P099 | MOLECULAR CHARACTERIZATION OF IDH1 AND IDH2 MUTATIONS IN SARDINIAN PATIENTS WITH ACUTE MYELOID LEUKEMIA PATIENTS: IDENTIFICATION OF RARE VARIANTS AND DOUBLE MUTATIONS

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations are well-recognized molecular events in acute myeloid leukemia (AML), and they occur at variable frequencies across different populations. In this single-center study, we analyzed Sardinian patients diagnosed with AML over the past 12 months at the Hematology and Bone Marrow Transplant Unit of the Businco Hospital in Cagliari Italy, using EasyPGX ready IDH1-2 assay. Overall, 36 consecutive newly diagnosed patients with AML were analyzed: 15, 41.6% were classified as AML with defining genetic abnormalities, and 21, 58.4% as AML, defined by differentiation. Nineteen (52.8%) patients underwent intensive chemotherapy, and 17, 47.2% less intensive treatment, mainly represented by the association of venetoclax and azacitidine. IDH1/2 mutations were detected in 14 out of 36 patients 38.9%, with a higher frequency than reported in the literature, where IDH1 mutations are found in 6-7% and IDH2 mutations in 8-10% of AML cases. Among the variants detected, the synonymous IDH1 G105G mutation was identified in 10 out of 36 patients 27.8%, an unexpectedly high frequency. This SNP (rs11554137), generally considered a polymorphism, has been described in approximately 10-15% of patients with diffuse gliomas and only rarely in AML, with an estimated frequency below 1.5%. Although its functional impact remains unclear, a possible role in splicing or gene regulation has been hypothesized. The point mutations observed in our cohort were consistent with the literature: IDH1 R132H in 2/36 patients (5.6%; literature 6-7%), IDH2 R140Q in 2/36 (5.6%; expected about 10%), and IDH2 R172K in 3/36 (8.3%; expected about 2-3%). Three patients harbored double mutations, including one case with co-occurrence of IDH1 G105G and R132H, previously reported in the literature, and two cases with simultaneous IDH1 G105G and IDH2 R172K mutations. This latter combination is extremely rare and not commonly described. Previous studies suggest mutual exclusivity between IDH1 and IDH2 mutations in the same leukemia, and the absence of reported cases with concurrent IDH1 G105G and IDH2 R172K highlights the uniqueness of our finding. These data suggest a potential molecular peculiarity of the Sardinian AML population and underscore the importance of comprehensive molecular profiling. More extensive cohort studies will be essential to better define the biological and prognostic implications of the observed mutations, particularly IDH1 G105G.