What are IDH1/2?
- Isocitrate Dehydrogenase 1 and 2 (IDH1/2) are metabolic enzymes that normally convert isocitrate to α-ketoglutarate (α-KG) in the TCA cycle.
- Mutations in *IDH1/2* (gain-of-function) cause production of 2-hydroxyglutarate (2-HG), an oncometabolite that disrupts epigenetics and blocks cell differentiation.
Key Features in AML
| Feature | IDH1 (R132) | IDH2 (R140/R172) |
|---|---|---|
| Frequency | ~7% of AML | ~10% of AML |
| Prognosis | Intermediate | Intermediate (R140 favorable) |
| Targeted Therapy | Ivosidenib (IDH1 inhibitor) | Enasidenib (IDH2 inhibitor) |
Clinical Impact
- Diagnosis: Tested via NGS or PCR at AML diagnosis (often co-occurs with NPM1 or *FLT3-ITD*).
- Treatment:
- Single-agent inhibitors (ivosidenib/enasidenib) for relapsed/refractory AML.
- Combination trials with chemotherapy or venetoclax (e.g., ivosidenib + azacitidine).
- Side Effects:
- Differentiation syndrome (like ATRA syndrome in APL; treat with steroids).
- QT prolongation (ivosidenib).