Molecular profiling of patients with cytogenetically normal acute myeloid leukemia and hyperleukocytosis

Cancer. 2022 Dec 15;128(24):4213-4222. doi: 10.1002/cncr.34495. Epub 2022 Oct 22.


Background: Acute myeloid leukemia (AML) with initial hyperleukocytosis is associated with high early mortality and a poor prognosis. The aims of this study were to delineate the underlying molecular landscape in the largest cytogenetic risk group, cytogenetically normal acute myeloid leukemia (CN-AML), and to assess the prognostic relevance of recurrent mutations in the context of hyperleukocytosis and clinical risk factors.

Methods: The authors performed a targeted sequencing of 49 recurrently mutated genes in 56 patients with newly diagnosed CN-AML and initial hyperleukocytosis of ≥100 G/L treated in the AMLCG99 study. The median number of mutated genes per patient was 5. The most common mutations occurred in FLT3 (73%), NPM1 (75%), and TET2 (45%).

Results: The predominant pathways affected by mutations were signaling (84% of patients), epigenetic modifiers (75% of patients), and nuclear transport (NPM1; 75%) of patients. AML with hyperleukocytosis was enriched for molecular subtypes that negatively affected the prognosis, including a high percentage of patients presenting with co-occurring mutations in signaling and epigenetic modifiers such as FLT3 internal tandem duplications and TET2 mutations.

Conclusions: Despite these unique molecular features, clinical risk factors, including high white blood count, hemoglobin level, and lactate dehydrogenase level at baseline, remained the predictors for overall survival and relapse-free survival in hyperleukocytotic CN-AML.

Keywords: acute myeloid leukemia (AML); hyperleukocytosis; molecular profiling; normal karyotype.

MeSH terms

  • Humans
  • Leukemia, Myeloid, Acute* / therapy
  • Mutation
  • Nuclear Proteins* / genetics
  • Nucleophosmin
  • Prognosis
  • fms-Like Tyrosine Kinase 3 / genetics


  • Nuclear Proteins
  • Nucleophosmin
  • fms-Like Tyrosine Kinase 3