Sandhya Kharbanda

In 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 semi-allogeneic transplantation without conditioning or immunosuppression. We conducted a phase 1 clinical trial of IUHCT in fetuses with Alpha 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 x 108 ± 2.67x107 cells/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 2/6 offspring but persisted in only one 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. NCT02986698

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

Impaired baseline lung function is associated with mortality after pediatric allogeneic hematopoietic cell transplantation (HCT), yet limited knowledge of the molecular pathways that characterize pretransplant lung function has hindered the development of lung-targeted interventions. In this study, we quantified the association between bronchoalveolar lavage (BAL) metatranscriptomes and paired pulmonary function tests performed a median of 1 to 2 weeks before allogeneic HCT in 104 children in The Netherlands. Abnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung injury–related mortality after HCT. Depletion of commensal supraglottic taxa, such as Haemophilus , and enrichment of nasal and skin taxa, such as Staphylococcus , in the BAL microbiome were associated with worse measures of lung capacity and gas diffusion. In addition, BAL gene expression signatures of alveolar epithelial activation, epithelial-mesenchymal transition, and down-regulated immunity were associated with impaired lung capacity and diffusion, suggesting a postinjury profibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT pulmonary function tests for the outcome of post-HCT mortality. These findings suggest a potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.