Electroencephalography in patients with immune effector cell-associated neurotoxicity syndrome (ICANS).

Age defining immune effector cell associated neurotoxicity syndromes in aggressive large B cell lymphoma patients treated with axicabtagene ciloleucel.

Predictors and Outcomes of Immune Effector Cell Associated Neurotoxicity Syndrome in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy for Aggressive B-Cell Non-Hodgkin Lymphoma

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Chimeric Antigen Receptor T-Cell Therapy Associated Cerebral Glucose Hypometabolism (CART-CGHM): A Novel Cerebral Metabolic Complication

2516 Background: ICANS is a complication of CAR T-cell therapy, yet risk factors and quantitative diagnostic criteria, particularly neuroimaging criteria, remain incompletely characterized. We implemented a novel application of a deep learning (DL)-based MRI approach alongside clinical and liquid biomarkers to better characterize neurotoxicity after CAR T-cell therapy. Methods: We analyzed all patients with non-Hodgkin lymphoma (NHL) or acute lymphoblastic leukemia (ALL) who underwent CAR T-cell therapy at UCSD with a commercial product from 2018-2024. ICANS was graded as per American Society for Transplantation and Cellular Therapy (gr1-4). Variables included stage, performance status, and prior receipt of high-dose methotrexate (HD MTX), intrathecal (IT) chemotherapy, central nervous system (CNS) involvement, CNS-directed radiotherapy (CNS RT), and extracranial RT. Labs obtained pre-infusion, 3 days post-infusion, and during ICANS (or 7 days post-infusion for those without ICANS) were evaluated. Available post-infusion brain MRIs were processed with a 3D U-Net convolutional neural network to quantify T2 FLAIR hyperintensity volumetrics. Linear mixed regression models accounting for zero inflation assessed longitudinal DL-derived FLAIR. Multivariable regression models assessed factors associated with ICANS. Results: Of 163 patients (89% NHL, 11% ALL), 52 had IT chemotherapy, 27 had HD MTX, 24 had prior CNS disease, and 22 had prior CNS RT. Most (106) received axicabtagene ciloleucel (34 tisagenlecleucel, 23 brexucabtagene autoleucel) and most had CRS (133, 82%). ICANS occurred in 73 (45%) at a median of 7 days post-infusion (39 gr1-2, 34 gr3-4). Post-infusion, 21 patients had ³1 brain MRI (93 MRIs total). Baseline factors associated with ICANS were lactate dehydrogenase (LDH; odds ratio [OR] 1.03 p = 0.002) and prior IT chemotherapy (OR 2.5 p = 0.01). There was a trend toward association of gr3-4 ICANS with HD MTX (OR 2.8 p = 0.07). Post-infusion, CRS grade was associated with ICANS (OR 2.8 p < 0.001). LDH (1.02 p = 0.004) and C-reactive protein (OR 1.2 p < 0.001) were elevated during ICANS. Patients with ICANS had significantly greater FLAIR (intercept 23.8 cm³ p < 0.001) and there was increased FLAIR over time across all patients (b = 3.3 cm³ p = 0.05). There was a trend toward association between higher ICANS grade and DL-derived FLAIR (p = 0.09). Conclusions: Here, we demonstrate a novel application of DL-based MRI quantification of ICANS post-CAR T-cell therapy. This metric, along with clinical features, emerged as potential quantitative biomarkers of ICANS. These findings warrant further investigation and have informed a prospective study, including standardized brain MRI pre- and post-infusion, to develop a comprehensive phenotype of neurotoxicity following CAR T-cell therapy.

CAR T-cell therapy for solid tumours

Utilization of Investigations for Neurotoxicity in CD19 and BCMA CART Recipients

Demographic Characteristics, Incidence and Outcomes of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome in Patients Undergoing CAR T-Cell Therapy: An Analysis of the National Inpatient Sample (NIS) - 2021

e19506 Background: Chimeric antigen receptor (CAR) T-cell immunotherapy is a revolutionary treatment modality which has gained attention for its potential in treating multiple refractory hematological malignancies. Significant toxicities associated with CAR T- cell therapy remain a major concern. Cytokine release syndrome (CRS) and Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) are seen early on post CAR-T cell therapy. To date, the treatment of ICANS has largely been limited to supportive care and corticosteroids. More recently, some early clinical data investigated the use of Anakinra as a promising agent in prevention and treatment of severe ICANS. Methods: We analyze three cases in which Anakinra was used to treat high-grade ICANS concurrently with high dose steroids. Results: A 51-year-old woman with high grade DLBCL and secondary CNS involvement was treated with Tisagenlecleucel CAR-T therapy. On day 2, patient became altered and was diagnosed with ICANS Grade II. High dose steroids were started leading to resolution of ICANS. However, patient’s mentation worsened by day 7, progressing to ICANS Grade IV by day 8, and Anakinra 100 mg IV was added to the steroid regimen. By day 11, after 4 doses of Anakinra, patient’s neurotoxicity completely resolved. Patient achieved a PR by day 30 after CAR-T cell infusion. In the second case, a 65-year-old man with DLBCL and leptomeningeal involvement developed ICANS Grade II on day 1 after Tisagenlecleucel CAR-T therapy and was started on high dose steroids. By day 4, neurotoxicity worsened and progressed to ICANS Grade IV. On day 5 patient was transferred to ICU for a mechanical ventilation, and Anakinra 100 mg IV was added and continued daily for 7 days. By day 12, neurotoxicity improved to ICANS grade II and patient was extubated. Meanwhile, high dose steroids were tapered. His condition acutely worsened by day 19, prompting transfer to the ICU and re-initiation of Anakinra concurrently with steroids. His family decided against further escalation of care on day 22. Patient was transitioned to comfort care and died 23 days post CAR-T cell infusion. In the third case, a 65-year-old man with mantle cell lymphoma was treated with Brexucabtagene autoleucel CAR-T therapy. On day 8, patient developed ICANS Grade I which rapidly progressed to Grade IV. High dose steroids were started and ICANS improved to Grade II on Day 9. However, on Day 10 patient’s mentation again worsened and one dose of Anakinra 100mg IV was added to the steroid regimen. By day 11, ICANS completely resolved, and patient was ultimately discharged home on day 15. Patient was able to achieve interval CR by day 30 after CAR-T cell infusion. Conclusions: In the reported cases, ICANS improved following administration of Anakinra, adding support to the idea that Anakinra may be beneficial in treatment of high-grade ICANS. Future studies are needed to better understand the overall efficacy and the ideal timeline for administration.

Association of Bridging Therapy Utilization with Clinical Outcomes in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

e18891 Background: CAR-T therapy represents the most significant advancement in the treatment of HM in the past 5 years. Life-threatening complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may occur leading to significant morbidity and mortality. We aimed to describes the frequency of CRS and ICANS and the time to onset of each post CAR-T therapy administration in real-world, U.S. patients. Methods: Patients (pts) with HM who received any FDA-approved CAR-T therapy were identified from a U.S. EMR database containing de-identified healthcare data for > 40M patients from > 500 hospitals and 30 healthcare systems (including academic centers). Confirmation of CAR-t treatment was based on ≥1 procedure code for general administration of CAR-T therapy (e.g., XW033C3, introduction of engineered autologous chimeric antigen receptor t-cell immunotherapy into peripheral vein) or a specific approved CAR-T (I.e., XW033K7, introduction of idecabtagene vicleucel immunotherapy into peripheral vein) between 2017 and 2022. Diagnosis of CRS or any ICAN was based ≥1 related ICD-10 diagnosis code (e.g., CRS = D89.83X). Frequency of occurrence of CRS, symptoms of CRS, ICANS symptoms, and severity of CRS or ICANS is described (severity based on validated clinical algorithm). Time to CRS and ICANS was calculated as the interval from CAR-T administration to first reported diagnosis, respectively. Results: 212 pts met the study criteria including 77 b-cell lymphoma, 64 multiple myeloma, 47 follicular lymphoma, 13 mantle cell lymphoma and 11 acute lymphoblastic leukemia pts. The majority were male (54.7%); median age was 60 years. Overall, 100 (47.2%) pts were diagnosed with CRS (any grade) while 82 (38.7%) pts experienced any ICAN symptoms. The top three CRS symptoms were fever (57.5%), hypotension (31.1%) and tachycardia (21.2%). The top three ICANS symptoms were obtundation (18.4%), confusion (12.7%), and delirium (12.7%). Of CRS pts, 25.0% experienced severe symptoms, including renal insufficiency (10.0%), atrial fibrillation (9.0%), ventricular tachycardia (7.0%), and cardiac failure (2.0%). The median time to development of CRS was 2 days (range 0-23 days). Of pts. experiencing ICANS, 72.0% experienced any mild symptom and 53.7% experienced any severe symptom, including obtundation (47.6%), aphasia (13.4%), and seizures (1.2%). The median time to development of ICANS post CAR-T therapy was 6 days (range 0-26 days). Conclusions: Our study is the first real-world, U.S. evaluation of the frequency and time to toxicities associated with CAR-t therapy across multiple hematologic malignancies. While well-described in RCTs these data highlight the need for the continued development of clinical and therapeutic approaches to minimize their impact on the effectiveness of CAR-T.

Feasibility of outpatient administration of axicabtagene ciloleucel and brexucabtagene autoleucel using telemedicine tools: The Vanderbilt experience.

Cognitive and Psychological Recovery from the Immune Effector Cell Associated Neurotoxicity Syndrome Following Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Prophylactic Corticosteroids Allow Safe Outpatient Administration of Axicabtagene Ciloleucel with Comparable Toxicities to Other CAR-T Therapies in Large Cell Lymphoma

Introduction: The efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL) is limited by acute toxic events, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Identification of biomarkers of toxicities can allow for selection of high-risk patients and elucidate targetable mechanisms for mitigation. Previous biomarker studies have been constrained by relatively narrow panels of potential mediators and limited time points. Here, we employed NULISA, a novel ultrasensitive assay capable of simultaneously quantifying 204 inflammatory proteins from a single sample, to identify temporal proteome associations with acute toxicities in anti-CD19 CAR T-cell treated patients. Methods: Baseline and post-treatment peripheral blood samples from 80 patients with LBCL who underwent anti-CD19 CAR-T cell therapy were collected within specific time intervals. Plasma samples (n=480) were analyzed with NULISA. CRS and ICANS were graded according to ASTCT consensus criteria. Patients were grouped according to their maximum CRS and ICANS scores. Differential protein abundance across the toxicity groups was assessed using linear mixed effects models fit for each protein, including a time by toxicity group interaction. Proteins showing significant associations were subjected to pathway enrichment and network analysis. Results: Severe CRS and ICANS patient groups showed proteome upregulation beginning on day 1-2 and peaking at day 6-9, followed by extensive downregulation on day 11-16. The strongest upregulated pathway associations of severe CRS and ICANS were inflammatory response, IL-17 signaling, non-genomic action of vitamin D3, regulation of leukocyte proliferation, and cellular extravasation. Downregulated pathways included anti-microbial humoral response and TNFs binding to receptors. In addition to the previously identified inflammatory proteins IL-6, IFNγ, sIL-2Rα, CXCL8, CCL2, our analysis revealed significant association of several novel immune regulators and mediators. These included upregulated Th2 cytokines, IL-17A, IL-22, GZMB, CTLA4, IFNA1;IFNA13, and downregulated S100A12, IL-12B, CCL22, BDNF and TNFSFs, revealing exquisite temporal orchestration of lymphoid and myeloid activities during CRS and ICANS development. Conclusions: This study represents the most comprehensive characterization of immune response to CAR T-cell therapy to date. Using the novel NULISA technology, we identified new proteins and functional pathways associated with CAR T-cell-induced toxicity, implicating them as potential biomarkers. These previously unidentified factors also provide a platform to further investigate the causative immune mechanisms of acute toxicities in CAR-T cell therapy. Citation Format: Riley Kirkpatrick, Joanne Beer, Manishkumar S. Patel, Akansha Jalota, Agrima Mian, Ishara S. Ariyapala, Qinyu Hao, Wei Feng, Xiao-Jun Ma, Yuling Luo, Brian T. Hill, Neetu Gupta. Identification of novel biomarkers of immune toxicity from CAR T-cell therapy using ultrasensitive NULISA™ proteome technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3867.