Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Schlenk, Richard F.; Döhner, Konstanze; Krauter, Jürgen; Fröhling, Stefan; Corbacioglu, Andrea; Bullinger, Lars; Habdank, Marianne; Späth, Daniela; Morgan, Michael; Benner, Axel; Schlegelberger, Brigitte; Heil, Gerhard; Ganser, Arnold; Döhner, Hartmut

doi:10.1056/nejmoa074306

Cited by 1,628Acute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processesChronic Myeloid Leukemia Treatments

Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Schlenk, Richard F., Döhner, Konstanze, Krauter, Jürgen, Fröhling, Stefan, Corbacioglu, Andrea, Bullinger, Lars, Habdank, Marianne, Späth, Daniela +6 more·2008·New England Journal of Medicine

DOI 10.1056/nejmoa074306

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Abstract

BACKGROUND: Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein alpha gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients. METHODS: We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation. RESULTS: A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD. CONCLUSIONS: Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML.

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NPM1 is one of the most commonly mutated genes in AML, occurring in approximately 50% of adult and 20% of childhood AML with normal karyotypes.
“Nucleophosmin (NPM1) is one of the most commonly mutated genes in AML, occurring in approximately 50% of adult and 20% of childhood AML with normal karyotypes [193, 194].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [194]

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Authors: Schlenk, R. F., Döhner, K., Krauter, J., Fröhling, S., Corbacioglu, A., Bullinger, L., Habdank, M., Späth, D., Morgan, M., Benner, A., Schlegelberger, B., Heil, G., Ganser, A., & Döhner, H.
Affiliations: University Hospital Ulm (DE)
Medizinische Hochschule Hannover (DE)
German Cancer Research Center (DE)
ORCID: Schlenk, Richard F.
Döhner, Konstanze
Fröhling, Stefan
Bullinger, Lars
Benner, Axel
Schlegelberger, Brigitte
Ganser, Arnold
Döhner, Hartmut
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2008-05
Volume: 358
Issue: 18
Pages: 1909-1918
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa074306
OpenAlex: W2043216151
Cited by: 1,628
References: 45
Citations by year: 2026: 19 · 2025: 28 · 2024: 32 · 2023: 56 · 2022: 56 · 2021: 59 · 2020: 65 · 2019: 87 · 2018: 64 · 2017: 92 · 2016: 98 · 2015: 123 · 2014: 130 · 2013: 123 · 2012: 156
FWCI: 94.50
Type: journal article
Language: en
Open access: closed
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
Keywords: cytogenetically normal acute myeloid leukemia, NPM1 mutation, FLT3-ITD, FLT3 tyrosine kinase domain mutation, CEBPA mutation, MLL partial tandem duplication, NRAS mutation, complete remission, relapse risk, overall survival, HLA-matched related donor, allogeneic hematopoietic stem cell transplantation, post-remission therapy
MeSH terms: Nucleophosmin, Adolescent, Adult, Female, Genetic Markers, Genotype, Humans, Male, Middle Aged, Mutation, Nuclear Proteins, Oncogene Proteins, Viral, Remission Induction, Leukemia, Myeloid, Acute, Treatment Outcome, CCAAT-Enhancer-Binding Protein-alpha, Stem Cell Transplantation, Myeloid-Lymphoid Leukemia Protein, fms-Like Tyrosine Kinase 3, Kaplan-Meier Estimate

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Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

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