Article Type : Case Report
Authors : Zenzri Y, Daoud N, El Benna H, Berrazaga Y and Boussen H
Keywords : Crizotinib; Bergamot; Hepatotoxicity
Non-small cell lung cancer (NSCLC) is the leading
cause of cancer death. The identification of oncogene tic driver mutation in
lung cancer led to a therapeutic revolution by the discovery of targetable
genetic alterations including the anaplastic lymphoma kinase (ALK) fusion
oncogene and ROS1. The tyrosine kinase inhibitor “Crizotinib” improved clinical
outcome and prolonged responses. Severe hepatotoxicity is a rare adverse event.
We report a case of Crizotinib-induced acute hepatitis with a probable
drug-bergamot interaction.
Crizotinib is a targeted therapy, tyrosine kinase
inhibitor that proved its efficacy in advanced non-small cell lung cancer
(NSCLC). At a conventional oral dose of 250 mg, twice daily, it is
well-tolerated and the most frequently occurring adverse events graded 1, 2 are
visual disorders, gastrointestinal symptoms (diarrhea, nausea-vomiting, anorexia,
and constipation), peripheral edema and neutropenia [1]. The mechanism of
Criztotinib hepatotoxicity is unknown. Grade 3-4 liver toxicity is an unusual
side effect. We present here a case of Crizotinib-induced severe
hepatotoxicity.
A 61–year-old nonsmoker woman, without medical
comorbidities or hepatic previous disease, presents with a 4-months history of
isolated dry cough. Physical examination was normal. Etiological work-up showed
the presence on CT-scan of a bulky right lung lesion, with contralateral
axillary and supraclavicular lymph nodes with right pleural effusion.
Bronchoscopy showed tumor localized
to right upper lobar bronchus
and biopsies have concluded a primary lung adenocarcinoma with positive TTF1 on
immunohistochemistry (IHC). We performed a screening for anaplastic lymphoma
kinase (ALK), epidermal growth factor receptor (EGFR) and ROS 1. ROS1 rearrangement was identified. Additional work-up showed
the presence on brain magnetic resonance imaging (MRI) of cerebral, bone and
lymph nodes metastases. She was diagnosed with stage IV lung cancer in February
2019. The patient's full blood count, renal and liver function tests
were normal. The patient was started on tablet Crizotinib 250 mg twice
per day ten days after diagnosis. Crizotinib was given as monotherapy for front
line management. During the follow-up, 53 days after the beginning of
Crizotinib, she presented to the emergency department with complaints of
fatigue, vomiting, anorexia and nausea since 2 days. The clinical examination
was normal. There was neither hepatomegaly nor jaundice. A complete blood
count, kidney and liver tests were performed. Liver tests showed highly
increased ALT at 2413 IU/l (45 times the upper limit of normal), AST at 1062
IU/l ( 25 times the upper limit of normal), prothrombin time (PT) at 62%, while
ALP, GGT and bilirubin were normal. She was admitted to the hospitalist team
for management of acute hepatitis. An abdominal ultrasound was normal for liver
parenchyma and bile ducts without obstruction or ischemic hepatitis. Hepatitis
B markers were negative for HBs Antigen and HBc antibodies as well as PCR
testing for HCV, cytomegalovirus, herpes simplex virus and Epstein–Barr virus.
The patient reported having consumed Bergamot
orange during Crizotinib treatment. We decided to stop the treatment and the
bergamot intake. One month after livers tests normalization, we decided to
restart it at a half dose of 250 mg once daily. However, 2 days after drug reintroduction, liver tests showed
hepatic cytolysis and we stopped definitely Crizotinib. Ceritinib was the second-line drug received during three
months. Treatment was started at a dose of 750 mg/day. Regular liver enzyme testing was carried out during
treatment. The tests were normal. A progression of the disease was noted after
3 months of Ceritinib. The patient is on third line chemotherapy by pemetrexed
and carboplatin.
This report describes a durg –induced acute
hepatitis by Crizotinib, a small molecule inhibitor with multiple targets, including ALK, c-MET, and ROS1. Crizotinib is approved for the
treatment of a distinct subgroup of NSCLC mediated by rearrangements of ALK or
ROS1 [2,3]. The PROFILE 1 and subsequent randomized studies proved Crizotinib
efficacy, safety and its superiority compared with chemotherapy. The most
common adverse events of Crizotinib include diarrhea, constipation, abdominal
pain, anorexia, nausea, visual disturbances, fatigue and peripheral edema.
Potentially serious adverse effects include interstitial lung disease and QT
prolongation [4]. In a recent meta-analysis about 1,908 patients from 10
clinical trials, ALT and AST all-grades increase were observed in 25.2 and 26%,
respectively, while grade 3 and 4 were reported in 7 and 9.9%. Sub-group analysis
showed a higher incidence of liver toxicities for ceritinib compared
to Crizotinib and alectinib [5]. Renault et al reported the first case
with crizotinib-induced acute hepatitis, who relapsed after reintroduction of
the treatment [6-10]. Profile 1014, a phase 3 study has demonstrated that grade
3 or 4 elevated aminotransferases were noted in 24 patients receiving
Crizotinib. A majority of these adverse events were reversible on dose
interruption. Four cases of fatal hepatic failure have been reported in the
literature (Table 1).
Table
1:
Case reports of Crizotinib-induced fatal hepatic failure.
|
Autours |
Dose of Crizotinib |
Therapy line |
Occurrence time of fulminant liver failure |
|
Sato |
400 mg every day |
First line |
Day 29 |
|
Van Geel |
250 mg twice a day |
Second line |
Day 24 |
|
Adhikari |
250 mg twice a day |
First line |
Day 39 |
|
Zhang |
250 mg twice a day |
First line |
Day 46 |
That the underlying mechanism was partly an
allergic reaction to Crizotinib or its metabolites. Dose reduction associated
with oral steroids following crizotinib-induced hepatotoxicity did not improve
the hepatitis. Oral desensitization may be considered as a good option
following hepatitis [11]. Moreover, Ceritinib which is a small molecule
tyrosine kinase receptor inhibitor could be an alternative treatment when
crizotinib causes hepatotoxicity [12]. Specific risk factors for
Crizotinib-induced hepatitis remain unclear. General risk factors of
drug-induced hepatotoxicity are reported to be female sex, pregnancy, older
age, excessive alcohol intake, smoking, HBV or HCV infection, HIV infection and
genetic variability [13,14]. The use
of CYP3A inducers and inhibitors like grapefruit juice must be interrupted
since it may increase the plasma concentration of Crizotinib [15]. In our case,
the patient reported having
consumed Bergamot orange during treatment. Bergamot tin is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot
orange. Bergamot tin was tested
for its inhibitory effects on hydroxylase and O-dealkylase activities of human
cytochrome P450 is enzymes CYP 3A4 and CYP 1B1 [16]. This could explain the
enhancement of liver toxicity observed in our patient. Crizotinib-induced
hepatotoxicity usually occurs within the first two months of treatment.
Monitoring liver function tests every two weeks is mandatory during this
period. A thorough knowledge of the metabolism and pharmacologic properties of the treatment is important to prevent side effects.
Although Crizotinib is usually well
tolerated, it can cause acute hepatitis in lung cancer patient. Regular liver
enzyme testing should be carried out during the first two months of Crizotinib
treatment. Further work should explore underlying mechanisms of
these severe cases to identify risk factors that can induce hepatotoxicity.
Not applicable