Location and type of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia

Koszarska, Magdalena and Bors, Andras and Feczko, Angela and Meggyesi, Nóra and Batai, Arpad and Csomor, Judit and Adam, Emma and Kozma, Andras and Orbán, Tamás I. and Lovas, Nora and Matrai, Zoltan and Sipos, Andrea and Karaszi, Eva and Dolgos, Janos and Fekete, Sandor and Reichardt, Judit and Lehoczky, Eniko and Masszi, Tamas and Tordai, Attila and Andrikovics, Hajnalka (2013) Location and type of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia. LEUKEMIA&LYMPHOMA, 54 (5). pp. 1028-1035. ISSN 1042-8194

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Abstract

Background: Mutations of isocitrate dehydrogenase 1 and 2 are novel common genetic alterations identified in acute myeloid leukemia. Aims: To investigate the frequency, clinical associations and prognostic effect of isocitrate dehydrogenase 1 and 2 mutations together, followed by a detailed investigation of particular mutations. Methods: A consecutive cohort of 376 patients diagnosed with acute myeloid leukemia were enrolled to compare clinical characteristics. Prognostic impact was analyzed for 314 patients younger than 60 years treated with curative intention. Isocitrate dehydrogenase 1 and 2 mutations were screened using allele-specific PCR and high resolution melting, followed by a confirmatory sequencing. Results: Isocitrate dehydrogenase (IDH) 1 and 2 mutations were mutually exclusive, detected in 8.5% and 7.5% of the cases respectively. Presence of mutations was associated with older age (p=0.001), higher platelet count (p=0.001), intermediate risk karyotype (p<0.0001), nucleophosmin1 mutation (p=0.022), and with lower mRNA expression level of ABCG2 gene (p=0.006), as compared to mutation negative cases. Remission, relapse rates and overall survival were not different in IDH-mutation positive patients. Interestingly, particular mutations differred in association with nucleophosmin1 mutation: co-occurrence was observed in 14.3% of R132C vs. 70% of R132H carriers (p=0.02); and in 47.4% of R140Q vs. 0% R172K carriers (p=0.02) of IDH1 and IDH2 genes, respectively. R132H negatively influenced overall survival compared to isocitrate dehidrogenase 1 and 2 negative (p=0.02) or to R132C (p=0.019) patients. Conclusions: IDH mutations are frequent recurrent mutations in acute myeloid leukemia. Although a general common pathogenetic role is proposed, our results indicate that differences in clinical characteristics and treatment outcome may exist among disctinct mutations of both genes.

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