event-free survival (d) of patients with AML harboring NPM1 mutation in conjunction with wild-type DNMT3A (NPM1 group) or mutant DNMT3A (NPM1/DNMT3A group). Overall survival (e) of patients with CN-AML harboring NPM1 mutations with concomitant FLT3 (NPM1/FLT3 group) or DNMT3A (NPM1/DNMT3A group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Survival analysis by mutation status. Overall survival (a) and event-free survival (b) of de novo acute myeloid leukemia patients younger than 60 years of age with concomitant mutations in DNMT3A, FLT3, and NPM1 (AMLDNMT3A/FLT3/NPM1) in comparison to those within other mutation subgroups in this study. Overall survival (c) and event-free survival (d) of patients with AML harboring NPM1 mutation in conjunction with wild-type DNMT3A (NPM1 group) or mutant DNMT3A (NPM1/DNMT3A group). Overall survival (e) of patients with CN-AML harboring NPM1 mutations with concomitant FLT3 (NPM1/FLT3 group) or DNMT3A (NPM1/DNMT3A group).
Mentions: Younger (<60 years) patients with AMLDNMT3A/FLT3/NPM1 had a significantly shorter EFS (p = 0.047) and a tendency towards shorter OS (p = 0.095) compared to those in the other mutation groups (Figure 4a-b). Although patients with AMLDNMT3A/FLT3/NPM1 tended to have shorter OS compared to those in the other mutation groups, the difference was not significant in the entire group as well as within the CN-AML group (p = 0.211 and p = 0.209, respectively). Importantly, there was no significant difference in OS among AMLDNMT3A/FLT3/NPM1 patients with FLT3-ITD and FLT3-TKD mutations types (p = 0.822).Figure 4

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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Related in: MedlinePlus