Grade 1:
ALT/AST < 3 x ULN

Grade 1:
1) Maintain TKI dose.

Grade 1:
Liver and coagulation counts should be checked weekly/every 14 days.

Grade 2:
3 x ULN ≤ ALT/AST ≤ 5 x ULN without bilirubin elevation (bilirubin <2 x ULN) + without hypersensitivity symptoms (e.g., fever, rash).

Grade 2:
1) Pause TKI
2) Review the patient’s medication list.
Consider the interaction between TKI and other medication as the cause of the liver impact (use the interaktionsdatabasen.dk, if necessary)
3) TKI may be resumed at a reduced dose when grade ≤ 1 and liver and coagulation counts should be checked weekly.
If recurrence of liver tox (ALT/AST > 3 x ULN) after re-introduction, TKI should be paused again and, if possible, further reduced. Otherwise, TKI should be discontinued and another medicinal product tried.

Grade 2:
Check liver and coagulation counts weekly or more frequently until grade ≤1. The patient shall be contacted and asked about symptoms.

Grade 3:
5 x ULN <ALAT/ASAT ≤ 8 x ULN without elevated bilirubin (conjugated bilirubin <2 x ULN or without symptoms of hypersensitivity).

Grade 3:
1) Pause TKI.
2) Blood tests to rule out other aetiology: Hepatitis A, B, C and E, CMV and EBV
3) Consider US of liver.
4) TKI may be resumed at a reduced dose when grade ≤ 1 and liver and coagulation counts should be checked weekly.
5) In event of recurrence of liver tox: repeat 1) and 4), where TKI is started at a further reduced dose.

Grade 3:
Check liver and coagulation counts weekly or more frequently until grade ≤1. The patient shall be contacted and asked about symptoms.
Slightly elevated unconjugated bilirubin, may be seen in patients with Gilbert’s syndrome.

Grade 4:
ALT/AST > 8 x ULN or ALT/AST > 3 x ULN with elevated bilirubin (conjugated bilirubin > 2 x ULN with conjugated bilirubin > 35%) or with symptoms of hypersensitivity.

Grade 4:
1) Discontinue TKI.
2) Follow points 2), 3) and 4) under Grade 3.
3) When grade 1 liver tox, another TKI can be tried at a reduced dose with control of liver and coagulation counts weekly.

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