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

5 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    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, K. A., Cortes, J., Kantarjian, H. M., & 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