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We report a case of a 25-year-old woman with chronic myeloid leukaemia who was randomised to dasatinib 100 mg orally daily in a clinical trial. The patient was advised to avoid pregnancy while on treatment due to its teratogenic potential. Five months later, the patient was found to be 6 weeks pregnant. Once pregnancy was confirmed, dasatinib was immediately stopped and the patient was taken off the trial. She was managed conservatively during the remainder of her pregnancy with close observation only. She delivered a healthy infant at 37 weeks' gestation without any documented birth defects. Dasatinib has been shown in animal studies to cause fetal toxicities, but the effect of exposure during conception and pregnancy in humans is not known. We provide a full report of a successful pregnancy in a patient who was exposed to dasatinib during the first trimester; we also give a brief literature review.
Chronic myeloid leukaemia (CML) is a myeloproliferative disorder with an incidence of 2 cases per 100 000 people and represents 7–20% of all leukaemia cases.1 2 Although it is an uncommon entity, CML is one of the few leukaemias that has a defined pathogenesis: a translocation of the Philadelphia chromosome ((Ph)/t(9;22)(q34;q11)) results in a constitutively activated tyrosine kinase BCR-ABL.3 4 Rational targeted treatment with BCR-ABL tyrosine kinase inhibitors (TKIs) has revolutionised the treatment and natural history of CML by improving overall survival with long-term remissions.1 2 5 6 Dasatinib is an oral TKI that binds to the active and inactive forms of BCR-ABL. Dasatinib has been shown in animal studies to cause fetal toxicities, but the effect of exposure during conception and pregnancy in humans is not known. Here, we report the normal pregnancy outcome of a 25-year-old woman with CML who was exposed to dasatinib during the first 6 weeks of gestation. We provide a detailed clinical analysis in conjunction with a brief literature review.
The patient is a 25-year-old woman who was found to have an elevated white blood cell count (WBC) of 16 000/mm3 as an incidental finding during a follow-up visit to her primary care physician. Review of systems included constitutional, cardiovascular, respiratory, gastrointestinal, hematologic symptoms and was positive for night sweats and unintentional weight loss of 15 lbs in 1 year. Past medical history was not significant. On physical examination, there were no palpable enlarged lymph nodes, organomegaly or signs of bleeding. Repeat complete blood count revealed a WBC of 27 000/mm3 with normal differential, haemoglobin and haematocrit of 15 mg/dl and 43%, and platelets of 854 000/mm3. Further work-up included a bone marrow aspiration and biopsy, which demonstrated a hypercellular bone marrow due to granulocytic hyperplasia with abundant megakaryocytes consistent with CML in chronic phase (CP-CML). Metaphase cytogenetic analysis demonstrated a three-way translocation involving chromosomes 9, 22 and 15 (t(9;22;15)) in 9 of 10 cells examined, and fluorescence in-situ hybridisation for BCR/ABL t(9;22) was positive in 98% of the cells examined. There was no evidence of other cytogenetic or molecular abnormalities. CT chest/abdomen/pelvis did not reveal any systemic disease. The patient was enrolled in phase II clinical trial (ECOG-S0325) studying imatinib mesylate at two different doses and dasatinib in CP-CML and was randomised to dasatinib 100 mg orally daily. The patient was counselled about the teratogenic potential of the agent and was advised to avoid pregnancy while on treatment. She achieved haematological response within 4 weeks and tolerated the treatment very well.
Five months later, while on dasatinib treatment, the patient was found to be 6 weeks pregnant. Once pregnancy was confirmed, dasatinib was immediately stopped and the patient was taken off the trial. After detailed counselling, termination of the pregnancy was strongly recommended by a high-risk obstetrician but she elected to continue her pregnancy. Meanwhile CML haematological relapse occurred with mild leukocytosis and thrombocytosis. She did not require treatment and she was managed conservatively during the remainder of her pregnancy with close observation only. She delivered a healthy infant at 37 weeks' gestation without any documented birth defects. The patient was restarted on dasatinib 100 mg orally daily shortly after her delivery and did not breast feed while on treatment. At 2 years' follow-up post-delivery, she maintains her molecular remission and her daughter has met all of her developmental milestones.
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 10
There 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.14
CML during pregnancy has been traditionally managed by leukopheresis,15 hydroxyurea16 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.25
There 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.
Competing interests None.
Patient consent Obtained.