Cardiac birth defects in a twin infant born to a woman with chronic myeloid leukemia on dasatinib

Introduction

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), dramatically extending the lifespan of patients who previously had a less than 20% chance of surviving eight years past their initial diagnosis. ¹ However, with the remarkable advances in survival from these selective inhibitors of the constitutively active BCR-ABL oncoprotein, new challenges have arisen for the approximately 36.5% of patients who are diagnosed with CML during their childbearing years. ² The effect of TKIs on embryofetal development has not been well elucidated, with animal studies demonstrating associated teratogenicity; yet, multiple case reports of patients exposed to TKIs during pregnancy describe successful pregnancy outcomes.^3–7 Despite the fact that continuous TKI therapy remains essential for disease control, current expert recommendations for management of pregnant women with CML include interferon-alpha, hydroxyurea, leukapheresis, or cessation of all CML-directed therapy. Here, we describe a case of a woman with CML who was exposed to the second-generation TKI dasatinib during the first 12 weeks of her dichorionic diamniotic twin pregnancy and subsequently delivered two low-birth weight infants, one with severe cardiac malformations.

Case presentation

The patient was a 30-year-old female from El Salvador with no prior medical history who was diagnosed with Philadelphia chromosome positive CML in chronic phase at age 22. The patient was briefly started on hydroxyurea and then switched to the first-generation TKI imatinib at a dose of 400 mg daily. Three years after her initial diagnosis, the patient experienced molecular relapse, with the percentage of BCR-ABL/ABL transcripts rising to 37.9%. She then underwent a bone marrow aspiration and biopsy, which revealed a normocellular marrow (50–60% cellularity) with granulocytic left-shift and hypolobated megakaryocytes with less than 5% blasts. Cytogenetic analysis showed an abnormal female karyotype {46,XX,t(9;22)(q34;q11.2)[13]/46, XX[7]} with 13 of 20 metaphase cells exhibiting the t(9;22)(q34;q11.2) BCR/ABL translocation. The patient was subsequently started on dasatinib. Two years later, the patient had a planned pregnancy in which she discontinued dasatinib prior to the pregnancy and her white blood cell (WBC) count was managed with hydroxyurea during pregnancy. She delivered a healthy infant at 34 weeks via a scheduled cesarean section. After her pregnancy, she re-started her dasatinib and achieved complete molecular remission.

Two years later, while on dasatinib therapy, the patient was found to be pregnant, with a dichorionic diamniotic intrauterine pregnancy confirmed by ultrasound. The patient was taking dasatinib 100 mg daily up until week 12 of her pregnancy, at which point she discontinued the medication and transitioned to interferon-alpha injections. Her BCR-ABL/ABL ratio rose from 2.6% at week 12 of her pregnancy to 96.5% at week 27 with a concomitant rise in her WBC count to 31,000/mm³, at which time her interferon-alpha-2b dose was increased from 3 million units to 5 million units three times a week. The patient had notable side effects from the medication including malaise, rhinitis and nausea. At 34 weeks and 4 days, the patient had a scheduled primary low transverse cesarean section delivering a baby boy weighing 2.1 kg and a baby girl weighing 2.4 kg with Apgar scores of 9 and 9 at 1 and 5 min, respectively, for both. The girl was born premature, but otherwise healthy, without any abnormalities noted at two-month follow-up. The male infant had a large, posterior, maligned ventricular septal defect, a bicuspid aortic valve with mild hypoplasia of the ascending and transverse aorta and a moderate size patent foramen ovale. The boy subsequently underwent pulmonary artery banding and patent ductus arteriosus ligation.

Discussion

This case is the first, to our knowledge, to report cardiovascular abnormalities in a twin infant born to a woman taking dasatinib during pregnancy. Congenital cardiovascular anomalies often stem from aberrations during the critical period of organogenesis from the third to eighth gestational week, ⁸ which overlaps with the time period our patient was taking dasatinib. However, despite the evidence to the contrary, multiple case reports have described successful pregnancies and healthy infants in women who had taken dasatinib during pregnancy. For example, a 25-year-old woman with CML delivered a healthy male infant at 33 weeks, despite taking 70 mg of dasatinib twice daily for the first-trimester of her pregnancy. ³ Likewise, an 18-year-old woman taking 100 mg of dasatinib daily during the first trimester of her pregnancy delivered a healthy baby who had met all developmental milestones at two-year follow-up. ⁴ Similarly, a 23-year-old female with CML on dasatinib 70 mg daily for five weeks post-conception delivered a healthy infant with no abnormalities noted at nine-month follow-up. ⁵ Furthermore, limited post-marketing data of patients with CML on phase 1 to 3 clinical trials of dasatinib identified two patients who had taken the medication during pregnancy who subsequently gave birth to infants without congenital defects. ⁶

Nonetheless, Bristol–Myers Squibb pharmacovigilance database shows an increased percentage of fetal malformations and spontaneous abortions in women taking dasatinib at some point during their pregnancy. ⁹ Seven congenital abnormalities were detected among 46 women with known exposure to dasatinib during their pregnancy – 2 in 20 live births, 2 in 8 spontaneous abortions and 3 in 18 elective abortions. Of the known congenital defects, one infant had renal tract abnormalities, two had hydrops fetalis and another had encephalocele and premature closure of the cranial vault sutures. Interestingly, no cardiac defects were identified in the database. One of the cases, published in a case report, describes a woman who had switched to dasatinib after six weeks of imatinib therapy and had an ultrasound at 16 weeks demonstrating fetal hydrops with subcutaneous edema, pleural effusion, and ascites. ¹⁰ Measurement of dasatinib concentration in fetal plasma and amniotic fluid confirmed transplacental transfer.

The exact mechanism underlying the probable teratogenicity of TKIs, and dasatinib in particular, has not been well elucidated; however second-generation TKIs are known to have effects on multiple receptor tyrosine kinases, including the mast/stem cell growth factor receptor, platelet-derived growth factor α, the proto-oncogene tyrosine-protein kinase Src and the ephrin receptor kinases. ¹¹ These off-target effects have been implicated as a possible mechanism for fetal toxicity, with inhibition of platelet-derived growth factor α thought to be responsible for the renal tract abnormalities noted above. ⁹ Well-orchestrated animal studies have enabled more detailed characterization of the teratogenic potential of this medication and have provided insight into the mechanism of toxicity. A study of pregnant rats and rabbits found low concentrations of dasatinib responsible for skeletal malformations, generalized edema and microhepatia in exposed fetuses. ¹² Moreover, a study of the distribution of dasatinib in pregnant rats found uneven radioactive uptake in maternal tissues, with even, yet reduced, uptake in fetal tissues, suggesting a diffusion-mediated process that may underlie the observed toxicity. ¹³ Interestingly, experiments of the second-generation TKI nilotinib at standard doses in rabbits and rats did not demonstrate teratogenicity ¹² ; however, at excessive doses, they did induce apparent defects. In studies of the first-generation TKI imatinib, preclinical experiments demonstrated embryofetal toxicity in animals at therapeutic doses, and a large retrospective review of the drug identified 9.6% of infants with birth defects – mainly bony abnormalities and exomphalos – in mothers who had been on the medication during the course of their pregnancy. ¹⁴

Current accepted recommendations are for women with CML to avoid TKIs during pregnancy and only consider them should their disease status acutely worsen.^15,16 Guidelines from the National Comprehensive Cancer Network specify unique criteria for safe discontinuation of TKIs in patients with CML, including maintaining a stable molecular response for two or more years, completing at least three years of TKI therapy and undergoing monthly molecular monitoring for six months following TKI discontinuation. ¹⁷ These guidelines are applicable to reproductive age females with CML, who, with appropriate preconception counseling, should ideally stop TKIs prior to conception only after achieving and maintaining deep molecular remission for approximately two or more years. ¹⁸ The evidence for a prolonged treatment-free remission (TFR) after TKI discontinuation stems from multiple prospective studies including the multicenter Stop Imatinib trial, ¹⁹ the TWISTER study of the Australasian Leukaemia & Lymphoma Group, ²⁰ and the Japanese Dasatinib Discontinuation trial ²¹ among others, which cumulatively show the feasibility of a sustained molecular response after first-line TKI discontinuation in approximately ∼40% of patients. Interim results from 821 patients with CML in the European Stop Tyrosine Kinase Inhibitor study found that approximately half of patients who discontinued TKI therapy had no evidence of molecular recurrence at 24 months, with increased duration of TKI therapy positively correlating with TFR. ²²

For pregnant patients with CML, frequent ultrasonography and molecular monitoring are strongly advised during the course of pregnancy. To ensure hematologic control, alternative agents such as interferon alpha and, after the second trimester, hydroxyurea can be used. ¹⁸ Interferon alpha, which has a high molecular weight and is not genotoxic, has proven to be safe in animal studies and systematic clinical review show no increased rates of birth defects or adverse pregnancy outcomes.^23–25 On the other hand, hydroxyurea, which inhibits DNA synthesis, has demonstrated teratogenicity during early pregnancy and is only considered safe after the second trimester.^26,27 While supportive measures such as leukapheresis and plateletpheresis remain options during pregnancy, in patients with advanced progression of their CML during pregnancy, one can consider a TKI after the placenta is formed at around 14 weeks. In such a scenario, nilotinib or imatinib are the preferred agents given they do not cross the placenta in a significant concentration. ¹⁸

In conclusion, our case adds relevant insight into the potential teratogenicity of dasatinib in pregnant women and supports recommendations to avoid this medication during pregnancy.