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BCR-ABL mutations

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Stephen Ting
Topic Author

8 years 8 months ago #1048 by Stephen Ting

BCR-ABL mutations was created by Stephen Ting

Patient is a 38 year old male with no co-morbidities. Presented with BM confirmed chronic phase CML with haemoglobin 100 g/l, white cell 368 x 109/L and platelets of 319 x 109/L.
Bcr-Abl 151% reduced to 0.056% within the year on Dasatinib 100 mg.
He has just acquired a significant pleural effusion requiring drainage.
I will recommence him on 70 mg.
In preparation for the potential of a recurrent effusion, I would like to look for the T35I mutation.

Question 1. At 0.056% - can this be done from peripheral blood or will he need a marrow?

Question 2. Can I request for a screen of all the other Bcr-Abl mutations that are associated with TKI-specific sensitivities?

Question 3. If required, would you consider as next line, Posatinib regardless of the T35I mutation result?

Thanks in advance
Stephen

Tim Hughes
Topic Author

8 years 8 months ago #1049 by Tim Hughes

Replied by Tim Hughes on topic BCR-ABL mutations

The T315I mutation has been more frequently associated with dasatinib so I understand your concern. It might be technically challenging to look for the T315I mutation at this level of BCR-ABL. However I don’t think a mutation screen is indicated at the moment. He has achieved MMR at 12 months, so the chances of finding any mutation by conventional sequencing is very low. I guess your concern is that he will now be receiving a lower dose of dasatinib and is therefore prone to developing a resistant mutation. I think as long as he maintains and hopefully improves his molecular response I wouldn't be greatly concerned about resistance emerging even on a modified dose of dasatinib. Having said this, I would still be aiming to get him back on full dose dasatinib if at all possible over the next few months – and it often is possible in this setting.

As long as his molecular response is stable and his pleural effusions are not symptomatic I wouldn't switch him to another TKI. If molecular response is lost and/or he develops problematic recurrent effusions I would probably switch to nilotinib. The risk of vascular events is too high to justify ponatinib use in this case unless T315I does emerge or he is also resistant or intolerant to nilotinib.

Jeff Lipton
Topic Author

8 years 8 months ago #1050 by Jeff Lipton

Replied by Jeff Lipton on topic BCR-ABL mutations

Agree with Tim. The chance of finding a mutation with this degree of response is very unlikely and there is no role in my mind for mutation screening on a routine basis using standard Sanger sequencing (15-20% sensitivity). A mutation search should be triggered by a loss of response, usually a loss of MMR before one will be picked up. High resolution mutation testing (<1% sensitivity), as a predictor for future mutation development is an exploratory test, which should not be deemed as standard.
In regard to pushing the dose back to 100mg. This might not be necessary if the patient retains response to 70mg. There are recent data from the French OPTIM study which suggests that based on dasatinib blood levels, the optimal dose of dasatinib may be around 70-80mg. I would restart when you have the cleared the effusion and monitor, increasing the dose only if there appears to be loss of response.
Definitely feel that with one effusion and no loss of response with dose modification, there is no need to switch TKIs.

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