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Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel., (© 2024. The Author(s).)

The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly because of the expanding indications for standard-of-care treatment and the development of new investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential in facilitating the widespread use. Preemptive interventions to prevent more severe toxicities have improved safety, facilitating CAR T-cell therapy in medically frail populations and in those at high risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic because it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside. At present, two CART products that target CD19 are commercially available: tisagenlecleucel and axicabtagene ciloleucel. They have demonstrated remarkable efficacy for their particular indications. One challenge is to compare the safety among commercially available and clinical trial CART treatments due to the use of different grading models to assess the severity of cytokine release syndrome and neurotoxicity. An unmet need exists to harmonize current grading models in order to develop uniform treatment strategies to manage these toxicities. Here, we attempt to summarize the evolution of the various grading systems for cytokine release syndrome and neurotoxicity and also highlight the major differences among them, whenever applicable., Competing Interests: Declaration of Competing Interest JCC: consultancy for Kite/Gilead, Novartis, Genentech, Bayer, and Karyopharm. Speaker Bureau for Genentech. MDJ: consultancy: Kite/Gilead. MAK-D: no relevant financial COI in relation to this manuscript. Other non-relevant COI (Consultancy: Pharmacyclics, Daiichi Sankyo; Speaker bureau: Seattle Genetics, Alexion Pharmaceuticals, Incyte Corp.)., (Copyright © 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Background: Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T., Objectives: The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T., Methods: The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death., Results: The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab., Conclusions: Among adults, cardiac injury and CV events are common post-CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

PurposeAxicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.Patients and methodsData were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.ResultsOf 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.ConclusionThe safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

Two CD19 chimeric antigen receptor (CAR) T cell therapies are now approved by the US Food and Drug Administration for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and histological variants: axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) (Neelapu I et al i , [6]; Schuster I et al i , [9]). Clinically, it remains unclear as to when the HLH features of CRS are significant enough to consider treatment with therapies used for non-CAR T-associated HLH, such as etoposide or methotrexate (Neelapu I et al i , [8]). Our case series suggests that the timing of onset of CAR T-associated HLH may differ between patients, with concern when delayed or recurrent HLH symptoms occur with a rising ferritin level, which is when HLH-directed therapies should be considered. [Extracted from the article]

Background A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokineś analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. Results 41 patients were identified. Median age was 64 years old (76% male). Non-severe (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that wasńt evident from standard biomarkers. Conclusions We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically. [ABSTRACT FROM AUTHOR]