A 45 year old obese lady with chr phase CML. Was on Imatinib generic version for the last 2 yrs. Was doing well. Since 4 months having raised liver enzymes- 10 times upper limit of normal. Once bilirubin went up to 8.2mg/dl. Was seen by gastroenterologist and worked up. All tests negative - impression drug induced. Stopped the drugs for 2 weeks. Drug changed to Geevev once LFt returned to normal. Had for 1 month again started increasing. Then stopped and restarted on tasigna. Was doing well for 1 month. Now again liver enzymes are 10 times normal. bilirubin normal She is asymptomatic. Her last Br/Abl level was 8% - 6 months ago.
What to do next? suggestions please.

It is not possible to help without more information.
Where is this patients living? Is she taking other drugs or herbs? Is she drinking alcohol?
It is difficult that a patient on imatinib has a increase of bilirubine up to 8.2.
It is difficult that a patient on nilotinib has an increase of liver enzymes up to 10 times upper limit of normal, and no increase of bilirubine.
I would go back to imatinib, 300 mg once daily, monitoring liver and qPCR every 4 weeks – if it is possible. If it is not possible, I would advise Dasatinib 50 mg once daily – but will Dasatinib be available?
Best regards, Michele Baccarani

This patient is from Kerala, India. She was not on any other medications. She is obese, BMI 42. She is not an alcoholic. If you stop the drug for one week, the enzymes comes down.On rechallenge, it again goes up. Even with generic, it is the first time I am observing this phenomenon.
That was why it was posted here, to get a view from the experts. dasatinib is available in India

Late transaminitis with increased bilirubin is a rare but known complication of imatinib thrapy. Most occurs early and resolves with a drug holiday or on rare occasion a short course of corticosteroid. I think the stop and restart trial that you did confirms an association with imatinib and nilotinib and it would appear that you have eliminated most of the other obvious issues. There are a couple outstanding that should be looked at. These include iron overload syndromes including hemochromatosis and autoimmune hepatitis. I think these need to be considered. It is also a thought to consider a liver biopsy. Whether this is a primary TKI effect or whether the TKI is bringing out an underlying borderline problem should be settled. Rather than continue to push imatinib or nilotinib, I would agree with Michele"s thought about dasatinib and the dose. Hepatitis is not a common side effect of dasatinib.
The other thing to be considered here is that the response is 8% at at least 2 years of therapy. It is not reported here whether this is the best response or whether response has been lost somewhat with the drug holidays. Either way, this is a very sub-optimal response regardless of what guideline you use to assess. I think this needs some work up as well with a bone marrow looking for clonal progression and with TK mutation testing to look for resistance. Even if dasatinib is tolerated from the liver perspective, you need to be sure that it is the best choice from a CML perspective.