Class: Oral, selective IDH2 inhibitor
Indication
- Relapsed or refractory AML with a susceptible IDH2 mutation (R140Q or R172K).
- Approved for adults (NCCN, FDA).
- Not frontline (unless in clinical trials).
Mechanism of Action
- Mutant IDH2 produces 2-hydroxyglutarate (2-HG), an oncometabolite that blocks cellular differentiation.
- Enasidenib inhibits mutant IDH2 → reduces 2-HG → restores differentiation of leukemic blasts.
Dose
- 100 mg orally once daily (with or without food).
- Continue until progression or unacceptable toxicity.
- Treatment may take several months to show response (median ~3–4 months).
Key Adverse Effects
- Differentiation syndrome (can be life-threatening):
- Fever, dyspnea, weight gain, pulmonary infiltrates, effusions, hypotension.
- Treat promptly with dexamethasone 10 mg IV q12h and supportive care (hold enasidenib if severe).
- Indirect hyperbilirubinemia (common, usually not hepatic injury → due to UGT1A1 inhibition).
- Leukocytosis (manage with hydroxyurea if symptomatic).
- Other: Nausea, diarrhea, fatigue, decreased appetite, electrolyte abnormalities.
Monitoring
- CBC and blood chemistries (esp. bilirubin, electrolytes).
- Monitor for differentiation syndrome signs/symptoms throughout therapy.
- Assess IDH2 mutation status with an FDA-approved test before starting.
Clinical Notes
- Responses may be delayed → do not stop early unless progression/toxicity.
- Often used as a bridge to transplant in eligible patients.
- Oral administration makes it more convenient than IV options.
Summary:
Enasidenib is an oral IDH2 inhibitor used in relapsed/refractory AML with IDH2 mutation. Its hallmark risk is differentiation syndrome, which requires high suspicion and prompt steroids.