In utero hematopoietic cell transplantation in fetuses with α-thalassemia major: a phase 1 clinical trial.

abstractIn utero hematopoietic cell transplantation (IUHCT) has the potential to treat patients who have hemoglobinopathies by harnessing the unique period of fetal tolerance to maternal cells, thereby enabling semiallogeneic transplantation without conditioning or immunosuppression. We conducted a phase 1 clinical trial of IUHCT in fetuses with α-thalassemia major (ATM), a diagnosis that requires serial in utero transfusions (IUT) for survival. We also analyzed outcomes in fetuses with ATM treated with IUT alone in the same time period. Six fetuses underwent transplantation with maternal CD34+ cells (1.33 × 108 ± 2.67 × 107 cells per kg + 1% T cells) at 23.1 ± 1.1 weeks' gestation. All received serial IUT and were delivered at, or near, term. Perinatal outcomes were broadly similar to those undergoing IUT alone. Two mothers received prophylactic antibiotics because of late positive cultures of harvested cells (without fetal adverse events). Low-level maternal microchimerism was detected in all recipients; T-cell hyporeactivity to maternal antigens was detected in 2 of 6 offspring but persisted in only 1 child. Cord blood from ATM-affected pregnancies demonstrated marked expansion of host hematopoietic stem and progenitor cells compared with healthy controls, suggesting a competitive disadvantage for donor cells in this disease context. Neurodevelopmental assessments were largely reassuring, with high quality-of-life scores. Overall, this protocol was safe and feasible but demonstrates the limitations of IUHCT for ATM without concurrent bone marrow conditioning. The favorable perinatal and neurologic outcomes in most offspring underscore the benefits of prenatal transfusions and the unmet medical need for developing definitive therapies for ATM. This trial was registered at www.clinicaltrials.gov as NCT02986698.