Clinical Case Discussion Forum
To share and enhance best practice management of CML, experts and interested clinicians can discuss difficult or interesting CML cases here. Physicians submit a brief history of the patient and the case for discussion using this forum.
Losing molecular response to multiple TKI without any KD mutation
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?
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.
Totally agree with Dr Rosti 's idea.
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.
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.