Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

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.

[1]  W. Hiddemann,et al.  Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. , 2005, Blood.

[2]  G. Ehninger,et al.  Analysis of Flt3-activating Mutations in 979 Patients with Acute Myelogenous Leukemia: Association with Fab Subtypes and Identification of Subgroups with Poor Prognosis , 2022 .

[3]  T. Naoe,et al.  Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis , 2005, Leukemia.

[4]  Hartmut Döhner,et al.  Acute myeloid leukaemia , 2006, The Lancet.

[5]  S. Fröhling,et al.  Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  C. Marshall,et al.  Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia , 1985, Nature.

[7]  R. Tibshirani,et al.  Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. , 2004, The New England journal of medicine.

[8]  C. Bloomfield,et al.  Cytogenetics in acute leukemia. , 2004, Blood reviews.

[9]  W. Hiddemann,et al.  Analysis of FLT 3 length mutations in 1003 patients with acute myeloid leukemia : correlation to cytogenetics , FAB subtype , and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease , 2002 .

[10]  Paola Fazi,et al.  Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. , 2005, The New England journal of medicine.

[11]  H. Kaneko,et al.  Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. , 1996, Leukemia.

[12]  C. Bloomfield,et al.  Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  M. Caligiuri,et al.  Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. , 2001, Cancer research.

[14]  M. Caligiuri,et al.  Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. , 1998, Cancer research.

[15]  Bob Löwenberg,et al.  Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. , 2005, Blood.

[16]  F. Schmidt.  Meta-Analysis , 2008 .

[17]  H. Dombret,et al.  Prognosis of inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of 110 cases from the French AML Intergroup. , 2003, Blood.

[18]  Bob Löwenberg,et al.  Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. , 2003, The hematology journal : the official journal of the European Haematology Association.

[19]  Stefan Fröhling,et al.  Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. , 2005, Blood.

[20]  J. Griffin,et al.  The roles of FLT3 in hematopoiesis and leukemia. , 2002, Blood.

[21]  C. Bloomfield,et al.  Influence of new molecular prognostic markers in patients with karyotypically normal acute myeloid leukemia: recent advances , 2007, Current opinion in hematology.

[22]  C. Nerlov.  C/EBPalpha mutations in acute myeloid leukaemias. , 2004, Nature reviews. Cancer.

[23]  Augustin Ferrant,et al.  Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? , 2007, Blood.

[24]  R. Hills,et al.  No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. , 2005, Blood.

[25]  C. Bloomfield,et al.  Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). , 2002, Blood.

[26]  C. Bloomfield,et al.  Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Pu Zhang,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia , 2001, Nature Genetics.

[28]  Sunil J Rao,et al.  Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis , 2003 .

[29]  C. Nerlov.  C/EBPα mutations in acute myeloid leukaemias , 2004, Nature Reviews Cancer.

[30]  S. Fröhling,et al.  CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Axel Benner,et al.  Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. , 2002, Blood.

[32]  K. Döhner,et al.  Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  M. Caligiuri,et al.  Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. , 1994, Cancer research.

[34]  G. Behre,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. , 2001, Nature genetics.

[35]  R. Verhaak,et al.  Prognostically useful gene-expression profiles in acute myeloid leukemia. , 2004, The New England journal of medicine.

[36]  Suzanne Schubbert,et al.  Deregulated Ras signaling in developmental disorders: new tricks for an old dog. , 2007, Current opinion in genetics & development.

[37]  Martin Dugas,et al.  Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. , 2002 .

[38]  J. Cayuela,et al.  Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). , 2002, Blood.

[39]  J. Radich,et al.  The role of FLT3 in haematopoietic malignancies , 2003, Nature Reviews Cancer.

[40]  Daniel J Sargent,et al.  Clinical trial designs for predictive marker validation in cancer treatment trials. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  K Wheatley,et al.  The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. , 1998, Blood.

[42]  Bob Löwenberg,et al.  Acute myeloid leukemia and acute promyelocytic leukemia. , 2003, Hematology. American Society of Hematology. Education Program.

[43]  S. Korsmeyer,et al.  The role of MLL in hematopoiesis and leukemia , 2002, Current opinion in hematology.

[44]  Gerhard Ehninger,et al.  Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). , 2006, Blood.

[45]  A. Mead,et al.  FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. , 2007, Blood.

[46]  Pier Paolo Pandolfi,et al.  Nucleophosmin and cancer , 2006, Nature Reviews Cancer.

[47]  山本 幸也,et al.  Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies , 2002 .