Crizotinib
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Liver injury : case report An approximately 66-year-old woman developed cholestatic and mixed type of liver injury during treatment with crizotinib for lung adenocarcinoma. The woman was diagnosed with stage IV lung adenocarcinoma in November 2017 (i.e. at the age of 66 years). Prior to the initiation of chemotherapy, hepatitis viral screening revealed positive result for hepatitis B surface surface (anti-HBs) antibody, total hepatitis B surface core (antiHBc) antibody and hepatitis B surface e (anti-HBe) antibody. She started receiving first-line therapy with cisplatin and pemetrexed. Following 3 cycles of cisplatin and pemetrexed, a partial response was noted. However, the serum creatinine levels had increased to 1.0 mg/dL and the estimated glomerular filtration rate was 43 mL/min. Additionally, molecular testing of the bronchial biopsy tissue demonstrated ROS1 rearrangements. From March 2018, she started receiving second-line therapy with crizotinib 250mg twice daily [route not stated]. Twenty-three days following the initiation of crizotinib, blood tests revealed increased level of ALT. The woman started receiving treatment with ursodeoxycholic acid. After 7 days, she presented with loss of taste. Blood tests showed an increased level of CRP to 7.34 mg/dL as well as worsening of liver function tests. Serum aminotransferases and ALP showed grade 1 toxicity levels with a normal total bilirubin. Glutathione was added. The following day, she presented to the emergency department with a high fever and general fatigue. After 3 days (on day 35 of crizotinib administration), she was admitted because of a continuous high fever. Blood tests showed elevated levels of eosinophils, serum amino-transferases and CRP, and ALP showed grade 2 toxicity levels. An abdominal CT and ultrasonography demonstrated a fatty liver. Hepatitis A and C were excluded. Re-test for hepatitis B DNA was found to be negative. Antibodies to cytomegalovirus and Epstein-Barr virus were also found to be negative. The pattern of liver injury was diagnosed as a cholestatic and mixed type of liver injury. Crizotinib therapy was stopped. Despite discontinuation of crizotinib, her ALP level remained increased. Therefire, the dose of ursodeoxycholic acid was doubled, following which her symptoms resolved. A drug-induced lymphocyte stimulation test was found to be positive for crizotinib. Twenty-four days later, when serum transaminases and CRP normalised, the woman was re-initiated on crizotinib (for oral desensitisation) at 100 mg/day. The dose of crizotinib was gradually increased to 300 mg/day and then to 400 mg/day. When the dose of crizotinib was increased to 300 mg/day or 400 mg/day, a slight increase in ALT level was noted. Her liver toxicity was attributed to crizotinib based on the following findings; dechallenge of crizotinib improved liver toxicity and rechallenge of crizotinib induced similar liver toxicity recurrence. In December 2018, 8 months following the reinitiation of crizotinib, she was noted to have a stable disease with manageabl
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