II. Indications
- Acute Myelogenous Leukemia (IDH1/2+ new or advanced/refractory)
III. Mechanism
- Isocitrate Dehydrogenase (IDH)
- Isocitrate Dehydrogenase is a cytoplasmic enzyme that decarboxylating isocitrate to alpha ketoglutarate
- Rate limiting step of the TCA Cycle (Kreb Cycle)
- Isocitrate Dehydrogenase (IDH) has 3 forms with the same activity (the first 2 are associated with cancers)
- IDH1 is found in cytoplasm (and encoded by gene 2q33)
- IDH2 is found in mitochondria (and encoded by gene 15q26)
- IDH1 Mutations
- Associated with Acute Myelogenous Leukemia (similar to IDH2)
- In contrast to IDH2, IDH1 is also associated with other cancers (e.g. glioblastoma, low grade gliomas)
- Triggers abnormal levels of 2-Hydroxyglutarate (2-HG)
- 2-HG inhibits histone and DNA demethylases
- Alters gene expression, and may promote cancer growth
IV. Medications
- Ivosidenib (Tibsovo)
- Risk of Differentiation Syndrome, Prolonged QTc, Guillain Barre Syndrome
- Avoid with high fat meals (increased risk of toxicity)
V. Dosing
- See other references for disease specific dosing protocols
VI. Safety
- Avoid in Lactation
- Avoid in pregnancy (all trimesters, pregnancy category X)
- Use reliable Contraception
- Monitoring
VII. Adverse Effects
- Differentiation Syndrome (Ivosidenib)
- Life threatening condition, rapid myeloid cell proliferation and differentiation
- May present with acute respiratory distress, Acute Kidney Injury, fever, edema
- Onset in the first 10 weeks of therapy requiring prompt initiation of Corticosteroids
-
Prolonged QTc (Ivosidenib)
- Avoid in known QTc Prolongation or Serum Electrolyte abnormalities (Hypomagnesemia, Hypokalemia)
- Avoid with other Medication Causes of QTc Prolongation
- Guillain Barre Syndrome (Ivosidenib)
- Other reported adverse effects
- Edema
- Hepatotoxicity
VIII. Drug Interactions
- Strong CYP3A4 Inhibitors
- Decrease Ivosidenib dose
- Strong CYP3A4 Inducers
- Avoid with Ivosidenib
-
CYP3A4 substrates with narrow Therapeutic Index
- Avoid with Ivosidenib
-
Medication Causes of QTc Prolongation
- Avoid with Ivosidenib