Comparison of Hepatotoxicity Associated With New BCR-ABL Tyrosine Kinase Inhibitors vs Imatinib Among Patients With Chronic Myeloid Leukemia
Authors: Zhe Wang, Xiaoyu Wang, Zhen Wang, Yuyi Feng, Yaqin Jia, Lili Jiang, Yangliu Xia, Jun Cao, Yong Liu
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Although BCR-ABL fusion oncoprotein tyrosine kinase inhibitors (BCR-ABL TKIs) can substantially improve the survival rate of chronic myeloid leukemia (CML), they are clinically accompanied by severe hepatotoxicity. <h3>Objective</h3> To compare the relative risk (RR) of hepatotoxicity of new-generation BCR-ABL TKIs with that of imatinib, and to provide an overall assessment of the clinical benefit. <h3>Data Sources</h3> PubMed, Embase, Cochrane library databases, and ClinicalTrials.gov were searched for clinical trials published between January 2000 and April 2020. <h3>Study Selection</h3> Study selection was conducted independently by 2 investigators according to the inclusion and exclusion criteria published previously in the protocol: only randomized phase 2 or phase 3 clinical trials that compared bosutinib, dasatinib, nilotinib, or ponatinib with imatinib were included. Among the 2666 records identified, 9 studies finally fulfilled the established criteria. <h3>Data Extraction and Synthesis</h3> Two investigators extracted study characteristics and data independently using a standardized data extraction form. Data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. When substantial heterogeneity was observed, pooled estimates were calculated based on the random-effect model; otherwise, the fixed-effect model was used. <h3>Main Outcomes and Measures</h3> Data extracted included study characteristics, baseline patient information, interventions and data on all-grade and high-grade (grades 3 and 4) elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, overall survival, and major molecular response (MMR). The RRs and 95% CIs were calculated using the inverse variance method. <h3>Results</h3> Nine trials involving 3475 patients were analyzed; the median (range) age was 49 (18-91) years; 2059 (59.2%) were male patients. Increased risks were observed for each new-generation TKI except for dasatinib. Patients receiving new-generation TKIs were more likely to experience all grades of ALT elevation (pooled RR, 2.89; 95% CI, 1.78-4.69;<i>P</i> &lt; .001) and grades 3 and 4 ALT elevation (pooled RR, 4.36; 95% CI, 2.00-9.50;<i>P</i> &lt; .001) compared with those receiving imatinib. Patients receiving new-generation TKIs were also more likely to experience all grades of AST elevation (pooled RR, 2.20; 95% CI, 1.63-2.98;<i>P</i> &lt; .001) and grades 3 and 4 AST elevation (pooled RR, 2.65; 95% CI, 1.59-4.42;<i>P</i> &lt; .001) compared with those receiving imatinib. New-generation TKIs were associated with a significantly higher rate of MMR at 1 year compared with imatinib (pooled RR, 1.59; 95% CI, 1.44-1.75;<i>P</i> &lt; .001). No statistical difference in overall survival at 1 year was found between new-generation TKIs and imatinib (pooled RR, 1.00; 95% CI, 1.00-1.01;<i>P</i> = .33). <h3>Conclusions and Relevance</h3> When compared to imatinib, bosutinib, nilotinib, and ponatinib had higher relative risks of hepatotoxicity. Treatment with new-generation TKIs was associated with a higher MMR rate at 1 year but not with 1-year overall survival.