Enasidenib and ivosidenib in AML

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Isocitrate dehydrogenases (IDH1/2) are crucial enzymes in cellular metabolism, producing NADPH.
• Mutations in IDH1/2 are prevalent in acute myeloid leukemia (AML), conferring neomorphic activity.
• Mutant IDH enzymes generate R-2-hydroxyglutarate (R-2-HG), an oncometabolite that disrupts cellular functions and promotes leukemia.

Purpose of the Study:

• To discuss the role of IDH mutations in AML pathogenesis.
• To highlight the therapeutic potential of targeting mutant IDH enzymes.
• To review the clinical efficacy of IDH inhibitors in AML treatment.

Main Methods:

• Analysis of IDH enzyme function and mutation-associated metabolic alterations.
• Evaluation of R-2-HG production and its impact on cellular differentiation.
• Review of clinical trial data for IDH inhibitors (enasidenib, ivosidenib) in AML.

Main Results:

• Mutant IDH enzymes exhibit neomorphic activity, producing the oncometabolite R-2-HG.
• High levels of R-2-HG interfere with αKG-dependent enzymes, leading to blocked differentiation.
• Inhibition of mutant IDH enzymes reduces R-2-HG and restores myeloid differentiation.
• Enasidenib and ivosidenib demonstrate clinical activity in relapsed/refractory AML.

Conclusions:

• Targeting mutant IDH1/2 enzymes represents a promising therapeutic strategy in AML.
• IDH inhibitors like enasidenib and ivosidenib are effective as single agents for R/R AML.
• Combinatorial therapies involving IDH inhibitors may further enhance treatment outcomes in AML.