To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen ...receptor T-cell therapy.
Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial.
The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (
< .001), but persistence was not different (
= .73). Event-free and overall survival were worse in the HTBC (
= .004,
< .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (
= .18).
Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.
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<.0001) and in cumulative inpatient LOS (p=0.001, Figure 1), which remained significant after adjustment for disease burden (p=0.032 and p<.0001).
ICU admission was required for 23% (95% CI, 17-29) of the cohort, starting at a median of day +5 (IQR +4 to +6.5). ICU admission was more frequent for patients with high disease burden than those with low disease burden 68% (95% CI, 52-81) vs. 11% (95% CI, 7-17), p<.0001. Among the 48 patients admitted to the ICU, resources utilized included vasoactive agents (n=36, 75%), non-invasive or invasive mechanical ventilation (n=24, 50%), and renal replacement therapy (RRT; n=4, 8%). In the 30-day follow-up period, median ICU LOS was 7 days (IQR 3-11.5), but 6 (12.5%) patients remained in the ICU after day +30. Among patients who required vasoactives, invasive mechanical ventilation, or RRT, the median duration of resource utilization was 5, 7.2, and 2 days, respectively. Seventy five percent (n=36) of patients admitted to the ICU received tocilizumab. Predicted median risk of mortality was 6.02% (IQR 5.04-7.32%) by PIM 2 and 10.74% (IQR 6.78-27.08%) by PRISM 3 scores. However, observed 30-day mortality was 1% (n=2) across the cohort, or 4% among ICU patients. From 2012-2019, there was a decrease in proportion of patients requiring ICU admission (p=0.001), but no significant changes in cumulative ICU LOS (Figure 1).
Other than high disease burden, baseline patient characteristics were not significantly associated with inpatient/ICU admission or inpatient/ICU LOS.
Conclusion: In a cohort of 213 pediatric patients with ALL who received CART19, over 90% were safely infused in the outpatient setting. Though the majority of patients required at least one inpatient admission, the proportion of patients admitted to the hospital or ICU and cumulative inpatient LOS in the 30 days post-infusion decreased over the past 7 years. Mortality was 1%. Additional analyses will investigate the impact of changes in supportive care practices on resource utilization outcomes.
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Grupp:GSK: Consultancy; Cure Genetics: Consultancy; Humanigen: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Novartis: Consultancy, Research Funding; Roche: Consultancy; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards. Maude:Novartis: Consultancy; Kite: Consultancy.
CART19-related toxicities may require treatment inpatient or in the ICU. We sought to describe inpatient/ICU resource utilization within 30 days of CART19 infusion and evaluate trends in resource ...utilization from 2012-2019.
We identified patients (pts) with ALL treated with CART19 on a clinical trial (NCT01626495, NCT02906371, and NCT02374333) or with the commercial product, tisagenlecleucel, at Children's Hospital of Philadelphia. Demographic, pharmacy, and inpatient data were extracted from the EHR from day of infusion (d0) to d+30 using a semi-automated EPIC data query tool. The Virtual Pediatric Systems database was queried for resource utilization data and PRISM 3 and PIM 2 severity of illness scores. Log-binomial and linear regression were used to estimate the association of patient characteristics with inpatient/ICU admission and inpatient/ICU length of stay (LOS). Similar models were used to estimate trends over time.
The analyses included 213 pts. Median age was 12y (range 1-29y); 60% were male. Prior to CART19, 42% had an alloHCT. Pre-infusion, 19% had high tumor burden (HTB), defined as bone marrow blasts ≥40%. From 2012-2019, the proportion of pts with prior alloHCT or HTB decreased (Table 1).
CART19 was infused in the outpatient setting in 198 (93%) pts. From d0 to d+30, 149 (70%) had ≥1 inpatient admission, starting at a median of d+2 (IQR +1 to +6). Among admitted pts, median cumulative inpatient LOS was 7d (IQR 4-13). From 2012-2019, there were linear trends toward decreases in proportion of pts admitted (p<.001) and in inpatient LOS (p<.001, Figure 1). These decreases persisted after adjustment for HTB (p=0.03 and p<.001).
ICU admission was required for 49 (23%) pts, starting at a median of day +5 (IQR +4 to +7). ICU admission was more frequent for pts with HTB HTB, 68% (95% CI, 52-81) vs. low burden, 11% (95% CI, 7-17), p<.001. Among ICU pts, resources utilized included tocilizumab (n=36, 75%), vasoactives (n=36, 75%), invasive mechanical ventilation (n=18, 8%), and dialysis (n=4, 8%). In the 30d follow-up period, median ICU LOS was 7d (IQR 3-12), but 6 (13%) pts remained in the ICU after d+30. Median duration of vasoactive, mechanical ventilation, and dialysis use was 5d, 7d and 2d, respectively. Predicted median risk of mortality was 6% (IQR 5-7) by PIM 2 and 11% (IQR 7-27) by PRISM 3 scores. However, observed 30d mortality was 1% (n=2) across the cohort, or 4% among ICU pts. From 2012-2019, there was a decrease in ICU admissions (p<.01), but no significant change in ICU LOS (Figure 1).
Other than HTB, baseline characteristics were not associated with inpatient/ICU admission or LOS.
In a cohort of 213 pediatric pts, over 90% were safely infused with CART19 in the outpatient setting. Though 70% required at least one admission, the proportion of pts admitted to the hospital or ICU and cumulative inpatient LOS decreased over the past 7 years.
Patients (pts) receiving CTL019 (tisagenlecleucel) for B-ALL with high tumor burden (HTB) are at high risk for developing severe CRS. Tocilizumab, an IL-6 receptor antibody, is a vital component of ...severe CRS management; however, its role in preventing severe CRS is not known. We sought to determine the effectiveness of preemptive tocilizumab (PT) administration in decreasing the rate of grade (gr) 4 CRS in HTB pts.
We conducted a pilot trial of risk-adapted PT after CTL019 (NCT02906371). HTB pts, defined as ≥40% bone marrow (BM) blasts immediately before infusion, received a single dose of PT for high persistent fever (2 temperatures ≥38.5C in 24hr). The primary endpoint was frequency of gr4 CRS (Penn scale), with an observed rate of ≤5/15 predefined as clinically meaningful. Secondary endpoints included complete remission (CR) rate and ICU length of stay (LOS). A comparator cohort with HTB who received standard CRS management (stdCRS) was identified from the initial CTL019 trial (NCT01626495).
Characteristics of the PT (n=15) and stdCRS (n=26) HTB cohorts are shown in Table 1. All pts developed gr≥2 CRS; median time to fever was longer in the PT cohort PT, 3d (IQR 2-9); stdCRS, 2d (IQR 1-7), p=0.03. Gr4 CRS was observed in 4/15 (27%) pts in the PT cohort vs. 13/26 (50%) in the prior stdCRS cohort RR 0.53 (95% CI, 0.21-1.34), p=0.18. In the stdCRS cohort, gr4 CRS was associated with earlier onset of fever (p=0.04). In patients with earlier CRS onset (fever by day +4), gr4 CRS was observed in 4/9 (44%) vs. 13/21 (62%) in the PT and stdCRS cohorts RR 0.72 (95% CI, 0.32-1.60), p=0.42. Except for a trend toward fewer vasoactive days in the PT cohort, ICU LOS and resource utilization were not significantly different (Table 2). The CR rate at day 28 was similar in the PT and stdCRS cohorts (87% vs. 85%, p=1.00).
Risk-adapted PT administration reduced gr4 CRS, meeting the predefined study endpoint, without impacting the CR rate. A secondary comparison to a prior trial showed a clinically meaningful decrease in the rate of gr4 CRS from 50% to 27%; however, the analysis was not powered to detect a statistically significant difference. Ongoing analyses will evaluate CAR T cell expansion, duration of remission, and additional safety endpoints, including rates of neurotoxicity.
The authors propose a restructuring of the "food as health" paradigm to "food as well-being." This requires shifting from an emphasis on restraint and restrictions to a more positive, holistic ...understanding of the role of food in overall well-being. The authors propose the concept of food well-being (FWB), defined as a positive psychological, physical, emotional, and social relationship with food at both individual and societal levels. The authors define and explain the five primary domains of FWB: food socialization, food literacy, food marketing, food availability, and food policy. The FWB framework employs a richer definition of food and highlights the need for research that bridges other disciplines and paradigms outside and within marketing. Further research should develop and refine the understanding of each domain with the ultimate goal of moving the field toward this embodiment of food as well-being.
Food well-being (FWB) is defined as “a positive psychological, physical, emotional, and social relationship with food at both the individual and societal levels” (Block et al., 2011, p. 6). This ...article seeks to advance our understanding of FWB along two dimensions. First, we discuss how awareness of consumer goals, as well as motivation and readiness to change, may help us to understand consumer preparedness to advance FWB. Second, we deconstruct the automatic and deliberative influences on food decision making into cognitive and emotional information that guide food choices and can be used by consumers to advance their own FWB. We close with a discussion of how measurement and strategies to influence FWB may allow researchers, policymakers, and industry to help consumers advance FWB.
Crossing over during meiotic prophase I is required for sexual reproduction in mice and contributes to genome-wide genetic diversity. Here we report on the characterization of an ...N-ethyl-N-nitrosourea-induced, recessive allele called mei4, which causes sterility in both sexes owing to meiotic defects. In mutant spermatocytes, chromosomes fail to congress properly at the metaphase plate, leading to arrest and apoptosis before the first meiotic division. Mutant oocytes have a similar chromosomal phenotype but in vitro can undergo meiotic divisions and fertilization before arresting. During late meiotic prophase in mei4 mutant males, absence of cyclin dependent kinase 2 and mismatch repair protein association from chromosome cores is correlated with the premature separation of bivalents at diplonema owing to lack of chiasmata. We have identified the causative mutation, a transversion in the 5' splice donor site of exon 1 in the mouse ortholog of Human Enhancer of Invasion 10 (Hei10; also known as Gm288 in mouse and CCNB1IP1 in human), a putative B-type cyclin E3 ubiquitin ligase. Importantly, orthologs of Hei10 are found exclusively in deuterostomes and not in more ancestral protostomes such as yeast, worms, or flies. The cloning and characterization of the mei4 allele of Hei10 demonstrates a novel link between cell cycle regulation and mismatch repair during prophase I.
To compare the effectiveness of surgical stabilization of rib fractures (SSRFs) to nonoperative management in severe chest wall injury.
SSRF has been shown to improve outcomes in patients with ...clinical flail chest and respiratory failure. However, the effect of SSRF outcomes in severe chest wall injuries without clinical flail chest is unknown.
Randomized controlled trial comparing SSRF to nonoperative management in severe chest wall injury, defined as: (1) a radiographic flail segment without clinical flail or (2) ≥5 consecutive rib fractures or (3) any rib fracture with bicortical displacement. Randomization was stratified by the unit of admission as a proxy for injury severity. Primary outcome was hospital length of stay (LOS). Secondary outcomes included intensive care unit (ICU) LOS, ventilator days, opioid exposure, mortality, and incidences of pneumonia and tracheostomy. Quality of life at 1, 3, and 6 months was measured using the EQ-5D-5L survey.
Eighty-four patients were randomized in an intention-to-treat analysis (usual care = 42, SSRF = 42). Baseline characteristics were similar between groups. The numbers of total fractures, displaced fractures, and segmental fractures per patient were also similar, as were the incidences of displaced fractures and radiographic flail segments. Hospital LOS was greater in the SSRF group. ICU LOS and ventilator days were similar. After adjusting for the stratification variable, hospital LOS remained greater in the SSRF group (RR: 1.48, 95% CI: 1.17-1.88). ICU LOS (RR: 1.65, 95% CI: 0.94-2.92) and ventilator days (RR: 1.49, 95% CI: 0.61--3.69) remained similar. Subgroup analysis showed that patients with displaced fractures were more likely to have LOS outcomes similar to their usual care counterparts. At 1 month, SSRF patients had greater impairment in mobility 3 (2-3) vs 2 (1-2), P = 0.012 and self-care 2 (1-2) vs 2 (2-3), P = 0.034 dimensions of the EQ-5D-5L.
In severe chest wall injury, even in the absence of clinical flail chest, the majority of patients still reported moderate to extreme pain and impairment of usual physical activity at one month. SSRF increased hospital LOS and did not provide any quality of life benefit for up to 6 months.
The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former ...heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.
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