Jane Apperley: Fertility part 1 – Side effects of CML treatments during pregnancy

Professor Jane Apperley is an expert in chronic myeloid leukaemia (CML). As part of our focus on fertility this month, she explains more on treatments available to women diagnosed with CML during a pregnancy.

History of treatment of CML

Since the 1990s when the first TKI (Tyrosine kinase inhibitor) was introduced as a treatment for CML, our knowledge of CML and how it can be treated effectively has dramatically improved. Imatinib is just one example of a TKI, a targeted therapy that works by selectively disabling or blocking certain signals from cancer cells to stop their division, rather than killing all dividing cells in the way that chemotherapy does. This more targeted manner of treatment has become the standard of care in CML patients and it has completely revolutionised the way the disease is managed, dramatically improving long-term survival in the majority of patients.

Imatinib was the very first TKI to be developed and it is still the most commonly used. Once a CML diagnosis is confirmed, doctors will prescribe a TKI to try and get you into a state of remission. CML Patients who demonstrate major molecular response (MMR) after two years of treatment (i.e they have very low detectable amounts of a marker protein called BCR-ABL in the blood) have been shown to live a completely normal lifespan, no different to someone without cancer. The success of TKI’s on improving the survival of patients with CML, means that the quality of life in these patients is the next issue that needs addressing. During her appearance at the 2017 CML horizons conference, Prof. Jane Apperley spoke about the therapeutic challenges faced by CML patients who are either pregnant or are planning to start a family in the future. Despite the obvious success of TKIs as a treatment for CML, their safety in pregnancy and the effects they have on fertility is a big concern for patients.

Negative effects of TKI’s during pregnancy

There is no evidence to suggest that TKIs affect fertility (i.e your ability to become pregnant). However it is very important to use contraception when taking a TKI, as becoming pregnant while on a TKI can significantly increase the risk of congenital birth defects in the children that are born to the patient.

Unfortunately, the first conclusive information to suggest that women trying for a baby should not be on TKIs came from a study that looked at 180 female patients who accidentally became pregnant on Imatinib, before it was widely known to be a problem.  Although most women quickly stopped taking imatinib as soon as they found out they were pregnant, abnormalities were found to occur in 9% of the children that were born.

Examples of abnormalities in these children included; horseshoe kidneys (where kidneys don’t properly separate to opposite sides of the body), twisting of the intestines, or problems with fusion of some of the bones within the spine. These problems have been found with all TKIs, not just imatinib.

Being diagnosed with CML whilst pregnant

There is never a good time to be diagnosed with CML, but when you have just realised you are pregnant definitely isn’t the best time. What is supposed to be the happiest time of your life can sometimes be turned upside down by the unfortunate diagnosis of CML.

Because blood tests are a routinely taken during pregnancy to check that the baby is healthy, sometimes pregnancy is the very first time that a woman ever has a blood test. Rather unusually, this means that the diagnosis of CML occurs relatively frequently during pregnancy. Having said this, diagnosis still only occurs in less than 1 per 100,000 pregnancies as CML is normally a disease that occurs in the elderly.

It is possible to manage CML very well during pregnancy without chemotherapy or TKIs, leaving the baby being completely unaffected. Below are the options that will generally be considered in this situation:

Treatment options when pregnant during diagnosis of CML

No treatment – Quite often the white blood cell count in pregnant women is at a very low level, as the disease has only recently arisen. These patients may be able to get through the whole pregnancy without having any treatment at all, and then go on to begin treatment with TKI’s after giving birth.

Leukapheresis- Leukapheresis is a procedure in which blood is briefly taken out of the patient and the white blood cells are selectively filtered out and removed. This keeps white cell count down to a manageable level during the pregnancy. This method might need to be performed more than once a week early on but will lower to about once a month after white blood cell count has decreased.

Interferon- Interferon is a drug that used to be used to treat CML before the TKIs were developed. It has since been proven to be safe to use during pregnancy.

Family planning when already diagnosed with CML

Fortunately for men, being diagnosed with CML will not stop them from having children whilst undergoing treatment. Research has conclusively shown that men can continue taking TKIs when trying to conceive a child without bringing harm to the child or mother in anyway.

However, this is not the case for women. As mentioned earlier, all TKIs can have harmful effects on unborn child when taken during the lead up to conception and for this reason it is strongly suggested that TKIs should not be used when trying for a child or during the pregnancy. The problems associated with TKI’s and pregnancy are not to say a woman can’t have children whilst they have CML, many women with CML go on to have children as there are various ways around using TKIs before and during pregnancy. If you are wanting to have children at the time of diagnosis or perhaps further into the future, you should talk to your doctor who can refer you to a fertility specialist.

Advice for patients already taking a TKI but wanting a child

Staying off all treatments during conception and pregnancy – In the best-case scenario the patient will have achieved a “deep response” to her TKIs (MMR). If this deep response has been shown to have lasted for a significant amount of time (e.g 1-2 years) it may be an option to withhold from taking the drug completely throughout conception and pregnancy, restarting on the TKI after giving birth.

As it is uncommon to become pregnant straight away after trying for a child, the extra time you spend off the drug when trying to conceive must be closely recorded and carefully taken into account. You may have to limit the period in which you are trying to conceive to around 6 months, as this time must be added on to the entire pregnancy (9 months). Research has shown that 15 months is about the maximum amount of time a patient can safely stay off TKIs after reaching a deep response. If you do not conceive within 6 months, it may therefore be necessary to go back on to the TKIs and retry once more after reaching a similar level of deep remission. In most of the patients that do this, the disease will slowly start to return however the majority of patients can safely manage to stay off the drug for the entire pregnancy. Your blood count will be closely monitored during this process by your haematologist to ensure the procedure remains safe.

Some women will have CML that is not as responsive to TKIs meaning they cannot achieve a deep response, or they cannot maintain such a response for as long as 1-2 years. These patients may require additional help from the IVF clinic to ensure they become pregnant as soon as they stop taking TKIs, meaning they are off the drug for as short amount of time as possible.

Breastfeeding when on TKIs?

It has also been proven that Imatinib can be secreted in breast milk and this is also thought to be true for the rest of the TKIs. Although the doses ingested by the infant are likely to be very small, the effects that even low amounts of TKI may have during a new born child’s development are unknown. It is therefore not recommended for women to breastfeed when on TKIs.

Because each expecting mother will have her blood monitored throughout her pregnancy, the haemotologist will be able to tell you if it is safe to continue to stay off TKIs for longer in order to breast feed after giving birth. Otherwise you may need to resume taking TKIs immediately after giving birth and feed the baby in a different way, perhaps with donated breast milk.

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