Lorlatinib-induced visual and auditory hallucinations: a case report
Jun Hakamata1, Hideo Nakata2,
Hiroshi Muramatsu1, Keita
Masuzawa3,4, Hideki Terai5,
Shinnosuke Ikemura3,6, Koichi
Fukunaga3, Tohru Aomori1,2
1Department of Pharmacy, Keio University Hospital,
Tokyo, Japan
2Division of Hospital Pharmacy Science, Faculty of
Pharmacy, Keio University, Tokyo, Japan
3Division of Pulmonary Medicine, Department of
Medicine, Keio University School of Medicine, Tokyo, Japan
4Division of Pulmonary Medicine, Department of
Medicine, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
5Keio University Hospital Clinical and Translational
Research Center, Tokyo, Japan
6Department of Cancer center, Keio University
Hospital, Tokyo, Japan
Correspondence
Jun Hakamata, Department of Pharmacy, Keio University Hospital 35
Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Phone & Fax: +81-3-3353-1211 E-mail:
jun.hkmt@adst.keio.ac.jp
What is known and objective:
Lorlatinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor
for the treatment of non-small-cell lung cancer. We report a case in
which visual and auditory hallucinations developed while receiving
lorlatinib.
Case summary:
A 72-year-old Japanese man developed grade 2-3 visual and auditory
hallucinations while taking lorlatinib. The hallucinations disappeared
after discontinuing the lorlatinib, but grade 1 hallucinations developed
after readministration. The hallucinations were a suspected adverse drug
reaction. Lorlatinib was discontinued due to worsening general condition
but the auditory hallucinations did not improve.
What is new and conclusion:
This case is significant because lorlatinib is still infrequently
administered, having been approved as recently as November 2018 in
Japan.
Keyword: lorlatinib, hallucinations, non-small-cell lung cancer,
Japanese patient
Key Clinical Message:Lorlatinib can cause visual and auditory
hallucinations. And, it is necessary to keep in mind that hallucinations
can persist even after discontinuation in patients who develop
hallucinations while receiving lorlatinib.
What is known and objective
Around 3%–5% of patients with non-small-cell lung cancer (NSCLC) are
positive for anaplastic lymphoma kinase (ALK) and they are susceptible
to treatment with an ALK tyrosine kinase inhibitor
(ALK-TKI).1-3 In Japan, crizotinib, alectinib, and
ceritinib are used in the primary treatment of ALK-positive NSCLC, but
relapse can still occur due to secondary mutations in the ALK domain and
exacerbations in the central nervous system (CNS).4,5
Lorlatinib, a third-generation ALK-TKI targeting ALK and c-ros oncogene
1 (ROS1) kinases, is expected to be effective in patients with ALK-TKI
resistance.6 It is designed to penetrate the
blood-brain barrier and it has efficacy against known ALK resistance as
well as brain metastasis.7,8
It was approved in Japan in November 2018 and therefore has not been
administered in a large number of cases as yet.
CNS disorders have been reported as characteristic adverse events
associated with lorlatinib. A safety analysis of a phase I/II trial of
lorlatinib (n=295) recorded the following effects as CNS disorders:
cognitive effects in 23.1% of patients (1.7% grade 3-4); mood effects
in 21.0% (1.4% grade 3-4); and speech effects in 14.2% (0.3% grade
3-4).7 However, there have been no detailed reports on
hallucinations caused by lorlatinib among patients with the CNS
disorders.
Here, we report in detail a case in which lorlatinib administration was
associated with visual and auditory hallucinations, with the auditory
hallucinations persisting after lorlatinib was discontinued.
Case summary
The patient was a 72-year-old man (height, 166.3 cm; weight, 58.6 kg)
who was admitted with right heart failure. He had a history of cerebral
infarction, type 2 diabetes, hypertension, non-sustained ventricular
tachycardia, and constrictive pericarditis and no history of allergic
reaction. He was receiving alectinib for ALK-positive NSCLC. On
admission, computed tomography showed ground-glass opacity in the lungs,
so the alectinib was discontinued due to suspected drug-induced lung
injury and steroids were started. After the lung injury showed
improvement, alectinib was switched to lorlatinib 100 mg/day. At the
time of switching to lorlatinib, both renal and liver function was
normal. On the day 4 after lorlatinib was initiated, he experienced
auditory hallucinations, followed by visual hallucinations 3 days later.
The hallucinations were diagnosed as grade 2–3 CNS disorders. He
reported hearing music playing outside the window or close to him,
loudly or faintly, and involving familiar and unfamiliar tunes. In
particular, he said the music was faint when talking with people. The
visual hallucinations ranged from mild, such as curtains approaching him
up close and stuffed animals emerging from the ceiling, to severe ,
including his bed turning into an airplane or train and seeing a variety
of magnificent views and cityscapes from the window. Concomitant
medications were the same as before admission and before the visual and
auditory hallucinations developed: vonoprazan fumarate (10 mg/day), a
precipitated calcium carbonate/cholecalciferol/magnesium carbonate
mixture (2 tablets/day), rosuvastatin calcium (2.5 mg/day), aspirin (100
mg/day), a trimethoprim/sulfamethoxazole mixture (1 tablets/day),
magnesium oxide (990 mg/day), prednisolone (10 mg/day), and torasemide
(4 mg/day). Lorlatinib was discontinued the day after the onset of
visual hallucinations, but both the visual and auditory hallucinations
persisted for a further 3 days before disappearing on day 4 after
discontinuation. Lorlatinib was restarted at 50 mg /day on day 5 after
discontinuation, and the visual and auditory hallucinations reappeared
the following day. He reported that the visual hallucinations were less
powerful and that the auditory hallucinations were about half as loud as
before. The specific visual hallucinations included curtains approaching
him up close, stuffed animals emerging from the ceiling, and ceiling
lights moving. The auditory hallucinations included various pieces of
music playing outside the window and above his head. He was diagnosed
with grade 1 CNS disorder. There were no findings suspicious for brain
metastasis and no medications that could cause delirium. Also,
psychiatrists determined that delirium was unlikely because of the lack
of cognitive decline and disorientation. Six months later, his general
condition deteriorated and lorlatinib was discontinued. However, grade 1
auditory hallucinations persisted, sometimes as singing but mostly
instrumental and with familiar and unfamilar pieces. He often
experienced these hallucinations in the morning, during quiet times
before going to bed, and when it was quiet during the daytime. We show
the course of this case in fig.1.
Lorlatinib is expected to be effective against unresectable advanced or
recurrent ALK-positive NSCLC that is resistant or intolerant to an ALK
tyrosine kinase inhibitor.8-10 In our case, there was
no organic cause of the visual and auditory hallucinations such as brain
damage or brain metastasis and there was no history of psychotic
symptoms. Therefore, we suspected the hallucinations to be drug-induced.
Auditory hallucinations developed on day 4 and visual hallucinations on
day 7 after starting to take lorlatinib 100 mg. Given that the half-life
of lorlatinib is 20.8±3.80 h, the blood concentration of lorlatinib
theoretically reached a steady state on day 4-5 after the onset of
auditory hallucinations. Moreover, the auditory hallucinations
disappeared on day 5 after its discontinuation and the visual and
auditory hallucinations reappeared after its resumption.
In a study by Bauer, among the CNS disorders by lorlatinib, median time
to onset of mood effects was 43 days (range, 1–452 days), that of
cognitive effects was 53 days (range, 1–423), speech effects was 42
days (range, 1–404).7 However, there were no reports
about the time to onset of visual and auditory hallucinations.
We also considered whether concomitant prednisolone may have caused the
visual and auditory hallucinations. Prednisolone, a steroid, is
administered for drug-induced pneumonitis. In a study on steroid-induced
psychiatric syndromes by Lewis and Smith, 43% of cases developed
symptoms during the first week of treatment, 57% within the first 2
weeks, and 93% within 6 weeks.11 Based on these
findings, it would seem unlikely that prednisolone induced the
hallucinations in our patient because they developed 2 months after its
initiation. In another study, psychiatric symptoms were noted in 1.3%
of 463 patients on prednisolone 40 mg/day, 4.6% of 175 patients on
41-80 mg/day, and 18.4% of 38 patients taking 80 mg/day or
more.12 In the aforementioned study by Lewis and
Smith, 23% of the patients had been receiving less than 40 mg/day of
prednisone before the onset of psychiatric symptoms, whereas 77% had
been receiving more than 40 mg/day.11 Therefore, the
psychological symptoms caused by prednisolone are presumed to be
dose-dependent. Psychiatric symptoms were unlikely in the present case
because the prednisolone dose at onset of the hallucinations was low (10
mg/day).
Lorlatinib has been shown to be effective against brain metastasis owing
to its high blood–brain barrier penetration.8,9However, the frequency of adverse events in the CNS is reported to be
39.7%. These adverse events include mainly cognitive effects, mood
effects, and speech effects7, and there are no
detailed reports on visual or auditory hallucinations. We suspect that
the mechanism behind the visual and auditory hallucinations is related
to the effect of lorlatinib on the CNS, but the mechanism remains to be
clarified. Because the risk factors associated with adverse events in
the CNS are unknown, further study is warranted.
To evaluate the accuracy of the
relationship between suspected drug and adverse event, we used the
adverse drug reactions probability scale proposed by Naranjo et al. In
this case, the hallucinations were classified as “possible” because
the score was 7points (table 1).13
In this case, grade 1 auditory hallucinations persisted after lorlatinib
was discontinued. Bauer et al. reported that the median time to
resolution of CNS disorders by discontinuing lorlatinib was 12.5 days
(range 2–112).7 However, the hallucinations did not
improve in our case, and therefore it is necessary to keep in mind that
hallucinations could persist even after discontinuation in patients who
develop hallucinations while receiving lorlatinib.
What is new and conclusion
We encountered a patient who developed visual and auditory
hallucinations caused by lorlatinib. To our knowledge, this is the first
detailed report of lorlatinib-induced hallucinations and the persistence
of auditory hallucinations after discontinuation. Such scarcity of
reports is probably due to the infrequent use of lorlatinib to date.
Conflicts of interest: The authors have no conflicts of interest to
declare.
Funding information: None.
Author contributions: JH: contributed to acquisition of data, drafting
the manuscript, final revision of the manuscript, and participated
sufficiently in the work. HN, HM, KM, HT, SI, KF, and TA: made
significant contribution toward editing of the manuscript.
Acknowledgement: The authors thank Sugita of ThinkSCIENCE, Inc. for
proofreading our paper.
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