Imatinib and liver toxicity

Abstract

Imatinib is a specific tyrosine kinase inhibitor which has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukaemia and c-KIT (CD117)-positive gastrointestinal stromal tumours. It has been associated with hepatotoxicity ranging from abnormal liver function tests to acute liver failure along with chronic hepatitis B reactivation. We report the case of a patient who was started on adjuvant treatment with imatinib following resection of a primary gastrointestinal stromal cell tumour of jejunum and developed severe hepatotoxicity. There was no history of risk factors for liver disease, and a search for the underlying causes of hepatotoxicity was unremarkable. Imatinib was stopped and she was treated with steroids which resulted in dramatic improvement of liver function tests. Liver biopsy in this case was not performed because liver function tests improved following discontinuation of imatinib and treatment with steroids. Repeat imaging did not reveal any evidence of tumour recurrence.

Background

Imatinib mesilate (Glivec) is a specific tyrosine kinase inhibitor (TKI) with activity against BCR-ABL fusion protein, c-KIT and platelet-derived growth factor receptor.^{1 2} Philadelphia chromosome-positive chronic myeloid leukaemia (CML) and c-KIT (CD 117)-positive gastrointestinal stromal tumours (GISTs) are a group of disorders where constitutively expressed tyrosine kinase results in unregulated cell growth and proliferation.

Initially imatinib was approved for the treatment CML but subsequent studies revealed its effectiveness as adjuvant therapy following resection of c-KIT (CD 117)-positive GISTs.^{3 4} It has now been approved for both these disorders and is administered orally in a dose of 600 mg per day for CML and 400 mg per day for GISTs.⁵

Most patients tolerate imatinib very well although it can be associated with hepatotoxicity in the form of abnormal liver function tests (LFTs) which in severe cases can lead to acute liver failure. We report a case where a patient developed hepatotoxicity while undergoing treatment with adjuvant imatinib following GIST resection.

Case presentation

A 49-year-old woman was diagnosed with a 10.5 cm proximal jejunal GIST which was treated with resection. Histological examination of the specimen suggested high risk of progression due to a mitotic rate >5 per 50 high-power field, size >10 cm and the small bowel location. Mutational analysis revealed a deletion of six nucleotides in exon 11 of the KIT gene in the tumour DNA sample. Because of the sensitivity of such deletions to TKIs, she was then commenced on adjuvant therapy with imatinib 400 mg, orally once a day. Her medical history was unremarkable with no comorbidities and also there was no family history of liver disease. She was not on any regular medications and her baseline bloods including LFTs checked before starting imatinib were within normal limits.

Within a few weeks of being started on imatinib, she developed fatigue and nausea. Blood tests checked after 12 weeks of imatinib therapy revealed mild transaminitis with alanine aminotransferase (ALT) 72 U/L along with normal aspartate aminotransferase (AST), alkaline phosphatase (ALP) and bilirubin. Blood eosinophil count at that stage was also normal. She was continued on imatinib with a plan to monitor her blood tests closely. Repeat LFTs during the following weeks showed a continuous increase in levels with a blood sample taken after 4 weeks revealing ALT 582 U/L, AST 481 U/L and ALP 149 U/L with normal bilirubin. There was mild eosinophilia on the full blood count (FBC) with eosinophil count 0.54×19⁹/ L (0.02–0.50×10⁹/ L). At that point, imatinib was stopped, ‘liver screen’ blood tests were performed and an urgent ultrasound scan of the abdomen organised. Repeat staging CT scan of the chest/abdomen/pelvis was also requested, and she was referred to the liver clinic for further assessment.

During her assessment in the liver clinic, which was 17 days after imatinib discontinuation, she was noticed to have ongoing nausea, fatigue and weight loss of about 1 kg over the past few months. Her only other medication was metoclopramide which she had been taking as required for nausea, and she denied using any other drugs including no over-the-counter or herbal medications. There were no risk factors for underlying liver disease and no relevant family history. Her examination was unremarkable apart from mild conjunctival jaundice, and there was no evidence of rash or organomegaly.

Her blood tests at the clinic revealed further deterioration in LFTs with ALT 1614 U/L, AST 1347 U/L, ALP 230 U/L and bilirubin 48 µmol/L, along with prothrombin time (PT) 15 s (range 9–13 s). Pattern of liver injury was defined by calculating R factor which is the ratio of ALT and AST and in her case R factor value was 21.1, suggestive of hepatocellular liver injury (R>5 hepatocellular injury, R<2 cholestatic injury and R 2–5 mixed liver injury). She was then admitted to hospital from clinic with a plan to perform liver biopsy if her blood results did not settle.

Investigations

Her diagnostic work-up revealed normal FBC with normal eosinophils (0.34×19⁹/ L). Ultrasound abdomen did not reveal any structural liver abnormality. Spleen size was normal, the portal vein and hepatic veins were patent and there was no evidence of ascites. Viral hepatitis screen including hepatitis A virus, hepatitis E virus, hepatitis B virus (HBV), hepatitis C virus, Epstein-Barr virus, cytomegalovirus and adenoviruses was negative. Liver autoantibodies, immunoglobulins, ferritin, ceruloplasmin, alpha-1-antitrypsin and alpha-fetoprotein were all normal.

Her repeat CT scan showed static appearances with no evidence of disease recurrence. A cyst was seen in the left lobe of the liver along with tiny intrapulmonary nodules as noted previously. She remained tired with nausea, but never developed encephalopathy or ascites.

Treatment

Her LFTs did not improve during an initial few days observation in hospital, therefore she was commenced on intravenous methylprednisolone. Following this, her LFTs started to improve dramatically with repeat bloods after 1 week showing ALT 725 U/L, AST 144 U/L, ALP 203 U/L and bilirubin 33 µmol/L. In view of the improving LFTs, it was decided not to perform liver biopsy given the risks versus benefits. Intravenous methylprednisolone was then changed to a tapering dose of oral prednisolone and she was discharged home. She subsequently had close follow-up in the liver clinic to monitor her LFTs and any symptoms or signs.

Outcome and follow-up

She remained well and her LFTs continued to improve, eventually returning to normal in about 10 weeks. The graph in figure 1 shows the pattern of her LFTs during this period.

Figure 1.

Pattern of liver function tests (LFTs). ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

She also had a further CT scan after 13 weeks of discharge from hospital which showed no recurrence of the disease but revealed progressive ground glass changes at both lung bases, raising the possibility of imatinib-related interstitial lung disease. She was asymptomatic and was referred to the respiratory team. Her subsequent imaging organised by the respiratory team revealed significant improvement in lung changes.

Discussion

Imatinib has dramatically improved the treatment of GISTs and is associated with a progression-free survival of 41 months in metastatic or locally advanced GISTs.⁶ Hepatotoxicity is a rare but recognised serious adverse event associated with imatinib, seen in 5% in randomised phase III trials of both GISTs and patients with CML treated with the drug.^{7 8} Most of these patients present with transient mild elevation of liver enzymes, which resolve after dose reductions or discontinuation of the drug. However, acute liver failure has also been reported during imatinib treatment.⁹ The onset of acute liver injury may range from a few days to several years from starting imatinib.¹⁰ The pattern of liver injury is usually hepatocellular in most cases, although cholestatic derangements have also been described.¹¹ In addition, reactivation of chronic HBV infection as a consequence of immunosuppression has been reported following treatment with imatinib.¹²

The mechanism of liver injury appears to be drug-induced hypersensitivity based on liver biopsy findings; however, in some patients an immuno-allergic mechanism may be the underlying phenomenon.^{13 14} Prospective studies of patients with pre-existing mildly abnormal LFTs (bilirubin ≤1.5 × ULN and AST>ULN) regardless of the underlying cause have shown that imatinib can be safely used in this situation.^{15 16} However, close follow-up is mandatory in these patients to detect any deterioration of liver function at an early stage. The manufacturer of imatinib recommends that LFTs should be closely monitored during treatment with this drug, and if bilirubin rises to >3 × ULN or if transaminase levels to >5 × ULN, then the drug should be withheld until bilirubin levels have returned to <1.5 × ULN and transaminases to <2.5 × ULN.¹⁷

The work-up for imatinib-associated liver toxicity includes discontinuation of the drug and a full ‘liver screen’ to exclude other causes of liver injury. If LFTs do not settle, then liver biopsy should be considered to confirm diagnosis. Histological changes reported in case series include inflammation, fatty degeneration or necrosis of the liver cells.¹⁸ Pharmacokinetics of imatinib may be affected by the agents that induce or inhibit CYP450 3A4, and measurement of blood imatinib levels may be helpful in assessing potential drug interactions in such cases.¹⁹

Steroids are the main stay of treatment for established hepatotoxicity and generally result in normalisation of LFTs within 2–4 weeks.²⁰ Sunitinib malate, another multitargeted TKI, has been approved as a second-line option for patients with GIST who are intolerant or resistant to imatinib.¹⁹ However, evidence from case reports is not particularly encouraging and hepatotoxicity has been reported.²¹

Imatinib rechallenge has also been reported in a few cases but has resulted in further episodes of hepatotoxicity (table 1). Ferrero et al reported a series of five cases where prednisone or methylprednisolone at 25–40 mg/day resolved the hepatotoxicity in 3–8 weeks and allowed imatinib to be resumed at full doses.²⁰ Steroids were then tapered off over 3–5 months without recurrence of hepatotoxicity. In another case report, where liver damage was considered to be secondary to a drug interaction with Panax Ginseng, imatinib was restarted and continued successfully.²² Also in one case, liver histology was similar to auto-immune hepatitis which was the reason to consider a successful rechallenge.²³

Table 1.

Previously reported cases of imatinib-induced liver damage in patients with gastrointestinal stromal tumours

Reference	Onset of hepatotoxicity	Liver biopsy	Outcome
EvanWalker EJ et al12	6 months	Liver biopsy was not performed. Explant liver pathology revealed massive necrosis with +ve HBsAg staining in hepatocytes, consistent with hepatitis B virus reactivation.	Fulminant liver failure treated effectively with living-related donor liver transplant and antiviral medication.
Yachoui et al 25	11 days	Liver biopsy was not performed.	Liver function tests started to improve after 1 week of imatinib discontinuation and eventually returned to normal.
Seidel et al 26	6 months	Liver biopsy was not performed. MRI liver revealed changes consistent with liver cirrhosis.	Liver function tests started to improve immediately after imatinib discontinuation and returned to normal within 8 weeks. Rechallenge of imatinib was associated with another episode of hepatotoxicity after 14 days of re-exposure.
Tonyali et al 18	10 weeks	Central haemorrhagic necrosis with loss of hepatocytes.	Imatinib was stopped and prednisolone was started. Liver function test normalised within 9 weeks of treatment.
Alberti et al23	4 weeks	Interface hepatitis with piecemeal necrosis.	Imatinib was stopped and treated with prednisolone and ursodeoxycholic acid. Imatinib successfully restarted.
Pariente et al 27	7 weeks	Portal and periportal fibrosis, bridging fibrosis and periportal necrosis.	Rechallenge twice including one with 2.5% of therapeutic dose resulted in hepatoxicity. Eventually treated with sunitinib.

Table 1 shows a summary of the previously reported cases of imatinib-related hepatotoxicity in patients with GISTs.

Imatinib-related pulmonary toxicity is rare and varies from hypersensitivity reactions to interstitial lung disease, cryptogenic organising pneumonia and nodular opacities. These appear to respond well to imatinib discontinuation and treatment with steroids.²⁴

Learning points.

• This case highlights the importance of monitoring liver function tests (LFTs) in patients being treated with imatinib.

• Imatinib-related hepatotoxicity is usually reversible with discontinuation of the drug.

• Although liver biopsy may be required to confirm the diagnosis, it can be avoided if LFTs improve following discontinuation of imatinib which may take 1–4 weeks.

• As it is, it looks like stopping drug and giving steroids is used for all patients.