Incident cardiac abnormalities after CAR-T cell therapy in children: a single center experience

Background Chimeric antigen receptor (CAR) T-cell immunotherapy is increasingly used for refractory lymphoma but may lead to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Imaging may assist in clinical management. Associations between CRS or ICANS grade and imaging findings remain not fully established. Purpose To determine associations between imaging findings and clinical grade of CRS or ICANS, evaluate response patterns, and assess imaging use following CAR T-cell treatment. Materials and Methods Patients with refractory B-cell lymphoma who received CAR T-cell infusion between 2018 and 2020 at a single center were analyzed retrospectively. Clinical CRS or ICANS toxicity grade was assessed using American Society for Transplantation and Cellular Therapy, or ASTCT, consensus grading. Thoracic and head images (radiographs, CT scans, MRI scans) were evaluated. Associations between imaging findings and clinical CRS or ICANS grade were analyzed. Wilcoxon signed-rank and χ2 tests were used to assess associations between thoracic imaging findings, clinical CRS toxicity grade, and imaging-based response. Response to therapy was evaluated according to Deauville five-point scale criteria. Results A total of 38 patients (mean age ± standard deviation, 59 years ± 10; 23 men) who received CAR T-cell infusion were included. Of these, 24 (63% [95% CI: 48, 79]) and 11 (29% [95% CI: 14, 44]) experienced clinical grade 1 or higher CRS and ICANS, respectively. Patients with grade 2 or higher CRS were more likely to have thoracic images with abnormal findings (10 of 14 patients [71%; 95% CI: 47, 96] vs five of 24 patients [21%; 95% CI: 4, 37]; P = .002) and more likely to have imaging evidence of pleural effusions (five of 14 [36%; 95% CI: 10, 62] vs two of 24 [8.3%; 95% CI: 0, 20]; P = .04) and atelectasis (eight of 14 [57%; 95% CI: 30, 84] vs six of 24 [25%; 95% CI: 7, 43]; P = .048). Positive imaging findings were identified in three of seven patients (43%) with grade 2 or higher ICANS who underwent neuroimaging. The best treatment response included 20 of 36 patients (56% [95% CI: 39, 72]) with complete response, seven of 36 (19% [95% CI: 6, 33]) with partial response, one of 36 (2.8% [95% CI: 0, 8]) with stable disease, and eight of 36 (22% [95% CI: 8, 36]) with progressive disease. Conclusion Thoracic imaging findings, including pleural effusions and atelectasis, correlated with cytokine release syndrome grade following chimeric antigen receptor (CAR) T-cell infusion. CAR T-cell therapy yielded high response rates. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Langer in this issue.

Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T)

Acute Kidney Injury After the CAR-T Therapy Tisagenlecleucel

Outcomes of Patients Requiring ICU Admission after CD19 Directed CAR T-Cells

Introduction: As Chimeric Antigen Receptor T cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but their association is not fully investigated. Therefore, we designed a prospective study to clarify the association between the grade of CRS and cardiac dysfunction in the DLBCL patients after CAR-T therapy. Methods: In this prospective study, 14 DLBCL patients who underwent CAR-T therapy from July 2020 to May 2021 were enrolled. Before and after CAR-T therapy, we collected the levels of troponin T (TnT) as a marker for myocardial damage, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) as markers for systolic function, and E/e’ and left atrial volume index (LAVI) as markers for diastolic function. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely the low-CRS Group (CRS<3) and the high-CRS Group (CRS≧3). The markers for cardiac injury and dysfunction were further analyzed in both groups. Results: Average age was 56.4 years and 7 patients (50%) were female. The number of patients in the low-CRS and high-CRS Group were 11 and 3, respectively. Before CAR-T therapy, there were no differences in cardiac function between the two groups. From the hyper-early phase of CAR-T therapy, the increase of TnT, E/e’ and LAVI from the baseline were significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.023, 0.039, and 0.024, respectively). Subsequently, the decrease of GLS from the baseline became significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.049). These results indicated that cardiac dysfunction after CAR-T therapy occurred in the order of myocardial damage, diastolic dysfunction, and systolic dysfunction. Conclusion: We for the first time demonstrated the association between high-grade CRS and cardiac dysfunction after CAR-T therapy through a prospective study.

Cytokine Release Syndrome (CRS) Is Not Required for CAR-T Cell Efficacy in Aggressive Large B-NHL

Severe Cytokine Release Syndrome Associated with Worse Outcomes in Recipients of a Haploidentical Stem Cell Transplant

Shortening the ex vivo culture of CD19-specific CAR T-cells retains potent efficacy against acute lymphoblastic leukemia without CAR T-cell-related encephalopathy syndrome or severe cytokine release syndrome.

Early Cytopenias and Infections Following Chimeric Antigen Receptor T-Cell Therapy: A Single Center Experience

Safety and Antitumor Effects of CD19-Specific Autologous Chimeric Antigen Receptor-Modified T (CAR-T) Cells Expressing the Inducible Caspase 9 Safety Switch (iC9-CAR19 T Cells) in Adult Acute Lymphoblastic Leukemia (ALL)

Adverse Events Following CAR T-Cell Therapy: A Single Institution Retrospective Analysis of Toxicities Following CAR T-Cell Therapy for Children and Young Adults with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia

Severe Cytokine Release Syndrome Is Associated with Impaired Hematopoietic Recovery after CD19-Targeted CAR-T Cell Therapy

Tocilizumab Administration in CAR-T Cell Associated Cytokine Release Syndrome Induces Hypofibrinogenemia

Background:Autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy tisagenlecleucel has demonstrated efficacy with a favorable risk/benefit profile in adults with relapsed or refractory diffuse large B‐cell lymphoma (r/r DLBCL) in the phase 2 JULIET trial. CAR T‐cell therapy is associated with unique toxicities, e.g., cytokine release syndrome (CRS) and neurotoxicity (NT), that require specialized management. It is important to understand how patient (pt) characteristics (e.g., age) and prior lymphodepleting (LD) chemotherapy regimens could inform risk and management of CRS and NT.Aims:This JULIET post‐hoc analysis aims to understand unique safety profiles associated with CAR T‐cell therapy in adults with r/r DLBCL treated with tisagenlecleucel, stratified by age or LD chemotherapy use.Methods:CRS and NT events observed in JULIET were graded with approaches common to CAR T‐cell therapy (CRS: Penn, Lee; NT: Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR‐T Related Encephalopathy Syndrome [mCRES]). Penn grades were reported per trial protocol; other grades were obtained via expert consensus grading (ASH2018 Schuster #4190; Maziarz #4183). Four medical experts independently re‐graded CRS using the Lee scale while blinded to original Penn grades, and graded NT using CTCAE and mCRES. Experts discussed grading assessments and reconciled disagreements at live meetings. Per the investigational charter, in cases that could not be reconciled, the most conservative final assessment of any reviewer determined final grading for any individual case.This analysis stratified JULIET pts who received tisagenlecleucel by age at screening (<65 or ≥65 years old [yo]) or LD chemotherapy use before infusion and type (fludarabine+cyclophosphamide [FC], bendamustine [B], or no LD therapy [permitted if white blood cell count ≤1,000 cells/μL ≥1wk pre‐infusion]). Demographics, disease characteristics, medical history, and CRS and NT grades were summarized and compared among subgroups.Results:Of 111 JULIET pts infused with tisagenlecleucel as of Dec 8, 2017, 86 were <65yo and 25 were ≥65yo. Overall, pts were similar in demographics and medical history, except that more pts aged <65yo received prior HSCT (<65 vs ≥65yo: 55.8% vs 24.0%, p < 0.01). The rates of any CRS grade (Lee: 59.3% vs 48.0%; Penn: 60.5% vs 48.0%), and grade ≥3 (Lee: 19.8% vs 8.0%; Penn: 22.1% vs 20.0%) were similar between age subgroups (Table 1). Among 64 pts with CRS per Penn (<65yo n = 52; ≥65yo n = 12), there were no differences in time to CRS onset, CRS duration, or proportions of pts with tocilizumab use. Overall, NT grades were similar between two subgroups with numerically higher rates in older pts: any grade (CTCAE: 43.0% vs 52.0%; mCRES: 14.0% vs 28.0%), grade ≥3 (CTCAE: 12.8% vs 20.0%; mCRES: 9.3% vs 24.0%). No grade 5 CRS or NT was observed in any JULIET pts. In stratification based on LD therapy (FC n = 81; B n = 22; no LD therapy n = 8), CRS and NT grades were similar across three subgroups (Table 1). Again, among CRS patients in LD therapy subgroups, no differences were observed regarding CRS characteristics and tocilizumab use.Summary/Conclusion:This JULIET post‐hoc analysis observed similar rates of CRS and NT grades using various grading approaches among pts aged <65 vs ≥65yo. In the only CAR T‐cell study for an approved product allowing different LD chemotherapies, no differences in safety were observed across LD regimens used in JULIET. These findings will inform clinical decision making in CAR T‐cell therapy use in r/r DLBCL.image

Title: Association of CAR-T product type with incidence of cancer Therapy–Related cardiac dysfunction (CTRCD)