Case report

Crizotinib-induced acute hepatitis: First case with relapse after reintroduction with reduced dose

Multikinase inhibitors (MKI) are targeted molecular agents that have revolutionized cancer management. However, there is a paucity of data concerning MKI-related liver injury risk and clinical guidelines for the management of liver toxicity in patients receiving MKI for cancer are scarce.

We conducted a PubMed search of articles in English published from January 2000 to December 2018 related to hepatotoxicity of the 29 FDA-approved MKIs at doses used in clinical practice. The search terms were the international non-proprietary name of each agent cross-referenced with «hepatotoxicity», «hepatitis», «hepatic adverse event», or «liver failure», and «phase II clinical trial», «phase III clinical trial», or «case report».

Following this search, 140 relevant studies and 99 case reports were considered. Although asymptomatic elevation of aminotransferase levels has been frequently observed in MKI clinical trials, clinically significant hepatotoxicity is a rare event. In most cases, the interval between treatment initiation and the onset of liver injury is between one week and two months. Liver toxicity is often hepatocellular and less frequently mixed. Life-threatening MKI-induced hepatic injury has been described, involving fulminant liver failure or death. Starting from existing data, a description of MKI-related liver events, grading of hepatotoxicity risk, and recommendations for management are also given for various MKI molecules.

All MKIs can potentially cause liver injury, which is sometimes irreversible. As there is still no strategy available to prevent MKI-related hepatotoxicity, early detection remains crucial. The surveillance of liver function during treatment may help in the early detection of hepatotoxicity. Furthermore, the exclusion of potential causes of hepatic injury is essential to avoid unnecessary MKI withdrawal.

We report two cases of acute hepatitis induced by crizotinib in patients with ALK-rearranged non-small cell lung cancer (NSCLC) who were treated after by a second generation of ALK inhibitor without any incident. These cases suggest that ceritinib could be used as an alternative agent when crizotinib is responsible for hepatitis.

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.

Le crizotinib (XALKORI^™, Pfizer) est un inhibiteur de la tyrosine kinase de ALK, de MET et de ROS1, actuellement indiqué en seconde ligne thérapeutique des cancers broncho-pulmonaires réarrangés pour ALK. Un groupe d’experts s’est réuni afin de proposer, à partir de l’analyse des données des études PROFILE, des éléments de prise en charge pour optimiser la tolérance du traitement. Les thématiques discutées ont comporté la prévention et le traitement des principaux effets secondaires fréquents ou spécifiques du crizotinib: troubles visuels, troubles digestifs, effets cardiaques, élévation des transaminases, hypogonadisme. En pratique, les patients doivent être informés des précautions à prendre pour la conduite automobile ou de machines en situation de faible luminosité. Les troubles digestifs liés au crizotinib sont exceptionnellement persistants ou sévères. Les mesures hygiéno-diététiques et les traitements symptomatiques permettent de les contrôler. Il est nécessaire de réaliser un électrocardiogramme avant l’introduction du traitement par crizotinib, à la recherche d’un allongement de la durée de l’intervalle QT. Il faut évoquer la possibilité de torsades de pointes face à la survenue de malaises ou de syncopes. Un hypogonadisme doit être évoqué en cas de fatigue, de baisse de la libido, voire de dépression; compte tenu du fait que ces symptômes peuvent être liés au cancer, un dosage matinal de la testostéronémie doit être réalisé pour identifier les patients devant recevoir une supplémentation. Enfin, une surveillance du bilan hépatique, comportant un dosage des transaminases et de la bilirubine, est nécessaire. En conclusion, ces éléments pratiques d’optimisation représentent un outil pour le clinicien dans la prise en charge du traitement par crizotinib chez le patient porteur de cancer broncho-pulmonaire réarrangé pour ALK, dans l’attente de données académiques spécifiques basées sur le suivi de larges cohortes de patients traités au long cours par crizotinib.

Crizotinib (XALKORI^™, Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK-rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib.