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Michael J. Mauro, MD: I'm Dr Michael Mauro, and welcome to the Medscape InDiscussion podcast series on chronic myeloid leukemia (CML). Today, we're going to discuss pregnancy, family planning, and fertility for patients with a diagnosis of CML, which is not a topic generally mixed with leukemia very often.
I'm delighted to have my guest, Professor Jane Apperley, to discuss this topic today. Professor Apperley is the campus director for the Hammersmith White City campuses of the Imperial College London, having previously served as chair of the center of hematology at Imperial College and as the clinical director for clinical hematology at the Associated University Hospital. She's also been president of both the European Group for Blood and Marrow Transplant and the British Society of Blood and Marrow Transplant; lastly, she's been the European Vice President of the Center for International Blood and Marrow Transplant Research. She is a leader in our field, an expert, and a great conversationalist. Welcome to InDiscussion, Jane.
Jane Apperley, MD, PhD: You're very welcome, Mike. Thanks for having me.
Mauro: Not to be stereotypical, but I usually ask an icebreaker question. It's really just to help us get a sense for what people are thinking about in CML. We've had a lot of advances, but the icebreaker question for me is what is that best thing that has happened in CML? Or if it hasn't happened yet, what's the thing we need to have happen?
Apperley: You probably know that I started out my professional life in hematology as a bone marrow transplanter. That's how I got interested in CML. Up until about 2002, it was a primary indication for allogeneic transplant. The greatest thing that's happened to CML and to me is obviously the advent of the tyrosine kinase inhibitors (TKIs) because I'm no longer having very depressing conversations about patients who were ineligible for transplant or were facing transplant but maybe didn't have a donor. I can now talk to them about taking a tablet, and the majority of them will do very well. There's no doubt that the best thing that's happened in the past 25 years is TKIs. There's still quite a lot of work to do. We still have patients who don't respond very well. We still have patients who present in advanced phase. So the story isn't over just yet.
Mauro: Very well said. I'll age myself a little bit. I grew up on the entrée of all the work that you did and others to set the previous standard of treatment and then was lucky enough in the TKI era to be able to help develop this spoil of riches, as many of us call it, for therapy. You're absolutely right. We have more work to do. It's clearly not done.
We're going to talk about something specific today, which is pregnancy. A good way to think about it is: We are facing this in two different fronts. A pregnancy that's occurring concomitantly with CML or probably a little bit more commonly, and hopefully something we can tackle and have control over, is pregnancy considerations for people with CML. Let's maybe talk about the first case, which is the most difficult. Give me your thoughts on how often and how challenging that can be.
Apperley: The issue of CML in pregnancy obviously antedates the TKIs. I've been interested in this topic for a very long time largely because of the background of allogeneic transplant that we were aware that we would induce infertility in men and women in those days because we used total body irradiation. We were already starting to work on ways of preserving fertility. For post-pubertal boys and for men, it's not that difficult because you can cryopreserve sperm. But for women, we were pioneering. We were fortunate enough at the Hammersmith to have guy called Robert Winston, who was a very famous voice in in vitro fertilization. We were sending young women to him for oocyte or ovarian cryopreservation back in the early 90s. It goes back a long way. Women, young women, who presented with their CML in pregnancy, which is bizarrely more common than you might imagine — about 1 in 100,000 pregnancies is associated with CML — when they go for their booking appointment, it's often the first time they've ever had a blood count. We probably have maybe two patients present each year at the Hammersmith who've been found to have an elevated white cell count at the time of their booking appointment.
Mauro: We were probably just about to jump into the same question. Exactly as you just proposed, it might be the first time someone has blood counts. Much like an adult is diagnosed with CML sort of inadvertently or unexpectedly with blood counts for a procedure or a well check. Unpacking that, how do we manage the woman who's in the clinic and is now in the hematologist clinic because of probable or confirmed diagnosis of CML in pregnancy?
Apperley: Of course, your initial approach is identical to the approach of anybody with a probable, new CML diagnosis. You do the tests you need to do to prove that they have the disease, but in this particular case, it's absolutely critical that you identify the phase of the disease because the range of presentations in pregnancy can be quite wide. Fortunately, I have only ever seen one patient present with their CML in blast crisis at the time of their pregnancy. The conversation that you would have with that patient is very different from the conversation you would have with a patient who was clearly in chronic phase. There are nuances, of course, but we would still probably favor termination of the pregnancy if somebody presented in frank blast crisis.
Mauro: I can understand that.
Apperley: We obviously have a conversation with the woman and the partner and what they want and what the risks are to proceeding [with the pregnancy], et cetera. By and large, most women would probably elect to terminate. Obviously, social circumstances prevail for other decisions. For the woman who's clearly in chronic phase, often you're fortunate because it's the first time they've ever had a blood count, and they're going in feeling relatively well and just delighted about the pregnancy. The blood count is often very low. It may be well under 100. It may be 25 or 40. In which case you can just afford to wait. You don't have to do anything. If the white count rises, which it inevitably does, there are various ways of trying to handle that. We are fortunate in the center that we're at that we have ready access to pheresis. We would commonly use pheresis to maintain the white count. We've developed rather arbitrary rules because the situation's very rare, but we pherese if the patient is symptomatic, or if the white count is above or obviously heading to above about a hundred.
As you know, the platelet count, might be anything, and it might be very high, so you have to be clear about your expectations of the pheresis. What we've found is that the white cell count comes down very nicely as does the platelet count, but the platelet count then overshoots, so you end up with an even higher platelet count than you started with maybe 3 or 4 days later. Then you have to consider use of things like aspirin or low molecular weight heparin depending on where you are in the pregnancy.
We have found that with regular pheresis, and that very much depends on the patient's count and how often you do it, that gradually, the white cell count comes down to the point that by the time you get to the third trimester, the pheresis is often not necessary anymore. I don't know whether that's something as simplistic as a dilutional effect, but if we can pherese regularly enough to get the count under 100, we normally get away with it in the final trimester.
Not everybody has access to pheresis. It doesn't work perfectly for every patient, so then what can you do? I would try at all costs to avoid hydroxycarbamide, certainly in the first trimester. Interferon is obviously considered very safe in pregnancy because many of us are used to using interferon in the myeloproliferative neoplasms. I think the one thing you have to remember about interferon is that if you go back to the original studies in the 70s and 80s, it doesn't work very quickly. You can't start interferon and have the expectation that you now have with the TKI that the blood count will normalize within the next couple of weeks because often, it takes months. As long as you know what you're dealing with and what your expectations are, you can normally manage most patients. The jury is still out a little bit, but increasingly, we think that the TKIs are probably safe in the third trimester. No doubt we'll come back to discussing that for the planned or unplanned pregnancy in established CML. The effect on the developing fetus seems to be during the period of organogenesis, so probably late in the second trimester. In the third trimester, you're probably safe to use a TKI.
Mauro: Fantastic.
Apperley: I know you've got lots of other questions to ask me, but the TKIs would be imatinib and nilotinib. We would certainly avoid dasatinib for reasons we can go into later. We have so little information on bosutinib, ponatinib, and asciminib that we're not really very comfortable recommending any of those.
Mauro: That's a fantastic step-by-step. I think we're offering best practices or best practical advice given the fact that some of these ideas aren't necessarily completely supported and completely sanctioned by the drug label and the manufacturer. I think what we're talking about is very practical.
Before we go to the TKIs, I have to ask you about the conversation you mentioned, the very difficult conversation with the woman who is in blast phase. This may be a little bit more common and an easier conversation but still potentially complicated. How do you talk to the couple about the what-ifs that can happen during pregnancy? I think this applies for the untreated and the treated patient because in my experience, it's a very tenuous situation. The other conversation is with the obstetrician and sort of coaching them through this woman's risk for complications and delivery and how the complications may not be as stiff as the patient and obstetrician might think.
Apperley: And the baby's risk, of course. It has to be a very sensitive and nuanced conversation. Probably the most important thing to try to establish at the very beginning is to get a feel of what the couple want, certainly what the mother wants. The diagnosis of the leukemia will have come as a huge shock at a time when most people are extremely happy about the fact that they're pregnant. The fact that the CML is already advanced is obviously even worse news. Some couples will already have children. Some couples will be absolutely desperate for a child. Their feelings and their expectations and their desires have to be taken into account with every conversation. But nonetheless, you have to spell out the facts that if it's very early in the pregnancy and they're in blast crisis, you could either use a TKI alone or you could use acute myeloid leukemia (AML) type chemotherapy and that might be subtly different as to whether it's myeloblastic or lymphoblastic or you could use some combination of both of those. If you use a TKI alone, you'll probably get temporary control of their blast crisis, but you'll put the fetus at risk. If you use high-dose chemotherapy, which has been used with some modifications for certain drugs, in AML presenting in pregnancy, sometimes you can get away with it, and sometimes you run into big problems, particularly if the mother becomes neutropenic and septic, and struggles potentially even with septic shock. Treatment is just as difficult as it is with any patient with high-grade disease and more complicated by the fact that the physician always feels their hands are tied by compromising because of the fetus. We all know that in blast crisis and in AML, you're better off not compromising. That's why unless there's a big societal pressure on the couple to continue with the pregnancy, I would generally try and steer them toward termination, obviously conscious of whether the mother is not young or if it's their first baby and this has been something that they've been working at for a long time. The end result is that blast crisis has a dismal prognosis and even if you manage to get to the end of the pregnancy and successfully deliver a fetus, if you haven't treated the blast crisis adequately, the mother probably isn't going to be a mother for very long.
Mauro: That's actually the question I had. I don't want to be pessimistic. I'm a very strong supporter of fertility for women with CML, and I find myself feeling the need to talk to couples and women, even in chronic phase, even when they're doing well, and maybe even if they're doing very well and they're entering into a combination treatment cessation and pregnancy approach that we need to be prepared that things might not always work out. I get the same sense from many women and couples that they're willing to really do anything to preserve the health of the fetus, and they almost look aside from their own health sometimes, which I think is tricky. I have a case right now exactly like that, where someone needs to be treated again during their pregnancy, and they're very hesitant because of fear of ill effects to the fetus.
Apperley: Yes. Obviously, it's nice to be as healthy as possible for as long as possible, but once the disease is controlled, as perhaps it is in your patient, or at least the blood count's okay and maybe they're in complete cytogenetic remission, the patient will feel well, so they can't imagine what it would be like to have disease progression and potential death. So their focus is on the baby rather than on what might happen to them. It is our responsibility to make it very clear that in that situation, we cannot guarantee that the mother will not have disease progression
Mauro: I find myself looking the partner square in the eye and saying, "Let's make sure there's a plan to take care of this person we're bringing into the world because things can go in many different ways." That is a little bit of the challenge or the tougher part of CML. People do very well, feel well, and that symptomatic or progressive CML is an unknown. Let's pivot now and talk about something that's probably a little bit more an area where we have control over, which is the woman who is in treatment and we're hopefully, co-piloting or piloting with them their treatment and their deep remission or their remission of some kind, and they'd like to get pregnant. Now that's a big topic, but you touched on TKIs, which could be safe. What about the entrée into this for the woman who's thinking about becoming pregnant? What's your best advice there?
Apperley: The best advice, but it doesn't always work out like this, is that the woman should get herself into exactly the same position as any other patient who might be offered a trial of discontinuation for treatment-free remission. The patient would want to be on a TKI for a prolonged period of time and respond extremely deeply and to be in at least molecular remission for 1 or 2 years. Then the clinician would manage them exactly as you would manage a patient having a trial of discontinuation. What we say, which is the best situation you can have is, we already know that about 50% of patients who enter treatment-free remission will be successful, and 50% won't be. The majority of that 50% will know that they have molecular recurrence within the first 6 months. So we take the patient off their TKI, and we send them away to try to become pregnant. The advice I give is to time limit it because as they go through the next few weeks and months, they will fall into the category of being somebody whose polymerase chain reaction (PCR) test is still undetectable, in which case you can leave them off their TKI indefinitely. They may become pregnant, and they may not, but at some point, they'll have a successful treatment-free remission attempt.
The other scenarios are that the patient becomes pregnant, but the PCR is rising. Now, if you've gone from literally zero, and become pregnant quite quickly within that first 6 months, then I think in the vast majority of cases, we would get that individual through their pregnancy without having to think about treatment. If their PCR is rising and they're not pregnant, then we would advise restarting their TKI and waiting a while longer and trying again. That brings a whole pile of different discussions, which might include discussing which TKI they stopped. Should you put them back on something a bit more potent, accepting it might have a few more side effects to try and deepen their response as fast as possible? You may have an individual in front of you who is in their 40s, who doesn't really have time to go back on a TKI for another 2 or 3 years and deepen their response. In which case, what we would normally do in our very well set up center is refer them to the in vitro fertilization unit and get either eggs or embryos taken and cryopreserved, or in case of embryos, they could even be freshly implanted because you have to take the patient off the drug for the hyperstimulation cycle.
Once the eggs are collected or the embryos are created, you can time the pregnancy, of course, and you can get the patient into a slightly better situation. You can get them back to zero and then, go ahead with a reimplantation attempt. If they're lucky, they'll end up with just 9 months off drug. And as I say, if you started from zero, by and large, we can get people through their 9 months. That's the best possible situation, right? They've got a very deep response, but most people are not in that position.
Mauro: Jane, women need you at the chalkboard to go over the play-by-play for this topic, because I think many listeners or even us we've heard colleagues say, "pregnancy and CML? That's not going to be successful." No, we need to dismiss these ideas. I've heard women come to me very despondent. It's clear there are paths forward that you're so eloquently outlining. I know they're very uncertain and they're very variable, but there are definitely options. Let's cover the TKIs a little bit further. You mentioned imatinib and nilotinib is probably the medications we feel the most comfortable with in pregnancy in general and others with either uncertainty or data. Any more comments there?
Apperley: Yes, obviously we've had imatinib for many years now. The first patient was treated in 1998, so 25 years. The initial scare about imatinib in pregnancy came from the very first trials where women became pregnant on the clinical trials, probably because they'd not paid too much attention to the instruction that they should use adequate contraception, but that's life; these things happen. All those pregnancies, of course, because they were in the context of clinical trials were reported to the pharmacovigilance section of the pharmaceutical company. They helped one of my clinical research fellows and together with Jorge Cortes at MD Anderson put together the experience that we had outside clinical trials and that they had at that time. It was quite disturbing because obviously, a lot of the women who became pregnant elected for termination because they hadn't planned the pregnancy.
But for those who wanted to go through with the pregnancy, the incidence of congenital abnormalities was much higher than what you would see in the healthy population. But more importantly, the range of abnormalities that were seen were quite dramatic: hemivertebrae, abnormalities of the renal tract, horseshoe kidneys, single kidneys, and very unpleasantly exomphalos, where the contents of the abdomen are outside on the abdominal wall. First of all, those sorts of things are vanishingly rare, but when you have a cluster of them, you know something's going on. Then it was revealed that there was a mouse strain, where PDGFRA had been cut out and that these were exactly the same abnormalities that were seen in the litters of mice without PDGFRA. The assumption was that this was working through PDGFRA inhibition.
Now, of course, what happens once you recognize that and you publish is that it changes everybody's way of managing patients. Then you get several years of virtually no abnormalities being reported because obviously, the moment the patients become pregnant, they get taken off the drug because of the risk. Then you get complacency and, "Oh, well, we haven't seen any abnormalities. So, you know, it probably doesn't happen. It was probably bad luck." I would caution against thinking that. I think we've changed our behavior. We try to get people with unplanned pregnancies who are on any of these drugs off of them. The imatinib data were followed by dasatinib and bosutinib data, which were very similar but albeit in very much smaller numbers. The dasatinib data were disturbing for the fact that one patient delivered a fetus with hydrops fetalis but had not started the dasatinib until the middle of the second trimester. This goes against our previous sayings about the effects being during the period of organogenesis. Of course, it's one patient, and that could have happened to that patient irrespective of the CML and irrespective of the dasatinib, but there was another incidence of hydrops fetalis in that group where the dasatinib had been given in the first trimester. I think it was just very, very uncomfortable. We advise very much against using dasatinib.
Then, I was trying to manage all my patients without giving them any TKIs at all, but other places in the world don't have the facilities of pheresis, they don't have easy access to interferon, and obviously, a lot of the interferon companies have stopped producing interferon. Data were emerging, particularly from our Russian colleagues, of the relatively safe use of nilotinib in the third trimester. If you lost control of the counts and you couldn't get it back with interferon, then nilotinib seemed to be given in the third trimester with good effect and with no adverse effect on the fetus and a little bit with imatinib as well. I think it's not a thing you can put into trial. As you very rightly said early on, the drug company label is not to have any of these drugs at all during pregnancy. So what we're advising is obviously off-license use, and we have to be aware of that. But if you're really struggling with somebody's count, and they're at 30 weeks, then I probably wouldn't have much hesitation in starting imatinib or nilotinib and then having a word with the obstetrician about perhaps inducing the birth a little earlier than it would occur naturally, and perhaps taking the patient off the drug for a few days beforehand. But these are all conversations you'd have with the obstetrician and with the patient around how good the control of the count was and how much leeway you've got.
There's virtually no data for bosutinib. I mean the numbers that were described were very small. Similarly ponatinib and asciminib, there's virtually no data for women. There's some data emerging for men who seem to be able to continue their drug while conceiving babies without any harmful effect on the baby or the pregnant mother. So it's much more comfortable for men.
Mauro: We might have to have a season 2 to talk about the men. In a quick word: breastfeeding. Okay? Not okay?
Apperley: The imatinib and nilotinib are secreted in very small amounts in the breast milk. If you really wanted to protect your baby from any adverse effect of a TKI, you wouldn't breastfeed. But I have had women who have been adamant that they wanted to breastfeed, and I suspect the concentration is so small that most of the time, you'll get away with it.
Mauro: I try to see if we can continue the treatment, the TKI-free period, while the women are at least having that early breastfeeding occur.
Apperley: I mean, if their PCR is still low, then, absolutely, by all means, they can breastfeed and stay off the drug. But if their counts are beginning to rise, it's a different situation.
Mauro: Wow. We have covered a lot. We've talked to Dr Jane Apperley from the UK Hammersmith about pregnancy and the newly diagnosed patient seeking pregnancy during CML treatment, all the tools we have at our disposal and some of the realities that both physicians and patients must think about. Thank you for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on chronic myeloid leukemia. This is Dr Michael Mauro for the Medscape InDiscussion podcast.
Resources
New Challenges in Human in Vitro Fertilization
Treatment-Free Remission: the New Goal in CML Therapy
The Effects of Imatinib on Pregnancy Outcome
Stage Specific Requirement of Platelet-Derived Growth Factor Receptor-Α in Embryonic Development
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Cite this: What Do We Need To Know About Pregnancy, and Family Planning for Patients Diagnosed With Chronic Myeloid Leukemia? - Medscape - Oct 24, 2023.
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