Introduction
Xospata (gilteritinib) is an oral, potent, selective FLT3 inhibitor developed by Astellas Pharma for the treatment of relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations. Approved by the FDA in November 2018, it represents a targeted therapeutic approach for this genetically defined subset of AML patients who historically have had poor outcomes with conventional chemotherapy.
Mechanism of Action
Gilteritinib is a small molecule inhibitor that selectively targets FMS-like tyrosine kinase 3 (FLT3) receptors. It demonstrates potent activity against both internal tandem duplication (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) mutations. The drug binds to the ATP-binding pocket of FLT3, inhibiting autophosphorylation and downstream signaling pathways including STAT5, MAPK, and AKT. This targeted inhibition disrupts the proliferation and survival signals in leukemic cells harboring FLT3 mutations, leading to apoptosis of malignant cells while sparing normal hematopoiesis.
Indications
Xospata is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a confirmed FLT3 mutation as detected by an FDA-approved test. This indication received accelerated approval based on response rates and continued approval is contingent upon verification of clinical benefit in confirmatory trials.
Dosage and Administration
Standard dosing: 120 mg orally once daily with or without food Duration: Continue until disease progression or unacceptable toxicity Administration: Tablets should be swallowed whole with water; do not crush, break, or chew Dose modifications:- For adverse reactions: Consider dose reduction to 80 mg daily
- Hepatic impairment: No dose adjustment recommended for mild to moderate impairment (Child-Pugh A and B); use caution in severe impairment (Child-Pugh C)
- Renal impairment: No dose adjustment recommended for mild to moderate impairment (eGFR 30-89 mL/min); use caution in severe impairment (eGFR <30 mL/min)
- Elderly patients: No dose adjustment required based on age alone
Pharmacokinetics
Absorption: Median Tmax is 4-6 hours post-dose; administration with high-fat meal decreases AUC by 12% and Cmax by 26% Distribution: Mean volume of distribution is 1132 L; protein binding is >99% Metabolism: Primarily metabolized via CYP3A4 with minor contributions from CYP2C8 and UGT1A4 Elimination: Mean elimination half-life is 113 hours; fecal excretion (64.5%) predominates over renal excretion (16.4%) Special populations: No clinically significant differences based on age, sex, race, or body weightContraindications
- Hypersensitivity to gilteritinib or any component of the formulation
- Concomitant use with strong CYP3A inducers due to risk of reduced efficacy
Warnings and Precautions
Posterior Reversible Encephalopathy Syndrome (PRES): Occurred in <1% of patients; discontinue if PRES is suspected Prolonged QT Interval: Median increase of 9.9 msec observed; monitor ECGs and electrolytes periodically Pancreatitis: Occurred in 4% of patients; monitor for symptoms Differentiation Syndrome: Occurred in 3% of patients; may be fatal if not treated with corticosteroids and hemodynamic monitoring Embryo-Fetal Toxicity: Can cause fetal harm; advise patients of reproductive potential to use effective contraceptionDrug Interactions
Strong CYP3A inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) Strong CYP3A inhibitors: Consider alternative agents or monitor for increased gilteritinib exposure (e.g., ketoconazole, itraconazole) QT-prolonging drugs: Use with caution and monitor ECG (e.g., antiarrhythmics, fluoroquinolones, antipsychotics) P-gp substrates: May increase concentrations of narrow therapeutic index P-gp substrates (e.g., digoxin)Adverse Effects
Most common (≥20%):- Musculoskeletal pain (62%)
- Transaminase increased (52%)
- Fatigue (44%)
- Fever (40%)
- Diarrhea (38%)
- Dyspnea (37%)
- Edema (35%)
- Rash (35%)
- Nausea (34%)
- Cough (32%)
- Constipation (31%)
- Eye disorders (30%)
- Dizziness (30%)
- Hypotension (29%)
- Vomiting (28%)
- Acute kidney injury (27%)
- Differentiation syndrome (3%)
- Posterior reversible encephalopathy syndrome (<1%)
- Prolonged QT interval (1%)
- Pancreatitis (4%)
Monitoring Parameters
Baseline:- FLT3 mutation status confirmation
- ECG with QTc measurement
- Complete blood count with differential
- Comprehensive metabolic panel (including hepatic and renal function)
- Electrolytes (potassium, magnesium, calcium)
- Pancreatic enzymes
- ECG at least weekly during first month, then monthly
- Electrolytes at least weekly during first month, then monthly
- Liver function tests every 2 weeks for first month, then monthly
- Complete blood counts weekly until recovery
- Monitor for signs/symptoms of differentiation syndrome daily during first weeks
- Monitor for neurological symptoms suggestive of PRES
Patient Education
- Take Xospata exactly as prescribed at the same time each day
- Do not stop taking without consulting your healthcare provider
- Report any signs of infection, fever, or unusual bleeding/bruising
- Immediately report symptoms of differentiation syndrome (fever, cough, difficulty breathing, rash, swelling)
- Report neurological symptoms (seizures, headache, visual changes, confusion)
- Avoid pregnancy; use effective contraception during treatment and for at least 6 months after last dose
- Inform all healthcare providers about Xospata use before starting any new medications
- Do not consume grapefruit or grapefruit juice during treatment
- Store at room temperature in original container
References
1. FDA Prescribing Information: Xospata (gilteritinib). November 2018. 2. Perl AE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-1740. 3. Larrosa-Garcia M, et al. FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2020;19(6):1243-1254. 4. Dhillon S. Gilteritinib: First Global Approval. Drugs. 2019;79(3):331-339. 5. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2023. 6. Short NJ, et al. Advances in the Treatment of Acute Myeloid Leukemia: New Drugs and New Challenges. Cancer Discov. 2020;10(4):506-525.