New-Generation BCR-ABL TKIs Linked to Increased Risk of Hepatotoxicity in Patients With Chronic Myeloid Leukemia

Drug-induced hepatotoxicity is a concern because half of the currently available oral drugs are associated with hepatotoxicity, including some used to treat chronic myeloid leukemia (CML).

A team of researchers in China sought to determine the relative hepatotoxicology associated with new-generation BCR-ABL fusion oncoprotein tyrosine kinase inhibitors (BCR-ABL TKIs) used to treat patients with CML. To better understand how these drugs affect liver function in patients with CML, the researchers analyzed data from 9 clinical trials including a total of 3475 patients published between 2000 and 2020. Their results were published in JAMA Network Open.

This study compared all-grade and high-grade (grades 3 and 4) ALT and AST elevation in patients treated with new generation TKIs with those of patients treated with imatinib, which was the first tyrosine kinase inhibitor. Studies were included only if they compared bosutinib, dasatinib, nilotinib, or ponatinib with imatinib.

The new-generation TKIs were found to associate with increased risk of hepatotoxicity, with the exception of dasatinib. In fact, patients treated with these TKIs were more likely to develop all grade and grade 3-4 ALT elevation compared with those treated with imatinib. All grade and grade 3-4 AST elevation also were associated with these TKIs.

“This meta-analysis found a significant increase in the risk of hepatotoxicity associated with the use of bosutinib, nilotinib, and ponatinib compared with imatinib,” the researchers wrote.

They suggest clinicians be aware of the risk of liver damage for patients with CML treated with bosutinib, nilotinib, or ponatinib and take care to monitor hepatic function frequently in those patients.

Study limitations included a lack of reporting of hepatic adverse events in many of the studies that were included in the analysis. Additional information that access to individual data would have provided, such as number of deaths due to liver failure and baseline hepatic risk factors for each study group, would also have been useful.

Hepatotoxicity risk with nilotinib may to be dose related. Therefore, further research is needed to determine more about the dosages for each TKI that will achieve the optimum risk-benefit balance. 

Disclosures: This research was supported by the National Key Research and Development Program of China and the Fundamental Research Funds for the Central Universities.

Reference

Wang Z, Wang X, Wang Z, et al. Comparison of hepatotoxicity associated with new BCR-ABL tyrosine kinase inhibitors vs imatinib among patients with chronic myeloid leukemia: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(7):e2120165. doi:10.1001/jamanetworkopen.2021.20165