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.