TKIs Still an Option in Some Pregnant Patients With Chronic Myeloid Leukemia

Elisabetta Abruzzese, MD

Around the world, the management of chronic myeloid leukemia (CML) involves the use of effective tyrosine kinase inhibitors (TKIs). However, when treating the disease in women who are pregnant, oncologists are advised to proceed with caution as no official guidelines exist for this scenario.

In 2020, Elisabetta Abruzzese, MD of S. Eugenio Hospital and colleagues published evidence-based recommendations in the journal Therapeutic Advances in Hematology. The topic was later discussed in a presentation during the 2021 Society of Hematologic Oncology Annual Meeting.

During the talk, Abruzzese explained that there is a different way to manage CML if a patient already has the disease and becomes pregnant compared with patients who develop CML after becoming pregnant. Moreover, oncologists should be precise about when treatment starts and stops and when it is most appropriate to use the watch and wait approach.

In an interview with Targeted Oncology™ during the SOHO Annual meeting, Abruzzese, provided key recommendations for managing pregnancy and CML.

TARGETED ONCOLOGY™: Can you discuss the prevalence of CML in women who are pregnant? How do outcomes tend to differ for these patients?

Abruzzese: The management of pregnancy in CML has the changed a lot in the past 10 years. We now have some recommendations that can help clinicians get through this. We basically distinguish among the 2 main topics, which are patients that get pregnant and discover CML while they are pregnant and patients with CML already treated for CML, who get pregnant during treatment. Depending on what kind of situation a physician has, there are different approaches they can take.

Generally, TKIs that are the main drug that can be used in in CML patients must be stopped at first pregnancy tests because they can be toxic and are teratogenic. This means that they can impact on the on the organs and fetal development, especially during the first week of pregnancy. The teratogenesis is the most dangerous during the fifth until the tenth week of gestation. This means that a TKI can be used until the first pregnancy test turn positive around the fourth week of gestation and must be stopped around the fifth and the sixth week that are the most dangerous. But, 2 of those drugs mainly, imatinib [Gleeva] and nilotinib (Tasigna) pass poorly in the placenta and this means that after the 16th week of gestation when organogenesis has ended, and placenta is formed, if necessary, they can be used again to prevent progression of the CML.

What are the key recommendations for managing CML and pregnancy that you provided during your SOHO presentation?

There were 3 main point on this topic. The first, as a described is knowing when to start or stop a TKI. So, when you stop the treatment not only for pregnancy, but also for in inducing T follicular regulatory cells (TFr). The first 3 months are the most dangerous, meaning that also patients that are in deep molecular response could relapse and have an increase of the transcript, because these months are important for organogenesis. In the first trimester of pregnancy in general, we should avoid the risk of giving drugs.

The second point is knowing what kind of drug to use if drugs are needed during pregnancy. And the drugs that can be used are certainly interferon, which is not a TKI. In CML, we have experience of using both pegylated interferon and standard interference. When used during pregnancy, interferon does not impact organogenesis. After this period after placenta is formed, you can consider imatinib or nilotinib. For bosutinib [Bosulif] and ponatinib [Iclusig]. We don't have enough experiences, so we should stick with the 2 TKIS which we have experience after the 12th week of gestation.

It’s also important to mention that drug are not always necessary. We need to keep in mind that the CML is not an acute illness when is in chronic pain, so we have time to start treatment. So, it is necessary that we keep the values of the white blood cells below 50,000 100,000 or 500,000 or 1 million for platletes., Those limits should not be exceeded. But you don't necessarily need to start treatment and I'm talking especially on patients that are diagnosed with CML at the same time of pregnancy. You can assume that they are already in remission and you can follow up after you stop patients and only retreat if cytogenetic remission is lost. Physicians don’t need to retreat the patient when they lose major molecular remission.

The third point is related to molecular monitoring. Of course, when you start treatment, molecular monitoring is very important because it allows you to know if there is an exponential rise of the transcript and you can anticipate that you need to start the treatment or restart the treatment or if the transcript is just fluctuating. In this case, you don't have to restart treatment. So, it's important to have a lab that can have a rapid turnover for those exams. What is good about this is that you can have the results in a few days, and you don't have to wait a month to receive those results.

One other thing that we mentioned in the paper we wrote last year, is to work on a team. We work with OB/GYN with neonatologists and urologists, and we follow the patient during pregnancy and also before and after pregnancy. This is very important that we give a patient confidence that she's taken care of from each side of the coin.

Regarding the management of blood counts, how would you advise clinicians on how often to perform blood tests on these patients?

Blood tests should be taken before they start treatment, so we are talking about someone was discovering pregnancy at onset of the CML. We mainly follow up the patient at first every 15 days, then if we can see that the values are stable, we can follow the patient every month with a CBC.

With a patient that’s onset, meaning that her CBC count is not normal and is among the 15,000 20,000, 30,000, 40,000 range, we followed the couple of patients that were at onset and they never moved from those values. Those are the patients who can be followed without any kind of treatment throughout the pregnancy. After they delivered, we started the treatment 1 wee after and everything was fine.

On the contrary, when you see that the white blood cells are rising, it’s best to start as soon as you they overcome the 50,000 with interferon, especially if we are in the first month of pregnancy. If the patients it at onset, and it's more than 16-20 weeks into their pregnancy, I would probably start with imatinib or nilotinib and follow that patient this way.

_Reference:

_{Abruzzese E, Mauro M, Apperley J, et al. Tyrosine kinase inhibitors and pregnancy in chronic myeloid leukemia: opinion, evidence, and recommendations. Ther Adv Hematol. 2020;11(2040620720966120). doi: 10.1177/2040620720966120}