ALBERT

Description: CD8+ T cell-numbers rapidly expand and then contract after exposure to their cognate antigen. Here we show that the sustained frequencies of transgene product-specific CD8+ T cells elicited by replication-defective adenovirus vectors are linked to persistence of low levels of transcriptionally active adenovirus vector genomes at the site of inoculation, in liver, and lymphatic tissues. Continuously produced small amounts of antigen maintain fully active effector CD8+ T cells, while also allowing for their differentiation into central memory cells. The long-term persistence of adenoviral vectors may be highly advantageous for their use as vaccines against pathogens for which T-cell–mediated protection requires both fully activated T cells for immediate control of virus-infected cells and central memory CD8+ T cells that, because of their higher proliferative capacity, may be suited best to eliminate cells infected by pathogens that escaped the initial wave of effector T cells.

Description: Background: CD19-targeted chimeric antigen receptor T cell therapy (CART19) has demonstrated remarkable clinical efficacy in treating relapsed/refractory B cell ALL, but associated toxicities may require treatment in inpatient or intensive care units (ICU). We sought to: (1) describe inpatient and ICU resource utilization within 30 days of CART19 infusion; and (2) evaluate trends in resource utilization from 2012-2019. Methods: We identified patients treated with CART19 on a clinical trial (NCT01626495, NCT02906371, and NCT02374333) or with the commercial product, tisagenlecleucel, at Children's Hospital of Philadelphia. Patients who received a prior cell therapy product were excluded. Demographic, pharmacy, and inpatient data were extracted from the electronic medical record from day of infusion (day 0) to day +30, censored at disease progression or death, using a semi-automated EPIC data query tool (ExtractEHR). The Virtual Pediatric Systems (VPS) database was queried for clinical data, resource utilization data, and Pediatric Risk of Mortality (PRISM) 3 and Pediatric Index of Mortality (PIM) 2 severity of illness scores. Log-binomial regression and linear regression were used to estimate the association of patient characteristics with the need for inpatient/ICU admission and inpatient/ICU length of stay (LOS), respectively. Similar models were used to estimate trends in outcomes from 2012-2019. Results: A total of 213 patients were included in the analyses. Median patient age was 12.4 years (range 1.4-29.1) at infusion; 60% were male, 66% were Caucasian, and 80% were non-Hispanic. Prior to CART19, 42% had an allogeneic hematopoietic cell transplant (alloHCT). At time of infusion, 19% had high disease burden, defined as bone marrow blasts ≥40% by flow cytometry. From 2012-2019, the proportion of patients with prior alloHCT or high disease burden decreased (Table 1). CART19 was infused in the outpatient setting in 93% of patients. In the 30 days after infusion, 70% had at least one inpatient admission, starting at a median of day +2 (IQR +1 to +6). Among the 149 patients admitted, median cumulative inpatient LOS was 7 days (IQR 4-13). Cumulative LOS increased with increasing grade of cytokine release syndrome (CRS). Median LOS was 0, 5, and 15 days for patients with no, mild, and severe CRS, respectively. From 2012-2019, there were linear trends toward decreases in proportion of patients admitted (p

Description: Infectious complications are major contributors to morbidity and mortality in children with leukemia; however, clinical trial reporting is incomplete (Miller 2016 J Clin Oncol). Using administrative data to identify SS events could improve estimates of incidence and clinical impact. However, accurate SS determination is challenging, and the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) definition is often modified for individual studies. ICD-9 codes, assigned at discharge, do not permit precise timing estimates. We hypothesized PHIS resource utilization (RU) codes could identify vasopressor exposures as proxies for IPSCC-defined SS events. We present the operating characteristics of our methods and use the approach to estimate SS incidence for a national cohort. We previously identified and validated a longitudinal cohort of children aged 0-21 with newly diagnosed ALL using PHIS billing and diagnosis codes (Fisher 2014 Med Care), expanded through 12/31/2013. PHIS RU data were used to identify distinct vasopressor exposure patterns hypothesized to represent true SS (Figure 1). Epinephrine alone with asparaginase within ± 3 days was considered anaphylaxis rather than SS. We captured vasopressor patterns occurring ≥7 days from first chemotherapy until the first of: 30 days prior to relapse, 10 days prior to stem cell transplantation, or 3 years from diagnosis. We reviewed charts of all patients with ALL diagnosed from 2004 to 2013 at the Children's Hospital of Philadelphia (CHOP) to establish the SS gold-standard. We assumed true SS events would be associated with blood cultures. Each blood culture triggered a chart review and was classified by IPSCC sepsis criteria. A PHIS RU-defined vasopressor exposure had to be within ±14 days of the chart-defined SS to be considered a true positive. We predicted a patient may meet criteria for a PHIS vasopressor exposure if vasopressors were ordered to the bedside for impending SS but ultimately not administered. For CHOP patients with available electronic medication administration record (MAR) data (1/1/2011-12/31/2013), we assessed whether using vasopressor orders marked as "given" or "given or held at bedside" resulted in different operating characteristics relative to gold standard IPSCC SS events. We calculated sensitivity and positive predictive value (PPV) of PHIS RU exposure patterns for IPSCC SS, then used them to estimate SS incidence for the entire PHIS cohort and for certain risk group subsets. We identified 360 patients common to both PHIS and CHOP chart review cohorts. Chart review revealed 38 events meeting IPSCC SS criteria. PHIS RU data identified vasopressor exposure patterns in 35 of these 38 SS events within ±14 days (sensitivity 92%). PHIS RU data identified an additional 43 vasopressor patterns that did not correlate with a chart review IPSCC SS event (PPV: 35/78, 45%). When considering chart-defined sepsis event of any severity (ie, not restricted to SS), the PPV for PHIS-defined vasopressor events increased to 88%. MAR data were available for 149 patients to delineate whether ordered vasopressors were given or held. Among these 149 patients, 10 SS events met IPSCC criteria by chart review. Restricting RU-identified vasopressor exposure events to patients who actually received vasopressors resulted in sensitivity of 70% and PPV 77%; including orders where vasopressors were given or held, the sensitivity increased to 100% and PPV decreased to 55%. Using PHIS RU vasopressor patterns, we estimated an incidence of 12.6% (95% CI 12.0 - 13.3 %) of patients ever experiencing SS in the PHIS ALL cohort. Infants, children aged ≥10 years, with public insurance, or receiving daunorubicin all had significantly higher SS rates than the cohort baseline (Table 1). PHIS RU-defined vasopressor exposure patterns have a high sensitivity for IPSCC-defined SS but a low PPV. The PPV may be the result of including patients with vasopressors ordered but not given; however, IPSCC-defined SS excludes children with fluid-responsive shock. The low PPV suggests this RU-defined approach results in "overcapture" of SS, but the gold standard definition may be too restrictive. Vasopressor exposure patterns from RU data may identify patients with SS or impending SS that can augment incomplete clinical trial data collection. PHIS RU SS incidence estimates for a national pediatric ALL cohort exceed 12%, with even higher rates in high-risk subgroups. Disclosures Fisher: Merck: Research Funding; Pfizer: Research Funding.

Description: Key Points Cytokine release syndrome caused by T cell-directed therapies may be driven by abnormal macrophage activation and hemophagocytic syndrome. Cytokine-directed therapy can be effective against life-threatening cytokine release syndrome.

Description: Introduction: During the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), 3 distinct phenotypes have emerged in children. The majority of children have mild or no symptoms. Similar to adults, a minority of children can be severely affected with respiratory distress requiring intensive care. Finally, they may develop a phenomenon presumed unique to children termed Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a hyperinflammatory syndrome characterized by fever and organ dysfunction (particularly cardiac) in the setting of recent COVID-19 infection. Reports from the adult literature have invoked thrombotic microangiopathy (TMA) and complement activation as a potential cause for severe manifestations of COVID-19 (Zhang et al. NEJM. 2020; Campbell et al. Circulation 2020). Soluble C5b9 (sC5b-9), the terminal complement complex, has been implicated as a marker of hematopoietic stem cell transplant associated TMA (HSCT-TMA; Jodele et al. Blood 2014). We sought to elucidate the role of terminal complement activation and TMA in the different pediatric disease phenotypes. Methods: We enrolled children admitted to the Children's Hospital of Philadelphia during the COVID-19 pandemic who had evidence of SARS-CoV-2 infection on reverse transcriptase polymerase chain reaction (RT-PCR) from mucosa, or met clinical criteria for MIS-C. Patients (pts) were classified in to 3 categories: minimal COVID-19 symptoms or incidental finding of SARS-CoV-2 infection, severe COVID-19 requiring ventilatory support, or MIS-C. To investigate the role of TMA in children with COVID-19 we measured sC5b-9 in plasma of pts with the 3 manifestations of SARS-CoV-2, and in healthy controls. sC5b9 was measured in triplicate at two dilutions by ELISA. Proinflammatory cytokines were measured using V-Plex Pro-inflammatory Panel 1 Human Kits and analyzed on a QuickPlex SQ120. P-values were computed using Dunn's multiple comparisons test after Kruskal-Wallis testing. Blood smears were examined by a hematologist and hematopathologist for schistocytes. Results: 50 pts were enrolled on whom complete sC5b9 data were available: minimal COVID-19 (N=18), severe COVID-19 (N=11), and MIS-C (N=21). Plasma was obtained on healthy controls (N=26). The median sC5b9 level in healthy controls (57 ng/mL) differed significantly (p