480 Biomedical (United States)

Inborn errors of immunity (IEI) are characterized by impaired lymphoid or myeloid immune cell function, resulting in recurrent infections, end-organ damage, and increased premature mortality. Allogeneic hematopoietic cell transplantation (allo-HCT) constitutes a curative treatment option for many IEI. Allo-HCT in this patient population poses unique challenges that necessitate the utilization of a conditioning regimen that affords rapid and stable engraftment, reduced organ toxicity, and low rates of graft-versus-host disease (GVHD). Evaluate survival, engraftment, and toxicity after reduced intensity conditioning (RIC) allo-HCT in patients with IEI. This IRB-approved, multicenter phase 2 clinical trial aimed to estimate the overall (OS) and characterize longitudinal engraftment of patients with IEI undergoing allo-HCT using an optimized reduced-intensity conditioning (RIC) regimen. The regimen consisted of alemtuzumab on days -14 through -12 (cumulative dose 45 mg in patients weighing ≥ 10 kg, 30 mg if < 10 kg), fludarabine on days -8 through -4 (150 mg/m² or 5 mg/kg in patients weighing <10 kg), thiotepa on day -4 (8 mg/kg total) and melphalan on day -3 (140 mg/m² or 4.7 mg/kg in patients weighing <10 kg). Graft sources included bone marrow (BM), peripheral blood stem cells (PBSCs), or umbilical cord blood (UCB). Twenty-eight pediatric and young adult patients with IEI received study treatment. The 1-year and 3-year overall survival (OS) for the entire cohort was 96.3% (95% CI: 76.5 to 99.5) and 87.5% (95% CI: 66.0 to 95.8), respectively. Event-free survival (EFS) was significantly lower in infants [1-year EFS 57.1% (95% CI: 17.2 to 83.7) and 3-year EFS 38.1% (95% CI: 6.1 to 71.6)] compared to older children [1-year EFS 90.5% (95% CI: 67.0 to 97.5) and 3-year EFS 84.4% (95% CI: 58.7 to 94.8)] (P = .0007) owing to higher rates of treatment failure (TF, loss of donor chimerism or recurrence of IEI). The cumulative incidence of TF in infants was 42.9% (95% CI: 7.6% to 75.7%) at 1 year and 61.9% (95% CI: 10.4% to 90.3%) at 3 years compared to 9.5% (95% CI: 1.5% to 26.6%) at 1 and 3 years in older children (P = .004). Most infants (4/5,80%) with TF were successfully salvaged with second allo-HCT. The cumulative incidence of Grade II-IV acute and chronic GVHD was 10.7% (95% CI: 2.6 to 25.4) and 12.9% (95% CI: 3.0 to 30.2), respectively. Immune reconstitution was robust in most patients, with timely lymphocyte subset recovery, restored thymopoiesis, and independence of immunoglobulin administration. This RIC allo-HCT regimen for treatment of IEI had excellent OS with resolution of underlying immune abnormality, reconstitution of normal immune function, and low rates of GVHD. Future efforts will focus on optimizing engraftment in infants.

Journal Article Patrick Kyba. Covenants without the Sword: Public Opinion and British Defence Policy, 1931–1935. Waterloo, Canada: Wilfrid Laurier University Press; distributed by Humanities Press, Atlantic Highlands, N.J. 1983. Pp. xiii, 218. $11.00 Get access Kyba Patrick. Covenants without the Sword: Public Opinion and British Defence Policy, 1931–1935. Waterloo, Canada: Wilfrid Laurier University Press; distributed by Humanities Press, Atlantic Highlands, N.J. 1983. Pp. xiii, 218. $11.00. Robert P. Shay, Jr. Robert P. Shay, Jr. Watertown, Massachusetts Search for other works by this author on: Oxford Academic Google Scholar The American Historical Review, Volume 89, Issue 3, June 1984, Page 775, https://doi.org/10.1086/ahr/89.3.775 Published: 01 June 1984