In Vivo Expansion of Co-Transplanted T Cells Impacts on Tumor Re-Initiating Activity of Human Acute Myeloid Leukemia in NSG Mice

Human cells from acute myeloid leukemia (AML) patients are frequently transplanted into immune-compromised mouse strains to provide an in vivo environment for studies on the biology of the disease. Since frequencies of leukemia re-initiating cells are low and a unique cell surface phenotype that includes all tumor re-initiating activity remains unknown, the underlying mechanisms leading to limitations in the xenotransplantation assay need to be understood and overcome to obtain robust engraftment of AML-containing samples. We report here that in the NSG xenotransplantation assay, the large majority of mononucleated cells from patients with AML fail to establish a reproducible myeloid engraftment despite high donor chimerism. Instead, donor-derived cells mainly consist of polyclonal disease-unrelated expanded co-transplanted human T lymphocytes that induce xenogeneic graft versus host disease and mask the engraftment of human AML in mice. Engraftment of mainly myeloid cell types can be enforced by the prevention of T cell expansion through the depletion of lymphocytes from the graft prior transplantation

Iron Overload in Allogeneic Hematopoietic Cell Transplantation Outcome: A Meta-Analysis

AbstractAn elevated ferritin level before allogeneic hematopoietic cell transplantation (HCT) is an adverse prognostic factor for overall survival (OS) and nonrelapse mortality. Because ferritin is an imperfect surrogate of iron stores, the prognostic role of iron overload remains unclear. We conducted a patient-level meta-analysis of 4 studies that used magnetic resonance imaging to estimate pre-HCT liver iron content (LIC). An elevated LIC was not associated with a significant increase in mortality: the hazard ratio (HR) for mortality associated with LIC > 7 mg/g dry weight (primary endpoint) was 1.4 (P = .18). In contrast, ferritin >1000 ng/mL was a significant prognostic factor (HR for mortality, 1.7; P = .036). There was, however, no significant association between ferritin > 2500 and mortality. This meta-analysis suggests that iron overload, as assessed by LIC, is not a strong prognostic factor for OS in a general adult HCT population. Our data also suggest that ferritin is an inadequate surrogate for iron overload in HCT

A Flexible Analysis Tool for the Quantitative Acoustic Assessment of Infant Cry

Lincoln Memorial (by Henry Bacon, 1922), distant view from the base of the Washington Monumen

Earlier corticosteroid use for adverse event management in patients receiving axicabtagene ciloleucel for large B-cell lymphoma

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel–related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel

Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM?3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes

The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia