CML accounts for 15% of adult leukaemias in Western countries and can occur at any age, although the incidence of the disease increases with age.
7 The pathogenesis of CML is based on a reciprocal translocation
t(9;22), which encodes the cytoplasmic fusion protein BCR-ABL.
8 This protein has constitutive tyrosine kinase activity, which results in self-renewing haematopoietic stem cell proliferation. Approximately 95% of CML patients harbour the BCR-ABL fusion gene turning almost into a mandatory characteristic of the disease.
9 10There are three TKIs for use in the treatment of patients with CML: imatinib, dasatinib and nilotinib. Dasatinib, currently a second-generation TKI, targets several kinases, including BCR-ABL, ABL, ephrin type-A receptor 2, kit, platelet derived growth factor receptor and sarcoma family members.
11 Results from phase II trials led to the Food and Drug Administration (FDA) approval of dasatinib for use in imatinib-resistant CML.
12 13 Hochhaus
et al12 reported a 91% complete haematological response (CHR) and 59% major cytogenetic response in CP-CML patients who were intolerant or resistant to imatinib. However, the use of second-generation TKIs, such as nilotinib or dasatinib, in the front-line setting has still been under investigation. In a phase II study conducted at the M.D. Anderson Cancer Center (MDACC), dasatinib as a frontline treatment showed CCyR and major molecular response rates of 94% and 36% at 6 months, respectively.
14CML during pregnancy has been traditionally managed by leukopheresis,
15 hydroxyurea
16 and interferon (IFN).
17 The therapeutic management of CML in pregnant women with targeted treatments often poses substantial challenges to both patients and their physicians. In general, TKIs are not recommended during pregnancy based on the results of animal studies that have suggested an embryotoxic effect of these agents.
18–20 However, little is known about the potential toxicity of TKIs on human embryos.
Ault and colleagues were the first to publish a series of 19 pregnancies in which either the male or female partner was undergoing treatment with imatinib. Although 3 pregnancies ended with spontaneous abortions and 1 with an elective termination, 16 pregnancies were identified to be uneventful.
21 Pye
et al22 have recently reported the pregnancy outcome of 125 women who were exposed to imatinib during pregnancy. In total, 50% delivered a healthy baby, 28% elected to have a termination and 14% had a spontaneous abortion. Altogether, 12% of the infants had serious fetal abnormalities, including cleft palate, polydactyly, meningocele, hydrocephalus, cerebellar hypoplasia, atrial septal defect, hypospadias, hypoplastic lungs and renal agenesis. Cole
et al23 conducted a thorough review of the English language literature on women who became pregnant while taking imatinib and identified a total of 217 reported pregnancy events. Of these, 171 carried their pregnancy to term, 24 had spontaneous abortions and 62 had unknown outcomes. Among the 109 pregnancies in which the patient intended to carry the child to term, 36 (33%) had complications, including spontaneous abortion in 24 patients, stillbirth in 1 patient, malformations in 9 patients and low birth weight in 2 patients. Klamová
et al24 reported the outcome of a CML patient whose pregnancy was confirmed at 21 weeks' gestation after 10 months of imatinib treatment. Similar to our case, the patient lost her haematological remission during pregnancy. She was treated with IFN and she gave birth to a completely healthy newborn in the 38th week of pregnancy.
Due to more recent marketing of dasatinib in the treatment of CML, very limited data are available on the effects of inadvertent exposure during pregnancy. Despite the manufacturer's requirement for contraception while on treatment with dasatinib,
20 occasional pregnancies have been reported. Dasatinib has been shown to be teratogenic in rats and to be extensively distributed in murine maternal tissues and secreted into milk.
25There are only two reports in the medical literature of successful pregnancies while patients were taking dasatinib; thus, making our case the third report. The first case was described in an 18-year-old woman with CML who had a normal pregnancy outcome after exposure to dasatinib in the first trimester.
26 The second case reported a 38-year-old man who conceived a healthy baby while on dasatinib treatment.
27 Another study on the use of dasatinib during early pregnancy has been published in abstract form and presented at the American Society of Hematology meeting in 2008.
28 Among the eight female patients found to be pregnant while on dasatinib treatment, two cases of spontaneous abortion and three cases of induced abortion were reported. Of the two spontaneous abortions, the first was at 8 weeks' gestation and birth defects of the fetus were not reported. The other was at 9 weeks' gestation in a patient taking dasatinib for over 2 years. Both patients were active smokers. Of the three deliveries, the first patient had a normal healthy infant. The second patient was on dasatinib for at least 5 months when she had a positive pregnancy test with an estimated gestation of 4 weeks. The infant was reported as ‘small for dates’ but did not have obvious birth defects. In the final case, the patient was on dasatinib 100 mg orally daily for approximately 5 months when a pregnancy at 21 weeks' gestation was discovered. Her pregnancy course was uneventful at the time of publication.
Nilotinib, another second-generation TKI, is classified as category D in pregnancy by the FDA with studies in rabbits showing increased fetal mortality, abortion and decreased gestational weights at a dose of 300 mg/kg/day (approximately half of the exposure used in humans based on area-under-curve) with an overall lack of data in humans.
19 Conchon
et al29 described a 30-year-old woman with CML who became pregnant for the second time while on nilotinib at 7.4 weeks' gestation and delivered a male infant without congenital malformations at 33 weeks.
Learning points- There are few published data to facilitate the counselling of women who conceive while taking TKIs.
- Although this case and other recent reports show that favourable outcomes are possible for women with CP-CML during pregnancy, patients receiving dasatinib should be advised to practice adequate contraception because of a real risk of spontaneous abortion and acquired fetal abnormalities.
- Currently, the treatment of pregnant CML patients may be possible with IFN, which only ineffectively passes through the placental barrier due to its large size, or leukopheresis, which can be used as a short-term treatment strategy.
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