Introduction

Ivosidenib is an orally available small molecule inhibitor of isocitrate dehydrogenase 2 which is used as an antineoplastic agent in the treatment of selected cases of acute myeloid leukemia (AML). Ivosidenib is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to be the cause of rare instances of clinically apparent acute liver injury.

Background

Ivosidenib (eye" voe sid' i nib) is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), an enzyme rearranged and mutated in some forms of leukemia and lymphoma. The mutated IDH promotes unregulated cell growth and proliferation and is overexpressed in some leukemias. Ivosidenib has been found to inhibit mutated IDH1 and in several clinical trials was found to induce objective responses in a proportion of patients with refractory AML with detectable IDH1 mutations. Ivosidenib received accelerated approval for use refractory or relapsed AML with mutated IDH1 in the United States in 2018. A specific small molecule inhibitor of IDH2, enasidenib, was approved as therapy of AML with mutations in IDH2 in 2017. These two IDH inhibitors appear to have similar efficacy against their respective mutated enzyme as well as similar adverse effects. Ivosidenib is available in tablets of 250 mg under the brand name Tibsovo. The dose is 500 mg once daily, continued until progressive disease or intolerable toxicity occurs. Side effects are common and can include fatigue, arthralgia, fever, diarrhea, nausea, abdominal pain, dyspnea, cough, peripheral edema, mucositis and rash. Uncommon, but potentially severe side effects include differentiation syndrome, QTc prolongation, Guillian Barre’ syndrome, and embryo-fetal toxicity.

Hepatotoxicity

Elevations in serum aminotransferase levels are common during ivosidenib therapy occurring in 15% to 20% of patients, but rising above 5 times the upper limit of the normal range in only 1% to 2%. Ivosidenib 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 IDH inhibitors, their potential for causing liver injury is not well defined.

In prelicensure studies, ivosidenib therapy was associated with "differentiation syndrome" in 5% of patients, which was sometimes severe and life-threatening. Differentiation syndrome is marked by rapid proliferation of myeloid cells and symptoms of respiratory distress, accompanied by hypoxia, pulmonary infiltrates and pleural effusions. Other manifestations include renal impairment, fever, lymphadenopathy, bone pain, peripheral edema and weight gain. Liver dysfunction can also occur but is generally overshadowed by the more severe systemic manifestations. The onset of differentiation syndrome is generally within 2 to 8 weeks of starting therapy and the course can be severe. Management includes stopping ivosidenib and use of corticosteroids and hydroxyurea in more severe cases. Patients can be restarted on ivosidenib once the syndrome resolves.

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

Mechanism of Injury

The possible cause of the liver injury due to ivosidenib is not known. Ivosidenib 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

Ivosidenib 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.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors