Venous thromboembolism (VTE) is a common and impactful complication of cancer. Several clinical prediction rules have been devised to estimate the risk of a thrombotic event in this patient population, however they are associated with limitations. We aimed to develop a predictive model of cancer-associated VTE using machine learning as a means to better integrate all available data, improve prediction accuracy and allow applicability regardless of timing for systemic therapy administration. A retrospective cohort was used to fit and validate the models, consisting of adult patients who had next generation sequencing performed on their solid tumor for the years 2014 to 2019. A deep learning survival model limited to demographic, cancer-specific, laboratory and pharmacological predictors was selected based on results from training data for 23,800 individuals and was evaluated on an internal validation set including 5,951 individuals, yielding a time-dependent concordance index of 0.72 (95% CI = 0.70–0.74) for the first 6 months of observation. Adapted models also performed well overall compared to the Khorana Score (KS) in two external cohorts of individuals starting systemic therapy; in an external validation set of 1,250 patients, the C-index was 0.71 (95% CI = 0.65–0.77) for the deep learning model vs 0.66 (95% CI = 0.59–0.72) for the KS and in a smaller external cohort of 358 patients the C-index was 0.59 (95% CI = 0.50–0.69) for the deep learning model vs 0.56 (95% CI = 0.48–0.64) for the KS. The proportions of patients accurately reclassified by the deep learning model were 25% and 26% respectively. In this large cohort of patients with a broad range of solid malignancies and at different phases of systemic therapy, the use of deep learning resulted in improved accuracy for VTE incidence predictions. Additional studies are needed to further assess the validity of this model.
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Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.
Introduction: Treatment options for acute myeloid leukaemia (AML) patients have increased in recent years as several novel targeted medications for AML patients have been introduced. The aim of this study was to identify the integration of novel treatment concepts in the standard of care for AML patients, using real-world treatment information and to investigate evidence for therapeutic benefits of novel agents in this population. Methods: 255 haemato-oncologists in EU5 countries participated in a retrospective longitudinal reporting of patients with AML, who started therapy between January 2018 and March 2020. Data recorded for each patient included cytogenetic and European LeukemiaNet (ELN) prognostic factors, medical history, treatment pathway starting with first-line therapy, response and survival data. Results: Data of 1,015 AML patients were available and 967 were considered sufficient in data quality to analyse for the goal of this analysis. The age distribution was balanced below and above the age of 65 years (506 patients < 65 years and 461 elderly patients, i.e., ≥ 65 years of age). Most of the population, i.e., 706 patients (73%, [95% CI 70%-76%]) received intensified therapies based on anthracycline/cytarabine regimen that are considered standard of care. Gemtuzumab ozogamicin was added to intensive chemotherapy backbone for 17 patients (2.4%, [95% CI 1.3%-3.5%]). 416 patients treated with intensive chemotherapy were identified as having FLT3-mutated AML. 34 patients (8.1%, [95% CI 5.5%-10.8%]) from the FLT3-mutated group were treated with midostaurin combined with intensive chemotherapy. Overall, 261 patients (27% [95% CI 24%-30%] of all analysed patients) were treated with lower intensity regimens, i.e., azacitidine, decitabine, and low-dose cytarabine, with or without combination with venetoclax. Most of the patients in the low-intensity therapy group were in the elderly population (253 patients, 97%, [95% CI 95%-99%]). Venetoclax was combined with low-intensity therapies in 75 patients (29%, [95% CI 23%-34%]). In an exploratory analysis, venetoclax combined with low-intensity chemotherapy demonstrates a trend for improving the complete response rate in comparison to chemotherapy-only patients. Conclusions: In EU5, less than 50% of AML patients are treated with novel agents combined with chemotherapy backbone. Following FDA approval of venetoclax for AML, usage of venetoclax-containing low-intensity regimens has been observed in EU5. Although approved for targeted AML patient populations (i.e. CD33-mutated, FLT3-mutated patients), only approximately 10% of appropriate patients are receiving gemtuzumab ozogamicin and midostaurin in the first-line setting. Disclosures Ruiz: IQVIA: Current Employment. Heitner Enschede:Abbott: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; JNJ: Current equity holder in publicly-traded company; Lilly: Current equity holder in publicly-traded company. OffLabel Disclosure: Many AML patients are not candidates for intensive chemotherapy because of their age, comorbidities, etc. The development of combination regimens comprising low-intensity treatments and new agents is the need of the hour in AML treatment. Venetoclax's use in AML has been approved by FDA but not EMA (as of 01 Aug 2020). Despite this, AML patients in EU5 are observed to be receiving venetoclax in combination with low-intensity treatments, as a result of this growing need
Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.
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