New-Generation TKIs Linked To CML Hepatotoxicity

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: A meta-analysis of nine clinical trials shows a higher rate of hepatotoxicity in chronic myeloid leukaemia (CML) patients who receive the new-generation BCL–ABL tyrosine kinase inhibitors (TKIs) bosutinib, nilotinib or ponatinib than in those treated with the first-generation agent imatinib.

Use of these TKIs may warrant “frequent hepatic function monitoring”, suggest Yong Liu, from the Dalian University of Technology in Panjin, China, and co-authors in JAMA Network Open.

The team reviewed data from phase II and III clinical trials comparing new-generation TKIs with imatinib in a total of 3475 patients with chronic phase CML, 59% of whom were male, with a median age of 49 years.

Patients receiving a new-generation TKI were a significant 2.89 times more likely to have an any-grade alanine aminotransferase (ALT) increase than those given imatinib and a significant 4.36 times more likely to have a grade 3 or 4 ALT increase.

New-generation TKIs were also associated with a significant 2.20-fold increased risk of an any-grade aspartate aminotransferase (AST) elevation versus imatinib and patients treated with new-generation TKIs were a significant 2.65 times more likely to have a grade 3 or 4 AST rise.

Individually, the relative risks (RRs) of any-grade ALT elevation with use of bosutinib, nilotinib and ponatinib versus imatinib were a significant 4.27, 2.54 and 9.97, respectively, with corresponding RRs for any-grade AST elevations of 3.16, 1.82 and 2.96.

By contrast, use of the new-generation TKI dasatinib did not confer an increased risk of ALT or AST elevation compared with imatinib, the researchers report.

The likelihood of a patient achieving a major molecular response (MMR) was significantly higher with receipt of a new-generation TKI than with imatinib (RR=1.59). There was a comparable improvement in the RR for MMR for each of the new-generation TKIs (RRs=1.37–2.08) and all RRs were statistically significant except for ponatinib.

However, the MMR benefit did not translate into a significant improvement in 1-year overall survival with a new-generation TKI versus imatinib in the pooled analysis or for the individual agents, report Yong Liu et al.

Discussing the optimal treatment for individual patient characteristics, the researchers recommend that imatinib should be the “first choice” for older individuals where the focus is on improving survival, with a switch to dasatinib following recurrence or intolerance.

“For patients with newly diagnosed [chronic phase] CML without baseline hepatic impairment comorbidities and for whom achieving a deep molecular response is the predominant objective, dasatinib remains […] an excellent choice”, they advise.

“In cases of treatment failure, bosutinib and nilotinib are preferred. Particularly, the use of bosutinib and nilotinib as first-line treatments requires a screening for potential risk factors (eg, serum transaminases)”, the authors continue.

“Ponatinib should be reserved for patients with advanced disease, with the T315I variant, or for whom other treatments cannot be used.”

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;4:e2120165. Published online 22 July 2021. doi:10.1001/jamanetworkopen.2021.20165