Isocitrate Dehydrogenase (IDH) 1 and 2 are enzymes that, when mutated, produce an oncometabolite called 2-hydroxyglutarate (2-HG). This molecule blocks the normal differentiation of myeloid cells, causing them to remain in an immature, leukemic state.
Clinical Significance
- Predictive Biomarkers: Mutations in IDH1 and IDH2 are generally mutually exclusive and serve as critical targets for FDA-approved therapies.
- Targeted Therapies:
- IDH1 Inhibitors: Ivosidenib and Olutasidenib.
- IDH2 Inhibitor: Enasidenib.
- Treatment Settings: These agents are used for relapsed/refractory (R/R) disease or for newly diagnosed patients who are ineligible for intensive chemotherapy due to age ($\ge 75$) or comorbidities. Notably, Ivosidenib is also FDA-approved for R/R MDS.
Therapeutic Protocols
For patients with an IDH1 mutation who are unfit for intensive therapy, the combination of Ivosidenib plus Azacitidine is a Category 1 recommendation, having shown superior overall survival and complete remission rates compared to Azacitidine alone.
Key Toxicities
Managing these agents requires monitoring for several high-yield adverse effects:
- Differentiation Syndrome (Black Box Warning): Occurs as leukemic cells are forced to mature. It is managed with immediate dexamethasone 10 mg IV every 12 hours and potential drug interruption if symptoms are severe.
- IDH1-Specific (Ivosidenib): Requires weekly ECGs initially due to the risk of QTc prolongation.
- IDH2-Specific (Enasidenib): Often causes indirect hyperbilirubinemia due to off-target inhibition of UGT1A1; this is typically not a sign of liver toxicity.
- Leukocytosis: Both can cause rapid myeloid proliferation, which may require temporary management with hydroxyurea.
Synonyms
Isocitrate Dehydrogenase