Background: Despite the potential for durable disease remission seen with Chimeric Antigen Receptor (CAR-T) and T-Cell Receptor (TCR-T) therapies, their use is limited by the potential for acute toxicity from Cytokine-Release Syndrome (CRS).Across all grades, CRS has seen rates as high as 100% in some trials of patients receiving CAR-T, and up to 15% receiving TCR-T. Prior research indicates an association of hematologic abnormalities with CRS. Due to smaller average trial size and limited adoption, to date, of CAR and TCR therapies, there have been no large-scale studies to date exploring these associations with CRS severity in a wide range of patients across treatment types. This study sought to address these evidence gaps using retrospective analysis of pooled clinical trial data in Acute Lymphocytic Leukemia (ALL), using, to our knowledge, the single largest data repository of of CAR-T and TCR-T clinical patient data, with high resolution measurements across a spectrum of clinical domains. Methods: Eligible Phase I, II and III completed clinical trials in Acute Lymphocytic Leukemia (ALL), with patients receiving either CAR-T or TCR-T, were identified from the Medidata Enterprise Data Store, which comprises over 22,000 historical clinical trials, for de-identified retrospective aggregate analyses. Baseline characteristics, including demographics, medical history, prior treatment regimens were assessed and stratified by treatment type. Pre-trial history of hematologic conditions, such as neutropenia and anemia, were also assessed. Using Common Terminology Criteria for Adverse Events (CTCAE) 4.03, patients were assigned to categories of any CRS, mild CRS (grade 1) and moderate-to-severe CRS (2+). Hematologic function was assessed at baseline through first exposure to treatment, including counts of erythrocytes, neutrophils, eosinophils and basophils. Baseline marrow blast cell percentage was assessed as a marker of tumor burden. Univariate analyses of associations between pre-treatment baseline variables and CRS were conducted using Wilcoxon signed rank tests. Results: The pooled CT data contained 1,410 ALL patients, of whom over 60% were 18 year of age or greater. Baseline blood chemistries indicated 21% with anemia, 12% with thrombocytopenia, 6% neutropenic and 5.3% with elevated LDH. Although CAR-T patients accounted for 14.9% of the cohort, 47% of CRS events observed were associated with CAR-T treatment. In line with expectations from prior literature, factors associated with moderate-to-severe CRS included prior history of anemia, reduced platelet levels, low neutrophil counts, and delayed neutrophil recovery. Nearly all cases of moderate-to-severe CRS occurred in subjects exhibiting both low neutrophil and low platelet counts (Figure 1). Similar associations were seen in patients with pretreatment history of anemia (Figure 2). Consistent with literature on tumor burden and CRS, patients without CRS tended to have lower marrow blast percentages. Lymphocyte levels at baseline were far lower in patients receiving CAR-T therapy, with slower recovery than in patients receiving TCR-T. While consistent with CAR-T pre-treatment lymphodepletion, this finding was noteworthy given the association of neutropenia with CRS. Conclusions: Overall findings suggest patterns of routine hematologic function at baseline can potentially be used to assess risk of moderate-to-severe CRS in patients receiving CAR-T and TCR-T agents. The association with these markers could also suggest a mechanism of CRS as a function of tumor cell concentration, modified by the strength and presence of innate immunity mechanisms such as granulocytes, and potentially mediated by intermediates such as macrophages, in line with emerging literature., Further analysis may facilitate development of predictive algorithms to identify patients at greater risk for severe CRS prior to as well as shortly after treatment. This has implications for enhancing supportive care for patients receiving CAR- and TCR therapies. Additionally, a data-driven stratification of patients by risk of CRS will allow improved utilization and management of care resources. Figure 1 Figure 1. Disclosures Agarwal: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Socolov: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Buderi: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Rusli: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Bouzit: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Talwai: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Itzkovich: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment. Galaznik: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment, Current equity holder in publicly-traded company. Aptekar: Medidata Acorn AI, a Dassault Systèmes Company: Current Employment.
Objectives: Heart failure is a major cause of morbidity and mortality in developing and in industrialized regions. The aim of our study was to calculate the annual health insurance treatment cost of heart failure in Hungary. Methods: The data were derived from the financial database of the Hungarian National Health Insurance Fund Administration (NHIFA), the only health care financing agency in Hungary. We analyzed the number of patients and the health insurance treatment cost for the year 2018. The following cost categories were included into the study: out-patient care, laboratory diagnostics, medical imaging, acute in-patient care, chronic in-patient care and drugs. Patients with heart failure were identified with the following codes of the International Classification of Diseases 10 th revision: I-50. Results: The number of patients admitted to inpatient care was 123,000 (47.2% men and 52.8% women) with a mean age of 74.24 years (men: 70.96 years; women: 77.18 years). Number of patients underwent out-patient hospital care was 205,794 (50.0 % men and 50.0% women) with a mean age of 72.58 years (men: 69.75 years; women: 75.41 years). For the treatment of patients with heart failure in 2018 the Hungarian National Health Insurance Fund Administration spent 47.589 billion Hungarian Forint (HUF) which equals 149.244 million Euros (EUR) or 176.094 million American Dollars (USD). Major cost drivers were acute inpatient care (84.5% of total health insurance costs), chronic inpatient care (7.0%) and pharmaceuticals (5.1%). Conclusions: Heart failure represents a significant burden for the Hungarian health insurance system. The disease is equally common in women and men. There is a significant difference (5-6 years) in the onset of the disease between women and men; men are affected in younger age.
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