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Kovy, P.1; Kozma, A.1; Adam, E.1; Borsy, A.1; Bors, A.1; Meggyesi, N.1; Dolgos, J.2; Lovas, N.2; Mikala, G.2; Remenyi, P.2; Andrikovics, H.1

doi: 10.1097/01.HS9.0000562464.12241.81
Poster Session II: Acute myeloid leukemia - Clinical

1Laboratory of Molecular Genetics

2Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Budapest, Hungary

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Isocitrate dehydrogenase 1/2 (IDH1/2) enzymes catalyse the oxidative decarboxylation of isocitrate to α-ketoglutarate. IDH1 or 2 mutations results in the production of 2-hydroxyglutarate instead of α-ketoglutarate with consequential DNA hypermethylation. These mutations are found in solid tumours and haematological disorders as well. It is unclear, whether IDH mutations represent pre-leukemic or leukemic-driver mutations. They occur at low frequency in MDS or MPN with high leukemic transformation rate. Some IDH mutations are frequently associated with well-defined AML-drivers like nucleophosmin1 (NPM1) mutations.

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In our study, first we investigated (i) the frequency and the associations of IDH mutations with other mutations and cytogenetic alterations, and (ii) the stability of IDH1/2 mutations in samples drawn at diagnosis and relapse in acute myeloid leukaemia (AML) patients.

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We analysed 748 AML patients diagnosed between January 2001 and May 2018 at our single centre. Karyotyping and fluorescent in situ hybridisation were performed by standard techniques. NPM1 and fms-like tyrosine kinase internal tandem duplication (FLT3-ITD) mutations were analysed by fragment analysis, the FLT3 tyrosine kinase domain (FLT3-TKD) mutations by restriction fragment length polymorphism. IDH mutations were tested by high resolution melting, allele specific PCR and Sanger sequencing.

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In the cohort with 748 AML patients, the IDH1 mutation was 8.6% (R132H:28/64, R132C:26/64, other R132:10/64) and the IDH2 mutation was 11% (R140Q:65/82, R172K:17/82). IDH1 R132 and IDH2 R140Q mainly associated with normal karyotype [IDH1 R132: 58.3% (28/48; p = 0.0135), IDH2 R140Q 67.3% (33/49; p = 0.0002) versus IDH1/2 negatives 39.3% (197/501)]. IDH2 R172K associated with intermedier, but not normal karyotype [70.6% (12/15) in comparison with IDH1/2 negative AML patients 9.4% (47/501); p < 0.0001]. In IDH negative cases NPM1 occurred in 24.3% (146/600). The IDH1 R132H and R132C were associated with NPM1 mutation in 85.7% (24/28) and 15.4% (4/26) (p < 0.0001 R132H versus R132C or IDH-negative cases) respectively. In contrast to IDH2 R140Q co-occurring with NPM1 in 49.2% (32/65), IDH2 R172K is not associated with NPM1 (0/17) at all (p = 0.0001). The mutant IDH1 R132 and IDH2 R140Q was associated with FLT3-ITD in (20.3%, 13/64; 26.2% 17/65), and FLT3-TKD in (11.5% 7/61; 6.3% 4/64) of the cases respectively. In IDH2 R172K-positive cases no FLT3-ITD or TKD mutations were detectable. The IDH1 was constantly present in 96.3% (102/106), the IDH2 in 97.3% (111/114) of diagnosis and relapse sample pairs. Progression (the appearance of IDH mutation at relapse) was observed in 2 cases, while regression (the disappearance of mutation at relapse) in 5 cases.

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Our study confirmed that IDH mutations are frequent genetic alterations in AML (19.6%). Although IDH1/2 mutations are frequently associated with normal or intermedier risk karyotype, and NPM1 mutations, markedly different co-occurrence patterns were observed between different IDH mutations (IDH1 R132C vs. R132H or IDH2 R140Q vs. R172K). The stabile presentations of IDH mutations in diagnosis and relapse sample pairs suggest an early development of IDH mutations in AML multistep pathogenesis in majority of AML cases.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.