Comparison of Hepatotoxicity Associated With New BCR-ABL Tyrosine Kinase Inhibitors vs Imatinib Among Patients With Chronic Myeloid Leukemia

Abstract

IMPORTANCE 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. OBJECTIVE 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. DATA SOURCES PubMed, Embase, Cochrane library databases, and ClinicalTrials.gov were searched for clinical trials published between January 2000 and April 2020.STUDY SELECTION 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. DATA EXTRACTION AND SYNTHESISTwo 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. MAIN OUTCOMES AND MEASURESData 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. RESULTSNine 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; P < .001) and grades 3 and 4 ALT elevation (pooled RR, 4.36; 95% CI, 2.00-9.50; P < .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; P < .001) and grades 3 and 4 AST elevation (pooled RR, 2.65; 95% CI, 1.59-4.42; P < .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; P < .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; P = .33).

Kinetic of liver enzymes and serum electrolytes in HCV, HBV, and HIV negative chronic phase chronic myeloid leukemia patients treated with imatinib or nilotinib

“…29 A previous study reported a lowgrade elevation in serum ALT and/or AST in 25% to 30% and a high-grade elevation in approximately 2% of patients treated with TKIs. 32 Also, Khelifa et al, (2022) reported that elevated hepatic enzymes (grade 3 or 4) were seen in 10% to 15% of patients treated with Nilotinib but rarely progress to hepatitis. 33 The systematic review and meta-analysis by Wang et al, (20121) which included 9 trials involving 3475 patients showed that patients received new-generation TKIs were more likely to experience all grades of ALT and AST elevation compared with those received Imatinib (p<0.001).…”

“…32 Also, Khelifa et al, (2022) reported that elevated hepatic enzymes (grade 3 or 4) were seen in 10% to 15% of patients treated with Nilotinib but rarely progress to hepatitis. 33 The systematic review and meta-analysis by Wang et al, (20121) which included 9 trials involving 3475 patients showed that patients received new-generation TKIs were more likely to experience all grades of ALT and AST elevation compared with those received Imatinib (p<0.001). New-generation TKIs drugs were associated with a significantly higher rate of MMR at 1 year compared with Imatinib (p< 0.001).…”

Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies

“…Dasatinib-induced hyperbilirubinemia is rare in patients with CML-CP or accelerated phase disease (1%); nevertheless, it is more common in those with blast phase disease (4–5%) ( 58 ). A recent meta-analysis showed that bosutinib, nilotinib, or ponatinib were associated with a higher risk of hepatotoxicity than imatinib; however, dasatinib was not linked to a significantly increased risk ( 59 ). The mechanism of dasatinib-related hepatotoxicity remains unclear.…”

Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells

“…BCR::ABL1‐dependent activation of Src kinase also contributes to the pathogenesis of CML 3 . BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib and dasatinib are currently the first‐line agents for the treatment of CML 4 . Compared to conventional interferon therapy, these inhibitors have markedly improved the 5‐year survival rate of chronic phase CML patients to more than 90% 5 .…”