A CML Patient with Unintentional Bosutinib Exposure During the First Trimester of Pregnancy

Chronic myeloid leukemia (CML) is a BCR-ABL1-driven myeloproliferative neoplasm that predominantly affects adults; however, an increasing number of cases are diagnosed in women of reproductive age [1] .The management of CML during pregnancy remains challenging due to the potential teratogenic effects of tyrosine kinase inhibitors (TKIs), particularly during the first trimester.Current recommendations advise discontinuation of TKIs upon confirmation of pregnancy, with close monitoring and consideration of interferon- when treatment is required [1,2] .These recommendations are consistent with the European LeukemiaNet (ELN) 2020 guidelines for the management of chronic myeloid leukemia [3] .Data on newer TKIs, including bosutinib, are extremely limited, and their use during pregnancy is generally discouraged.We report a 37-year-old woman with CML who conceived while receiving bosutinib and subsequently delivered a healthy infant.The patient was initially diagnosed after incidental leukocytosis and thrombocytosis, with a BCR-ABL1 transcript level of 11.3% and a low ELTS score (Table 1).First-line imatinib therapy was complicated by grade 3 neutropenia and cutaneous toxicity, necessitating dose reduction and intermittent treatment interruptions due to intolerance.Due to loss of molecular response at six months, treatment was switched to bosutinib (500 mg/day).Tyrosine kinase domain mutation analysis was not performed prior to initiating bosutinib, as the suboptimal molecular response was attributed primarily to treatment intolerance and irregular imatinib exposure rather than suspected primary resistance.Despite counseling on contraception, the patient unknowingly continued bosutinib during early pregnancy.Pregnancy was recognized approximately three months after bosutinib initiation, and the drug was discontinued at 12 weeks of gestation.Non-invasive prenatal testing (NIPT) revealed a rare autosomal abnormality consistent with monosomy 7.However, detailed fetal evaluation, including ultrasound, amniocentesis, karyotyping, and chromosomal microarray analysis, showed normal results.During pregnancy, the patient was closely monitored with monthly follow-up visits.No loss of hematologic response or clinical deterioration was observed, and BCR-ABL1 transcript levels remained stable throughout pregnancy.Initiation of imatinib therapy after the third trimester was discussed with the patient; however, she declined imatinib treatment.Interferon-alpha therapy was also not administered due to limited availability throughout pregnancy, and the patient was therefore managed with close monitoring.At 38 weeks, a healthy male infant was delivered via cesarean section, with no congenital anomalies.Postnatal follow-up up to 11 months demonstrated normal growth and neurodevelopment.Further investigations, including placental and maternal genetic analyses, did not identify the source of the monosomy 7 detected by NIPT. u n c o r r e c t e d p r o o fThis case adds to the very limited literature on bosutinib exposure during pregnancy.Available data suggest that, unlike imatinib and nilotinib, bosutinib may have a higher potential for placental transfer, although human evidence remains scarce [4-6] .In previously reported cases, bosutinib exposure early in pregnancy was not associated with congenital malformations, particularly when discontinued after pregnancy recognition [7] .An additional notable finding in this case was the discordant NIPT result.Maternal malignancies, including hematological cancers, are known to contribute to false-positive NIPT findings due to circulating tumor-derived cell-free DNA [8] .Despite extensive evaluation, the origin of the monosomy 7 signal could not be determined, highlighting the diagnostic challenges in such cases.In conclusion, this report describes a successful pregnancy outcome following first-trimester exposure to bosutinib in a patient with CML, without apparent teratogenic effects.It also underscores the potential for misleading NIPT results in the context of maternal malignancy.Further accumulation of real-world data is essential to better inform the management of CML during pregnancy and to clarify the safety profile of newer TKIs.However, TKI therapy during pregnancy should be considered with caution and is generally avoided, particularly during the first trimester.Evidence regarding bosutinib exposure during pregnancy remains scarce, and its use is discouraged, particularly given its relatively high placental transfer and limited safety data.