Gilteritinib – Potent FLT3/AXL Inhibitor Targeted Therapy
Gilteritinib is an oral, highly selective, potent second-generation small-molecule tyrosine kinase inhibitor engineered for the precision treatment of specific aggressive subtypes of acute myeloid leukemia (AML). The primary target of the drug is the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3), which plays a pivotal role in the proliferation, survival, and differentiation of hematopoietic progenitor cells. Gilteritinib is unique in that it demonstrates combined activity against the two major types of FLT3 mutations: internal tandem duplications (FLT3-ITD), which correlate with an extremely high risk of relapse, and tyrosine kinase domain (FLT3-TKD) mutations, which frequently drive resistance to first-generation kinase inhibitors. Its mechanism of action involves competitive blockade of the ATP-binding site of the receptor, halting its autophosphorylation, disrupting downstream intracellular signaling cascades (including the MAPK/ERK, PI3K/AKT/mTOR, and STAT5 pathways), and inducing apoptosis in leukemic blast cells. Additionally, the drug inhibits AXL kinase, which is co-expressed on AML cells and participates in tumor cell survival mechanisms.
The clinical uniqueness of gilteritinib lies in its ability to overcome primary and secondary resistance within bone marrow tumor cells, enabling achieve complete remission in patients with relapsed or refractory disease without requiring aggressive cytotoxic chemotherapy regimens. The drug exhibits high bioavailability upon oral administration, reaching steady-state plasma concentrations within approximately 7 to 15 days of continuous dosing. Gilteritinib is characterized by a prolonged elimination half-life (around 113 hours), is primarily metabolized in the liver by the cytochrome CYP3A4 isoenzyme, and is excreted predominantly in the feces as unchanged drug.
The drug is administered orally. Prior to initiating therapy, verification of the FLT3 mutation status (ITD or TKD) using a validated molecular-genetic diagnostic assay is mandatory. Continuous clinical monitoring of blood counts, biochemistry parameters, and the QTc interval is required throughout treatment.
Indications
Gilteritinib is indicated as a precision targeted monotherapy for adult patients with the following malignant hematological disease:
- Relapsed or Refractory Acute Myeloid Leukemia (AML): treatment of adult patients with relapsed or refractory acute myeloid leukemia harboring a confirmed FLT3 mutation (either ITD or TKD).
Dosage and administration
The dosing regimen of gilteritinib is continuous and structured for long-term daily administration, with provisions for step-by-step dose modification based on clinical response and patient tolerability.
- Standard Dose: the recommended initial dose is 120 mg (three 40 mg tablets) taken orally once daily.
- Schedule and Duration: the drug is taken daily within conventional 28-day cycles. Therapy should be continued as long as the patient derives clinical benefit or until unacceptable systemic toxicity occurs. Treatment response assessment is typically performed after completion of at least one cycle.
- Administration Method: tablets must be swallowed whole at approximately the same time each day, with or without food. Tablets must not be broken, crushed, or chewed, and should be administered with a sufficient volume of water.
- Missed Dose: if a dose is missed, it should be taken as soon as possible on the same day, provided the next scheduled dose is more than 12 hours away. A double dose must not be taken on the following day to compensate.
- Dose Modification: if a therapeutic response is not achieved after 4 weeks of treatment, the dose may be escalated to 200 mg once daily. If the QTc interval extends beyond 500 ms or Differentiation Syndrome develops, therapy must be withheld until stabilization, with a subsequent dose reduction to 80 mg.
