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Acute Myeloid Leukemia |
1 Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
2 Department of Internal Medicine II, University of Kiel, Kiel, Germany
3 Department of Internal Medicine III, Klinikum rechts der Isar, University of Munich, Munich, Germany
4 Department of Internal Medicine I, University of Homburg, Germany
5 Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany
6 Department of Internal Medicine I, Krankenhaus der Barmherzigen Brüder, Trier, Germany
7 Department of Internal Medicine III, Hanuschkrankenhaus, Vienna, Austria
8 Department of Internal Medicine II, Klinikum; Karlsruhe, Karlsruhe, Germany
9 Central Unit Biostatistics, German Cancer Research Center, Heidelberg, Germany
Correspondence: Richard F. Schlenk, Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany. E-mail:richard.schlenk{at}uniklinik-ulm.de
Background: In a previous randomized trial, AML HD98B, we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with acute myeloid leukemia. The objectives of this study were to evaluate the prognostic impact of gene mutations and to identify predictive genetic factors for the all-trans retinoic acid treatment effect.
Design and Methods: Data from mutation analyses of the NPM1, CEBPA, FLT3, and MLL genes were correlated with outcome in patients 61 years and older treated within the AML HD98B trial.
Results: The frequencies of mutations were: NPM1, 23%; CEBPA, 8.5% (analysis restricted to patients with a normal karyotype); FLT3 internal tandem duplications (ITD), 17%; FLT3 tyrosine kinase domain mutations, 5%; and MLL partial tandem duplications, 4.5%. The genotype mutant NPM1 was positively and adverse cytogenetics as well as higher white blood cell count negatively correlated with achievement of complete remission. In Cox regression analysis, a significant interaction between the genotype mutant NPM1 without FLT3-ITD and treatment with all-trans retinoic acid was identified, in that the beneficial effect of all-trans retinoic acid on relapse-free and overall survival was restricted to this subgroup of patients. Other significant factors for survival were age, adverse cytogenetics, and logarithm of white cell count.
Conclusions: In elderly patients with acute myeloid leukemia, NPM1 mutations are associated with achievement of complete remission, and the genotype ‘mutant NPM1 without FLT3-ITD’ appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy (ClinicalTrials.gov Identifier: NCT00151242).
Key words: acute myeloid leukemia, all-trans retinoic acid, nucleophosmin-1 mutation, predictive factor.
Related Article
Haematologica 2009 94: 10-16.
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