Cytokine Release Syndrome Grade Research Articles

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy offers durable remissions in hematologic malignancies but carries a substantial risk of cancer therapy–related cardiac dysfunction (CTRCD). Current imaging strategies are predominantly event-driven, initiated after overt cardiovascular deterioration, leading to underdiagnosis of subclinical or evolving dysfunction. Cytokine release syndrome (CRS), a near-universal CAR-T complication, represents a biologically and temporally linked trigger for cardiac injury. We hypothesized that CRS-guided echocardiography, independent of MACE, would improve CTRCD detection and enable earlier intervention. Methods: We retrospectively analyzed 81 CAR-T recipients with pre- and post-treatment echocardiograms. CTRCD was defined by: (1) LVEF <50% or >10% decline, (2) >15% GLS reduction, or (3) either (LVEF or GLS). Surveillance performance was compared between CRS- and MACE-triggered imaging. Univariable and stratified logistic regression assessed associations between CRS grade and CTRCD risk. ROC analysis evaluated GLS reduction as a predictor of LVEF-defined CTRCD. Results: CTRCD occurred in 46.3% of patients based on the composite “LVEF or GLS” definition; LVEF-defined CTRCD occurred in 44.6%, GLS-defined CTRCD in 27.5%, and dual-criteria CTRCD (both LVEF and GLS abnormalities) in 24.5%. CRS occurred in 85.1%, mostly Grades 1–2. CRS-based surveillance detected 93.5% of all CTRCD cases and 100% of GLS-only and dual-criteria cases, compared to 48.4–58.3% detection via MACE-based imaging. MACE-based surveillance missed over 50% of affected patients across all CTRCD definitions. Logistic regression models revealed elevated CTRCD risk with any CRS exposure; Grade 1 CRS conferred the strongest odds (OR 5.11, p = 0.055). Quasi-complete separation occurred in GLS-only and dual-criteria models, as all CTRCD cases occurred in patients with CRS. ROC analysis showed that GLS reduction >8.63% predicted LVEF-defined CTRCD with an AUC of 0.766 (sensitivity 66.7%, specificity 87.5%). Conclusion: CRS is a powerful and reproducible trigger for detecting CTRCD defined by LVEF and/or GLS. Compared to MACE-driven imaging, CRS-based surveillance offers greater sensitivity and earlier detection of subclinical dysfunction. Event-triggered imaging misses over half of cases. Our findings support integrating CRS-based surveillance into post-CAR-T care to improve early detection, risk stratification, and cardioprotection.

Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated substantial efficacy in relapsed and/or refractory multiple myeloma. While toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have been well characterized, the incidence and clinical consequences of the coagulopathy associated with CRS remain underexplored. Methods: We conducted a prospective analysis of 108 adult patients with multiple myeloma or light chain amyloidosis treated with the academic anti-BCMA CAR-T HBI0101 in a single-center trial (NCT04720313). Coagulopathy was evaluated via serial fibrinogen measurements, with hypofibrinogenemia defined as <200 mg/dL and severe coagulopathy as <100 mg/dL. Laboratory markers, tocilizumab and blood product use, and thrombotic and bleeding complications were recorded. Patients received a short (3-day) or extended course of enoxaparin thromboprophylaxis as well as fresh frozen plasma in cases of severe coagulopathy. Results: CRS grades 1–3 occurred in 100 patients (93%). Hypofibrinogenemia was observed in 79 patients (73%), including 20 (19%) with severe coagulopathy. Fibrinogen levels were significantly associated with CRS severity (p < 0.001), number of tocilizumab doses (p < 0.001), peak levels of the inflammation markers LDH (p = 0.001) and ferritin (p = 0.006), and neutropenia (p = 0.33). Five thrombotic events (4.6%) and three minor bleeding events (2.7%) occurred within 3 months post-CAR-T infusion and were not associated with degree of coagulopathy or CRS. No cases of major bleeding or fatal thrombosis occurred. Conclusions: CRS-related coagulopathy is common following BCMA-targeted CAR-T treatment and correlates closely with CRS severity. Despite the high rate of laboratory coagulopathy, thrombosis and bleeding events were infrequent, suggesting the benefit of the prophylactic strategies used.

Studies of cardiovascular (CV) events after chimeric antigen receptor T-cell (CAR-T) therapy have mostly focused on patients with lymphoma. We evaluated the incidence, timing and prognostic significance of in-hospital and post-discharge CV events in patients with multiple myeloma (MM) receiving CAR-T therapy. We conducted a retrospective analysis of MM patients treated with CAR-T between 2018 and 2024. CV events (heart failure, arrhythmias, myocardial infarction and stroke) and all-cause mortality were assessed separately during hospitalization and post-discharge. Time-dependent Cox regression was used to evaluate associations with mortality. Among 256 patients, 11.7% (n = 30) experienced in-hospital CV events, most commonly atrial arrhythmias (5.5%) and new left ventricular (LV) dysfunction (3.9%), with a median onset of 8 (Q1, Q3: 5, 11) days. Ninety percent of those with LV dysfunction recovered function. Independent predictors of in-hospital CV events included age >65, prior atrial fibrillation, antiplatelet use, cytokine release syndrome grade ≥2 and higher immune effector cell-associated neurotoxicity syndrome grade. Post-discharge CV events were less common (7.8%), occurring at a median of 13 (Q1, Q3: 7, 22) months. Only post-discharge CV events were associated with higher post-discharge all-cause mortality. There were no in-hospital CV deaths and one post-discharge CV death. In this large MM CAR-T cohort, in-hospital CV events were relatively uncommon, reversible and not linked to mortality. In contrast, post-discharge CV events, while rare, predicted worse survival.

Relmacabtagene autoleucel (relma-cel) demonstrated significant clinical outcomes for ≥3 lines of treatment for relapsed or refractory (R/R) follicular lymphoma (FL) in the RELIANCE study. The primary end-point was the complete response rate (CRR) at 3 months. Key secondary end-points included the duration of response (DOR), progression-free survival (PFS), overall survival (OS) and frequency/severity of adverse events (AEs). Relma-cel-treated patients (N = 28) had a median age of 54 years (range: 36-71 years), and more than 60% of the patients received ≥3 lines of prior systemic therapies. The median follow-up was 24.4 months. As previously reported, in the primary analyses set (n = 27), the 3-month CRR was 85.2% and the 3-month overall response rate was 100.0%. The median DOR, PFS and OS were not reached. As updated in this article, the estimated 2-year PFS and OS rates were 80.3% and 100% respectively. During the 90-day treatment-emergent period (N = 28), no patients had cytokine release syndrome of grade ≥3, and neurological toxicity of grade ≥3 occurred in only one patient treated with 100 × 106 chimeric antigen receptor T cells. Neutropenia (39.3%) was the most common grade ≥3 treatment-emergent adverse event. There were no AEs leading to death. Relma-cel demonstrated durable remissions and manageable safety without new safety signals during the 2-year follow-up in patients with R/R FL (ClinicalTrials.gov, NCT04089215).

Cytokine release syndrome (CRS) is a common and potentially severe complication of cancer immunotherapy, including CAR T-cell therapies, bispecific T-cell engagers, and less commonly immune checkpoint inhibitors. Although extensive research has established guidelines for managing CRS in hematological malignancies, there is a growing need to address CRS in the context of solid organ tumors due to differences in tumor microenvironment, immunotherapy indications, and patient population. This review aims to provide an overview of CRS in solid tumors, outlining its pathophysiology, clinical presentation, and current management strategies. The complexities of CRS in solid tumors arise from challenges such as the immunosuppressive nature of the tumor microenvironment and the overlap of tumor-associated antigens with healthy tissues, potentially increasing the risk of severe on-target off-tumor toxicities. The review emphasizes early detection and grading of CRS as essential for patient safety and effective intervention. Management of CRS involves supportive care for mild cases, whereas severe presentations often require targeted therapies like tocilizumab, corticosteroids, and escalation to the intensive care unit for organ support. The decision to rechallenge or withhold immunotherapy requires careful consideration of patient-specific goals and risks. Emerging treatments such as other cytokine inhibitors, plasma exchange, and suicide gene systems are promising avenues for mitigating severe CRS. Future research focuses on refining risk stratification tools, novel therapeutic agents, and evaluating long-term outcomes. A deeper understanding of CRS in solid tumors will enable more personalized treatment approaches, enhancing the safety and efficacy of immunotherapies for this patient population.

Abstract Background Limited data are available on cardiac toxicity in children treated with CAR-T cells. Methods Study included 115 children undergoing CAR-T with available echocardiographic dCardiac toxicity was defined as incident left ventricular dysfunction (ejection fraction [EF] <53%) and/or pericardial effusion. Covariates included the occurrence and grading of cytokine release syndrome (CRS), type of CAR-T (GD-2 or CD-19) and dosage of previous exposure to cardiotoxic medications. Results Mean age was 12 ± 7.3 years; 62% were boys. All had normal baseline cardiac function. CRS of any grade occurred in 73% of patients (70% grade 1, 15% grade 2, 12% grade 3, and 3% grade 4).Cardiac toxicity was reported in 27% of patients, including 7 with EF reduction, 22 with pericardial effusion, and 2 with both. Comparing patients with (n=31) and without cardiac toxicity (n=84) no differences was observed at baseline in either EF (61±5 vs 62±4%) or Global Longitudinal Strain (GLS, -19.8±4 vs -20.2±2%). Conversely, a significant difference was observed in both GLS and EF two weeks after treatment (respectively -22.6±4.2 vs -18.5±4.9% and 58±6 vs 62±3% both p<0.02). Cardiac toxicity was more frequent in the GD-2 group (n=71) compared to the CD-19 group (n=44) (33% vs. 13%, p<0.04). It was also associated with the presence of CRS (34% vs. 14%, p<0.02), but not with CRS grading (p=0.2) or previous cardiotoxic medication exposure. Notably, cardiac toxicity was associated with a transient increase in LV mass (baseline: 44 ± 18 g/m2.16 vs. week 2: 53 ± 20 g/m2.16, p<0.05), which returned to baseline values by the end of the study (46 ± 16 g/m². 16; p=ns vs. baseline). Conclusion Incident cardiac dysfunction is common in children undergoing CAR-T therapy and is associated with the presence of CRS and the type of CAR-T cells infused.

Cytokine release syndrome risk model with T-cell engaging therapies.

Cytokine release syndrome (CRS) after graft infusion under anti-thymocyte globulin (ATG)-based haploidentical (haplo)-hematopoietic stem cell transplantation is unclear. The purpose of this study was to explore the clinical implications of CRS after graft infusion under ATG-based haplo-SCT. We retrospectively analyzed the data of 259 patients who underwent haplo-SCT, graded CRS, and evaluated transplant outcomes. CRS occurred in 103/259 (39.8%) of the recipients. Severe CRS (Grades 3-5) was not observed. Fever was the most common manifestation (89.3%), and all cases occurred only after peripheral blood stem cell (PBSC) infusion. According to the multivariable analysis, being older than 55 years (OR 2.486 (1.124-5.496), p = 0.024), having higher CRP levels during conditioning (OR 3.011 (95% CI, 1.766-5.134), p < 0.001), and receiving PBSC as the sole stem cell source (OR 2.478 (95% CI, 1.077-5.700), p = 0.033) could predict the development of CRS, whereas an HCT-CI score ≥ 2 was an independent risk factor for Grade 2 CRS (OR 4.259 (95% CI, 1.515-11.969, p = 0.006)). The 3-year OS was not significantly different between the two groups, with 79% (95% CI, 61-97) for Grade 2 CRS and 85% (95% CI, 80-90) for Grade 0-1 CRS (p = 0.288). The GRFS rates in the two groups were 69% (95% CI, 49-90) and 67% (95% CI, 60-74), respectively (p = 0.644). Our results suggest that CRS is common in patients receiving ATG-based haplo-SCT and does not affect survival.

Cytokine Release Syndrome and Neurotoxicity Following CD19 CAR-T in B-Cell Lymphoma.

This matching-adjusted indirect comparison evaluated the efficacy of epcoritamab vs standard of care (SOC), mosunetuzumab, or odronextamab, and assessed safety vs mosunetuzumab and odronextamab. Individual patient-level data from the EPCORE NHL-1 follicular lymphoma (FL) cohort for epcoritamab were used with pooled data from SCHOLAR-5 for SOC (mostly chemoimmunotherapy [CIT]), and aggregate data from GO29781 for mosunetuzumab and ELM-2 for odronextamab. Trial populations were match-adjusted using propensity score weights for key baseline characteristics. Compared with SOC/CIT, epcoritamab provided significantly higher response rates (overall response rate [ORR], 90.9% vs 56.8%; P < .001; complete response [CR] rate, 73.7% vs 32.0%; P < .001). Epcoritamab showed numerically higher ORR (90.9% vs 80.0%; P = .067) and CR rate (72.8% vs 60.0%; P = .159) vs mosunetuzumab. Epcoritamab provided significantly higher ORR (91.5% vs 80.5%; P = .026) and numerically lower CR rate (67.5% vs 73.4%; P = .428) vs odronextamab. Epcoritamab did not have any grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS; any grade) events compared with CRS (grade ≥3) in 2.2% and 3.9% and ICANS in 4.4% and 0.8% of patients treated with mosunetuzumab and odronextamab, respectively (P < .001). In addition to being a convenient subcutaneous option, epcoritamab showed significantly superior response rates and survival outcomes vs SOC/CIT among patients with relapsed or refractory FL after ≥2 systemic therapies. Epcoritamab also exhibited clinically relevant, numerically higher ORRs and demonstrated improved safety for CRS (grade ≥3) and ICANS vs mosunetuzumab or odronextamab. These trials were registered at www.ClinicalTrials.gov as #NCT03625037, #NCT02500407, and #NCT03888105.

e23351 Background: Chimeric Antigen Receptor T-Cell (CAR-T) Therapy has emerged as the groundbreaking therapy for hematologic malignancies. Despites its efficacy, CAR-T therapy is associated with significant cardiac or neurological side effects have been reported. However, inpatient burden in CAR-T related adverse effects has not been explored. This study aims to address the gap in current research by analyzing inpatient burden in CAR-T using National Inpatient Sample (NIS) 2022. Methods: We included patients 18 years or older in NIS 2022 and conducted a retrospective analysis. Cancer diagnoses were identified using the Clinical Classification Software (CCS) codes. Hospitalization mortality, severity, length of stay (LOS), and costs were analyzed using R. Results: Most of the patients were equal or older than 18 years for those who received CAR-T (95.61%). Multiple myeloma (MM) was the most common disease type among CAR-T patients (185/763 patients, 24.25%) followed by diffuse large B cell lymphoma (DLBCL) (70/763 patients, 9.17%) and acute lymphoblastic leukemia (ALL) (40/896 patients, 5.24%). About two thirds of CAR-T patients were males (493/763 patients, 64.61%). About six out of ten CAR-T patients developed cytokine release syndrome (CRS) (470/763 patients, 61.60%). Patients with CRS grade 2 or greater showed significantly longer median LOS than those who are without CRS (15 vs 13 days, p = 0.003). 26.08% of CAR-T patients were diagnosed with immune effector cell-associated neurotoxicity syndrome (ICANS). The median hospital costs were 2.46% higher for those who developed CRS than those who did not ($1.37 million vs $1.34 million). Grade 4 or 5 CRS caused statistically significant high mortality during hospitalizations compared to CAR-T patients without CRS grade 4 or 5 (44.44% vs 1.46%, p = 0.041). CAR-T patients who required intubation or vasopressors had a longer median LOS (intubation; 13 vs 29.5 days, p = 0.003, vasopressor; 13 vs 22 days, p = 0.048). CAR-T patients who required vasopressors during hospitalization had 29.08% of additional charges compared who did not (Median hospital charges $1.90 million vs $1.35 million). Conclusions: Inpatient burden of CAR-T was higher in patients who experienced severe side effects such as CRS or needed intubation or vasopressors during hospitalization. Further directions should focus on developing strategies to mitigate the adverse effects and improve patients’ outcomes, ultimately enhancing the safety and effectiveness of CAR-T therapy.

e19091 Background: Chimeric antigen receptor T-cell (CAR-T) therapies have transformed treatment landscape for hematologic malignancies since FDA approval in 2017. Managing cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are essential for safe and effective infusions in the outpatient setting. To date, the majority of CAR-T therapy has historically been delivered in major academic medical centers, preventing 41% or more of patients from receiving this potential lifesaving treatment. This retrospective analysis examines patients receiving CAR-T in an outpatient setting in a community hospital from 2019-2023. Patients were seen daily, admitted only with complications. An efficacy based comparative analysis of the clinical course, treatment-related toxicities, overall survival (OS), and progression-free survival (PFS) across Axicabtagene ciloleucel (Axi-cel) versus Lisocabtagene Maraleucel (Liso-cel) and Tisagenlecleucel (Tisa-cel) is referenced in the table below. Methods: The study consisted of 44 patients consecutive patients. This included 7 patients with follicular lymphoma, 36 patients with diffuse large B-cell lymphoma, and 1 patient with marginal cell lymphoma. 22 patients received treatment with Axi-cel, 6 patients were treated with Liso-cel, and 16 patients received Tisa-cel. 1 Axi-cel patient received prophylactic dexamethasone. Results: We used Axi-cel, which uses the CD28 co-stimulatory domain, compared to Liso-cel and Tisa-cel, which uses 4-1BB. The Axi-cel patients were younger, otherwise matched for bulk of disease and disease status and did not show a significant increase in toxicity compared to the Liso-cel and Tisa-cel patients. The PFS for the two groups were similar. Conclusions: This retrospective analysis confirms that outpatient CAR-T therapy can safely be administered in an outpatient community setting anticipated survival. This may allow more patients who cannot travel to receive this treatment. Comparative outcomes between CAR-T therapies. Axi-Cel (n=22) Liso-cel and Tisa-cel (n= 22) Median Age (years) 58.5 71.4 CRS All Grades n (%) 17 (77) 15 (68) CRS Grade 3/4 n (%) 0 (0) 1 (5) Neurotoxicity All Grades n (%) 13 (59) 9 (41) Neurotoxicity Grade 3/4 n (%) 1 (4.5) 3 (14) LDH &gt;300 units/L prior to treatment n(mean) 5 (586) 8 (520) Progression-Free Survival Mean (months) 32.6 28.2 Overall Survival Mean (months) 52 51

e19010 Background: Autonomic dysfunction (AD) is a phenomenon that has been identified in subsets of patients (pts) treated with chimeric antigen receptor T-cell therapy (CART) for hematologic malignancies. AD manifests as parasympathetic dysfunction with hypotension and tachycardia, unique from cytokine release syndrome, and often requires pharmacologic support with midodrine and/or the discontinuation of antihypertensives. The impact of AD on survival in CART pts has not been well studied. Our objective was to investigate the relationship between the presence of AD on survival outcomes and other toxicities in pts with lymphoma treated with CART. Methods: This retrospective single-institution study included adult pts with aggressive B-cell lymphomas (B-NHL) who received autologous CD-19 directed CART between 2018-2024. AD was defined by the addition of midodrine and/or the permanent discontinuation of antihypertensives after CART. CART-associated toxicities such as cytokine release syndrome (CRS) and neurotoxicity (NT) were measured. Median progression-free survival (mPFS) and overall survival (mOS) were determined by Kaplan-Meier. Results: Our study included 174 pts. Sex, race, presence of primary refractory disease, double hit lymphoma status, elevated LDH at apheresis, and use of bridging therapy were similar between AD and non-AD cohorts. Pts with post-CART AD were younger (58 vs 62 yrs in AD vs non-AD; p=0.03) more likely to receive axi-cel (p=0.03) and experience a higher incidence of CRS (p=0.047) and NT (p=0.01). Grade of CRS and NT were similar between AD and non-AD pts. AD pts had longer lasting CRS and required tocilizumab more often (p=0.01). Despite being younger, AD pts were twice as likely to be discharged with home physical therapy (p=0.05) and three times as likely to be discharged to a rehabilitation facility (p=0.01). Median follow-up for surviving pts was 18 months. Median PFS and OS were not different between AD and non-AD groups. However, mOS was significantly lower among pts who required midodrine (without changes to antihypertensives), as a marker of AD (p=0.01). Conclusions: The presence of AD in pts with B-NHL was associated with a higher incidence of CART toxicities including CRS and NT and a higher likelihood to require physical rehabilitation to improve functional outcomes post CART. The need for midodrine to manage AD post-CART was associated with decreased OS in B-NHL. Our findings support the consideration of AD as a predictor of functional, toxicity, and survival outcomes and should guide supportive care in the post-CART setting.

Safety, efficacy and total cost of point-of-care manufactured anti-CD19 CAR-T cell therapy in India: VELCART trial.

e24025 Background: With the expansion of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in hematologic malignancies, significant treatment adverse effects have been observed. The exploration of cardiovascular effects has been limited due to a paucity in the number of patients in previous studies. This study analyzes CAR-T Therapy related cardiovascular toxicities with a nation-wide dataset, the National Inpatient Sample (NIS) of the United States. Methods: NIS 2022 data were used to analyze the frequency of cardiovascular adverse events in patients aged 18 years and older. In subgroup analysis, relapsed acute lymphoblastic leukemia (ALL) and multiple myeloma (MM) patients were included in the analysis using the International Classification of Diseases (ICD)-10 code. The primary outcomes are the frequency of cardiovascular adverse effects, including arrhythmia, stroke, heart failure (HF), and cardiac arrest. Results: A total of 763 patients received CAR-T Therapy in NIS 2022. MM showed the highest incidence among disease types (24.25%). The distribution was as followed: Diffuse large B-Cell lymphoma (DLBCL) (9.17%), ALL (7.47%), follicular B cell lymphoma (2.36%), acute myeloblastic leukemia (AML) (1.83%), and mantle cell lymphoma (0.92%). In the relapsed ALL subgroup, the rate of atrial fibrillation and atrial flutter was significantly higher in the patients who received CAR-T Therapy compared to those who did not (15% vs 6.43%, p = 0.048). However, MM patients with CAR-T Therapy did not show significant difference in atrial fibrillation and atrial flutter (14.81% vs 19.38%, p = 0.313). The rates of HF, stroke, and cardiac arrest were not significant in the ALL and MM subgroups. Patients with cytokine release syndrome grade 3 or higher were associated with grater incidences of HF and stroke (HF; 16% vs 5.28%, p = 0.047, stroke; 0.81% vs 8%, p = 0.026). Conclusions: To our understanding, this is the first nation-wide study regarding cardiotoxicity in CAR-T Therapy, representing the general patient population in the United States. Relapsed ALL patients who received CAR-T Therapy showed higher rates of arrhythmias, including atrial fibrillation and atrial flutter than those who did not. Further studies in a larger population are warranted. In addition, cardiovascular adverse effects in CAR-T Therapy patients with B cell lymphoma should be further explored. This study underscores the critical need for vigilant cardiovascular monitoring and management in CAR-T Therapy recipients. Further research should elucidate the underlying mechanism of CAR-T Therapy related cardiotoxicity, developing strategies to mitigate the adverse effects.

7076 Background: HIV+ patients have an 18-fold increased risk of developing diffuse large B Cell Lymphoma (DLBCL). There is uncertainty in the literature regarding the safety and efficacy of chimeric antigen receptor T-cell (CAR-T) therapy in HIV+ patients. This study aims to evaluate the influence of HIV infection on outcomes in patients treated with CD19 targeting CAR-T therapy. Methods: This is a multicenter retrospective cohort study that included patients with co-diagnosis of DLBCL and HIV who received a CD19 targeting CAR-T in the TriNetX Network, a database of deidentified electronic medical records with over 130 million patient records. Outcomes comprised of 5-year mortality, development of cytokine release syndrome (CRS), development of immune effector cell-associated neurotoxicity syndrome (ICANS), risk of infection, hypogammaglobinemia, and treatment with Tocilizumab , G-CSF, or IVIG. Results: Eighty-one patients met inclusion criteria. The mean current age was 62 years old, 75.6% were White, 16.3% were Black, 11.6% were Asian, and 73.3% were male. Approximately 72% of patients received Fludarabine/Cyclophosphamide, while 19% received Bendamustine as lymphodepletion chemotherapy. Within the cohort, 42% died within 5 years; 58% developed infection following treatment with CD19 targeting CAR-T therapy. The risks for CRS and ICANS were 65% and 14%, respectively; 53% treated with tocilizumab. Approximately 46% of patients developed hypogammaglobinemia; 31% were treated with IVIG, and 44% were treated with G-CSF. Further analysis to assess effect of development of CRS on outcomes showed no significant difference in survival probability among patients with or without CRS. Conclusions: CD19 CAR-T therapies have emerged for patients with refractory or relapsed DLBCL; however, HIV+ patients have been excluded from all registration CAR-T Cell clinical trials. Compared to the general population, our study demonstrates HIV+ patients with DLBCL have a similar mortality and morbidity rates when treated with CD19 targeted CAR-T therapy, indicating that in the future perhaps these patients should not be excluded from clinical trials. Outcomes Patients in Cohort Patients with Outcome Risk (%) Mortality 81 34 42% CRS 81 53 65.4% CRS Grade 1 or 2 81 21 25.9% CRS 3, 4, or 5 81 20 24.7% ICANS 81 11 13.6% Overall Infection 81 47 58% Bacterial Infection 81 24 29.6% Viral Infections 81 23 28.4% Treatment with Tocilizumab 81 43 53.1% Hypogammaglobulinemia 81 37 45.7% Treatment with IVIG 81 25 30.9% Treatment with G-CSF 81 36 44.4%

2017 Background: CAR T therapy is a novel, promising approach in glioblastoma (GBM) but tumor heterogeneity can limit efficacy when a single antigen is targeted. We designed a second-generation CAR T molecule that targets epidermal growth factor receptor vIII (EGFRvIII) and also secretes a T-cell–engaging antibody molecule (TEAM) against wild-type EGFR. Methods: In a phase 1, first-in-human study (INCIPIENT, NCT05660369), patients with recurrent GBM with EGFRvIII mutation and/or EGFR amplification were eligible to receive up to 6 intraventricular doses of 10x106 CAR T cells via Ommaya catheter after lymphodepleting chemotherapy (LDC) with fludarabine and cyclophosphamide. Primary objective was safety and tolerability and secondary objective was preliminary tumor response determined by iRANO criteria. Results: CAR T manufacturing was successful for all patients. Seven patients (5 male) received at least 1 intraventricular infusion. Two patients received 2 infusions (1 for progressive disease (PD) and 1 without PD). One patient received 3 infusions after experiencing initial PD. No DLTs occurred. All patients experienced cytokine release syndrome (CRS) grade 1 lasting 0-9 days with only 1 patient experiencing CRS grade 2 for 1 day. One patient experienced ICANS grade 1 that lasted 2 days. All patients experienced tumor inflammation-associated neurotoxicity grade 1 with a duration of 2-9 days. Adverse events (grade 3-4) at least possibly related to CAR T were febrile neutropenia (N = 1) and neutrophil count decrease (N = 1). Toxicity was managed with supportive care without need for ICU monitoring and 3 patients received at least 1 dose of anakinra (max duration = 4 days, median = 1 day). Best response was stable disease (SD) in 5 patients with 1 patient achieving SD for 6 months after a single infusion and another experiencing a 33% decrease in tumor diameter after 2 infusions. All patients are alive 3-8 months after first infusion. From the preceding safety run-in arm of the study (without LDC), one patient survived 12 months and another is still alive &gt; 20 months after infusion. Conclusions: Intraventricular CARv3-TEAM-E infusions were well tolerated, even with multiple doses, and no DLTs were noted. Toxicity was manageable in all patients with supportive care and anakinra was administered to 3 patients. Steroids were not required to manage toxicity. A subset of patients experienced SD for several months. Clinical trial information: NCT05660369 .

e19003 Background: Chimeric antigen receptor T-cell therapies targeting CD19, like Axicabatagene ciloleucel (axicel) and Lisocabtagene maraleucel (lisocel), shown efficacy with a tolerable safety treating relapsed/refractory diffuse large B-cell lymphoma (RR DLBCL) in clinical trials. But real-world practice may not be similar. We present a real-world comparison using TriNetX data (TNX) and our experience in a rural Appalachian academic center (WVU). Methods: 2 cohorts were of interest: one with axicel and one with lisocel for RR DLBCL in TNX and WVU. 179 propensity score-matched patients (pts) were analyzed for TNX in each cohort. Total of 39 unmatched pts for WVU. The primary outcome was overall survival (OS). Secondary outcomes were relapse rate, rate of cytopenia 30 days after axicel or lisocel defined by platelet &lt; 50x10 3 /µL (Plt &lt; 50), Hgb &lt; 8 g/dL (Hgb &lt; 8), and ANC &lt; 500/µL, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Analysis methods included measures of association, number of instances, and Kaplan-Meier survival estimates. Results: Pts were predominantly Caucasian in both cohorts (TNX: 85.5% in axicel (TNX-A) and 87.7% in lisocel (TNX-L); WVU: 93.8% in axicel (WVU-A) and 100% in lisocel (WVU-L)). No difference in OS in TNX and WVU. Similar relapse rate were noted in TNX. 9.8% difference in relapse rate between WVU-A and WVU-L but not statistically significant. Significant difference in Hgb &lt; 8 and Plt &lt; 50 in WVU, but no difference in TNX. 49.4% more all grade CRS seen with WVU-A (p=0.007). 12.3% more all grade ICANS seen with TNX-A (p=0.009) and 39.8% more in WVU-A (p=0.032). Conclusions: TNX and WVU is comparable to trial data for more all grade ICANS noted in axicel compared to lisocel. More CRS noted with WVU population which is comparable to clinical trial data. Further clinical trials comparing axicel and lisocel is needed to better guide treatment for these pts. Summary of TNX and WVCI. TNX-A TNX-L p-value WVU-A WVU-L p-value Total # of Pts 179 179 - 16 23 0.612 Survival probability, % 35.9 38.2 0.124 50.0 63.4 0.430 Relapse Rate, % 27.9 22.9 0.275 18.8 28.6 0.702 CRS, % 49.7 41.3 0.111 81.3 31.8 0.007* ICANS, % 33.5 21.2 0.009* 62.5 22.7 0.032* Plt &lt; 50, % 31.1 21.9 0.122 68.8 27.3 0.027* Hgb &lt; 8, % 29.9 18.8 0.088 68.8 22.7 0.005* TNX-A: TNX axicel group, TNX-L: TNX lisocel group, WVU-A: WVU axicel group, WVU-L: WVU lisocel group. *Statistically significant result.

7542 Background: In recent years, three bispecific T-cell engager (BiTE) agents have been approved for Refractory/Relapsed Multiple Myeloma (rrMM). These have shown remarkable efficacy, particularly in patients who have failed multiple lines of prior therapy. However, there is a paucity of data to guide choice between available agents. Methods: We performed a multicenter, retrospective, propensity score matched (PSM), safety and efficacy comparison between anti-BCMA (Cohort 1: Teclistamab and Elranatamab) and anti-GPRC5D (Cohort 2: Talquetamab) therapy in rrMM, using TriNetX database. Patients with prior CAR-T therapy were excluded. Outcomes assessed included survival, remission rates, subsequent CAR-T therapy, subsequent alternate BiTE therapy, risk of infections, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hypogammaglobulinemia and IVIG use with a follow up of 2 years following treatment. Results: A total of 888 and 296 patients were identified in cohort 1 (C1) and cohort 2 (C2), respectively. The two cohorts were matched for 25 characteristics yielding 266 patients in the PSM analysis. No differences in survival probability (HR 0.95; 95% CI 0.65-1.39, p=0.83) or remission rates (C1 vs C2: 37.2 vs 35.0 %, p=0.588) were observed. Subsequent CAR-T therapy was used in 3.8% in C1 and 15% of patients in C2. Any grade CRS (C1 vs C2: 34.6 vs 48.1%, p=0.002) was more common in the Talquetamab cohort, with majority being grade&lt;3 CRS (C1 vs C2: 16.2 vs 27.8%, p=0.001). There was no difference observed for any grade ICANS (C1 vs C2: 14.7 vs 9.8%, p=0.08). No significant differences were found between rates of overall infection (C1 vs C2: 45.5 vs 43.6 %, p=0.63), bacterial (C1 vs C2: 23.3 vs 21.1%, p=0.53), viral (C1 vs C2: 28.6 vs 28.2 %, p=0.92), or fungal (C1 vs C2: 5.8 vs 8.9 %, p=0.29) infections rates. The incidence of hypogammaglobulinemia (C1 vs C2: 74.4 vs 77.8%, p=0.36) and treatment with IVIG (C1 vs C2: 52.3 vs 44.4 %, p=0.06) were similar across both groups. Conclusions: Our analysis of real-world patients with relapsed/refractory multiple myeloma (rrMM) showed similar efficacy and tolerability between anti-BCMA and GPRC5D BiTE therapies. However, the Talquetamab group had a higher rate of CRS, consistent with the high incidence observed in the phase 2 MonumenTAL-1 trial. The extent of comorbidities, safety profile of individual agents and plan for subsequent CAR-T cell therapy can guide the choice between available BiTE therapies. BiTE therapy: Demographics and outcomes. Outcome Cohort 1 Cohort 2 p-value Total # of pts 266 266 Mean Age (years) 67.2 67.4 0.82 Male/Female (%) 52.6 / 43.6 50.4 / 43.2 0.60/0.93 Mean duration of treatment (Days) 246 (Teclist)163 (Elra) 182 2-yr Survival 55 (54.5%) 53 (50.6%) 0.76 Complete Remission 99 (37.2%) 93 (35.0 %) 0.59 CRS 92 (34.6%) 128 (48.1%) 0.002

e19002 Background : The management of relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is associated with high morbidity and mortality. Chimeric antigen receptor (CAR) T-cell therapy against CD19 has emerged as a revolutionary treatment for r/r DLBCL. There are currently three FDA-approved CAR T-cell therapy products with two different co-stimulatory domains (CSD): axicabtagene ciloleucel (CD-28 CSD), tisagenlecleucel (4-1BB CSD), and lisocabtagene maraleucel (4-1BB CSD). CSDs mediate CAR-T anti-tumor effects while also influencing treatment-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Here, we report our real-world experience of CAR-T-cell products (CD28 vs. 4-1BB) in r/r DLBCL. Methods: We conducted a retrospective analysis of patients diagnosed with r/r DLBCL at our institute who received CAR-T therapy with 2 years of post-therapy follow-up. We collected data on baseline demographics, bridging therapy, lymphodepletion (LD) regimen, and specific CAR-T product used. Differences in clinical outcomes were determined between patients treated with CD28 vs. 4-1BB CAR-T cell products. Clinical endpoints included incidence and severity of CRS/ICANS, response rate, progression-free survival (PFS), and overall survival (OS). Survival functions were estimated using Kaplan-Meier estimators. Results: A total of 111 patients with r/r B-cell malignancies received CAR-T therapy at our institute between 2018 and 2023, of which 95 patients had r/r DLBCL diagnosis. The median age was 64 years. CRS occurred in 59 out of 95 patients (62.1%), with severe CRS (Grade 3 or 4) occurring in eight patients (13%). Fifty-four patients (57%) achieved a complete response (CR) after CAR-T therapy. Among the 54 patients who achieved CR, 22 died from treatment-related toxicities, including 7 deaths associated with COVID-19 infection. Moreover, 41 patients (43%) experienced disease progression post CAR-T therapy, and 95% of them (39 patients) died from r/r DLBCL. The median OS for the entire cohort was 14.8 months. Patients who experienced disease progression had a significantly shorter median OS of 5 months. No statistically significant differences were observed in PFS or OS based on time from apheresis to treatment, LD regimen used, or the CAR-T product (CD28 vs. 4-1BB). Conclusions: In our real-world experience, CAR-T cell therapy can cure approximately 30% of r/r DLBCL patients regardless of the cellular therapy product subtype utilized. Patients who progressed after CAR T-cell therapy prior to the availability of Bispecific T-cell engagers (BiTEs) had a dismal outcome, with most of them dying from lymphoma. In the absence of clinical trials or access to BiTEs-based therapy, early goals-of-care discussions and hospice should be considered for patients who progress after CAR T-cell therapy.