Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

Koji Sasaki, Rashmi Kanagal-Shamanna, Guillermo Montalban-Bravo, Rita Assi, Elias Jabbour, Farhad Ravandi, Tapan Kadia, Sherry Pierce, Koichi Takahashi, Graciela Nogueras Gonzalez, Keyur Patel, Kelly A. Soltysiak, Jorge Cortes, Hagop M. Kantarjian, Guillermo Garcia-Manero

Research output: Contribution to journalArticle

Abstract

Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%. Results: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P =.006); the median overall survival was 11 months and 27 months, respectively (P <.001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival. Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML.

Original languageEnglish (US)
Pages (from-to)765-774
Number of pages10
JournalCancer
Volume126
Issue number4
DOIs
StatePublished - Feb 15 2020
Externally publishedYes

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Gene Frequency
Acute Myeloid Leukemia
Mutation
Survival
Leukocyte Count
Cytogenetics
Multivariate Analysis
Bone Marrow

Keywords

  • ASXL1
  • DNMT3A
  • JAK2
  • TET2
  • TP53
  • acute myeloid leukemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sasaki, K., Kanagal-Shamanna, R., Montalban-Bravo, G., Assi, R., Jabbour, E., Ravandi, F., ... Garcia-Manero, G. (2020). Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. Cancer, 126(4), 765-774. https://doi.org/10.1002/cncr.32566

Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. / Sasaki, Koji; Kanagal-Shamanna, Rashmi; Montalban-Bravo, Guillermo; Assi, Rita; Jabbour, Elias; Ravandi, Farhad; Kadia, Tapan; Pierce, Sherry; Takahashi, Koichi; Nogueras Gonzalez, Graciela; Patel, Keyur; Soltysiak, Kelly A.; Cortes, Jorge; Kantarjian, Hagop M.; Garcia-Manero, Guillermo.

In: Cancer, Vol. 126, No. 4, 15.02.2020, p. 765-774.

Research output: Contribution to journalArticle

Sasaki, K, Kanagal-Shamanna, R, Montalban-Bravo, G, Assi, R, Jabbour, E, Ravandi, F, Kadia, T, Pierce, S, Takahashi, K, Nogueras Gonzalez, G, Patel, K, Soltysiak, KA, Cortes, J, Kantarjian, HM & Garcia-Manero, G 2020, 'Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia', Cancer, vol. 126, no. 4, pp. 765-774. https://doi.org/10.1002/cncr.32566
Sasaki, Koji ; Kanagal-Shamanna, Rashmi ; Montalban-Bravo, Guillermo ; Assi, Rita ; Jabbour, Elias ; Ravandi, Farhad ; Kadia, Tapan ; Pierce, Sherry ; Takahashi, Koichi ; Nogueras Gonzalez, Graciela ; Patel, Keyur ; Soltysiak, Kelly A. ; Cortes, Jorge ; Kantarjian, Hagop M. ; Garcia-Manero, Guillermo. / Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. In: Cancer. 2020 ; Vol. 126, No. 4. pp. 765-774.
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abstract = "Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5{\%}. Results: A total of 71 patients (17{\%}) had ASXL1 mutations, 104 patients (25{\%}) had DNMT3A mutations, 16 patients (4{\%}) had JAK2 mutations, 82 patients (20{\%}) had TET2 mutations, and 86 patients (20{\%}) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31{\%} (range, 1.17{\%}-58.62{\%}), the median VAF of DNMT3A was 41.76{\%} (range, 1.02{\%}-91.66{\%}), the median VAF of JAK2 was 46.70{\%} (range, 10.4{\%}-71.7{\%}), the median VAF of TET2 was 42.78{\%} (range, 2.26{\%}-95.32{\%}), and the median VAF of TP53 was 45.47{\%} (range, 1.15{\%}-93.74{\%}). The composite complete response rate was 60{\%}, and was 77{\%} in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P =.006); the median overall survival was 11 months and 27 months, respectively (P <.001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival. Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML.",
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author = "Koji Sasaki and Rashmi Kanagal-Shamanna and Guillermo Montalban-Bravo and Rita Assi and Elias Jabbour and Farhad Ravandi and Tapan Kadia and Sherry Pierce and Koichi Takahashi and {Nogueras Gonzalez}, Graciela and Keyur Patel and Soltysiak, {Kelly A.} and Jorge Cortes and Kantarjian, {Hagop M.} and Guillermo Garcia-Manero",
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TY - JOUR

T1 - Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia

AU - Sasaki, Koji

AU - Kanagal-Shamanna, Rashmi

AU - Montalban-Bravo, Guillermo

AU - Assi, Rita

AU - Jabbour, Elias

AU - Ravandi, Farhad

AU - Kadia, Tapan

AU - Pierce, Sherry

AU - Takahashi, Koichi

AU - Nogueras Gonzalez, Graciela

AU - Patel, Keyur

AU - Soltysiak, Kelly A.

AU - Cortes, Jorge

AU - Kantarjian, Hagop M.

AU - Garcia-Manero, Guillermo

PY - 2020/2/15

Y1 - 2020/2/15

N2 - Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%. Results: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P =.006); the median overall survival was 11 months and 27 months, respectively (P <.001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival. Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML.

AB - Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML). Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%. Results: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P =.006); the median overall survival was 11 months and 27 months, respectively (P <.001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival. Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML.

KW - ASXL1

KW - DNMT3A

KW - JAK2

KW - TET2

KW - TP53

KW - acute myeloid leukemia

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U2 - 10.1002/cncr.32566

DO - 10.1002/cncr.32566

M3 - Article

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AN - SCOPUS:85075500054

VL - 126

SP - 765

EP - 774

JO - Cancer

JF - Cancer

SN - 0008-543X

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