I have a 29-year old female patient with newly diagnosed chronic phase CML. She came off contraception about 3 months ago with the intention of becoming pregnant. She has a history of endometriosis so sought the advice of a gynaecologist who advised trying to conceive naturally for 6 months before considering fertility options. Her routine bloods showed Hb 138, Platelets 598 and WCC 12.5 and CML was confirmed. She is asymptomatic and does not have clinical splenomegaly.

I am unsure whether to delay her treatment while she tries to conceive or consider alternative treatments. Is there any data on patients taking imatinib who have become pregnant or CML diagnosed in pregnancy?

As a general rule I am very reluctant to delay treatment in newly diagnosed CML – even in cases that appear “early” based on WCC and other features. I still regard them as ticking time bombs that need to be defused as rapidly as possible. That may be overly dramatic but I suspect that in this young lady's cases the risk of transformation to blast crisis over the next 12 months if she is left untreated would still be about 10%. This is low but not a risk I am comfortable to take when the outlook for patients who do achieve a good response to TKI therapy in the first year is probably close to a normal life span.

If she were actually pregnant now then I would delay and get going with TKI therapy as soon as she delivers. However my recommendation (if she is not currently pregnant) would be to start a second gen TKI as soon as possible (coupled with reliable contraception) and re-assess the family options in 3-4 years when she will hopefully have achieved a deep molecular response. She is only 29, so this option is probably reasonable. I would advise against continuing to attempt pregnancy while on a TKI – there is a significant risk of TKI exposure to the developing fetus.

The endometriosis does complicate things quite a bit however. The possible option of delaying by 2-3 months while attempting in-vitro fertilisation could be considered in this case, if she was aware of the risk and still wanted to defer CML therapy.

I differ a little from Tim in that I would be a little more relaxed given her very early diagnosis and presumably low Sokal score. You don’t actually say when the diagnosis was made. If she is now pregnant then she might get through the pregnancy without any intervention. If her WCC is rising then we would intervene with regular pheresis (if possible locally) to keep her WCC below 100 and her platelets below 1000. If you cannot pherese then try to get her though to the 2nd trimester before any chemo: at that point the safest treatment will be interferon. I would certainly avoid imatinib through the pregnancy: there are good reasons to think that the damage it induces occurs early but the most recent data with Dasatinib suggests a possible effect in the 2nd trimester. Hydroxycarbamide is probably safe in the 3rd trimester but watch the baby’s counts on delivery

If she is not pregnant (and we are now at 6 months), then three choices: either start treatment and hope she gets a very good response (MMR), sustained for as long as possible (ideally 2 years) and then tries again, naturally or by IVF. Second possibility is to have a hyperstimulation cycle now and either reimplant fresh embryos now or freeze them for a later attempt and start treatment. This decision will clearly depend on her counts and rate of progress of her disease as indicated by her WCCC and platelets. If you are starting treatment now there might be a very good argument for giving her a second generation drug frontline to get as deep a response as possible as soon as possible.

I will offer another option which I have used successfully in more than half a dozen cases. I would start interferon and titrate the dose to hematologic remission. I have used both regular and pegylated interferon. With her counts being low, the likelihood of a good response is high and currently I have 3 patients who continued the interferon through breast feeding and actually wish to remain on the drug instead of switching to a TKI. All have achieved at least MMR and one MR4.5. Starting it early will have a good chance of preventing count progression during the pregnancy. If the counts start to take off, then hydroxyurea late in the pregnancy is an option, but so is leukopheresis which has no risk to the fetus.
Interferon is safe during pregnancy. The placenta secretes interferons as part of the fetal retension mechanism. The biggest side effect in its use here is the double whammy of pregnancy and interferon - fatigue.

Jeff, that sounds very reasonable - if she is actually pregnant when the diagnosis of CML is made. This lady was not - just trying to get pregnant. One of the issues where Jane and I differ is the need to get on to a TKI in this circumstance. Jane is fairly relaxed because this patient is low SOKAL, I am more anxious to get started as soon as possible with a TKI, get a good response, and then start thinking about the pregnancy question. Where do you stand on this issue?

Thanks to all of you. This is a fascinating discussion. In my opinion there is still a fourth and intermediate option to consider in this case: to start with a second generation TKI to get a good molecular response (at least MMR) as soon as possible and then to switch to IFN and to start the procedure for the pregnancy. This would most likely delay the pregnancy attempts for some months only, that should be acceptable for a patient who is only 29 years old. This would also allow to see the rapidity of the response that is also an important predictive factor. My only doubt is: are we sure that IFN is not decreasing the success rate of the procedure for getting pregnant?