Imatinib therapy is associated with mild liver dysfunction in up to 10% of patients, which often normalises despite continued imatinib use.4
Grade 3 or 4 hepatotoxicity occurs in less than 5% of patients.1 5
Severe hepatotoxicity usually resolves with imatinib dose reduction or interruption5
; however, it can recur with reintroduction of imatinib.6–9
This recurrent hepatotoxicity has been noted to be the second most common reason for permanent discontinuation of imatinib therapy,4
thus causing difficulties in the management of CML.
Imatinib-induced hepatotoxicity tends to occur during the first few months of therapy4 10
with a median delay of 22 weeks (range 1.7–104 weeks) after drug initiation among reported cases.11
Liver function tests, on the other hand, return to normal within about 7 weeks (range 2−20 weeks) of discontinuation of imatinib. Histopathological examination of biopsied liver samples reveals necrotic hepatitis associated with a non-specific inflammatory infiltrate in the majority of patients, while interface hepatitis and bridging necrosis can be seen in some cases.11
The mechanism of the hepatotoxicity is currently unclear, although on liver biopsy it appears to be drug-induced hypersensitivity.4 10
However, an immuno-allergic mechanism may play a role in some patients.11
When imatinib is used, it is recommended that liver function tests are monitored at baseline and regularly thereafter, for example, every few weeks for the first month and every month or 3 monthly thereafter. In case of hepatotoxicity, any hepatic toxins, particularly alcohol and acetaminophen, should be avoided.4 10 11
A thorough hepatic evaluation is recommended for grade 2 hepatotoxicity or higher.4
While imatinib can still be continued under close monitoring in the event of grade 1/2 hepatotoxicity, therapy must be interrupted if grade 3/4 hepatotoxicity ensues.4 10
It can be resumed at the same10
dose when liver function tests decrease to grade 1 or less. If it has been restarted at a reduced dose, the dose can be escalated if hepatotoxicity does not recur within 6–12 weeks.4
In cases of recurrent grade 3/4 hepatotoxicity, it is recommended that imatinib therapy is permanently discontinued.4 10
In resource-poor settings where patients may not be able to afford or access alternate therapy, the inability to use imatinib can cause serious problems in the management of CML. Furthermore, use of an alternate therapy, for example, second-line TKIs, can impose a huge economic burden on the health system. This is especially relevant in light of imatinib going off patent in 2015, which will dramatically reduce its cost.12
In this patient, it was possible to safely restart imatinib with concomitant use of oral prednisone. The introduction of corticosteroids into the patient's regimen has been previously shown in a few case reports to enable use of imatinib in patients who develop recurrent hepatotoxicity, even at reduced doses.6 9 13 14
Steroids used in these case reports included oral prednisone 25 mg daily tapered over 5–8 months,6
prednisone 30 mg daily tapered over 5 months,9
prednisone 20 mg daily (duration not mentioned)13
and prednisone 25 mg twice daily (duration not mentioned).14
The usefulness of corticosteroids may be based on their ability to suppress the inflammatory response in the liver as a part of drug-hypersensitivity or an immuno-allergic reaction.
- Imatinib can cause severe hepatotoxicity.
- Imatinib-induced hepatotoxicity is reversible with discontinuation of the drug but tends to recur with subsequent use.
- Recurrent grade 3/4 hepatotoxicity can necessitate permanent discontinuation of the drug.
- In such conditions, use of corticosteroids can enable successful reintroduction of the drug.