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Published on: September 20, 2016
Adverse impact of IDH1 and IDH2 mutations in primary AML: experience of the Spanish CETLAM group
J Nomdedéu1, M Hoyos, M Carricondo
1Hematology Department, Hosptial de Santa Creu i Sant Pau, Barcelona, Spain. jnomdedeu@santpau.es
Abstract:
The study of genetic lesions in AML cells is helpful to define the prognosis of patients with this disease. This study analyzed the frequency and clinical impact of recently described gene alterations, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations, in a series of homogeneously treated patients with primary (de novo) AML. Two-hundred and seventy-five patients enrolled in the CETLAM 2003 protocol were analyzed. IDH1 and IDH2 mutations were investigated by well-established melting curve-analysis and direct sequencing (R140 IDH2 mutations). To establish the percentage of the mutated allele a pyrosequencing method was used. Patients were also studied for NPM, FLT3, MLL, CEBPA, TET2 and WT1 mutations. IDH1 or IDH2 mutations were identified in 23.3% AML cases and in 22.5% of those with a normal karyotype. In this latter group, mutations were associated with short overall survival. This adverse effect was even more evident in patients with the NPM or CEBPA mutated/FLT3 wt genotype. In all the cases analyzed, the normal allele was detected, suggesting that both mutations act as dominant oncogenes. No adverse clinical impact was observed in cases with TET2 mutations. IDH1 and IDH2 mutations are common genetic alterations in normal karyotype AML. Favourable genotype NPM or CEBPA mutated/FLT3 wt can be further categorized according to the IDH1 and IDH2 mutational status.
Insights
Isocitrate dehydrogenase (IDH) mutations in acute myeloid leukemia (AML) are common, especially in normal karyotype AML. These IDH1 and IDH2 mutations are linked to shorter survival, particularly with specific genetic profiles.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Genetic lesions in acute myeloid leukemia (AML) are crucial for patient prognosis.
- Primary (de novo) AML requires analysis of specific gene alterations for better treatment outcomes.
Purpose of the Study:
- To investigate the frequency and clinical impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in primary AML.
- To determine if IDH1/IDH2 mutations affect overall survival in AML patients, particularly those with a normal karyotype.
Main Methods:
- Analysis of 275 primary AML patients from the CETLAM 2003 protocol.
- IDH1 and IDH2 mutations detected using melting curve analysis and direct sequencing; allele percentage determined by pyrosequencing.
- Additional mutations analyzed: NPM, FLT3, MLL, CEBPA, TET2, and WT1.
Main Results:
- IDH1 or IDH2 mutations were found in 23.3% of AML cases overall and 22.5% of normal karyotype AML.
- In normal karyotype AML, IDH1/IDH2 mutations correlated with shorter overall survival.
- This adverse effect was more pronounced in patients with NPM or CEBPA mutated/FLT3 wild-type (wt) genotypes.
- TET2 mutations showed no adverse clinical impact.
Conclusions:
- IDH1 and IDH2 mutations are frequent genetic alterations in normal karyotype AML.
- IDH1/IDH2 mutations can further stratify prognosis within favorable NPM or CEBPA mutated/FLT3 wt genotypes.
- The presence of the normal allele suggests IDH1/IDH2 mutations may function as dominant oncogenes.
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