Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

doi:10.1056/NEJMoa074306

Volume 358:1909-1918		May 1, 2008		Number 18

Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Richard F. Schlenk, M.D., Konstanze Döhner, M.D., Jürgen Krauter, M.D., Stefan Fröhling, M.D., Andrea Corbacioglu, Ph.D., Lars Bullinger, M.D., Marianne Habdank, Daniela Späth, Michael Morgan, Ph.D., Axel Benner, M.Sc., Brigitte Schlegelberger, M.D., Gerhard Heil, M.D., Arnold Ganser, M.D., Hartmut Döhner, M.D., for the German–Austrian Acute Myeloid Leukemia Study Group

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ABSTRACT

Background Mutations occur in several genes in cytogeneticallynormal acute myeloid leukemia (AML) cells: the nucleophosmingene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3),the CCAAT/enhancer binding protein ${alpha}$ gene (CEPBA), the myeloid–lymphoidor mixed-lineage leukemia gene (MLL), and the neuroblastomaRAS viral oncogene homolog (NRAS). We evaluated the associationsof 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 clinicaloutcome in 872 adults younger than 60 years of age with cytogeneticallynormal AML. Patients had been entered into one of four trialsof therapy for AML. In each study, patients with an HLA-matchedrelated donor were assigned to undergo stem-cell transplantation.

Results A total of 53% of patients had NPM1 mutations, 31% hadFLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosinekinase–domain mutations, 13% had CEBPA mutations, 7% hadMLL partial tandem duplications (PTDs), and 13% had NRAS mutations.The overall complete-remission rate was 77%. The genotype ofmutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, andyounger age were each significantly associated with completeremission. Of the 663 patients who received postremission therapy,150 underwent hematopoietic stem-cell transplantation from anHLA-matched related donor. Significant associations were foundbetween the risk of relapse or the risk of death during completeremission 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, 0.30to 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 anHLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44to 0.82). The benefit of the transplant was limited to the subgroupof patients with the prognostically adverse genotype FLT3-ITDor the genotype consisting of wild-type NPM1 and CEBPA withoutFLT3-ITD.

Conclusions Genotypes defined by the mutational status of NPM1,FLT3, CEBPA, and MLL are associated with the outcome of treatmentfor patients with cytogenetically normal AML.

Source Information

From the University Hospital of Ulm, Ulm (R.F.S., K.D., S.F., A.C., L.B., M.H., D.S., H.D.); Hannover Medical School, Hannover (J.K., M.M., B.S., G.H., A.G.); and the German Cancer Research Center, Heidelberg (A.B.) — all in Germany.

Drs. Schlenk and K. Döhner contributed equally to the article, as did Drs. Ganser and H. Döhner.

Address reprint requests to Dr. H. Döhner at the Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Straße 8, 89081 Ulm, Germany, or at hartmut.doehner{at}uniklinik-ulm.de.

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N Engl J Med 2008; 359:651-653, Aug 7, 2008. Correspondence

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