Acute Myeloid Leukemia (AML) is a blood and bone marrow malignancy that spreads quickly. Among its many subtypes, mutations in the FLT3 gene are some of the most aggressive and challenging to treat. However, medical advancements have paved the way for targeted therapies that change the course of the disease. One such breakthrough is Gilteritinib, marketed under the brand name Xospata, a tablet specifically developed to target FLT3 mutations in relapsed or refractory AML.
This blog post dives deep into Gilteritinib’s mechanism of action, clinical benefits, dosage, side effects, and patient experiences to help you understand how it’s transforming the landscape of AML treatment.
What Is Gilteritinib?
Astellas Pharma created the oral tyrosine kinase inhibitor (TKI) gilteritinib. It selectively inhibits FLT3 (FMS-like tyrosine kinase 3), a gene that, when mutated, promotes the proliferation and survival of leukemic cells. By blocking FLT3 signaling, Gilteritinib aims to reduce leukemic cell growth and induce remission.
Indication:
Gilteritinib is FDA-approved for adult patients with relapsed or refractory AML that carries FLT3 mutations, which include internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations.
How Does It Work?
A receptor tyrosine kinase implicated in hematopoietic stem cell proliferation is encoded by the FLT3 gene. When FLT3 is mutated, particularly in AML, the receptor becomes constitutively active, leading to uncontrolled cell growth.
Gilteritinib works by:
- Inhibiting FLT3/ITD and FLT3/TKD mutations.
- Also targeting AXL kinase, another enzyme implicated in AML progression and resistance to therapy.
- causing FLT3-mutant leukemia cells to undergo apoptosis, or programmed cell death.
- Clinical Trial Insights
- ADMIRAL Trial Highlights
- Gilteritinib and conventional chemotherapy were compared in the pivotal phase 3 ADMIRAL study for patients with relapsed or refractory FLT3-mutated AML.
- Clinical Trial Insights
- ADMIRAL Trial Highlights
- The ADMIRAL trial was a pivotal phase 3 clinical trial comparing Gilteritinib to standard chemotherapy in patients with relapsed/refractory FLT3-mutated AML.
Key Results:
- Median overall survival: 9.3 months (Gilteritinib) vs. 5.6 months (chemotherapy).
- Higher complete remission (CR) rates.
- Patients can stay out of the hospital longer thanks to improved oral administration and tolerability.
- These promising results led to FDA approval in 2018, and since then, Gilteritinib has been adopted widely across the world.
Dosage and Administration
- Recommended dose: 120 mg orally once daily.
- It is possible to take tablets either with or without food.
- Duration: Continue until the condition worsens or the toxicity becomes intolerable.
Physicians may adjust the dose based on:
- Drug interactions (especially with CYP3A4 inhibitors or inducers).
Side effects like liver enzyme elevation, differentiation syndrome, or prolonged QT interval on ECG.
Side Effects and Safety
Like all targeted therapies, Gilteritinib can cause side effects. While generally better tolerated than intensive chemotherapy, patients should be monitored regularly.
Common Side Effects:
- Fatigue
- Nausea
- Elevated liver enzymes (AST, ALT)
- Diarrhea
- Muscle and joint pain
- Fever
Serious Side Effects:
- Differentiation Syndrome (potentially life-threatening): Symptoms include fever, shortness of breath, weight gain, and lung infiltrates. Requires prompt steroid treatment.
- QT prolongation: Risk of arrhythmias; ECG monitoring recommended.
- Pancreatitis or Posterior Reversible Encephalopathy Syndrome (PRES): Rare but serious.
Patient Perspective
For many AML patients, especially those with relapsed or refractory disease, options are limited. Gilteritinib offers:
- A convenient oral therapy, reducing the need for hospitalization.
- a focused strategy using a customized treatment plan.
- Many patients report fewer side effects compared to chemotherapy, though side effects are still present and need careful monitoring.
Monitoring and Follow-Up
Patients on Gilteritinib require:
- Routine blood counts to monitor for myelosuppression.
- Liver function tests.
- Electrocardiograms (ECGs) for cardiac safety.
- FLT3 mutation testing (prior to starting therapy).
- Possible dose adjustments if side effects arise.
Drug Interactions
Gilteritinib is metabolized by the CYP3A4 enzyme, so it’s important to avoid:
- Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin).
- Strong CYP3A4 inducers (e.g., rifampin, phenytoin).
- Herbal products like St. John’s Wort.
Conclusion: A Promising Future
Gilteritinib represents a major advance in the treatment of FLT3-mutated AML. With targeted action, a manageable safety profile, and proven efficacy, it is redefining how we treat a traditionally difficult leukemia subtype.
While not a cure, it offers a better quality of life, longer survival, and hope for patients who previously had very limited options.
