Hospital Pharmacy - June 2019 - 163

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Fu et al
Table 1. Reported Cases of Hepatotoxicity Following Cytarabine Therapy.
Patient

Presentation

Other concurrent
hepatotoxic medications

Cytarabine exposure

A 72-year-old female
with acute myeloid
leukemia with 40% to
50% blasts(our case)

Became jaundiced and
experienced AMS 5
days after HiDAC

Posaconazole 300 mg once
daily on day 21 to day 26
Micafungin 100 mg once
daily on day 30 to day 34

Nine doses of HiDAC
1.5 g/m2 given Q12H

A 45-year-old male
with Philadelphia
chromosome positive
chronic myelogenous
leukemia.9

Became jaundiced
second week after
chemotherapy

Prochlorperazine 10 mg
for the first 6 days of
chemotherapy
Allopurinol, dosage and
frequency not reported

Twelve doses of HiDAC
3 g/m2 given Q12H

A 31-year-old male with
T-cell lymphoblastic
leukemia.9

Became jaundiced
7 days after
chemotherapy

Twelve doses of HiDAC
3 g/m2 given Q12H

A 45-year-old
Japanese female
with secondary
myelodysplastic
syndrome.10
A 15-year-old female
with relapsed AML.11

High-grade fever,
dyspnea, acute renal
failure on Day 4 of
chemotherapy

Prochlorperazine 10 mg
for the first 6 days of
chemotherapy
Allopurinol, dosage and
frequency not reported
None or not reported

Severe abdominal pain,
vomiting, diarrhea,
jaundice and grade
1 encephalopathy
25 days after
chemotherapy

Two doses of mitoxantrone
12 mg/m2

Six doses of HiDAC
3 g/m2 given Q12H

A 46-year-old male
with Janus kinase 2
positive, BCRABL negative
myelofibrosis.12

Not reported

None or not reported

Three doses of reduced
dose of HiDAC 1 g/m2

Low-dose cytarabine
10 mg/m2 SQ Q12H.
Discontinued after 9
doses

Pertinent laboratory or other
findings
Liver baseline: Normal with slightly
elevated T.bili
Liver dysfunction following
cytarabine: AST 7000 U/L,
ALT 4638 U/L, T.bili 2.3 mg/dL
Liver baseline: WNL on admission
Liver dysfunction following
cytarabine: AST 39 U/L,
AP 393 U/L, LDH 133 U/L,
T.bili 21 mg/dL. U/S negative
for gallstones or biliary system
dilatation.
Postmortem showed no evidence
of septic cholangitis or abscess
Liver baseline: Not reported
Liver dysfunction following
cytarabine: AST 10 U/L,
AP 103 U/L, LDH 131 U/L, T.bili
23 mg/dL. U/S normal
Liver baseline: WNL
Liver dysfunction following
cytarabine: AST 368 U/L, ALT
232 U/L, T.bili 1.3 mg/dL
Liver baseline: ALT 110 U/L
(WHO grade I), AP 2x ULN
Liver dysfunction following
cytarabine: AST 4500 U/L,
ALT 3330 U/L, LDH 15030 U/L,
AP 324 U/L, bilirubin up to
2.6 mg% (WHO grade III-IV).
U/S positive for hepatomegaly
Liver baseline: bilirubin 15.9 mg/dL
Liver dysfunction following
cytarabine: Bilirubin of
7.6 mg/dL and 3.2 mg/dL on day
6 and 18 of cytarabine therapy,
respectively.

Outcome
Care withdrawn per
family's request

Expired due to sepsis

Expired due to septic
shock

Discharged
without further
chemotherapy

Patient developed
encephalopathy and
expired

Leukemia-free greater
than 2 years
posttransplant

Note. HiDAC = high-dose cytarabine; T.bili = total bilirubin; AST = aspartate aminotransferase; ALT = alanine aminotransferase; WNL = within normal limit; AP = alkaline
phosphatase; LDH = lactate dehydrogenase; U/S = ultrasound; WHO = World Health Organization; ULN = upper limit of normal; AMS= altered mental status; Q12H = every
12 hours.

cytarabine, or to what extent.5,15,16 It is important to note that
while the existing case reports have similarity to our patient,
none of them exhibited the same degree of severity and quick
onset of hepatotoxicity. The inconsistency between the
reported laboratory values of LFTs and T.bili levels compared with the observed manifestation and severity of hepatotoxicity in the literature does not provide a clear
cause-effect relationship. Based on our patient's presentation, and published reports, there is not enough evidence to
suggest that bilirubin alone could have been a predictive
marker in hepatic injury for our patient.
The patient was not hypotensive during her HiDAC therapy, nor did she have a significant history of hepatic injury or
a positive hepatitis panel. It is possible given the age of our
patient, she was at a higher risk of hepatic injury, however;
data are lacking to prove this hypothesis. In addition, she
received a reduced dose of cytarabine empirically due to her
increased age. A recent study suggested that patients who
have a homozygous variant TT of NT5C2, a gene that

encodes metabolic enzymes for cytarabine, are at a higher
risk of hepatotoxicity. Within that retrospective study cohort,
a higher frequency of this homozygous variant was observed
in patients 65 years or older.17 Our patient was the oldest at
age 72 where other patient cases reported in the literature
were all below the age of 65. It is possible that our patient
had the homozygous TT variant of the NT5C2 gene and thus
was at a higher risk of cytarabine-related toxicity. Although
our patient was previously exposed to a lower dose of cytarabine, the extensive hepatic injury did not manifest until the
higher dose was given. The half-life of cytarabine is relatively short, within 1 to 3 hours in the elimination phase.11
Without other obvious concurrent hepatotoxic medications
or causes of the acute hepatic injury and lactic acidosis, we
assigned this drug reaction a score of 5 on the Naranjo scale;
it was probable that cytarabine, specifically, HiDAC, was
associated with the observed hepatotoxicity. Clinicians
should exercise caution when using cytarabine in elderly
patients with and without preexisting hepatic conditions.
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