Introduction
Idhifa (enasidenib) is an oral targeted therapy approved for the treatment of relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Developed by Celgene (now Bristol Myers Squibb), it represents a significant advancement in precision medicine for hematologic malignancies by specifically targeting the mutated IDH2 enzyme that drives leukemogenesis in this patient population.
Mechanism of Action
Enasidenib is a small molecule inhibitor that selectively targets mutant isocitrate dehydrogenase-2 (IDH2) enzymes. In AML patients with IDH2 mutations, these enzymes produce abnormally high levels of the oncometabolite 2-hydroxyglutarate (2-HG), which blocks normal hematopoietic differentiation and promotes leukemogenesis. Idhifa binds to and inhibits the mutant IDH2 enzyme, reducing 2-HG levels and allowing for differentiation of malignant myeloblasts into mature, functional myeloid cells. This differentiation effect distinguishes it from traditional cytotoxic chemotherapy.
Indications
Idhifa is FDA-approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation as detected by an FDA-approved test. The approval was based on results from a single-arm phase 1/2 clinical trial (AG221-C-001) that demonstrated complete remission (CR) or complete remission with partial hematologic recovery (CRh) in patients with IDH2-mutated AML.
Dosage and Administration
Standard dosing: 100 mg orally once daily with or without food until disease progression or unacceptable toxicity. Dose modifications:- For differentiation syndrome: Withhold dose if severe; resume when symptoms improve
- For non-infectious leukocytosis: Consider hydroxyurea or leukapheresis; may continue Idhifa
- For QT prolongation: Withhold and resume at reduced dose (50 mg daily) when QT interval returns to baseline
- For hepatotoxicity: Withhold and resume at reduced dose (50 mg daily) or permanently discontinue based on severity
- Renal impairment: No dosage adjustment recommended
- Hepatic impairment: Use with caution in severe impairment (Child-Pugh C)
- Elderly: No dosage adjustment recommended
Pharmacokinetics
Absorption: Median Tmax is 4 hours (range 1.5-12 hours). Administration with high-fat meal decreases Cmax by 38% and AUC by 25%, but this is not clinically significant. Distribution: Mean apparent volume of distribution is 29.2 L. Protein binding is approximately 98.5%, primarily to albumin. Metabolism: Primarily metabolized by CYP3A4 (83%) and to a lesser extent by CYP1A2, CYP2C19, and CYP2D6. Forms two major metabolites (AGI-16903 and AGI-8902) that are pharmacologically inactive. Elimination: Mean elimination half-life is 137 hours (5.7 days). Excretion is primarily fecal (89.1%) with minimal renal excretion (10.9%).Contraindications
Idhifa is contraindicated in patients with known hypersensitivity to enasidenib or any component of the formulation.
Warnings and Precautions
Differentiation Syndrome: Occurs in approximately 14% of patients, with 1% experiencing severe cases. May be fatal if not treated. Symptoms include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or renal dysfunction. Requires prompt treatment with corticosteroids and hemodynamic monitoring. QTc Prolongation: Idhifa can cause QT interval prolongation. Monitor electrocardiograms and electrolytes during treatment. Hepatotoxicity: Elevations in bilirubin (81%) and transaminases (50%) have been observed. Monitor liver function tests at least monthly. Tumor Lysis Syndrome: Has been reported; monitor patients with high tumor burden appropriately. Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential to use effective contraception.Drug Interactions
Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): May increase enasidenib exposure. Avoid concomitant use or monitor for increased adverse reactions. Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease enasidenib exposure. Avoid concomitant use. QT-prolonging drugs: Concomitant use may increase risk of QT prolongation. Monitor ECG and electrolytes more frequently. Acid-reducing agents: PPIs may decrease enasidenib absorption. Separate administration by at least 2 hours.Adverse Effects
Most common adverse reactions (≥20%):- Nausea (50%)
- Diarrhea (43%)
- Vomiting (34%)
- Decreased appetite (34%)
- Hypocalcemia (29%)
- Hypokalemia (28%)
- Fatigue (27%)
- Differentiation syndrome (14%)
- Tumor lysis syndrome (1%)
- QT prolongation
- Hepatotoxicity
Monitoring Parameters
- Complete blood counts with differential (weekly until stable, then monthly)
- Liver function tests (at least monthly)
- Electrolytes (particularly calcium and potassium)
- ECG monitoring (baseline, during dose escalation, and periodically)
- Signs and symptoms of differentiation syndrome
- IDH2 mutation status at diagnosis and relapse
- Pregnancy testing in women of reproductive potential
Patient Education
- Take Idhifa exactly as prescribed at the same time each day
- Do not stop taking without discussing with your healthcare provider
- Report immediately any symptoms of differentiation syndrome (fever, cough, difficulty breathing, rapid weight gain, swelling)
- Inform all healthcare providers about Idhifa use
- Use effective contraception during treatment and for at least 1 month after last dose
- Regular blood tests are necessary to monitor safety and effectiveness
- Store at room temperature in original container
- Report any new or worsening side effects to your healthcare team
References
1. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. 2. FDA. Idhifa (enasidenib) prescribing information. August 2017. 3. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732-741. 4. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. 5. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2023.