Evaluation of the maternal-fetal transfer of liposomal daunorubicin and cytarabine in an ex vivo human placenta perfusion model to inform Acute Myeloid Leukemia therapy Free

Background & significance: Acute myeloid leukemia (AML) in pregnancy poses a therapeutic challenge and necessitates multidisciplinary care by malignant hematology and maternal fetal medicine. Successful maternal and fetal outcomes have been reported in patients treated after 20 weeks of pregnancy; however, significant clinical difficulty arises when patients require treatment at an earlier gestational age as chemotherapy exposure in the first trimester is unequivocally fetotoxic.

Liposomal daunorubicin and cytarabine, approved for use in therapy-related AML and AML with myelodysplasia-related changes, has a molecular weight that may not allow for transfer across the placenta. In clinical practice, the safety and efficacy of chemotherapy use during pregnancy is primarily based upon empiric dosing regimens, anecdotal efficacy data, clinical experience, and limited case reports. The objective of this study will be to determine the fetal drug exposure based on concentration of liposomal daunorubicin and cytarabine that crosses the placental/trophoblastic barrier (PTB). If liposomal daunorubicin and cytarabine does not cross the placenta, it could be poised to become standard of care in patients diagnosed with AML during their first trimester of pregnancy.

Study design & methods: After securing funding and IRB approval, an ex vivo human placenta perfusion model will be utilized. Term human placentae (N=6) will be collected immediately after delivery. A single cotyledon will be localized, perfused and stabilized with Eagle's minimal essential medium. Antipyrine (100 mg/L) will be used as a reference compound. Liposomal daunorubicin 750 ng/mL or 2200 ng/mL and cytarabine 500 ng/mL or 2000 ng/mL were selected to represent clinically relevant plasma concentrations to mimic concentrations following IV administration. Placentas will be collected and re-perfused within 30 minutes. Serial samples will be collected every 10-minutes for total two hours. Liposomal daunorubicin concentrations will be measured with a validated high-performance liquid chromatography (HPLC) assay method with ultraviolet (UV) detection at 254 nm. Cytarabine concentrations will be measured with a validated HPLC assay method with UV detection at 275 nm. Placental transfer will be evaluated by computation of Transport Fraction (T)=C_{Fetal vein}-C_{Fetal artery}/C_{Maternal artery}-C_{Fetal artery}andClearance Index (Cl_I)= antipyrine clearance /chemo drug clearance.