Gilteritinib is an orally available small molecule inhibitor of FMS-like tyrosine kinase 3 (FLT3) which is used as an antineoplastic agent in the treatment of acute myeloid leukemia with FLT3 mutations. Gilteritinib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury.
Gilteritinib (gil" te ri' ti nib) is a potent small molecule inhibitor of FLT3 (FMS-like tyrosine kinase 3), a tyrosine kinase receptor that is mutated in to up one-third of patients with acute myeloid leukemia (AML). The mutated FLT3 activates an intracellular signaling cascade of RAS-MEK-PI3K-AKT-STAT-5, promoting unregulated cell growth and proliferation. Gilteritinib has been found to inhibit mutated FLT3 and in several clinical trials was found to induce objective responses in a proportion of patients with refractory AML with detectable FLT3 mutations. Gilteritinib received accelerated approval for this indication in the United States in 2018 and is available in tablets of 40 mg under the brand name Xospata. The recommended dose is 120 mg once daily, continued until progressive disease or intolerable toxicity occurs. Side effects are common and can include fatigue, myalgia, arthralgia, fever, diarrhea, nausea, abdominal pain, dizziness, headache, hypotension, cough and stomatitis. Uncommon, but potentially severe side effects include posterior reversible encephalopathy syndrome, febrile neutropenia and sepsis, QTc prolongation, pancreatitis, and embryo-fetal toxicity.
Elevations in serum aminotransferase levels are common during gilteritinib therapy occurring in 78% of patients and rising above 5 times the upper limit of the normal range in 12%. Gilteritinib has had limited clinical use but has not been linked to instances of acute liver injury with symptoms or jaundice. Because of the limited clinical experience with the use of FLT3 inhibitors, their potential for causing liver injury is not well defined.
Mechanism of Injury
The possible cause of the liver injury due to gilteritinib is not known. Gilteritinib is metabolized in the liver largely by the cytochrome P450 system (largely CYP 3A4) and is susceptible to drug-drug interactions with inhibitors or inducers of the microsomal enzyme system.
Outcome and Management
Gilteritinib therapy has been associated with transient serum aminotransferase elevations during therapy, but has not been linked to instances of acute liver injury with jaundice or symptoms. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to temporary discontinuation, which should be permanent if laboratory values do not improve significantly or resolve within a few weeks or if symptoms or jaundice arise.
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