Mutations in the genes encoding IDH1 and IDH2 were first reported in human gliomas in 2008 and later on also identified in a minority of patients with acute myeloid leukemia.
Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML.
IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation.
To evaluate the prognostic value of genetic mutations for acute myeloid leukemia (AML) patients, we examined the gene status for both fusion products such as AML1 (CBFα)-ETO, CBFβ-MYH11, PML-RARα, and MLL rearrangement as a result of chromosomal translocations and mutations in genes including FLT3, C-KIT, N-RAS, NPM1, CEBPA, WT1, ASXL1, DNMT3A, MLL, IDH1, IDH2, and TET2 in 1185 AML patients.
These findings supported initiation of the ongoing clinical trials of AG-221 in patients with <i>IDH2</i> mutation-positive advanced hematologic malignancies.<b>Significance:</b> Mutations in <i>IDH1/2</i> are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation.
For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia.
The analysis of these mutations in AML patients is of great importance as a prognostic factor due to their impact on survival and their use as potential therapeutic targets or as targets of inhibitors of IDH1(Ivosidenib, Tibsovo) and IDH2 (Enasidenib, Idhifa).
Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis.
The measurement of D-2-hydroxyglutarate in peripheral blood may be used as a biomarker for screening and follow-up of patients with IDH-mutated acute myeloid leukemia.
DNMT3A(mut) were found in 20.9% of AMLs and were associated with older age (P < .0001), higher white blood cell counts (P < .0001), cytogenetically normal AML (CN-AML; P < .0001), NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and IDH1/2 mutations (P < .0001).
Mutations of IDH1 and IDH2, which produce the oncometabolite 2-hydroxyglutarate (2HG), have been identified in several tumors, including acute myeloid leukemia.
Recurrent somatic mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes that result in the accumulation of D-2-hydroxyglutarate (D-2-HG) have been identified in malignant gliomas and in acute myeloid leukemia (AML).
Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.