Relative Risk of Hepatotoxicity Associated With BCR-ABL Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis

Background: The survival of patients with chronic myeloid leukemia (CML) has improved substantially in the last decade with the development of BCR-ABL tyrosine kinase inhibitors (BCR-ABL TKIs). However, clinically apparent liver disease and even death has been found with the treatment of ponatinib, and serious cases of liver injury were also associated with imatinib, nilotinib and dasatinib. The aim of this systematic review and meta-analysis was 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. Methods: Two independent investigators selected citations and clinical trials from PubMed, Embase, Cochrane library databases and clinicaltrials.gov from January 2000 to April 2020 to include RCTs comparing four new-generation BCR-ABL TKIs (dasatinib, bosutinib, nilotinib and ponatinib) with the first generation BCR-ABL TKI imatinib. Data extracted included study characteristics, baseline patient information, interventions and data on all grades and high grades alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, overall survival (OS), and major molecular response (MMR). The relative risk (RR) and 95% confidence interval (CI) were calculated using the inverse variance method. Findings: Nine trials involving 3475 patients were analyzed. Increased risks were observed for each new-generation TKI except for dasatinib. The pooled RRs of all grades ALT and grade 3-4 ALT elevation were 2.89 (95% CI 1.78-4.69; P<0.0001) and 4.36 (95% CI 2.00-9.50; P<0.0001), respectively. The pooled RRs of all grades AST and grade 3-4 AST elevation were 2.20 (95% CI 1.63-2.98; P<0.0001) and 2.65 (95% CI 1.59-4.42; P<0.0001), respectively. New-generation TKIs significantly increased the major molecular response (MMR) rate at 1 year (Pooled RR, 1.59; 95% CI, 1.44-1.75, P<0.0001). 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, P=0.33). Interpretation: Clinical trials indicated an increased risk of developing hepatotoxicity in patients treated with BCR-ABL TKIs. Our findings are of importance to provide personalized medication strategy and stresses the need for frequent hepatic function monitoring in patients treated with bosutinib, nilotinib, and ponatinib. Trial Registration: The review has been registered in the PROSPERO 2020 protocol: CRD42020202337. Funding Statement: This study was financially supported by the National Key Research and Development Program of China (2017YFC1702006). Declaration of Interests: The authors declare that there is no conflict of interests regarding the publication of this article.