Abstract
Acute myeloid leukemia is a genetically heterogeneous hematologic malignancy; approximately 20% of AML harbors a mutation in the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2. These recurrent mutations in key metabolic enzymes lead to the production of the oncometabolite 2-hydroxyglutarate, which promotes leukemogenesis through a block in normal myeloid differentiation. Since this discovery, selective oral inhibitors of mutant IDH1 and IDH2 have subsequently been developed and are now approved as single agent therapy, based on clinical efficacy observed within the original first-in-human trials. The investigation of IDH inhibitors in combination with standard therapies such as azacytidine, with intensive chemotherapy, and with other small molecule targeted therapies in rational combinations are currently under evaluation to further improve upon clinical efficacy.
Highlights
In concert with the sequencing of the first AML genome in 2008, the discovery of isocitrate dehydrogenase (IDH) mutations in AML was first described[1]
It is recognized that approximately 8% and 12% of acute myeloid leukemias harbor an IDH1 or IDH2 mutation, respectively, with IDH mutations present in a minority of other myeloid malignancies such as myelodysplastic syndrome (MDS) and accelerated myeloproliferative neoplasms (MPNs)[2,3]
Targeting IDH1 in AML Ivosidenib (TIBSOVO, formerly AG-120) is the first-inclass, selective and orally available mutant IDH1 inhibitor, with confirmed pre-clinical efficacy leading to robust 2HG inhibition and reinstatement of effective myeloid differentiation[26]
Summary
In concert with the sequencing of the first AML genome in 2008, the discovery of isocitrate dehydrogenase (IDH) mutations in AML was first described[1]. A azacytidine, V venetoclax, E Enasidenib, I Ivosidenib, Md age median age, yrs years, mo months, CR/CRi complete response/complete response with incomplete count recovery, mOS median overall survival, IDH Isocitrate Dehydrogenase, NR not reached, sAML secondary acute myeloid leukemia.
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