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Losing molecular response to multiple TKI without any KD mutation

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Prof. Akhil Ranjon Biswas
Topic Author

1 month 6 days ago - 1 month 4 days ago #2019 by Prof. Akhil Ranjon Biswas

Losing molecular response to multiple TKI without any KD mutation was created by Prof. Akhil Ranjon Biswas

From Bangladesh

A 29-year-old young man, whose CML risk status was not documented before initiation of treatment, consulted me while he was taking Imatinib for 2 months. He was in CHR at that time and achieved MMR at 3 months. However, he lost MMR at 12 month and loss of MMR was confirmed at 15 month. His KD mutation at that time came negative and his TKI was changed to Dasatinib.

He tolerated dasatinib very well and he achieved deep MR (MR 4.5) at 7 months of dasatinib. But at 11 months he lost his deep MR having BCR-ABL1 in IS 0.0606. I'm planning to repeat his q-PCR after 1-2 months.

Is it likely to be a BCR-ABL1 independent resistance to TKI? If so, should he proceed for allogenic stem cell transplantation now? or wait for further decision till loss of MMR? Should I try 3rd TKI now or after loss of MMR? Any combination with TKI can help? Should I check KD mutation once again?

Last edit: 1 month 4 days ago by arlene.

Gianantonio Rosti
Topic Author

1 month 4 days ago - 1 month 4 days ago #2020 by Gianantonio Rosti

Replied by Gianantonio Rosti on topic Losing molecular response to multiple TKI without any KD mutation

Firstly, there is no indication to repeat mutational analysis (in condition of MMR, the chance of finding a mutation is very, very low, null; not due to lack of sensitivity but because it is quite unlikely to find a mutation in MMR).

Secondly, the disease is quite sensitive to TKI treatment and the current ‘loss of DMR’ should be interpreted as an expected oscillation of the molecular level.

So, I suggest to go on with Dasatinib, next QPCR at 3-4 months after the previous one.

Hope this will help , I remain of course available for further interactions.

Last edit: 1 month 4 days ago by arlene.

Michael Mauro
Topic Author

1 month 3 days ago - 1 month 1 day ago #2021 by Michael Mauro

Replied by Michael Mauro on topic Losing molecular response to multiple TKI without any KD mutation

I agree with Dr Rosti in that in a relatively sensitive patient, fluctuation between deeper MR (below 0.01%) and >MMR response (0.1-0.01) is unlikely to yield TKD mutation, can be seen quite often during treatment and perhaps the only immediate action may be to re-examine the BCR-ABL level ahead of schedule to reassure against relapse PCR trend or loss of MMR.

Last edit: 1 month 1 day ago by arlene.

Qian Jiang
Topic Author

1 month 2 days ago #2022 by Qian Jiang

Replied by Qian Jiang on topic Losing molecular response to multiple TKI without any KD mutation

Totally agree with Dr Rosti 's idea.

Jeff Lipton
Topic Author

1 month 1 day ago #2023 by Jeff Lipton

Replied by Jeff Lipton on topic Losing molecular response to multiple TKI without any KD mutation

I agree completely with what Gianntonio has stated, but quite frankly I am a cynic. Losing response after this degree of response is not a common event. I do not see much in the discussion about a compliance review and would not be surprised if this is part of the issue. Would delve very deeply before doing anything. The next question I have is whether this was brand or generic DAS and if the latter, by any chance was the product changed? Efficacy and quality of generics in many countries are not standardized and even in my country the generics may have quality drug but the excipient may be different changing things like AEs and perhaps absorption.

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