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PCR Increase After Dose Reduction

Hello all,

Haven't checked in in a while but I wanted to get your thoughts on some recent trends with my wife's test results.

She has been taking nilotinib for 3.5 years without any noticeable side effects, but her liver enzymes have been consistently elevated, usually a bit below double the max normal range for ALT and AST. Five months ago on the advice of her doctor she reduced her dose from 2x150mg caps twice a day to 3x150mg caps once a day in the morning. She went in for a follow up a month after, and her PCR had gone up slightly to 0.0051 IS but liver enzymes were both within the normal range. Her doctor told her to continue and check again in another three months. At this last checkup, her PCR showed an increase to 0.070 IS, which seems quite significant to us. However, the doctor advised to continue on the current dose of 450mg once a day and to go for another checkup after three months.

Just hoping to hear about other people's experience with dose reduction and PCR bumps. If the trend continues, would returning to the initial protocol of twice a day be the best course of action? Would greatly appreciate any advice you have.

Thank you,

Chris

Her doctor is following protocol at three consecutive increases (one log) to establish a trend when a patient is already in MMR.
At this stage given that she remains in MMR (PCR < 0.1%), and I assume no blast cells, she has time for the protocol to play out.

However, it is likely that at next test her PCR has increased again and perhaps higher than 0.1%. She should be prepared to change drugs to another low dose prescription (i.e. 20 mg dasatinib or other TKI other than imatinib).

Dasatinib attacks higher order CML cells and works differently than nilotinib. It's possible that a CML clone has expanded and is not as responsive to nilotinib, but is quite likely to be crushed by dasatinib. I suggest low dose as her CML is already greatly reduced (dominant clone likely gone) and she should spare herself dasatinib side effects at full dose. No need for full dose at all. If I were in her shoes, I would change drugs now and not wait, only to get started on attacking the new CML genetic clone. She may find that her CML goes undetected quickly. I would only do this if her doctor agrees to low dose.

(note: Some research studies have suggested that switching or rotating TKIs may lead to a deeper molecular response in patients who have not achieved optimal response with a particular TKI or have developed resistance. The idea is that by changing to a different TKI, it may target the remaining leukemia cells and suppress the growth of resistant clones.

One of the reasons behind this approach is the fact that different TKIs have varying efficacy against specific BCR-ABL mutations. Switching to a more potent TKI may (and likely) overcome the specific resistance mechanisms and lead to improved treatment response.)

Hi Scuba,

Thanks so much for your informative reply. We spoke to another doctor in the meantime who made the same recommendation as you to consider a switch to dasatinib. However, her most recent test results came back today and she is back to PCRU! This is truly a maddeningly mysterious disease. As hard as it is not to be anxious, I guess it is really important to take the long view and not get too caught up on one or two results that are trending in the wrong direction. Thanks again for your insight.

Hi Chris,

That is great news!