PROGNOSTIC IMPACT OF ISOCITRATE DEHYDROGENASE ENZYME ISOFORMS IDH1 & IDH2 MUTATIONS IN ACUTE MYELOID LEUKEMIA

Abstract

Background: IDH1 & 2 mutations are one of the most common genomic abnormalities which have recently been described in acute myeloid leukemia (AML) patients. Mutant IDH1/2 enzymes have neomorphic activity and catalyze the reduction of ketoglutarate to an oncometabolite, which promotes DNA and histone hypermethylation, altered gene expression, and impaired hematopoietic differentiation. Aim of the work:To evaluate the prognostic impact of both IDH1 and IDH2 mutations in newly diagnosed AML patients and their correlation with different clinical and laboratory parameters. Patients and Methods: The present study was conducted on 56 de novo adult AML patients who attended Haematology/Oncology unit of Ain-Shams University Hospitals during the period from July 2017 till July 2018. They were assessed for the presence of IDH 1& 2 SNP mutations using Real-Time PCR Patients with MDS, biphenotypic leukemia and associated malignancy were excluded from our study. Results: Heterozygous mutations of IDH1 SNP rs11554137& IDH2R140Q SNP were detected in a percentage of 14.3% and 16.1% respectively. Upon assessing the clinical outcome at day 28, mutant IDH2R140Q SNP group showed significant unfavourable outcome(p=0.045). While at 6 months, all patients with IDH1 SNP rs11554137mutation died and seven out of nine patients with mutant IDH2R140Q died,so IDH1 SNP rs11554137 showed significant unfavourable outcome at 6 months(p=0.016).The survivors showed significantly younger age, lower mean platelets and blast counts, as well as negative IDH1 SNP rs11554137 (p= 0.014, 0.046, 0.009 and 0.016 respectively)Multivariate logistic regression analysis identified high BM blasts percentage as an independent prognostic predictor for 6 month mortality ( p=0.014, OR 1.049, 95% CI 1.010 to 1.090). Conclusion: IDH1 SNP rs11554137 in CN-AML is associated with unfavourable clinical outcome and worse DFS at 6months,and was univariate factor in non survivors patients.while IDH2R140Q was associated with unfavourable clinical outcome at day28 after induction.Including IDH1&IDH2 mutations in AML routine gene panel,will be valuable for prognostication.