Introduction

Quizartinib is an orally administered receptor tyrosine kinase FLT3 inhibitor that is used in combination with other cancer chemotherapeutic agents to treat adults with acute myelogenous leukemia who are positive for FLT3 internal tandem duplication. Quizartinib is associated with a high rate of liver enzyme elevations during therapy, but a similar rate occurs with comparator arms of chemotherapy, and it has not been shown to cause clinically apparent drug induced liver injury.

Background

Quizartinib (kwiz ar’ ti nib) is an orally available small molecule inhibitor of the receptor tyrosine kinase FLT3 that is used in combination with other chemotherapeutic agents to treat patients with acute myelogenous leukemia (AML) who have mutations in FLT3. AML is the most common cause of acute leukemia in adults, and at least 30% of patients have FLT3 mutations. The FLT3-internal tandem duplication mutation is associated with aggressive disease and poor response rates to standard chemotherapeutic regimens. Quizartinib is one of several inhibitors of FLT mutations and has special activity against the FLT3-internal tandem mutation. Quizartinib was shown to improve overall survival when combined with standard chemotherapy in both newly diagnosed and relapsed or refractory cases of AML with the FLT3-internal tandem mutation. Quizartinib was approved as therapy for adults with newly diagnosed AML with a FLT3 internal tandem duplication in 2023. It is given in combination with standard induction and consolidation chemotherapy and continued as a single agent for maintenance after consolidation. Quizartinib is available in tablets of 17.7 and 26.5 mg under the brand name Vanflyta. The recommended dose regimen varies by treatment phase from 26.5 to 53 mg once daily for different numbers of days in the 28-day cycle. Adverse events include febrile neutropenia, pneumonia, sepsis, diarrhea, nausea, abdominal pain, mucositis, headache, and respiratory tract infections. Laboratory abnormalities include decrease in neutrophils, lymphocytes, potassium, albumin, phosphorus, and magnesium and increases in alkaline phosphatase and creatine phosphokinase. Severe adverse events include QT interval prolongation, febrile neutropenia, sepsis, and embryo-fetal toxicity. Quizartinib should only be administered by health care workers with experience and expertise in managing acute leukemia, cancer chemotherapy, and their complications. Quizartinib is available only through a Risk Evaluation and Mitigation Strategy (REMS) program that requires careful monitoring for and attention to prolongation of the QT interval.

Hepatotoxicity

In the prelicensure clinical trials of quizartinib in patients with AML, ALT elevations were arose in 10% to 16% of patients and were above 5 times the upper limit of normal (ULN) in 1% to 3%. However, similar rates were reported in subjects receiving chemotherapy without quizartinib and in most instances the elevations were transient, asymptomatic, and not associated with elevations in serum bilirubin. Intermittent elevations in liver enzymes are not uncommon in patients with untreated AML due to bacterial, viral and opportunistic infections. In the registration trials of quizartinib there were uncommon instances of acute liver injury and hepatic failure, but all were attributable to other comorbidities and factors (multiorgan failure), and none were considered due to quizartinib. Since its approval in the United States, there have been no reported cases of clinically apparent liver injury associated with quizartinib therapy.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of serum aminotransferase elevations from quizartinib is unknown. Quizartinib is metabolized by the cytochrome P450 system, predominantly by CYP 3A4 and is susceptible to drug-drug interactions with inducers or inhibitors of the drug metabolizing enzyme which are best avoided during chemotherapy with its use.

Outcome and Management

The product label for quizartinib does not recommend routine monitoring of liver laboratory tests during therapy. Serum aminotransferase elevations above 5 times the upper limit of normal (if detected) should lead a search for alternative causes of liver enzyme elevations and, if none are found, to dose reduction or temporary cessation of treatment with careful monitoring. Cross sensitivity to liver injury has not been described with the other FLT kinase inhibitors.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

Other FLT3 Inhibitors: Gilteritinib, Midostaurin