I am one of the haematologists in gold coast.

Quick question - I have a 32 year old lady - on Imatinib 600 QD for CML - has achieved a CCR but not an MMR at 18 months. She wants to start a family as soon as her clinician tells her it is safe to proceed.

Depending on how she goes, I may consider to switch her to Nilotinib (or dasatinib) to achieve a CMR prior to any pregnancy plans.

However I am not aware of any data with the second gen TKIs.

My questions are:

(1) would you advice that this patient switch to nilotinib or dasatinib to give them a greater chance of achieving a stable response prior to a period of cessation while she attempts a pregnancy, and

(2) is there any evidence that the chances of a successful pregnancy would be reduced if the patient is switched to nilotinib or dasatinib.

Thanks a lot for sharing your opinion.

Regards,
Tara Cochrane

Hi Tara, addressing your two questions:

1. I agree that if she doesn't achieve MMR by 18 months it would be reasonable to consider nilotinib or dasatinib since ongoing imatinib would be quite unlikely to lead to CMR within the next 8 years based on our recent analysis. We know from ENESTcmr that switching will increase her chances of achieving CMR. Stable CMR would be the best platform for a period of cessation and attempted conception.

2. I haven't seen any data on fertility in relation to nilotinib or dasatinib so it is a good question to raise. Does anyone have any data here?

Lacking any data on the second question, I would still be inclined to switch to nilotinib or dasatinib in this young woman to enhance her chances of achieving a stable CMR and thus improving her chances of subsequent pregnancies and possibly functional cure.

Regards

Tim

Dear Tara!

I completely agree with Tim.

It is better to have CMR than no MMR. Therefore a patient is a candidate to TKI2.

As for me I haven't found the data that fertility can be influenced by TKI2.

We had a curious case of 2 subsequent pregnancies on dasatinib in a woman with previous 15 years of infertility. 2 healthy children were born.
As for nilotinib - we are going to switch a lady in the same situation as yours to nilotinib in order to achieve stable CMR.

The other issue is that a young CML female should be carefully examined by gynecologist from the very beginning in order to have time to resolve any fertility problems if they exist while she is gets her stable CMR.

Kind regards,
Ekaterina Chelysheva,
Hematology Research Center,
Moscow,
Russia

Dear Tara!

I completely agree with Tim.

It is better to have CMR than no MMR. Therefore a patient is a candidate to TKI2.

As for me I haven't found the data that fertility can be influenced by TKI2.

We had a curious case of 2 subsequent pregnancies on dasatinib in a woman with previous 15 years of infertility. 2 healthy children were born.
As for nilotinib - we are going to switch a lady in the same situation as yours to nilotinib in order to achieve stable CMR.

The other issue is that a young CML female should be carefully examined by gynecologist from the very beginning in order to have time to resolve any fertility problems if they exist while she is gets her stable CMR.

Kind regards,
Ekaterina Chelysheva,
Hematology Research Center,
Moscow,
Russia.

Further update - This young lady, CML diagnosed in in June 2011. Has been in a complete molecular remission (on 600mg Glivec) since Aug 2012.

She wants a baby – fertility tests done whilst on glivec show low ovarian reserve.

Anyway I ceased the Glivec 2 months ago, the BCR-ABL is now detectable at 0.011 – she is not pregnant yet but is about commence Clomid to induce ovulation.

Any suggestions? Should I commence interferon (if so what is your usual starting dose)?

Your patient has only had 4 years of TKI therapy so it is not surprising that she has not achieved TFR even though she has been in CMR for almost 3 years. Given the probable tempo of her rise in BCR-ABL she will rapidly lose cytogenetic and possibly also haematological response over the next few months. This doesn’t mean she has to restart imatinib – she may find the risk of 9-12 months of uncontrolled or poorly controlled CML over the period of her pregnancy quite acceptable. It is hard to put a figure on the risk of transformation over this period but it is probably less than 10%. If she does find this risk unacceptable then she can restart imatinib and wait another 3 or so years then try again. If she wants to forge ahead with a pregnancy attempt now despite the risk then you could consider giving her some interferon (low dose – maybe 1 million 3 times weekly initially) but I wouldn’t start until the second trimester.

Another possibility would be to proceed with the harvest and storage of fertilised eggs at this stage (now that she has progressed this far) allowing her to move straight into a pregnancy in a few years when TFR is more likely. This might allay some of her concerns about the delay involved in actually getting pregnant given her low ovarian reserves.

Very little of what I have suggested above is evidence-based. It might be interesting to get some wider discussion on this case.