A Case of Severe, Nilotinib-Induced Liver Injury

Belopolsky, Yuliya; Grinblatt, David L.; Dunnenberger, Henry M.; Sabatini, Linda M.; Joseph, Nora; Fimmel, Claus J.

doi:10.14309/crj.0000000000000003

Cited by 11 publications

(7 citation statements)

References 12 publications

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“…In comparison, only two of the five UGT1A1 NMs experienced high-grade toxicities [ 82 ]. Single patient case reports have described similar findings of severe nilotinib-induced hyperbilirubinemia among UGT1A1 PMs [ 83 , 84 , 85 , 86 ]. Some of the studies identified in our review proposed that UGT1A1 results may help avoid treatment delays and adverse events, but there is a lack of implementation studies assessing UGT1A1 -guided nilotinib prescribing.…”

Section: Resultsmentioning

confidence: 75%

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Nelson

Seligson

Bottiglieri

et al. 2021

Cancers

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Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.

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Section: Resultsmentioning

confidence: 75%

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Nelson

Seligson

Bottiglieri

et al. 2021

Cancers

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“…Severe liver injury was also reported in patients with CML treated with nilotinib and dasatinib. 10 , 11 However, among several studies comparing imatinib with the other BCR-ABL TKIs, 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 only one mentions hepatic effects without stratification study. 19 Hence, it is necessary to perform a meta-analysis focusing specifically on the relative risk of hepatotoxicity associated with each BCR-ABL TKI.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2021

JAMA Netw Open

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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).

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“…The incidence of grade 3 or 4 elevation of liver enzymes caused by nilotinib was reported 1 to 4% (2). Belopolsky et al reported a case of the patient with nilotinib-induced grade 4 hepatotoxicity, which was normalized after the cessation of nilotinib (3). In that report, the liver biopsy showed acute hepatitis with severe portal and lobular inflammation, although the exact types of infiltrating immune cells or their activation status were not studied (3).…”

Section: Discussionmentioning

confidence: 98%

“…Belopolsky et al reported a case of the patient with nilotinib-induced grade 4 hepatotoxicity, which was normalized after the cessation of nilotinib (3). In that report, the liver biopsy showed acute hepatitis with severe portal and lobular inflammation, although the exact types of infiltrating immune cells or their activation status were not studied (3). There have also been several case reports of imatinib-induced liver injury, which did not identify the actual "killer cells" in the liver.…”

Section: Discussionmentioning

confidence: 99%

Nilotinib-Induced Immune-Mediated Liver Injury: Corticosteroid as a Possible Therapeutic Option

et al. 2020

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Introduction: Nilotinib is a BCR-ABL tyrosine kinase inhibitor approved for chronic myeloid leukemia. We present a case of severe immune-mediated liver injury by nilotinib treatment. Case report: A 59-year-old woman was referred to the liver clinic because of elevated liver enzyme levels. One year prior, she was diagnosed as having chronic myeloid leukemia and treated with nilotinib therapy. The level of aspartate aminotransferase and alanine aminotransferase were 578 IU/L and 499 IU/L, respectively. Percutaneous needle liver biopsy showed extensive centrilobular infiltration of immune cells and destruction of the lobular architecture with minimal inflammation in the portal triad. Immunohistochemical staining showed that many CD8 + T cells and CD56 + cells infiltrated the site of inflammation. Multicolor fluorescence-activated cell-sorting analysis revealed that a considerable number of intrahepatic CD8+ T cells showed an activated phenotype compared with the healthy control. She was diagnosed with nilotinib-induced, immune-mediated liver injury. Prednisolone treatment (30 mg daily) was started and caused rapid normalization of liver enzyme levels. Conclusion: Nilotinib can cause immune-mediated liver injury. The use of corticosteroid can be treatment option in immune-mediated liver injury.

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A Case of Severe, Nilotinib-Induced Liver Injury

Cited by 11 publications

References 12 publications

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

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

Nilotinib-Induced Immune-Mediated Liver Injury: Corticosteroid as a Possible Therapeutic Option

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