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2 minute read
Acute myeloid leukemia (AML) is the most common leukemia among adults and has been challenging to treat with modern therapies.1, 2 This disease is highly heterogeneous and characterized by the rapid proliferation of undifferentiated myeloid cells that accumulate within the bone marrow. Several mutations and epigenetic abnormalities characteristic of AML have been targeted through chemotherapies or molecular inhibitors. Fortunately, the relentless pursuit of innovative, effective AML therapies has led to a deeper understanding of AML pathogenesis, such as the role of isocitrate dehydrogenase (IDH) mutations.3 IDH mutations have unique properties that, if properly targeted, may reshape AML patient outcomes and survival rates.
Unstable Gene Expression
The IDH family consists of three isoenzymes (IDH1, IDH2, and IDH3) and has an important role in the biosynthesis of metabolites involved in the tricarboxylic acid (TCA) cycle. Notably, IDH1 functions as a catalyst for reversible conversion of isocitrate to α-ketoglutarate in the cytosol as well as peroxisomes, yielding 1 NADPH. Downstream, α-ketoglutarate is reduced to D-2-hydroxyglutarate (D-2-HG) as part of the TCA cycle.3 Mutations in IDH1 are present in ~20% of AML patients and result from a single amino acid substitution at Arg132.4 This mutation induces an end-product shift that reduces α-ketoglutarate to R-2-HG instead. Unlike D-2-HG, R-2-HG competitively inhibits α-ketoglutarate-dependent enzymes, such as the TET family, and upon accumulation leads to impaired cellular differentiation and deregulation of DNA methylation. 3, 5 This alteration of DNA methylation and ultimately gene expression activates oncogenes and deactivates tumor-suppressor genes.6 The destabilizing features of IDH1 mutants have thus made this isoenzyme an interesting target for AML therapies.
IDH Focused Therapies
Since the identification of IDH mutations in 2008, the Food and Drug Administration (FDA) has approved two therapeutics for AML patients with IDH mutations, ivosidenib and enasidenib. Ivosidenib is a reversible, selective inhibitor that binds to the active site of mutated IDH1 to prevent the production of R-2-HG.7, 8, 9 Reduction in R-2-HG reportedly increases D-2-HG concentrations by 100x and restores DNA methylation and cellular differentiation in AML patients.10, 11 Though successful, resistance to ivosidenib and IDH inhibition has emerged, underlining the need for combination therapies that prevent IDH resistance.12
Triplet Therapy
There are no triplet regimens currently approved for use in AML, however, clinical trial results have demonstrated successful remission in relapsed and naïve AML patients.13, 14 For instance, an ongoing phase Ib/II study examining ivosidenib and venetoclax with or without azacytidine has shown successful remission in patients with AML IDH1 mutations.13 The durable response to this therapy is especially promising, as the safety profile of this triplet therapy is similar to doublet therapies such as azacytidine + venetoclax and azacytidine + ivosidenib.13, 15 The median event-free-survival (EFS) for patients treated with this new triplet therapy was 36 months13, while previous azacytidine + ivosidenib combination treatments have achieved median EFS or 24 months.16
The Therapeutic Pipeline
Prolonged EFS in AML patients receiving ivosidenib in combination with AML standards of care, such as venetoclax and azacytidine, has recently gained the attention of the European Commission (EC). In 2023, the EC announced the approval of ivosidenib in combination with azacitidine for AML patients with an IDH1 R132 mutation.18 Further, clinical studies evaluating the side effects and appropriate dosages of ivosidenib and venetoclax with or without azacytidine are underway. As more clinical data is released, access to more robust therapeutic treatments will become available to improve AML patient outcomes.
