CRS（细胞因子释放综合征）的高危人群，预防措施和预用药

BACKGROUND Cytokine release syndrome (CRS) is an adverse event associated with T-cell engaging (TCE) immuno-oncology therapies such as chimeric antigen receptor T cells (CAR-T), bispecific TCE antibodies and dual-affinity retargeting proteins. OBJECTIVE To develop a model to predict the preinfusion risk of CRS grade ≥2 for patients with solid tumors and hematologic malignancies such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) treated with TCE bispecific antibodies. STUDY DESIGN A TCE dataset including clinical trials from 2014 to 2019 evaluating non-CAR-T TCE therapies was sourced from the Medidata Enterprise Data Store, an anonymized data repository from completed clinical trials. The outcome of interest was the first CRS grade ≥2 occurring within 10 days of TCE therapy. Risk factors for CRS grade ≥2 were identified from the literature and preliminary data analysis. Features were measured prior to or at the first TCE treatment. Patients were included in the analysis dataset if they had a data element fill rate of >70% for the key features. Features were pruned by assessing multicollinearity across features. Logistic regression and tree-based models were trained. Across 100 iterations with different train-test splits, the average area under the receiver-operator characteristic (AUROC) curve was calculated for each model type. RESULTS A total of 715 patients (115 CRS grade ≥2 and 600 CRS grade <2) were included in the analysis; most patients had ALL (81%) and 19% had solid tumors or NHL. Patients who developed CRS grade ≥2 had a higher incidence of prior infections (38% versus 28%; P = 0.03) and a higher first dose of TCE therapy (P < 0.001). The best model to predict CRS grade ≥2 had a mean AUROC of 0.69 (95% confidence interval 0.66-0.72) on the test set. When patients were ranked based on their predicted probability of getting CRS grade ≥2 and divided into quartiles based on predicted CRS grade ≥2 risk (very low, low, high, very high), the very high-risk quartile developed CRS grade ≥2 at 5.9 times the rate (38.10% [interquartile range: 33.33-43.54]) compared to the very-low risk quartile (6.45% [3.44-8.82]; the sample average was 12.96% [9.25-24.07]). Compared to patients with very low CRS grade ≥2 risk, patients with very high CRS grade ≥2 risk had ALL as a disease type (99% versus 67%, P < 0.001), received a higher TCE dose (1.00 versus 0.61, P < 0.001), had a higher rate of prior infections (49% versus 12%, P < 0.001) and a higher serum creatinine (0.60 versus 0.32, P < 0.001). CONCLUSIONS Using the CRS grade ≥2 risk model, it was possible to stratify patients by risk categories. CRS grade ≥2 risk stratification may facilitate patient selection for TCE therapy and tailored pretreatment and monitoring of CRS to maximize treatment efficacy and safety.

Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T <6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p < 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.

Targeting CD3 × CD20 bispecific antibodies (BsAbs) represents a new milestone in the salvage therapy of relapsed/relapsed large B cell lymphoma and follicular lymphoma. However, cytokine release syndrome (CRS) remains one of the major concerns in clinical practice of CD3 × CD20 BsAbs. This study aimed to identify the potential predictive factors and to construct a nomogram of grade ≥ 2 CRS in CD3 × CD20 BsAbs in Chinese patients. A total of 87 consecutive patients with B-NHL who received CD3 × CD20 BsAbs at Sun Yat-sen University Cancer Center from January 2021 to December 2023 were included and analyzed. Clinical data were collected, and various methods including machine learning algorithms were introduced. The median age of the patients was 55 years, and the median number of previous treatment lines was 2. CRS occurred in 42 patients (48.3%), including 27 cases of grade 1, 9 cases of grade 2, 5 cases of grade 3, and 1 case of grade 5. Four variables were revealed and selected: bulky disease (> 5 cm), number of previous treatment lines (≥ 3), monocyte-to-lymphocyte ratio (MLR), and platelet count (PLT). Bootstrap resampling was introduced for both internal validation and model building. A predictive nomogram was ultimately established, with the ROC–AUC of 0.867 (95% CI 0.719–0.954). This study suggests four potential predictive factors and provides a feasible and easy-to-use nomogram for grade ≥ 2 CRS in Chinese patients for the first time, which is important for guiding personalized management and early intervention of CRS.

Cytokine release syndrome (CRS) after graft infusion under anti‐thymocyte globulin (ATG)–based haploidentical (haplo)‐hematopoietic stem cell transplantation is unclear.

Introduction:CD20xCD3 bispecific antibodies (BsAb) have been investigated and approved for use in B-cell non-Hodgkin lymphomas (B-NHLs) with manageable toxicities. The main adverse event of clinical interest is cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood and are the focus of this study. Methods: We performed a single center retrospective study of patients with B-NHL treated between September 2018 and April 2024 with investigational or commercial BsAb. We obtained baseline characteristics, safety and efficacy outcomes. Uni-and multivariate analysis were performed to identify associations between CRS and clinical variables of interest. Results:84 patients with B-NHLs were treated with BsAb (median age 66; 70.2% male; 92.8% Caucasian; 94% non-Hispanic; 87% ECOG 0-1). Histologic subtypes included diffuse large B-cell lymphoma (DLBCL) (n=46, 40.8%), follicular lymphoma (FL) (n=20, 23.8%), mantle cell lymphoma (MCL) (n=14, 16.7%), and Richter's transformation-DLBCL (n=4, 4.7%). BsAb was given as a single agent (n= 58, 69.0%) or in combination with other agents (n=26, 31.0%). Patients were treated frontline (n=10, 11.0%) or in the relapsed refractory (R/R) setting (n= 74, 89%) with a median of 3 (range 1-10) prior lines of therapy. 20 patients (23.3%) were previously treated with chimeric antigen receptor (CAR) T-cell therapy, 11 patients within 6 months prior to BsAb. Patients were treated with epcoritamab (Epco) (n=39, 46.4%), glofitamab (Glofit) (n=11, 13.1%), plamotamab (Plamo) (n=18, 21.4%) and mosunetuzumab (Mosun) (n=16, 19.1%). Complete response (CR) rate was 30.9% and overall response rate (ORR) was 61.8%. At median follow-up of 9.7 months, the median progression free survival (PFS) and median overall survival (OS) was 8.7 and 13.0 months, respectively. CRS of any grade occurred in 48 (57.1%) patients: grade 1 (n=19, 22.5%), grade 2 (n=27, 32.1%), and grade 3 (n=2, 2.4%). There was no instance of grade 4 CRS. The maximum grade CRS occurred most frequently after the 1st dose (n= 28, 2 Epco, 7 Glofit, 12 Plamo, 6 Mosun) followed by the 3rd dose (n=14, 13 Epco,1 Mosun). CRS was managed with additional steroids in 14 patients (29.2%) and tocilizumab in 15 patients (31.3%). 15 patients (31.3%) had recurrent CRS. BsAb was held or discontinued due to CRS in 6 (7.1%) and 2 (2.4%) patients, respectively. There were no deaths attributed to CRS. Only 4 patients (4.7%) experienced ICANS- grade 1 (n=3, 3.6%) and grade 3 (n=1, 1.2%). In univariate analysis, patients with DLBCL had lower associated risk of CRS (OR 0.28, 95% CI 0.11-0.69, p=0.008). There is a trend towards an increased risk of CRS in patients with MCL(OR 3.27, 95% CI 0.84-12.74, p=0.14). Patients with CRS had higher rate of bone marrow involvement (OR 4.80, 95% CI 1.46-15.82, p=0.01). There was no difference in CRS risk when assessing baseline demographics, BsAb drug, presence of bulky disease, ECOG, weight or BMI, baseline blood pressure, history of diabetes mellitus, use of granulocyte colony-stimulating factor, and prior bendamustine exposure. There were similar rates of prior CAR-T therapy within 6 months prior to BsAb in patients with or without CRS (OR 0.89, 95% CI 0.33-2.45, p=1.00). The mean absolute neutrophil counts (ANC, k /μl ) and albumin (Alb, g/dL) level at baseline (BL) and 1st full-dose BsAb were mildly but significantly lower in patients with CRS (ANC at BL: 3.6 vs 5.1, p =0.02; ANC at 1st full-dose: 4.1 vs 5.8, p=0.04; Alb at BL: 3.6 vs 3.8, p= 0.01; Alb at 1st full-dose: 3.5 vs. 3.9, p <0.001). Creatinine, liver enzymes, and inflammatory markers (ferritin, fibrinogen, C-reactive protein, d-dimer) did not differ between groups. CR, ORR, PFS and OS were not impacted by CRS. In multivariate analysis with histologic subtype, the association of bone marrow involvement of lymphoma and CRS risk had reduced significance (OR: 3.67, 95% CI 0.99-13.68, p=0.052). Conclusion:We report a lower risk of CRS in patients with DLBCL and trend towards higher risk in patients with MCL or patients with bone marrow involvement. CRS group had slightly lower ANC and albumin level. Inflammatory marker levels, prior CAR-T, and prior bendamustine did not impact the risk of CRS. Further studies in larger data sets are needed to identify patients of high CRS risk to allow for early management, and of low risk to allow for treatment in the outpatient setting.

Clinical trials have confirmed that chimeric antigen receptor (CAR) T cell therapies are revolutionizing approaches for treating several relapsed or refractory hematological tumors. Cytokine release syndrome (CRS) is an adverse event with high incidence during CAR-T treatment. A further understanding of the characteristics and related risk factors of CRS is important for effective management. A total of 142 patients with relapsed or refractory acute lymphocyte leukemia (ALL), lymphoma, or multiple myeloma (MM) received lymphodepletion chemotherapy followed by infusion of CAR-T cells. The characteristics of CRS at different time points after treatment were monitored and risk factors were analyzed. The incidence of CRS for ALL, lymphoma, and multiple myeloma were 82%, 90%, and 90% respectively. Fever was observed on a median of day 3 for ALL, day 1 for lymphoma, and day 8.5 for MM after CAR-T cell infusion, and the duration was different between grade 1–2 CRS and grade 3–5 CRS. Disease types, peak concentration of IL-6, and CRP were associated with CRS. For patients with ALL, numbers of lymphoblast in bone marrow before lymphodepletion, peak concentration of IL-6, and CRP were independent risk factors of CRS. Clinical stage of lymphoma patients and high tumor burden in marrow of MM patients were independent risk factors of CRS. In conclusion, the characteristics and risk factors of CRS in different B-cell hematological tumors are different and should be managed individually during CAR-T cell therapy.

Background and Objectives: Cytokine release syndrome (CRS) is an adverse event associated with T-cell engaging (TCE) therapies and multi-specific antibody therapies, like BiTEs or DARTs. We developed a risk model to predict the pre-infusion risk of significant CRS for patients treated with TCE therapies. A supplementary exploratory analysis evaluated the role of tumor burden and the use of bridging chemotherapy prior to the first dose of TCE infusion on the rate of sCRS. Methods: The TCE dataset was sourced from the Medidata Enterprise Data Store, an anonymized repository of data from completed clinical trials. The outcome of interest was the first sCRS occurring within 10 days of TCE therapy. sCRS was defined as CRS grade ≥ 2 and non-sCRS was defined as CRS grade <2 using the CTCAE 4.0 scale. CTCAE 4.0 was used as these trials gathered data using this version of the scale. Important risk factors of sCRS were identified from the literature and preliminary data analysis. All the features were measured at the time of, or prior to, the first TCE treatment. Patients were included in the analysis dataset if they had a data element fill rate of >70% in the key features. Features were pruned by assessing the multicollinearity across features to increase the stability of the models. Tumor burden was explored as a potential feature, but was not selected for the final model, as the range of tumor burden in most of the patients selected was narrow (see below). In order to compare different TCE therapies, first treatment doses were normalized by dividing patients' first dose by the mean of the first dose of TCE administered in each study. Logistic regression and tree-based models were trained. Across 100 iterations with different train-test splits, the average Area Under the Receiver-Operator Characteristic Curve (AUROC) was calculated for each model-type. Results: A total of 715 patients were included in the analysis (115 sCRS; 600 non-sCRS); the majority of patients had acute lymphoblastic leukemia (81%) and 19% of patients had solid tumors or Non-Hodgkin's lymphoma. Patients who developed sCRS had a higher incidence of infections prior to first TCE infusion, at 38% vs. 28% (p = 0.03). They also received a higher dose of TCE therapy (p< 0.001). The features selected for the model are listed in table 1. The best model to predict sCRS had a mean AUROC of 0.69 (95% CI 0.66-0.72) on the test set. When patients were ranked based on their predicted probability of getting sCRS and divided into quartiles based on predicted sCRS risk (very low, low, high, very high), the very high-risk quartile developed sCRS at 4x the rate (38% (0.347-0.413)) compared to the lowest quartile (5.7% ( 0.05-0.07); sample average was 16% (0.153-0.167) (figure 1). Compared to patients with very low sCRS risk, patients with very high sCRS risk had mainly ALL as a disease type (99% vs. 67%, p < 0.001), received a higher TCE dose (1.00 vs. 0.61, p < 0.001) and had a higher rate of infections prior to TCE treatment (49% vs. 12%, p < 0.001). Given the lack of uniform presence of disease burden in the predictive model cohort, a separate cohort of 945 ALL patients was analyzed to evaluate the impact of tumor burden on sCRS. 98% of patients received pre-TCE bridging therapy, resulting in median decline in %blasts from a maximum of 87% (84% vs. 88% for sCRS v/s non-sCRS patients; p = 0.157) to 0% (1% vs. 0% for sCRS v/s non-sCRS patients; p = 0.005) prior to TCE infusion. In the setting of these small ranges in tumor burden, neither total burden or most recent value prior to dosing was found to be significantly correlated with sCRS. Conclusion: Using the sCRS risk model, it was possible to stratify patients by risk categories. This could allow better selection of patients to receive TCE therapy and tailored pre-treatment and monitoring of CRS, which could in turn allow better resource allocation. As tumor burden can be a critical determinant of sCRS risk in other clinical settings where CRS is a relevant risk, future research is needed to further evaluate the impact of tumor burden on sCRS across different indications.

Cytokine release syndrome (CRS) is a severe clinical syndrome marked by drastic elevation of inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). Despite the current empirical therapeutic strategies, prediction of CRS onset and identification of high-risk individuals are not satisfactory due to poor understanding of the mechanisms underlying CRS-related immune dysfunction and risk factors for CRS. Recent studies have suggested that conditions such as stress, obesity, diabetes, and hypertension may contribute to the development of CRS. Here, we discuss potential connections between these conditions and CRS pathogenesis, with a focus on stress hormone catecholamine-mediated effects, hoping that the design of CRS therapeutic approaches ensues from a renewed perspective.

TK and SM are Co-first authors INTRODUCTION Treatment with chimeric antigen receptor (CAR) T-cells significantly improved outcomes in relapsed/refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). CAR-T activation and anti-tumor cytotoxicity are associated with bystander inflammatory reactions resulting in CRS and/or ICANS. Due to complex cytokine profiles, disease heterogeneity, and variability between commercial CAR-T products, identification of risk factors associated with CRS and/or ICANS has been challenging. In this study, we used plasma proteomic profiling at different timepoints to identify possible inflammatory mediators associated with CRS and ICANS METHODS We prospectively collected plasma samples from patients who received CAR-T cells therapy between 9/2021 to 12/2022 at several time points - before lymphodepletion chemotherapy on day -5 (relative to CAR-T cell infusion), prior to CAR T-cell infusion on day 0, and post CAR T-cell therapy on days 1, 2, 3, and 7. Protein profiling analyses were conducted at Eve Technologies (Calgary, Alberta, Canada) using an assay measuring 71 total cytokines and chemokines. Proteins levels were compared across different time points used Wilcoxon rank test, while features associated with CRS/ICANS were identified using logistic regression. Receiver operating characteristic (ROC) analysis used to identify variables predictive for CRS. Area under the curve (AUC) of at least 0.8 was used and best cutoffs were determined according to Youden index. P-values <0.05 were considered statistically significant. This study was supported in part by The Frederick A. Deluca Foundation. RESULTS Overall, 56 patients with available cytokine assays at all time points were included. The median age was 65 years (IQR: 57-74) and 70% were men. Of all patients, 26 (46%) had diffuse large B-cell lymphoma (DLBCL), 23 (41%) MM, 4 (7%) mantle cell lymphoma, and 3 (6) follicular lymphoma. Ide-cel (39%), liso-cel (36%), and axi-cel (17%) were the most used CAR-T cell products. All patients received lymphodepleting chemotherapy with fludarabine/cyclophosphamide. In total, 35 (63%) patients developed CRS (grade 1, 89%; grade 2, 8%; grade 3, 3%) and 18 (32%) patients developed ICANS (grade 1, 72%; grade 2, 22%; grade 3, 6%). Compared to patients who did not develop CRS, patients with CRS had lower median absolute lymphocyte counts at day -5 (0.02 x10 9/L vs. 0.05, p=0.0146), higher baseline CRP (13 vs. 4 mg/L, p=0.0005), and higher ferritin (914 vs. 442 mg/L, p=0.048). No differences in the type of CAR-T products (p=0.090), percentages of DLBCL or MM (p=0.270) were observed between CRS and no CRS cohorts ( Panel-A). First, we investigated the proteomic profiles at baseline for CRS odds. Hemoglobin (odd ratio [OR]: 0.6, 95%CI: 0.4-0.8) was associated with lower odds for CRS while IL6 (2.0, 1.2-3.3) and stem cell factor (scf 2.2, 1.2-4.2) were associated with higher odds of CRS. We then analyzed the differences in cytokine levels between day 0 and day 3 to select cytokines with significant changes for further analysis ( Panel-B). At day 3, groa (1.9, 1.1-3.3), IL3 (1.6, 1.2-2.1), IL5 (1.5, 1.2-1.9), IL6 (1.7, 1.3-2.3), IL10 (2.0, 1.3-3.0), TNFα (2.0, 1.1-3.6), and mcp2 (2.5, 1.2-5.3) were all associated with higher odds for CRS. Based on ROC analysis at day 3, best cutoff points to estimate CRS (value, sensitivity/specificity) for IL3 (3, 80%/90%), IL5 (197, 74%/85%), IL6 (11, 70%/85%), and IL10 (53, 74%/85%) were identified. Based on that, elevated IL3 (OR:24, 95%CI: 6-105), IL5 (11, 3-40), IL6 (21, 5-95), and IL10 (12, 3-46) were associated with higher odds for CRS. For ICANS, day 3 IL3 (1.5, 1.2-1.9), IL6 (1.2, 1.1-1.5), IL8 (2.1, 1.4-3.3), and IL10 (1.7, 1.3-2.4) were associated with higher odds for ICANS. Best cutoff points to estimate ICANS at day 3 (value, sensitivity/specificity) for IL3 (5, 78%/76%), IL6 (115, 78%/78%), IL10 (130, 81%/80%), and IL8 (21, 83%/81%) were identified. Based on that, elevated IL3 (OR:10, 95%CI: 3-37), IL6 (11, 3-43), IL10 (13, 3-51), and IL8 (19, 4-81) were associated with higher odds for ICANS. CONCLUSIONS In our comprehensive plasma proteomic profiles analysis, we identified cutoffs for IL3, IL6, IL5 and IL10 that may be predictive for CRS and ICANS regardless of CAR-T cell product. Our results are clinically applicable and may be used to recognize patients at risk for CRS and/or ICANS who may be eligible for prophylactic therapies.

CD19 chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable results in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the cytokine release syndrome (CRS) was presented in most patients as common toxicity and severe CRS (sCRS) characterized by the sharp increase in interleukin-6 (IL-6) could be life-threatening. We conducted a phase II clinical trial of ssCAR-T-19 cells, anti-CD19 CAR-T cells with shRNA targeting IL-6, in 61 patients with r/r B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT03275493. Fifty-two patients achieved CR while nine patients were considered NR. The median duration of response (DOR) and overall survival (OS) were not reached (>50 months). CRS developed in 81.97% of patients, including 54.10% with grades 1 to 2 (grade 1, 31.15%; grade 2, 22.95%) and 27.87% with grades 3 to 4 (grade 3, 26.23%; grade 4, 1.64%). sCRS occurs earlier than mild CRS (mCRS). A multivariable analysis of baseline characteristics identified high bone marrow disease burden and poor genetic risk before infusion as independent risk factors for sCRS. After infusion, patients with sCRS exhibited larger expansion of ssCAR-T-19 cells, higher peak levels of IL-6, IL-10, and IFN-γ, and suffered more severe hematological and non-hematological toxicities compared with those with mCRS.

Although chimeric antigen receptor (CAR)-T cell therapies are highly effective for B-cell lymphoma, they frequently cause cytokine release syndrome (CRS). High-grade CRS is serious and may require intensive care, yet reliable early predictive markers remain elusive. To identify risk factors for high-grade CRS, we retrospectively analyzed B-cell lymphoma patients who received CD19 CAR-T cell therapy. Of 106 patients analyzed, CRS occurred in 93 (88%), Grade ≥ 2 CRS in 28 (26%), and Grade ≥ 3 CRS in 6 (6%). Reticulocyte counts at infusion were significantly lower in patients who developed Grade ≥ 2 CRS (1.85 vs. 2.80 × 104/µL, p = 0.02). Multivariate analysis identified low reticulocyte count (< 15,000/µL; HR 2.21; 95% CI 1.01–4.86; p = 0.048), high metabolic tumor volume (> 100 mL), and use of axicabtagene ciloleucel as independent risk factors for Grade ≥ 2 CRS. Stratification by the reticulocyte cutoff showed higher 30-day cumulative incidence of CRS in patients with low counts, for both Grade ≥ 2 (42.9% vs. 19.7%, p = 0.012) and Grade ≥ 3 CRS (17.9% vs. 1.3%, p < 0.001). KyoTox-CRS, a risk-scoring system integrating these factors, effectively stratified these CRS risks. Early prediction of high-grade CRS based on the reticulocyte count at infusion may help to guide optimal risk-based management of CAR-T cell therapy.

An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. This retrospective study evaluated the clinical characteristics of severe CRS (sCRS, grade 3–4) induced by severe COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Grade 4 CRS was significantly more common in the COVID-19 group (15/40 (35.7%) vs. 5/41 (12.2%), P = 0.008). The CAR-T group had more dramatic increase in cytokines, including IL-2, IL-6, IL-10, and IFN-γ. Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml (16.1–70.0) vs. 3.3 (1.8–9.6), P < 0.001) and lg viral loads were correlated with lg IL-6 (R2 = 0.101; P < 0.001) and lg IL-10 (R2 = 0.105; P < 0.001). The independent risk factor for COVID-19-related sCRS was hypertension history (OR: 4.876, 95% CI: 2.038–11.668; P < 0.001). Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of severe COVID-19-related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.

ABSTRACT Introduction Cytokine release syndrome (CRS) is a common complication after T-replete HLA haploidentical hematopoietic cell transplantation (haplo-HCT) with PTCy. We aim to assess the incidence, severity, and impact of CRS on clinical outcomes of patients who received haplo-HCT using Beijing Protocol. Methods This was a single-enter retrospective analysis of 286 subjects who received haplo-HCT with Antithymocyte Globulin (ATG). Results We identified 147/268 (54.9%) patients who developed CRS, grade 1 CRS (32.5%) and grade ≥2 CRS (22.4%). Eight patients developed severe CRS. The incidence and severity of CRS did not show significant discrimination among patients who received different doses of ATG. By multivariable analysis, age and the disease status at transplantation were significantly associated with the occurrence of CRS (p =.000 and p = .021). In the univariate analysis for the severity of CRS, compared with CRS grade ≥2, patients with CRS grade 0-1 had higher 1-year overall survival (OS) (p = .009). The cumulative incidence of 100-day grades II-IV acute GVHD was 12.4%. The incidence did not show significant differences between patients with CRS or not. The devolvement of CRS is associated with worse OS, inferior disease-free survival, and higher nonrelapse mortality significantly. But the result appeared to be limited to patients in uncomplete remission status before transplantation. Discussion and Conclusions CRS is less frequent and milder with a protocol based on ATG. CRS can potentially affect the outcomes after haplo-HCT especially for patients in an uncomplete remission. Prospective clinical trials are needed to provide an appropriate scheme for CRS prophylaxis.

Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that can occur due to high-level immune activation. CRS can be triggered non-speci fi cally by T-cell engaging therapies administered to treat hematologic malignancies. 1-3 Clinical manifestations vary, from fever to more severe symptoms requiring hospitalization. 2 Although CRS severity is in fl uenced by disease status and underlying histology, prediction of CRS risk is currently not possible. 4 Identi fi cation of high-grade CRS risk factors is critical to inform decisions on patient management when administering T-cell engaging therapies. 5 Glo

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity. In this registry study by the Center for International Blood and Marrow Transplant Research, we studied CRS and ICANS in 1916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival (OS). Risk factors were assessed using Cox proportional hazards model. Among patients developing CRS (75.2%), 11.3% had grade ≥3 CRS. Among patients developing ICANS (43.5%), 47.7% had grade ≥3 ICANS. Among patients developing CRS, severe CRS rates decreased from 14.0% in 2018 to 9.2% in 2020 (P < .01). However, the proportion of severe ICANS in patients who developed ICANS remained statistically unchanged (41.5% in 2018 to 53.7% in 2020, P = .10). CRS and ICANS were correlated: 57.1% of patients with CRS also experienced ICANS, and CRS was reported in 97.5% of ICANS cases, suggesting a potential continuum between toxicities. Axicabtagene ciloleucel was associated with higher risk of any grade CRS (OR, 4.6; 95% CI, 3.65 to 5.81) and ICANS (OR, 5.85; 95% CI, 4.48 to 7.64) as well as early and severe forms of both complications. Older age, lower performance status, and elevated lactate dehydrogenase levels prior to infusion also variably predicted these toxicities. In a landmark analysis starting 30 days postinfusion, patients with severe CRS or severe ICANS had shorter OS compared to those without these toxicities. High grades of CRS improved over time likely related to earlier intervention, development of ICANS is intrinsically related with CRS. These findings underscore the need for effective strategies to mitigate these toxicities and improve CAR-T safety.

No abstract available

SC and IV administration of ALNUC, a 2+1 BCMA x CD3 T-cell engager (TCE), have been investigated in an open-label, phase 1 study in patients (pts) with RRMM (NCT03486067). IV ALNUC showed promising activity but elicited CRS in 76% of pts. ALNUC recruits T cells to BCMA-expressing myeloma target cells, leading to T-cell cytotoxic activity and cytokine release. Measuring T-cell activating factors and cytokine secretion in peripheral blood (PB) is a useful marker of ALNUC pharmacodynamic activity and risk of CRS. Aims

Chimeric antigen receptor (CAR) T-cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that has up to now been considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated the incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR T-cell therapy between January 2020 and May 2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose-dependent manner (r = -0.44, P=0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, P<0.001). We thus hypothesize that fibrinogen synthesis in CRS is up-regulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR T-cell therapy, and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 2148 81%, and 96% of patients had stage III-IV disease. The median total metabolic tumour volume was 673 cm3 (IQR 249-1221 cm3). Median time from diagnosis to first dose of R-CHOP was 15 days (IQR 11-21.5). Grade (Gr) ≥3 AEs were seen in 10/25 (40%) (Arm A) and 11/21 (52%) (Arm B). There were no Gr 5 AEs. Febrile neutropenia was observed in 1/25 (4%) and 6/21 (29%) and CRS Gr 1 in 5/25 (20%) and 5/21 (24%), respectively. There was 1 episode of Gr 2 CRS in Arm A after 10 mg glofitamab and no Gr 3-4 events. Peripheral neuropathy was limited to Gr 1-2 and occurred in 11/25 (44%) and 5/21 (24%) respectively. No ICANS was observed. The RDI was ≥90% for cyclophosphamide, doxorubicin, polatuzumab vedotin, vincristine and glofitamab in 93%, 93%, 100%, 76% and 88% of patients, respectively. There was 1 dose interruption of doxorubicin following a myocardial infarction, and 3 interruptions to glofitamab dosing, 2 for infection and 1 for rash. 41 treated pts had at least 1 efficacy assessment, with best overall response rate 100%. Of 25 pts who reached the end of induction (EOI) assessment, 19 (76%) demonstrated CR, 5 (20%) PR and 1 (5%) PD. To date, only one patient had PD during post-treatment follow up (best response CR). At a median follow up of 3.7 months (mo), the estimated PFS at 6-mo was 91% (Figure). Of the 5 pts with PR at EOI, none has progressed with median follow up 6.1 mo. Summary/Conclusion: Glofitamab with R-CHOP or Pola-R-CHP was deliverable with moderate rates of low-grade CRS and maintenance of RDI. The ability to enrol after 1 cycle of R-CHOP resulted in short time to treatment initiation and pragmatic inclusion of pts with high burden disease. Efficacy appears promising in this HR patient population. Updated results and ctDNA analysis will be presented. HemaSphere | 2023;7(S3) EHA2023 Hybrid Congress Copyright Information: (Online) ISSN: 2572-9241 © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open access Abstract Book distributed under the Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) which allows third parties to download the articles and share them with others as long as they credit the author and the Abstract Book, but they cannot change the content in any way or use them commercially. Abstract Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx.Book Citations: Authors, Title, HemaSphere, 2023;7(S3):pages. The individual abstract DOIs can be found at https://journals.lww.com/hemasphere/pages/default.aspx. Disclaimer: Articles published in the journal HemaSphere exclusively reflect the opinions of the authors. The authors are responsible for all content in their abstracts including accuracy of the facts, statements, citing resources, etc. 2149

Summary Background Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic leukaemia (r/r B-ALL); however, frequent relapse demands multi-targeted approaches. Methods We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use basis in a cohort of 10 heavily pretreated paediatric, adolescent, and young adult (AYA) patients with r/r B-ALL. Findings Most (9/10) of the patients had relapsed B-ALL, 7 having received previous anti-CD19 CAR T-cell therapy and 6 haematopoietic stem cell transplantation (HSCT). Two patients had Down syndrome. Increased high-grade CRS/ICANS and proinflammatory markers (IL-6, LDH and ferritin) correlated with patients with a high tumour burden (TB) before lymphodepletion. Complete remission on day +28 post-infusion was achieved in 8/10 patients (7 with MRD-), and 5/7 patients received HSCT as consolidative therapy within three months post-infusion. Two patients with early relapse after tandem anti-CD19/CD22 CAR received rescue therapy and HSCT. At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%–100%). Interpretation Tandem anti-CD19/CD22 CAR T-cell administration combined with consolidative HSCT is a promising therapeutic approach, though managing bridging therapy and reducing the TB prior to infusion remain key challenges (REALL_CART trial, NCT06709469, EudraCT 2023-509723-41-01). Funding This work was supported by a grant from the 10.13039/501100004587Instituto de Salud Carlos III to APM PI22/01226, two grants from CRIS Cancer Foundation to Beat Cancer as part of the projects “Advanced Cell Therapy Unit Hospital Universitario La Paz” and JM “Proyecto Mateo: CAR T-cell therapy for juvenile myelomonocytic leukaemia” and “Terapia avanzada CAR-T CD19/CD22”, Ayuda Nominativa de la Consejería de Investigación, 10.13039/100012818Comunidad de Madrid, Spain. Work in MI lab was funded by a grant from the 10.13039/501100004837Spanish Ministry of Science and Innovation (PID2020-114148RB-I00). VGG was granted with Río Hortega (AES 2022 exp. Nº. CM22/00078) and Juan Rodés (AES 2024 exp. Nº. JR24/00003) contracts from the 10.13039/501100004587Carlos III Health Institute (ISCIII) through the European Funds of the Recovery, Transformation and Resilience Plan and financed by the European Union NextGenerationEU.

Background: Chimeric antigen receptor T-cell therapy (CAR T-cell therapy) is associated with potentially life-threatening toxicities, most commonly cytokine release syndrome (CRS) and immune-effector-cell-associated neurotoxicity syndrome (ICANS). These frequent adverse events are managed with the IL-6 receptor antagonist tocilizumab and/or corticosteroids. The prophylactic and early use of corticosteroids for CRS and ICANS have previously been reported, but eventual negative impacts on CAR T-cell efficacy are feared. Methods: Retrospective comparative analysis of two patient cohorts with hematological malignancies treated with CAR T-cell therapy: 43 patients received early administration of 10 mg dexamethasone preceding each dose of tocilizumab (“early corticosteroid/ tocilizumab”, EcsTcz cohort) vs. 40 patients who received tocilizumab alone (“tocilizumab alone”, Tcz cohort) for treatment of low-grade CRS. Results: Despite overall higher CRS incidence (91% vs. 70%; p = 0.0249), no high-grade CRS was observed (0% vs. 10%; p = 0.0497) among patients receiving early corticosteroids in combination with tocilizumab. In terms of neurotoxicity, no worsening regarding incidence of ICANS (30% vs. 33%; p = 0.8177) or high-grade ICANS (20% vs. 14%; p = 0.5624) was observed in the EcsTcz cohort. Moreover, overall response rates (80% vs. 77%; p = 0.7936), complete response rates (50% vs. 44%; p = 0.6628), progression-free survival (p = 0.6345) and overall survival (p = 0.1215) were comparable for both cohorts. Conclusions: Our study suggests that the early use of corticosteroids in combination with the standard tocilizumab schedule for low-grade CRS following CAR T-cell therapy may significantly reduce the risk of high-grade CRS without negative impact on neurotoxicity or treatment outcome.

Background: Background: Patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) with high/poor risk according to the revised International Prognostic Index (IPI) who are treated with immunochemotherapy (IC) have a 4-y survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab is a subcutaneously administered, well-tolerated, bispecific antibody with single-agent antitumor activity in relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL). As its mechanism of action and safety profile are distinct from IC, epcoritamab is well suited for use in combination therapy and in earlier lines of therapy. Summary/Conclusion: Summary/Conclusion: Epcoritamab is the first subcutaneously administered bispecific antibody to be evaluated in combination with standard IC in pts with previously untreated DLBCL. These results show that epcoritamab + R-CHOP has a manageable safety profile. CRS events were observed to be mostly of low grade and were not associated with treatment discontinuation. Rates of overall response and CMR were high, and no relapses were reported as of the data cutoff date. Updated data will be presented at the meeting.

High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL. This trial has completed accrual. The primary outcome was complete response rate (CRR). Secondary outcomes were objective response rate (ORR), duration of response (DOR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), assessment of safety, central nervous system (CNS) relapse and blood levels of CAR T cells and cytokines. The primary endpoint in efficacy-evaluable patients (n = 37) was met, with 78% CRR (95% confidence interval (CI), 62–90) and 89% ORR (95% CI, 75–97). As of 17 May 2021 (median follow-up, 15.9 months), 73% of patients remained in objective response; median DOR, EFS and PFS were not reached. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in three patients (8%) and nine patients (23%), respectively. There were no treatment-related grade 5 events. Robust CAR T-cell expansion occurred in all patients with a median time to peak of 8 days. We conclude that axi-cel is highly effective as part of first-line therapy for high-risk LBCL, with a manageable safety profile. In a phase 2 trial, first-line treatment with axicabtagene ciloleucel, an autologous CD19-targeting CAR T-cell therapy, exhibited a high complete response rate and a manageable safety profile in adults with high-risk large B-cell lymphoma.

BACKGROUND Risk factors for invasive fungal infections (IFIs) after chimeric antigen receptor-modified T cells (CAR-T) treatment have been poorly studied. Here we are investigating the risk factors and prognosis of IFIs following CAR-T therapy. MATERIAL AND METHODS A case-control study was conducted on the medical records of CAR-T patients admitted to our center between June 2018 and December 2020. The case group (32) consisted of patients who developed IFIs within 60 days after CAR-T infusion, while the control group (298) consisted of patients who did not develop IFIs. The Cox Proportional Hazard Regression model was utilized to analyze the risk factors for the occurrence of IFIs, as well as the factors affecting the 1-year survival rate of patients. RESULT Cumulatively, 364 patients were included. Inflammatory cytokine release syndrome (CRS) grade (hazard ratio (HR) 2.34 confidential interval (CI)（1.03-5.30) P = 0.042), ventilation (HR 3.23 CI (1.20-8.71) P = 0.020) and lymphocyte deficiency duration (HR 1.06 CI (1.01-1.10) P = 0.015) were associated with IFIs. IFIs (HR 1.12 CI (0.52-2.41) P = 0.767) did not affect a patient's one-year survival, which was associated with lymphocyte deficiency (HR 1.04 CI (1.01-1.07) P = 0.004) and treatment with broad-spectrum antibacterial (HR 1.80 CI (1.03-3.11) P = 0.038) within 30 days prior to CAR-T infusion. CONCLUSION There is an increased risk of IFIs in patients with hematologic malignancies due to ventilation, high-grade CRS, and prolonged lymphocyte deficiency within 60 days after CAR-T infusion. Invasive fungal infection was not a risk factor for death within 1 year of CAR-T therapy, while broad-spectrum antibacterial therapy prior to infusion and prolonged lymphocyte deficiency were risk factors.

Background: Epcoritamab SC, a CD3xCD20 T-cell-engaging bispecific antibody, has recently been approved by the US FDA for the treatment of adults with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. As a single agent, epcoritamab SC has demonstrated deep, durable responses with a manageable safety profile in patients with R/R large B-cell lymphoma in the expansion portion of the phase 1/2 EPCORE ™ NHL-1 trial (NCT03625037). Cytokine release syndrome (CRS) events in the dose expansion part of the trial were primarily low grade (49.7% overall; 31.8% grade [G] 1, 15.3% G2, 2.5% G3); timing was predictable, and the majority of events occurred following the first full dose at cycle 1 day 15 (C1D15). To mitigate CRS in dose expansion, subcutaneous administration, step-up dosing, and premedication, including prednisolone, were used. Here, we present preliminary results from a DLBCL optimization cohort of the EPCORE NHL-1 trial that further investigates mitigating the risk of CRS in patients treated with epcoritamab SC monotherapy. Methods: Adult patients with R/R CD20 + DLBCL (previously treated with ≥2 lines of systemic therapy) were enrolled to receive epcoritamab SC in 28-d cycles as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received 2 step-up doses (step-up dose 1, 0.16 mg, and step-up dose 2, 0.8 mg) followed by 48-mg full doses. To further mitigate CRS, C1 of the optimization cohort included mandatory administration of dexamethasone 15 mg as premedication on D1, D8, D15, and D22 and as prophylaxis on D2-4, D9-11, D16-18, and D23-25, and diphenhydramine and acetaminophen as premedication on D1, D8, D15, and D22 with each dose. In C1, it was strongly recommended that patients be well hydrated and that antihypertensive medications be held for 24 h prior to epcoritamab SC administration. Patients were also encouraged to monitor their temperatures following the first 4 doses. Hospitalization and inpatient observation were optional. The primary endpoint was rate of G2 or higher CRS and all CRS events. Secondary pharmacokinetic/pharmacodynamic (PK/PD) analyses were performed. Results: As of April 21, 2023, 24 patients (median age, 65 y) had been treated in this DLBCL optimization cohort. The median number of prior lines of treatment was 3 (range, 2-10), 75% of patients were primary refractory, 71% had stage IV disease, and 58% had prior CAR T. With a median follow-up of 1.3 mo, 18 patients (75%) remained on treatment. The most common treatment-emergent AEs (TEAEs) of any grade were infections (38%; COVID-19, 8%), fatigue (21%), CRS (17%), headache (17%), anemia (13%), constipation (13%), decreased platelet count (13%), dyspnea (13%), hyponatremia (13%), insomnia (13%), and neutropenia (13%; febrile neutropenia, 4%). All CRS events were G1; 1 patient was treated with anticytokine therapy (tocilizumab); there were no treatment discontinuations due to CRS. The most commonly observed CRS symptom was fever (100%). Most CRS events (3/5 events) occurred following the first full dose on C1D15. The median time to CRS resolution was 3.5 d (range, 1-25) and all events resolved. Compared with the DLBCL expansion cohort, circulating interleukin 6 (IL-6) levels were decreased 24 h after the first full dose (C1D15) of epcoritamab SC ( Figure). The median circulating IL-6 level at C1D16 was lower in the dose optimization cohort at 6.92 pg/mL (2.97 pg/mL at C1D1 predose), compared with 21.24 pg/mL (2.45 pg/mL at C1D1 predose) in the DLBCL expansion cohort. The addition of dexamethasone and fluids in optimization did not appear to interfere with T-cell margination or T-cell activation, given that the fold-change values of T-cell absolute counts and percentage of activated T cells were similar between DLBCL optimization and expansion cohorts at C1D16. No patients experienced ICANS, clinical tumor lysis syndrome, or fatal TEAEs. Conclusions: Encouraging preliminary data from this DLBCL CRS optimization cohort, which incorporates prophylactic dexamethasone and hydration of patients during cycle 1, indicate that this approach is effective in decreasing rates and severity of CRS. Data with additional patients and follow-up will be presented.

Few prospective studies have examined posttransplant chimeric antigen receptor (CAR) T cell infusion as candidates for front‐line consolidation therapy for high‐risk multiple myeloma (MM) patients. This single‐arm exploratory clinical trial is the first to evaluate the safety and efficacy of sequential anti‐CD19 and anti‐BCMA CAR‐T cell infusion, followed by lenalidomide maintenance after autologous stem cell transplantation (ASCT), in 10 high‐risk newly diagnosed multiple myeloma (NDMM) patients. The treatment was generally well tolerated, with hematologic toxicities being the most common grade 3 or higher adverse events. All patients had cytokine release syndrome (CRS), which was grade 1 in 5 patients (50%) and grade 2 in 5 patients (50%). No neurotoxicity was observed after CAR‐T cell infusion. The overall response rate was 100%, with the best response being 90% for a stringent complete response (sCR), and 10% for a complete response (CR). At a median follow‐up of 42 (36–49) months, seven (70%) of 10 patients showed sustained minimal residual disease (MRD) negativity for more than 2 years. The median progression‐free survival (PFS) and overall survival (OS) were not reached. Although the sample size was small and there was a lack of control in this single‐arm study, the clinical benefits observed warrant ongoing randomized controlled trials.

Bispecific antibodies have improved progression-free survival and overall survival in relapsed/refractory haematologic malignancies, yet they are frequently associated with cytokine release syndrome (CRS), often necessitating tocilizumab and inpatient care during step-up dosing, thereby increasing treatment costs. Dipyrone (metamizole) is a widely used antipyretic in Brazil and may attenuate the initial inflammatory response when given prophylactically. To determine whether dipyrone prophylaxis reduces the incidence and severity of CRS and immune-effector-cell–associated neurotoxicity syndrome (ICANS) in patients treated with elranatamab, teclistamab, talquetamab or epcoritamab.Secondary objectives: to analyse infection and cytopenia rates during step-up dosing. Retrospective cohort including all patients who received the above bispecific antibodies between 01 Dec 2022 and 01 Jun 2025 at a private hospital in southern Brazil. Patients with uncontrolled infection at therapy start were excluded. Two groups were compared: fixed dipyrone prophylaxis (1 g PO or IV every 6 h) versus acetaminophen pre-medication only (1 g or 750 mg). Data were extracted from electronic medical records. (n = 14): CRS: 0/5 (0 %) in the dipyrone group vs 5/9 (56 %) in the acetaminophen group—grade 1 (11 %), grade 2 (33 %), grade 3 (11 %); no grade ≥ 4 in either group. Tocilizumab use: 0/5 (0 %) with dipyrone vs 4/9 (44 %) with acetaminophen. ICANS: 1/5 (20 %) vs 4/9 (44 %). Infections during step-up: 2/5 (40 %) vs 3/9 (33 %). Neutropenia: 1/5 (20 %) vs 1/9 (11 %). Thrombocytopenia: 1/5 (20 %) vs 0/9 (0 %). Dipyrone prophylaxis was associated with a markedly lower CRS incidence; none of the five dipyrone-treated patients developed CRS, whereas over half of those on acetaminophen did. Correspondingly, tocilizumab was required in 44 % of acetaminophen patients and in 0 % of the dipyrone group, reinforcing the potential benefit of dipyrone. Reduced CRS and absence of tocilizumab use may improve outpatient feasibility of bispecific therapy, particularly in resource-limited settings. ICANS frequency was also lower with dipyrone (20 % vs 44 %). Infection rates were comparable (40 % vs 33 %), suggesting dipyrone did not heighten infectious risk. Cytopenias appeared somewhat higher with dipyrone (40 % vs 11 %), but small sample size limits conclusions, and toxicity may derive from the bispecifics themselves. Preliminary data indicate that dipyrone prophylaxis may lower CRS incidence and eliminate the need for tocilizumab without a clear rise in serious adverse events. Multivariate analyses are in progress. Larger, controlled studies are warranted to confirm these findings and define the role of dipyrone in prophylactic strategies for bispecific antibody therapy.

Chimeric antigen receptor (CAR) T-cell therapy is curative for many patients with non-Hodgkin lymphoma (NHL). However, toxicity remains a significant barrier. Phosphoinositide 3-kinases (PI3K) inhibition can prevent IL-6 release by myeloid cells using in vitro models of CAR T induced cytokine release syndrome (CRS) (Amatya et al, ASH 2023). Duvelisib is an oral PI3K inhibitor with an established safety profile. Consequently, we performed a trial of duvelisib for CRS prophylaxis with standard-of-care (SoC) anti-CD19 CAR T-cell therapy for NHL (NCT05044039). This single center phase Ib trial enrolling patients with relapsed/refractory NHL eligible for SoC CAR T-cell therapy into three cohorts. The dose escalation (DE) cohort utilized a 3+3 design with two dose levels (15 mg and 25 mg BID) to establish the recommended phase 2 dose (RP2D) of duvelisib. The DE and standard dosing (SD) cohort received duvelisib from day -2 to +28. The extended dosing (ED) cohort received duvelisib from day -2 to +28 and then for 14 of 28 days for up to 5 cycles. The primary outcome is safety and tolerability, defined as dose limiting toxicities (DLTs) during the first 30 days of therapy. Patients receiving >50% of doses during the DLT period were evaluable for the primary outcome. Key secondary outcomes include incidence and severity of adverse events (AEs), CRS and immune effector cell associated neurotoxicity syndrome (ICANS), overall response rate (ORR), and progression-free survival (PFS). Patients receiving ≥1 dose of duvelisib were evaluable for the secondary outcomes. Since day -2 to +28 was identical across cohorts, CRS/ICANS are reported for all patients at the RP2D. For disease outcomes, patients in the DE/SD and ED cohorts were analyzed separately. CAR T-cell kinetics, T-cell subsets and cytokine levels were analyzed in peripheral blood. 42 patients were enrolled on the study (DE: 9, SD: 13, ED: 20). Median age was 68 years (range: 28–78), 95% were White, and 67% were male. Diagnoses included DLBCL (n = 20), MCL (6), FL (1) and PBMCL (1). Patients received axi-cel (22), liso-cel (14), brexu-cel (5) and tisa-cel (1). 40 patients were evaluable for the primary endpoint. No patient in any cohorts had a DLT and the RP2D was 25 mg BID. All 39 patients treated at the RP2D were evaluable for the secondary endpoints. 69% of patients experienced CRS at a median of 5 days following cell infusion (range 1-9). 68% did not have CRS in the first 3 days post-infusion. The CRS severity was low (grade 1: 54%, grade 2: 15%, grade 3/4: 0%). 83% (5/6) of patients with grade 2 CRS received axi-cel. ICANS occurred in 36% of patients at a median of 7 days (range: 4-17). The severity of ICANS was variable (grade 1: 18%, grade 2: 8%, grade 3/4: 10%). 71% (5/7) of patients with grade ≥2 ICANS received axi-cel. 39 patients treated at the RP2D were evaluable for disease response (DE/SD: 19, ED: 20). On day +100, the ORR was 53% and 56% with 42% and 44% achieving complete response (CR) in the DE/SD and ED cohorts, respectively. 8% of patients had progressive disease (PD) as best response. The median follow up was 356 days (SD: 547, ED: 206). The median PFS in the DE/SD and ED cohorts was 98 and 310 days, with a 1-year PFS of 35% and 42%. 15 patients had 23 serious adverse events (AEs) requiring hospitalization. 222 severe (grade ≥3) AEs were observed, including 139 severe hematologic AEs. Common non-ICANS/CRS, non-hematologic severe AEs included laboratory abnormalities (electrolyte: 10, LFT: 8) and infections (10), including one case of CMV reactivation. 12 patients enrolled in the study have died, 11 from progressive disease. One patient in the SD cohort died of neutropenic sepsis on day +50. CAR T-cell expansion by flow cytometry was robust. Compared to historical controls (n = 6), duvelisib-treated patients (n = 17) showed a trend toward higher numbers of CAR T cells, along with a significantly increased CD8+ central memory T cells (p = 0.04). Additional analyses are ongoing, including serum cytokine profiling. Results of this single center study demonstrate that the addition of duvelisib to CAR T-cell therapy is safe and may prevent grade 3-4 CRS. Duvelisib is also associated with delayed onset of CRS, which may enable outpatient administration of CAR T-cells. Though limited by clinical heterogeneity, ORR and 1-year PFS are comparable to prior reports, suggesting duvelisib does not significantly inhibit CAR T-cell function

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

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Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are improving with modern prophylaxis but still occur and outcomes are poor in steroid refractory cases. Severe CRS occurs in 5-10% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and dismal one-year overall survival between 25-30%. We previously demonstrated that JAK1 inhibition with itacitinib is effective in preventing aGVHD and CRS, with excellent long term GRFS and OS in a high-risk population undergoing allo-HCT. In this study we are testing ruxolitinib, a JAK1/2 inhibitor, which is approved for treatment of aGVHD and chronic GVHD in the prophylaxis setting. If safe, we will expand this approach to combine ruxolitinib and abatacept and reduce exposure to traditional immunosuppressants mycophenolate mofetil (MMF) and tacrolimus. We hope to establish the safety of this platform, which has the potential to effectively prevent aGVHD and CRS while reducing toxicity and potentially relapse. Here we report the initial clinical outcomes from our study of ruxolitinib +/- abatacept with haplo-HCT (NCT06008808). Methods: Patients with AML, ALL, MDS, or NHL in remission undergoing PB haplo-HCT are eligible for the study and treated on one of two regimens. Regimen 1: Ruxolitinib 5-10 mg BID on day -3 through 180 followed by a taper in addition to standard MMF days 5-28 and tacrolimus days 5-100 targeting serum level of 3-7 ng/mL. Regimen 2: Ruxolitinib at 5-10 mg BID on day -3 through 180 followed by a taper, abatacept 10 mg/kg IV on days +5, +14, +28, and +56, short course tacrolimus days 5-60, and MMF is eliminated. Myeloablative and reduced intensity conditioning are allowed. All patients received standard dose post-transplant cyclophosphamide. The primary endpoint is safety assessed by graft failure, grade III-IV aGVHD, and non-relapse mortality (NRM), assessed continuously with early stopping rules in place. Results: Seventeen of the planned 20 patients have completed enrollment to Regimen 1 and underwent haplo-HCT between 7/2024 and 7/2025. Regimen 2 has completed approval and activation and will open for enrollment when Regimen 1 is complete. Median age at transplant was 64 (41-75) and 15/17 patients are male. Diagnoses were AML (12), ALL (1), MDS (3) and NHL (1). Median follow up is 158 days, with 8/17 beyond 180 days. There were no cases of engraftment failure with short median times to neutrophil (14 days, range 12-20) and platelet (14 days, range 7-54) engraftment. There were no cases of grade III-IV acute GVHD. The incidence of grade II acute GVHD through day 100 was 12.5% (95% CI 2-36%). No patients developed aGVHD during their ruxolitinib taper. There were no cases of extensive chronic GVHD. There were no cases of severe CRS with 12 (80%) patients having grade 1 CRS, 1 (7%) having grade 2 CRS, and 2 (13%) having no CRS. There have been no cases of relapsed disease. Four (27%) patients had NRM – aspiration event after engraftment on day 21, influenza pneumonia on day 86, encephalopathy, failure to thrive and multiorgan failure on day 115, and one suicide on day 265. All but one – influenza – were deemed unrelated to ruxolitinib. Overall survival at day 180 was 78% (95% CI 45-92%) by Kaplan-Meier estimate. All evaluable patients (11/11) had full donor engraftment and >95% chimerism at day 100. Follow up and endpoints will be updated for the ASH 2025 meeting. Conclusions: Ruxolitinib with PB haplo-HCT appears safe, with no engraftment failure and prompt engraftment. Severe CRS has not been seen in this trial. Rates of acute and chronic GVHD are low, and no patients have relapsed during short follow-up to date. Four patients have experienced NRM, and while three cases were judged as not related to ruxolitinib, we continue to monitor toxicity with each enrollment. Regimen 2 – combining ruxolitinib with abatacept – is approved and will begin enrollment after completion of 20 patients on Regimen 1.

Introduction: Chimeric antigen receptor T cell therapy (CAR-T) and bispecific antibodies have revolutionized the management of hematological malignancies. Still, serious adverse events such as cytokine release syndrome (CRS) and immune effector-associated neurotoxicity syndrome (ICANS) remain an area of significant concern. Tocilizumab is currently approved for the treatment of CRS; however, we aim to investigate its potential role as a preventive agent. Methods: Following PRISMA guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov using MeSH terms and keywords for “ Tocilizumab”, “cytokine release syndrome”, and “immune effector-associated neurotoxicity syndrome.”  After screening of 552 references and excluding review articles, 11 studies reporting outcomes with prophylactic Tocilizumab in CAR-T and Bispecific antibody treated patients were included. For outcomes reported in two or more studies, a meta-analysis was conducted using a random-effects model in MetaXL to estimate the pooled prevalence, applying a double-arcsine transformation. Results were expressed as prevalence estimates with 95% confidence intervals (CIs). Some characteristics were described systematically. Results: A total of 430 patients from six retrospective and five prospective studies were included for analysis. The median age was 62 (21-87) years, and 50% (n = 189/374) were male. Underlying malignancies included multiple myeloma (MM) (80%, n= 346), diffuse large B-cell lymphoma (DLBCL) (14%, n = 61), mantle cell lymphoma (MCL) (2%, n = 8), follicular lymphoma (1%, n = 5), B-cell acute lymphoblastic leukemia (B-ALL) (0.5%, n = 2), and others (2%, n = 8). Among the total population, the MM were treated with Bispecific antibodies (n = 346, 80%), and the rest were treated with CAR-T cell therapy. The Bispecific antibodies used were Teclistamab. Eltranatamab, Talquetamab, and Linvoseltamab. The pooled rates for patients who developed CRS and ICANS were 28% (95% CI 0.24-0.33, p = 0.00, I2 = 95%) and 14% (95% CI 0.11-0.17, p = 0.00, I2 = 94%), respectively. The pooled rates for the development of grade 1, grade 2, grade 3, and grade 4 CRS were 18% (95% CI 0.15-0.22, p = 0.00, I2 = 87%), 8% (95% CI 0.05-0.11, p = 0.00, I2 = 88%), 2% (95% CI 0.00-0.05, p = 0.63, I2 = 0%), and 3% (95% CI 0.00-0.07, p = 0.48, I2 = 0%), respectively. The pooled rates for grade 1, grade 2, and grade 3 ICANS were 5% (95% CI 0.03-0.08, p = 0.00, I2 = 82%), 5% (95% CI 0.03-0.0.08, p = 0.00, I2 = 77%), and 6% (95% CI 0.03-0.10, p = 0.00, I2 = 93%), respectively. Among patients who developed CRS and ICANS, the pooled rates of resolution for CRS and ICANS with treatment were 100% (95% CI 0.99-1.00, p = 1.0, I2 = 0%), and 100% (95% CI, 0.99-1.00, p = 1.00, I2 = 0%), respectively. The pooled rates for patients who developed grade ≥3 anemia, neutropenia, and thrombocytopenia were 28% (95% CI 0.22-0.35, p = 0.00, I2 = 82%), 60% (95% CI 0054-0.66, p = 0.00, I2 = 89%), and 28 (95% CI 0.0.22-0.35, p = 0.00, I2 = 82%), respectively. The pooled rates of overall infections and grade 3 or higher infections were 47% (95% CI 0.41-0.52, p = 0.00, I2 = 72%) and 20% (95% CI 0.15-0.25, p = 0.52, I2 = 0%), respectively. The pooled rates for overall response (OR) and complete response (CR) to Bispecific antibodies and CAR-T cell therapy were 65% (95% CI 0.60-0.71, p = 0.42, I2 = 0%), and 35% (95% CI 0.0.27-0.43, p = 0.00, I2 = 85%), respectively. Conclusion: Tocilizumab is a viable option for preventing all grades of CRS and ICANS following CAR-T cell therapy and Bispecific antibodies. Randomized trials with larger patient populations are needed to further demonstrate its efficacy, safety, and the impact on treatment responses.

Introduction: Cytokine release syndrome (CRS) is a common and severe adverse effect reported with many chemotherapeutic agents, cellular therapies, and stem-cell transplantation. JAK-1 plays a crucial role in its pathophysiology. Itacitinib, a JAK-1 inhibitor, is currently under investigation for the prevention of CRS. We aim to explore the outcomes of these studies. Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (inception to May 2025) was conducted using MeSH terms for “cytokine release syndrome” and “Itacitinib.” After screening and excluding review articles, meta-analyses, and studies without a patient population of interest, two studies reporting the outcomes of Itacitinib in the prevention of CRS were selected for inclusion from a total of 280 references. Extracted data included patients' demographics, CRS rate, CRS grade, and overall survival (OS). Results: A total of 89 patients from one randomized controlled trial and one pilot study were included in this systematic review. Frigault et al. randomized 47 patients to either Itacitinib (n = 23, 49%, median age 66 years, 65% male) or placebo (n = 24, 51%, median age 64 years, 71% male). Patients were planned to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL). CRS rate was 65% (n = 12) in the Itacitnib arm and 80% (n = 20) in the placebo arm. The CRS rates for Grades 1 and 2 were 73% (n = 11) and 27% (n = 4), respectively, in the Itacitinib arm. No grade 3 or grade 4 CRS was observed. Immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm. No grade 4 ICANS occurred in either arm. There was no difference in the best overall response rate for lymphoma between the two arms. Abboud et al. treated 42 patients with Itacitinib after haploidentical transplantation. The median age was 60 years. Common underlying conditions included acute myeloid leukemia (AML) (60%) and myelodysplastic syndrome (MDS) (10%). The CRS rates for Grades 1 and 2 were 90% (n = 38) and 10% (n = 4), respectively. No grade 3 or 4 CRS was observed. There were no cases of grade III-IV acute graft-versus-host disease (GVHD). The cumulative incidence of grade II acute GVHD at 1 year was 20.5%. OS at 1 year was 80% (95% CI, 63-90). Conclusion: Itacitinib prophylaxis may prevent high-grade CRS and other immune-mediated adverse events such as ICANS and GVHD without reducing the treatment responses. Future high-quality trials with larger patient populations are required to validate these findings further.

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INTRODUCTION: Haploidentical stem cell transplant (haplo-HSCT) is associated with a high incidence of Cytokine Release Syndrome (CRS). Severe forms of CRS (grade 3-5) can evolve with serious organ damage, increased treatment-related mortality (TRM) and a higher risk of bloodstream infections. Standard haplo prophylaxis for graft-versus-host disease (GvHD) includes post transplant cyclophosphamide (PTCy) on days +3 and +4, and mycophenolate mofetil [MMF] and calcineurin inhibitor [CNI] from day +5 until day +35. Recent studies (Hunter et al., 2022) show that earlier immunosuppression initiation (IST) may reduce CRS incidence and improve outcomes. OBJECTIVE: To evaluate the incidence and severity of CRS (graded by CTCAE 5.0) and Intensive Care Unit (ICU) admissions after the implementation of an early IST protocol for GvHD prophylaxis. This protocol starts CNI on day -1 and MMF on day 0 (early), with PTCy infusion on days +3 and +4, compared to the standard GvHD prophylaxis regimen. STUDY DESIGN: This retrospective analysis includes 136 patients over 18 years old who underwent haplo-HSCT between 2016 and 2023 at Hospital A Beneficência Portuguesa de São Paulo, Brazil. Of these, 106 received standard GvHD prophylaxis. From January 2023 onwards, 30 patients received the early IST protocol. Data on microbiologically or clinically confirmed viral, bacterial, and fungal infections, and febrile neutropenia in absence of a clinically or microbiologically documented infection until day +100 were recorded. The study was approved by the local Ethics in Research Committee. RESULTS: The median ages were 47 and 45 years in standard and early GvHD prophylaxis groups, respectively. Over 90% of patients in both groups received peripheral blood stem cells. The most common diagnoses were acute myeloid leukemia (39,6% in standard vs 36,7% early prophylaxis), acute lymphoblastic leukemia (19,8% vs 33,3%) and Hodgkin's lymphoma (9,4% vs 10%). 34,9% patients in the standard group and 45,2% in the early IST group underwent myeloablative conditioning (p=0,30). The median follow up was 380 days. The overall incidence of CRS was 81.6% in standard vs. 60% in early prophylaxis group (p=0.008). The incidence of severe CRS was 5.6% in the standard group, with no cases in the early prophylaxis group (p=0.027). ICU admissions within the first 35 days post-transplant were not significantly different between cohorts (25% standard vs. 14% early prophylaxis, p=0.4). Overall survival at 180 days was similar between the groups (63% standard vs. 65% early prophylaxis, p=0.7). Engraftment failure at 45 days was also comparable (2.9% standard vs. 3.4% early prophylaxis, p=0.5). Acute GvHD grades II-IV was 35.8% in the standard vs 46.7% in the early prophylaxis group, with more severe cases (III-IV) in the latter (7,5% vs. 30%). The rate of infections and febrile neutropenia was high, 3.38 events per 100 patient-days, and it was higher for patients receiving early prophylaxis (rate ratio=1.38, 95% CI 1.11-1.72, p=0.003) CONCLUSIONS: Our study demonstrated that early initiation of CNI and MMF is associated with a reduced incidence of CRS, particularly in its severe form. However, we could not show an association with reduced ICU admissions or TRM with the current sample size in both groups. An increased incidence of severe GvHD was observed, which requires further investigation due to potential collection bias related to the study's retrospective nature. The incidence of infections until day+100 might also be higher with early prophylaxis, although there was no difference in short-term overall survival.

Background: Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplant (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. Objectives: In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplant cyclophosphamide- (PTCy-) based graft-versus-host disease (GVHD) prophylaxis. Study Design: Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (MAC vs RIC/NMA), and CRS grading (1, 2 vs 3-4). Instead of 22 controls, we chose 21 patients because there was only one control matched with one TOCI treatment patient in one stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (HR=3.4 or higher) in transplant outcomes using a two-sided 0.05 test. The power would be reduced to about 20-30% if the difference was moderate (HR=2.0) using the same test. Results: No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range: 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% CI: 0.28-1.06, P=0.08). Median time to platelet engraftment was 34 days (range: 20-81) in TOCI and 28 days (range: 12-94) in NO-TOCI group (HR=0.56; 95% CI: 0.25-1.22, P=0.19). Cumulative incidences of day +100 acute GVHD grades II-IV (P=0.97) and grades III-IV (P=0.47) were similar between the two groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% vs 24%; P=0.05). Rates of NRM (P=0.66), relapse (P=0.83), disease-free survival (P=0.86), and overall survival (P=0.73) were similar at 1-year post-HCT between the two groups. Conclusions: Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore, using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.

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Background Anti-thymocyte globulin (ATG)/Anti-T-lymphocyte globulin (ATLG) aids graft-versus-host disease (GVHD) prophylaxis in human leukocyte antigen-matched related and unrelated donor hematopoietic stem cell transplantation (HSCT). Its use is frequently accompanied by systemic infusion reactions attributable to cytokine release syndrome (CRS). However, detailed data on ATG/ATLG-induced CRS and its correlation with clinical outcome parameters are lacking. Objectives To analyze the incidence, characteristics, risk factors, and early clinical impact of CRS during ATG/ATLG administration before allogeneic HSCT according to the American Society of Transplantation and Cellular Therapy (ASTCT) CRS grading criteria. Study design We conducted a retrospective single-center analysis including consecutive recipients of allogeneic HSCT treated with ATG/ATLG as GVHD prophylaxis at the Medical University of Vienna, Austria, between January 1, 2014, and August 15, 2021. Multivariate regression models were used to explore risk factors of CRS and its association with clinical outcomes (acute GVHD II-IV, clinically significant cytomegalovirus infection, non-relapse mortality, overall survival) 6 months after HSCT. Results A total of 284 patients (median age: 54 [interquartile range: 45-61] years; f:m = 120:164) were included in the study. ATLG was used in 222 (78%) patients, ATG in 62 (22%) patients. 166 (58%) patients developed CRS grade ≥1 during ATG/ATLG administration. CRS was mostly mild, and 92% of the cases experienced CRS grades 1-2. Thirteen (5%) patients developed CRS grade 3, one patient CRS grade 4. No CRS-related death (grade 5) was observed. Patients with CRS showed a pronounced systemic inflammatory response as measured by inflammatory markers (i.e., C-reactive protein, interleukin-6, procalcitonin). In multivariate analysis, lymphoma as the underlying disease, high ATLG dose level of 60 mg/kg, and body weight were significantly associated with CRS. Patients with CRS grade ≥1 had a higher 6-month incidence of acute GVHD II-IV than non-CRS patients (24% vs. 14%, p=0.04). This effect remained statistically significant only for CRS grades 3-4 (subdistribution hazard ratio: 3.70 [95% confidence interval: 1.58-8.68]; p<0.01) after adjusting for relevant confounders. Other clinical outcome parameters were not affected by the occurrence of CRS. Conclusion In our cohort, CRS defined by ASTCT grading was a frequent but mostly mild complication following ATG/ATLG administration for GVHD prophylaxis. Our data suggest a possible interaction of (higher grade) CRS with increased risk for developing acute GVHD. Further studies to corroborate this finding are warranted, as it could inform the investigation of additional prophylactic interventions, such as interleukin-6 blockade, in this setting.

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Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and dismal one year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report the clinical outcomes from our pilot study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100, followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS (graded by Lee criteria). Peripheral blood and serum samples were banked prior to conditioning and on days -1, 1, 3, 7, 14, 28, 60, 100, end of treatment, and time of diagnosis of acute GVHD. Matched control samples were collected from patients undergoing haplo-HCT off clinical trials. Correlative studies include flow cytometry (FACS) with five 28-color panels for cellular subsets, mass cytometry (CyTOF) with 40-colors for intracellular signaling events, single cell RNA sequencing, and serum cytokine and chemokine measurements. Results: Twenty of a planned 20 patients completed enrollment and underwent haplo-HCT between 11/2019 and 3/2021. Median age at transplant was 49 (21-74). Diagnoses were AML (13), ALL (5) and NHL (2). Median follow up is 319 days, with 18/20 beyond 180 days. There were no cases of engraftment failure with short median times to neutrophil (14 days, range 12-20) and platelet (14 days, range 7-54) engraftment (historical 16 and 25 days, respectively). There were no cases of grade III-IV acute GVHD. The incidence of grade II acute GVHD on day 100 was 15%. Two patients developed grade I-II skin acute GVHD during itacitinib taper and responded to resumption of a higher dose. There were no cases of extensive chronic GVHD. There were no cases of severe CRS (historical rate 17%), with 90% of patients having grade 1 CRS and 10% having no CRS. Furthermore, no anti-IL6R or steroid therapy was used. Overall survival at day 180 was 90% (95% CI 75-100%) by Kaplan-Meier estimate. Incidence of relapse at 180 days was 5.5% (95% CI 0-15.6%). Refined GVHD and relapse-free survival at 180 days was 83% (95% CI 68-100%). All patients had full donor engraftment and >95% chimerism at day 100. FACS and CyTOF have been performed and analyzed for the day 28 time point from 14 patients and four controls. Flow cytometry revealed no difference in cell subset numbers between controls and patient samples. CyTOF revealed differences in intracellular signaling molecules between itacitinib and control patients - including higher Ki-67, pNF-κB, and Caspase3 in controls. Phospho-Stat1 and pStat3 were lower CD4 T subsets. FACS and CyTOF at remaining time points, single cell RNA sequencing, and serum cytokine and chemokine measurements are underway and will be presented at the ASH 2021 meeting. Conclusions: Itacitinib with PB haplo-HCT was safe with no engraftment failure and prompt engraftment. Rates of acute and chronic GVHD were low, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. Flow cytometry demonstrated comparable immune reconstitution in terms of cell lineage and number between treated patients and controls. Mass cytometry revealed lower Ki-67, pNF-κB, and caspase3 levels, among other markers, which suggest lower immune cell activity, proliferation, and apoptosis. An extension cohort of 20 additional patients is enrolling. Multi-platform correlative studies are underway, comparing samples from haplo-HCT patients treated with and without itacitinib. Figure 1 Figure 1. Uy: Astellas: Honoraria, Speakers Bureau; Novartis: Consultancy; Agios: Consultancy; Jazz: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; GlaxoSmithKline: Consultancy; Macrogenics: Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Pusic: Syndax: Other: Advisory Board. Schroeder: Equillium Inc: Honoraria; Janssen: Honoraria; Sanofi Genzyme: Honoraria.

Introduction/background: Cytokine release syndrome (CRS) is one of the most common adverse effects of bispecific antibodies (BsAbs) during the step-up dosing (SUD) phase of treatment. The addition of tocilizumab (Toci) at 8 mg/kg to pre-medication regimen (dexamethasone, acetaminophen and diphenhydramine) proved to be an effective mitigation strategy where CRS rates declined significantly from 72-80% to 14-30%. These findings prompted the National Cancer Comprehensive Network (NCCN) to recommend Toci as a pre-medication for CRS prophylaxis in the recent multiple myeloma guidelines. Based on published evidence regarding cytokine storm prevention with 4 mg/kg of Toci among patients with COVID-19 infections, we are reporting our center's experience using low-dose Toci (Toci-lo) for preventing CRS during the BsAbs SUD phase of treatment. Methods: Patients with relapsed/refractory multiple myeloma (RRMM) who were hospitalized for initiating BsAbs and received prophylactic Toci-lo administered prior to the first SUD per institutional guidelines were included (cohort 1). For comparison, a historic cohort of patients that did not receive Toci prophylaxis during the SUD phase was selected (cohort 2) using the institutional plasma cell disorders database after matching for the following: disease characteristics (high risk cytogenetic features, presence of extramedullary disease, elevated LDH), type of BsAbs, prior exposure to T-cell redirection therapies (TCRT) and absolute lymphocyte count. CRS was graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria. The Fisher's exact/Chi-square test was used to compare CRS rates between the two cohorts. Univariate/multivariate logistic regression analysis was performed to estimate the CRS risk with Toci prophylaxis. All statistical analyses were performed using IBM SPSS statistics (version 26). Results: 64 patients were included in the analysis (33 in cohort 1 and 31 in cohort 2); baseline characteristics were comparable between the two cohorts except for the number of prior lines of therapy (cohort 1: 5, range: 2-11 and cohort 2: 7, range: 3-12; p=0.01); 18% (n=6) and 19% (n=6) were exposed to TCRTs (chimeric antigen receptor- T cells, CAR T-cells: 2, BsAbs: 2 and both: 2) in cohorts 1 and 2, respectively; high risk cytogenetics [17p del, TP53, gain/amp 1q, t(4;14), t(14;16) and t(14;20)] were present in 52% (n=17) of the patients in cohort 1 and 29% (n=9) in cohort 2 (p=0.08). Extramedullary disease was found in 36% (n=12) of patients in cohort 1 compared to 23% (n=7) in cohort 2 (p=0.28). Teclistamab was administered to 58% of the patients in both cohorts 1 (n=19) and 2 (n=18). Talquetamab was administered to 32% (n=11) and 29% (n=9) of patients in cohorts 1 and 2, respectively. The remaining patients in both cohorts received elranatamab (cohort 1: 10% and cohort 2: 13%). The CRS rate was significantly lower in cohort 1 (n=7; 21%, 95% CI:10.7-37.8%) compared to cohort 2 (n=17; 55%, 95% CI: 38.0-70.8%; p=0.009). Based on univariate and multivariate analyses (adjusted for prior lines of therapy), prophylactic use of Toci-low was associated with a significant reduction in the incidence of CRS during the SUD phase with an odds ratio of 0.2 (95% CI: 0.06-0.65; p=0.01). All CRS events were treated with Toci 8 mg/kg. Most of the CRS events occurred following SUD1 (57% in cohort 1 and 58% in cohort 2). The rate of grade 2 CRS was 0% in cohort 1 compared to 17% in cohort 2 (n=3; p=0.50). Recurrent CRS events were noted only in a single patient from cohort 1 and 26.0% (n=6) in cohort 2 (p=0.64). The rate of neurotoxicity/immune effector cell-associated neurotoxicity syndrome (ICANS) was 6% in cohort 1 (n=3) and cohort 2 (n=2). One patient in each cohort developed grade 2 neurotoxicity/ICANS which resolved more than 48 hours following management per institutional guidelines. Cost-effectiveness analysis of Toci-lo will be shared at the ASH meeting. Conclusion: Based on our findings, a single prophylactic Toci-lo proved to be an effective approach which can be utilized as an option to reduce CRS incidence during the SUD phase of BsAbs treatment.

Not available.

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

Elranatamab is a BCMA-CD3 bispecific antibody approved for the treatment of relapsed or refractory multiple myeloma. Cytokine release syndrome is one of the most common adverse events associated with bispecific antibodies. We aimed to determine the optimal elranatamab dosing regimen for mitigating cytokine release syndrome. Safety, pharmacokinetics, and exposure–response were analyzed across four clinical studies (MagnetisMM-1, MagnetisMM-2, MagnetisMM-3, and MagnetisMM-9). Different priming regimens evaluated across these studies included a one-step-up dose priming regimen of 44 mg with or without premedication, a two-step-up dose priming regimen of 12 mg on day 1 and 32 mg on day 4 with premedication, and a two-step-up dose priming regimen of 4 mg on day 1 and 20 mg on day 4 with premedication. The maximum elranatamab serum concentration on day 1 was positively associated with any-grade and grade ≥ 2 cytokine release syndrome. A slower time to maximum serum concentration and a lower dose-normalized maximum serum concentration were observed with subcutaneous versus intravenous administration, supporting subcutaneous dosing to help mitigate cytokine release syndrome. Based on the incidence, severity, and predictable profile of cytokine release syndrome, the 12/32-mg priming-dose regimen with premedication was determined to be the optimal regimen before the first full dose of 76 mg on day 8. ClinicalTrials.gov identifiers: NCT03269136, NCT04798586, NCT04649359, and NCT05014412.

ABSTRACT Cytokine release syndrome (CRS) is a potentially life-threatening inflammatory condition that can occur after immune-based therapies, such as bispecific antibodies. We present the case of a 66-year-old woman with relapsed/refractory multiple myeloma who developed fatal CRS following treatment with Teclistamab, a bispecific antibody that targets CD3 on T cells and B-cell maturation antigen on myeloma cells. The patient had previously achieved remission with rituximab, bortezomib, and autologous stem cell transplantation but experienced a relapse after eight years. Teclistamab was initiated with a step-up dosing regimen. Before treatment, she received premedication with intravenous fluids, steroids, and tocilizumab. Despite this premedication, the patient was readmitted with fever, chills, and shortness of breath, leukopenia, and hypoxia. Imaging studies indicated pneumonia. During her hospitalization, her condition deteriorated rapidly, resulting in respiratory failure and refractory shock. She was transferred to the intensive care unit (ICU), where she required mechanical ventilation and multiple pressor support. Despite aggressive resuscitation efforts, she progressed to multi-organ failure, and the family ultimately chose to withdraw care. CRS is characterized by a systemic inflammatory response with rapid and excessive release of cytokines, particularly IL-6, IL-2, IL-10, IFN-γ, and GM-CSF. Severe CRS can clinically resemble sepsis. Management strategies include early recognition, supportive care, and immunomodulatory therapy, particularly with tocilizumab and corticosteroids. This case underscores the diagnostic and therapeutic challenges of differentiating severe CRS from infection. This case uniquely contributes to current understanding by highlighting the limitations of current premedication protocols and emphasizing the critical need for enhanced monitoring and rapid intervention protocols in managing Teclistamab-induced CRS. It highlights the critical need for prompt, targeted intervention to prevent fatal outcomes in patients receiving novel immunotherapies.

T‐cell engagers demonstrate promise in cancer immunotherapy but often cause severe cytokine release syndrome (CRS). Intrapatient dose escalation can mitigate CRS, but reduced cytokine levels may compromise therapeutic efficacy. We previously reported that a single 1000 μg/kg dose of ERY22, an anti‐GPC3/CD3 monkey surrogate T‐cell engager, induces life‐threatening CRS in cynomolgus monkeys, but that daily dose escalation from 1 to 1000 μg/kg almost completely prevented CRS in the monkeys without premedication with immunosuppressants. This study aimed to investigate whether T cells tolerized in vivo through dose escalation maintain antitumor cytotoxicity. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from animals that were administered daily doses ranging from 1 to 1000 μg/kg and then restimulated with ERY22 ex vivo. Cytokine concentrations in supernatants and cytotoxicity against target cells were examined in ex vivo experiments. We used ATAC‐seq to assess chromatin accessibility in T cells responding to daily dose escalation. Under tolerance‐induced conditions, ex vivo cytokine release was almost completely inhibited, whereas approximately half of the cytotoxic activity was retained. T‐cell chromatin states changed after ERY22 administration. Because the relevancy of the ex vivo cytotoxic assay to clinical effects is unknown, the impact of reduced cytotoxicity through dose escalation on actual cancer treatment efficacy remains unclear. Although this and species differences must be considered, our findings provide valuable insights into mechanisms underlying dose escalation–induced tolerance and may be useful for predicting human responses. A deeper understanding of these shared mechanisms is critical for advancing the clinical development of T‐cell engagers.

Introduction ABBV-383 is a differentiated BCMA x CD3 bispecific antibody (fully humanized IgG4) T-cell engager composed of a bivalent BCMA binding domain with high avidity, a low-affinity CD3-binding domain, and a present but silenced-Fc tail retaining the FcRn binding allowing for an extended half-life and thereby, enabling dosing convenience. ABBV-383 monotherapy has shown promising activity and improved CRS safety profile with modified dexamethasone (Dex) premedication in patients (pts) with RRMM (NCT03933735; Rodriguez et al., JCO 2024;42[suppl 16]:7531). Here, ER and CRS PK/PD analyses supporting the selection of optimal SUD for ABBV-383 are reported. Methods ER-efficacy (N=286) and -safety (N=290) analyses were conducted using logistic regression methodology (R version 4.3.2) combining data from escalation (0.025-120 mg Q3W) and expansion (20, 40, 60 mg Q3W and 60 mg Q4W) cohorts of phase 1 study NCT03933735 and Arm A of phase 1b study NCT05650632 evaluating step-up dose (2 or 4 mg on Day 1) with a full dose (60 mg on Day 4) in pts with RRMM. Pts received modified Dex with full dose in expansion cohorts of 60 mg Q4W and 2/60 mg Q4W. In all other cohorts with or without SUD, pts received low Dex. Based on prior knowledge (JCO 2024;42[suppl 16]:7541), the safety endpoints (CRS: any-grade and ≥ G2) were modeled with Cycle 1 total (unbound + bound to soluble BCMA) Cmax, while objective response rate (ORR) was modeled with free (unbound + partially bound to soluble BCMA) Cavg. CRS ER models included a priori selected Dex (low vs. modified) and SUD (yes vs. no) as predictors. Relevant pt-specific covariates were tested in all models. CRS PK/PD analyses included total PK, IL-6, and CRS data (N=199) from the first 3 cycles of the above phase 1/1b studies. A semi-mechanistic indirect response PK/IL-6 model was developed to correlate total PK and IL-6 (NONMEM 7.5). Maximal IL-6 concentrations were derived using post hoc estimates from the PK/IL-6 model and correlated with CRS events (logistic regression; R version 4.3.2). The models included effects of time-dependent Dex (low vs. modified) and SUD (yes vs. no). The overall modeling approach was assessed by comparing observed and predicted CRS rates. Simulations were conducted for various dosing regimens, including one or two SUD and Dex premedication scenarios to support the selection of the optimal SUD. Results Consistent with clinical observations (separate abstract submission), any-grade CRS model predicted probabilities suggested two key outcomes: 1) premedication with modified Dex improves the CRS safety profile compared to the low Dex (42% vs 69% for 60 mg Q4W); 2) modified Dex with SUD further improves the CRS safety profile of ABBV-383 compared to low Dex with SUD (29% vs 43% for 2/60 mg Q4W). Consistent with prior work, no ER relationship was observed for ≥ G2 CRS (p > 0.05). The ORR model resulted in a predicted probability of 68% ORR (closely matching with overall observed 64% ORR) with no impact of SUD and modified Dex. Only soluble BCMA was selected as a covariate in the ORR ER model. The final semi-mechanistic PK/IL-6 model well captured the observed IL-6 data, and the CRS rates (predicted by the logistic regression models) closely matched with the observed data. The CRS PK/PD analyses findings were consistent with the clinical observations and ER analyses key outcomes 1 and 2. The CRS PK/PD analyses predictions comparing the 1-SUD vs 2-SUD (untested) regimens with modified Dex suggested that 1) among the 2-SUD regimens with modified Dex, the 2/3/60 mg regimen would have the maximum reduction of 4% points in any-grade CRS compared to the 2/60 mg 1-SUD regimen, however, with substantial overlap of confidence intervals and with no decrease in ≥ G2 CRS (< 0.5% point); 2) 4 mg as an intermediate SUD in a 2-SUD regimen would lead to higher any-grade and ≥ G2 CRS rates (~9% and 3% points higher, respectively), compared to the 2/60 mg Q4W regimen. Conclusions ER and CRS PK/PD analyses suggested that modified Dex and SUD improve the CRS safety profile of ABBV-383 with no impact on efficacy (ORR) in pts with RRMM. The CRS PK/PD predictions indicated that implementation of 2-SUDs provide minimal additional or no improvement in CRS safety profile compared to 1-SUD. Overall, the 1-SUD dosing regimen of 2 mg with modified premedication prior to the full dose of 60 mg Q4W showed promising results and can be considered for future evaluation and studies.

Background Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has demonstrated promising activity in relapsed or refractory diffuse large B‑cell lymphoma. Cytokine release syndrome (CRS) is a key adverse event associated with T‑cell–engaging therapies; however, it typically occurs early after treatment initiation and is generally manageable with step‑up dosing and premedication. Evidence regarding the safety of delivering radiotherapy during late-phase epcoritamab therapy remains limited. Case presentation A 58-year-old man with diffuse large B-cell lymphoma received epcoritamab. On cycle 8 day 8, local radiotherapy (40 Gy in 20 fractions) was initiated for a residual abdominal lymph node lesion. Approximately 12 h after the second radiotherapy fraction, he developed fever (38 °C) and fatigue without hypotension or hypoxia and without neutropenia, consistent with a CRS-compatible febrile episode (grade 1 by the American Society for Transplantation and Cellular Therapy criteria). Blood cultures were obtained and empiric cefepime with acetaminophen was initiated, resulting in transient defervescence; however, fever recurred approximately 12 h after the third radiotherapy fraction. Blood cultures, (1,3)-β-D-glucan, and galactomannan assays were negative. Given the reproducible temporal association with radiotherapy, a CRS-compatible event was considered, and tocilizumab (8 mg/kg) was administered in line with standard CRS management guidance, with defervescence within 1 h. He remained afebrile thereafter and completed radiotherapy without recurrence. Conclusions CRS-compatible fever is uncommon after multiple cycles of epcoritamab. This case suggests a temporal association between radiotherapy and a CRS-compatible febrile episode during late-phase therapy and supports the possibility that radiotherapy acted as an inflammatory trigger. When radiotherapy is delivered during bispecific antibody therapy, fever should prompt concurrent evaluation for infection while keeping CRS in the differential diagnosis, and standard CRS management should be applied promptly when clinically indicated.

New therapeutic solutions have emerged in the last few decades with the growth and expansion of the field of cancer research. Amongst these new agents, immunotherapy has been prominent, particularly regarding the treatment of hematologic malignancies. One of the most worrisome complications of immunotherapy is cytokine release syndrome (CRS), which represents a supraphysiologic response resulting in excessive release of cytokines and a wide range of systemic manifestations. In this case report, we present a case of cytokine release syndrome following blinatumomab therapy despite premedication with dexamethasone.

No abstract available

CD3 bispecific constructs show promising therapeutic potential as anti-tumor antibodies, but it has concurrently been difficult to manage cytokine release syndrome (CRS) in clinical use. Currently, the most effective measure for reducing CRS is considered a combination of intra-patient/animal dose escalation and corticosteroid premedication. To examine how effectively an intra-animal ascending dose regimen without premedication would mitigate CRS, we compared plasma cytokine levels in two groups of cynomolgus monkeys; one group was given a single dose, and the other a three-fold daily ascending dose of a CD3 bispecific construct that targets and cross-reacts with both glypican 3 and CD3 (ERY22). Ascending doses up to 1000 μg/kg of ERY22 dramatically reduced the peak cytokine levels of IL-6, TNF-α, and IFN-γ, IL-2 as well the clinical severity of CRS compared with a single dose of 1000 μg/kg. Peak cytokine levels following the single and ascending doses were 60,095 pg/mL and 1221 pg/mL for IL-6; 353 pg/mL and 14 pg/mL for TNF-α; 123 pg/mL and 16 pg/mL for IFN-γ; and 2219 pg/mL and 42 pg/mL for IL-2. The tolerance acquired with daily ascending doses up to 1000 μg/kg remained in effect for the following weekly doses of 1000 μg/kg.

No abstract available

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.

Cetuximab (Cmab), an Immunoglobulin G1 monoclonal antibody targeting the epidermal growth factor receptor, is associated with Epidermal Growth Factor Receptor inhibitor-specific adverse drug reactions, such as skin toxicities and infusion-related reactions (IRRs). IRRs have been reported in 6–18% of patients receiving Cmab, with grade 3 and 4 reactions in 1–5% in head and neck cancer patients. Premedication with corticosteroids may prevent or dampen non-Immunoglobulin E (IgE) mediated infusion reactions. We encountered a case in which a grade 3 IRR occurred secondary to Cmab that was combined with 5-fluorouracil and cisplatin (5fluorouracil and Cisplatin +Cmab) chemotherapy for a recurrent and metastatic head and neck cancer patient who had received premedication consisting of chlorpheniramine 5mg, dexamethasone 13.2mg, and aprepitant 125mg. Non-IgE-mediated reaction and cytokine release syndrome can be prevented by premedication. The patient had grade 3 IRRs because of Cmab, even though we used a higher dose of corticosteroid, dexamethasone 13.2mg, and aprepitant. Severe IRRs because of Cmab occurred despite administration of a higher dose of dexamethasone, compared with the ordinary dose that ranges from 3.3 to 6.6mg. Furthermore, his rapid symptom after Cmab intravenous administration confirmed to typical IgE-mediated reaction even though he received high dose of dexamethasone and chlorpheniramine. To prevent a critical situation due to severe Cmab IRRs is early first aid treatment when a patient has hypertensive reactions. Monitoring for symptoms of Cmab-induced IRRs requires not only the supervision of oncologists, nurses, and pharmacists but also patient awareness of the condition.

TPS2685 Background: CLDN6 is an oncofetal protein expressed at high levels in many solid tumors while expressed at very low levels in adult normal tissues. The high target antigen density and slow rate of internalization makes it an attractive target in cancer therapeutics. CTIM-76, a CLDN6 x CD3 T cell engager bispecific antibody is engineered to bind with high selectivity to CLDN6 and redirect the immune system’s T cells to recognize and kill CLDN6-expressing cancer cells. CTIM-76 effectively inhibited tumor growth, inducing complete responses in ovarian cancer xenograft models. The first in human study of CTIM-76 in patients with advanced ovarian, endometrial, and testicular cancers (NCT06515613) is described here. Methods: Part 1 dose escalation exploring 9 ascending dose levels with a 3+3 design. The first two dose levels are single patient cohorts (22.5 µg starting dose), CTIM-76 delivered as weekly iv infusions, with step dosing and steroid premedication to minimize cytokine release syndrome. Approximately 40 patients with platinum resistant ovarian cancer, or endometrial or testicular cancers relapsed after standard of care will be enrolled. Tumors from patients with ovarian or endometrial cancer require prospective CLDN6 + confirmation by IHC (10% ≥ 1+), testicular cancer patients will not require prospective screening due to the known uniformly high prevalence of CLDN6. The primary objective is to evaluate safety and tolerability (incidence and severity of adverse events per NCI CTCAE v5.0) and establish the recommended dose for expansion. Secondary objectives include assessment of antitumor activity (RECIST v1.1, iRECIST), pharmacokinetics, and pharmacodynamic correlates of immune activation. Part 2 will evaluate two doses in approximately 30 patients with one tumor type, with efficacy and further safety as primary objectives. This multicenter study has currently five sites open for enrollment. The first patient was dosed in January 2025. Clinical trial information: NCT06515613 .

Abstract Purpose: PF-07062119 is an anti-GUCY2C/anti-CD3ε bispecific Fc antibody designed to elicit systemic antitumor immunity. This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity of PF-07062119 as monotherapy and in combination with sasanlimab or bevacizumab in patients with advanced gastrointestinal (GI) cancers expressing GUCY2C. Patients and Methods: Patients received escalating doses of PF-07062119 (45–3,700 μg SC) in part 1A. In part 1B, PF-07062119 was administered with either sasanlimab (300 mg SC) or bevacizumab (5 mg/kg i.v.). Primary endpoints were safety and tolerability; secondary endpoints included PK, immunogenicity, and efficacy. Results: A total of 79 patients were enrolled. In part 1A, maximum tolerated dose without a priming dose was 800 μg. Dose-limiting toxicities observed at this level were grade 3 cytokine release syndrome (CRS), colitis, and diarrhea. A 400 μg priming dose with premedication reduced CRS incidence, and recommended dose for expansion was 2,100 μg. Treatment-related grade 3/4 treatment-emergent adverse events (TEAE) were observed in 27 (34.2%) patients, with no grade 5 treatment-related TEAEs. Diarrhea remained the most clinically significant toxicity in part 1A. Combination therapy in part 1B did not result in significant additional toxicity. PK analyses demonstrated dose-proportional increases in exposure. The overall response rate was 2.5% across all cohorts. Conclusions: PF-07062119 monotherapy demonstrated a generally tolerable safety profile within the context of this early-phase study with evidence of clinical activity in patients with advanced/metastatic GI cancers. Significance: GUCY2C is universally expressed in colorectal cancer and ectopically expressed by other GI cancers. In this first-in-human phase I study, PF-07062119, an anti-GUCY2C/anti-CD3ε bispecific Fc antibody, demonstrated a generally tolerable safety profile with evidence of antitumor activity in patients with advanced GI cancers.

Abstract Introduction Uveal melanoma (UM) is a rare malignancy with poor outcomes in the metastatic setting and limited benefit from conventional systemic therapies. Tebentafusp, a novel bispecific fusion protein targeting glycoprotein 100 (gp100) in human leukocyte antigen A (HLA-A)*02:01–positive patients, has recently demonstrated a survival advantage, being approved in Brazil in 2025. However, its distinct toxicity profile, particularly cytokine-release syndrome, rash, and liver enzyme elevations, remain unfamiliar to many clinicians. Reporting early real-world experiences can provide valuable practical guidance for managing these adverse events in routine practice. Case Reports In this case series, we describe four adult HLA-A*02:01–positive patients with metastatic UM treated with tebentafusp at a single Brazilian center. All participants initiated therapy in an inpatient setting following standardized institutional routines designed for safe administration, including structured premedication, continuous monitoring, and predefined response algorithms for early infusion reactions. Across cases, predictable early reactions were successfully managed using protocol-based interventions—such as antihistamines, low-dose corticosteroids, intravenous fluids, and targeted supportive care—allowing uninterrupted dose escalation and subsequent transition to outpatient treatment. These cases illustrate the practical steps, decision pathways, and monitoring strategies that enable safe implementation of tebentafusp in real-world practice. Conclusion This case series highlights the characteristic toxicities associated with tebentafusp and emphasizes the importance of early recognition and proactive management strategies to ensure treatment continuation. Our experience provides pragmatic insights that may support oncologists in Brazil as they begin to integrate tebentafusp into the care of patients with metastatic UM.

171 Background: DOCE is a standard of care for pts with mCPRC after androgen receptor pathway inhibitor (ARPI) failure, but more effective regimens are needed. PAS is a first-in-class, bispecific T-cell engaging antibody that binds to the CD3 receptor complex on T cells and to human kallikrein 2 (KLK2), which is highly and specifically expressed in prostate tissue and PC cells. PAS was well tolerated (Grade 1 cytokine release syndrome [CRS] <10%) with Q6W outpatient dosing and promising single-agent activity in a first-in-human phase 1 study in heavily pretreated mCRPC (Stein, J Clin Oncol 2025;43:2515-26). Methods: The primary objective of this open-label, Phase 1b study in mCRPC (NCT05818683) was to determine the recommended phase 2 regimen of PAS + DOCE based on safety. PAS was administered at RP2R (300 mg IV Q6W, with step-up doses of 3.5 mg on day 1 and 18 mg on day 8) in combination with DOCE (fixed dose 75 mg/m 2 IV Q3W starting on day 15) in an outpatient setting. Corticosteroids were not administered except as premedication for DOCE. Hematopoietic growth factor support was allowed. Results: As of 28 August 2025, 51 pts (median [range] age 70y [55–84], visceral metastases 33.0%) had received ≥1 dose of PAS + DOCE (median duration to date: combo, 3.5 months, PAS, 4.9 months); 31/51 pts remain on therapy (20 on combo, 11 on PAS only). Pts were heavily pretreated with a median of 3 (range 1–9) prior therapies, including ARPI (100%), DOCE (43.1%), cabazitaxel (21.6%), Lutetium-177 vipivotide tetraxetan (19.6%). PAS and DOCE were readily combinable at their full monotherapy doses with no observed dose-limiting toxicities. Treatment-related adverse events (TRAEs) were consistent with DOCE in mCRPC (Table); frequent (>20%) TRAEs included fatigue (58.8%), alopecia (41.2%), diarrhea and nausea (31.4% each), peripheral edema (25.5%), dysgeusia (21.6%). 58.8% of pts had PAS-related TRAEs. PAS TRAEs (>10%) included fatigue (29.4%) and diarrhea (11.8%). No pts had CRS of any grade. Grade ≥3 TRAEs occurred in 27.5% of pts, related serious AE in 13.7%, and TRAE leading to treatment discontinuation in 13.7% (PAS-related, n=1 each). There were no fatal TRAEs. Confirmed PSA50 was 64.7% (75.0% in taxane-naïve). Confirmed PSA90 was 35.3% (46.4% in taxane-naïve). Conclusions: PAS was readily combinable with DOCE, demonstrating a safety profile consistent with DOCE alone, no CRS, and promising anti-tumor activity in heavily pretreated patients post-ARPI/taxanes. A confirmatory phase 3 trial is planned. Clinical trial information: NCT05818683 . SAFETY Overall (N=51) PAS-related DOCE-related ≥1 TRAE, n (%) 50 (98.0) 30 (58.8) 49 (96.1) Grade ≥3 TRAE, n (%) 14 (27.5) 1 (2.0) 14 (27.5) TEAE leading to discontinuation, n (%) 7 (13.7) 1 (2.0) 7 (13.7) CRS, n (%) 0 0 0 EFFICACY Overall (N=51) Taxane-naïve pts (n=28) Confirmed PSA50, n (%) 33 (64.7) 21 (75.0) Confirmed PSA90, n (%) 18 (35.3) 13 (46.4)

Background & Aim The most common side effect of CD19-directed CAR-T cell therapy is CRS. IL-6 blockade by toci typically results in rapid resolution of severe CRS in CTL019 treated pts; however, the ideal timing of toci remains unclear. Pts with high tumor burden (TB; defined as ≥40% marrow blasts) are at high risk for severe CRS. We hypothesized that preemptive toci administration early in the course of CRS in pts with high TB might decrease acute CRS severity without compromising efficacy. Methods, Results & Conclusion MTD We conducted a two-cohort, open-label study of the timing of toci on CTL019-associated CRS. Pts were 1-24 yo with CD19-expressing relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). CTL019 was manufactured at the UPenn Cell and Vaccine Production Facility. Enrolled pts were assigned to high (≥ 40%) or low ( 38.5 C measured twice in 24 hours (“early toci”) and subsequently treated per standard CRS algorithm. Primary endpoint: frequency of gr4 CRS (Penn scale) in ≤5/15 pts. Secondary endpoints: D28 tumor response, remission duration, additional toxicities. RES 78 pts were screened, all were enrolled. 65 pts were evaluable for analysis at data cutoff. 15 pts were assigned to HTBC, 50 pts to LTBC and all were infused with CTL019 (median dose 5.0 × 106 [range 5.6 × 105-3.9 × 107] CAR+ T cells/kg). The overall rate of gr4 CRS was 9% (27% in the HTBC, 4% in the LTBC, Table 1). The overall rate of gr1-4 CRS was 72% (100% in the HTBC, 64% in the LTBC). One pt in the HTBC died from CNS hemorrhage after gr4 CRS. All patients in the HTBC received the early toci intervention. The overall rate of gr3 and 4 CRS was lower than in two prior studies of CTL019 therapy in pediatric r/r B-ALL (18% vs 42% in CHP959 and 48% in ELIANA). The ORR at day 28 follow-up was 97% (87% HTBC, 100% LTBC, with 71% CR and 26% CRi, Table 2). CONC We defined clincially meaningful reduction in severe CRS if ≤5/15 subjects had gr4 CRS in the HTBC; this a priori defined primary end-point was met. Early administration of toci targeted to pts with high TB may reduce the incidence of severe CRS while maintaining excellent efficacy of CTL019 therapy. TB remains a major predictor of toxicity. Longer follow-up is ongoing to assess impact on duration of remission.

Introduction Anti-CD19 CAR T cells have emerged as a powerful immunotherapeutic tool for treating B-cell malignancies. Tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel) provided high durable response rates in pivotal trials and are approved by the FDA for treating relapsed/refractory B-cell malignancies. Despite impressive antitumor activity, CAR T therapy has unique toxicities. This includes CRS, a potentially life-threatening systemic inflammatory response affecting >50% of patients (pts) receiving tisa-cel or axi-cel with a range of clinical presentations and needs for intervention. Tocilizumab (TCZ; anti–IL-6R antibody) is approved for the treatment of severe or life-threatening CAR T–induced CRS. Although TCZ ± corticosteroids (CS) is effective in treating CRS, inpatient care is often required for close observation and CRS management adds significant costs to care. Additionally, TCZ- and CS-refractory CRS remains a challenge with poor outcomes. Therefore, preventing CRS vs treating established CRS may improve CAR T safety and expand access to pts who may not be otherwise eligible. Because several cytokines are involved in CRS pathogenesis, drugs blocking multiple inflammatory pathways may improve efficacy over IL-6 blockade alone. Furthermore, immune effector cell–associated neurotoxicity syndrome (ICANS), another common and potentially fatal side effect of CAR T therapy, does not respond to (and may be exacerbated by) TCZ. ITA is a potent and highly selective inhibitor of Janus kinase (JAK)-1, which mediates signaling of several inflammatory cytokines. In preclinical studies of CRS models, JAK1 inhibition with ITA significantly reduced serum levels of cytokines implicated in CRS, including IL-6, IL-12, and IFN-γ, without affecting antitumor activity of human CD19 CAR T cells in vivo, suggesting potential utility in the management of CRS. Objective To describe the study design of an ongoing trial investigating the safety and efficacy of ITA for the prevention of CRS in pts receiving CD19 CAR T cells. Methods Pts 12 years or older receiving axi-cel or tisa-cel for an approved hematologic malignant indication will be eligible for enrollment in this phase 2, single arm, open-label study. Approximately 62 pts will be treated (≥20 each to axi-cel and tisa-cel). Pts will receive an oral 200-mg dose of ITA once daily for ∼30 days (Day −3 to Day 26; CAR T infusion at Day 0; Figure 1). The primary endpoint is grade ≥2 CRS rate by Day 14; secondary endpoints include incidence and duration of any grade ICANS by Day 28, duration of all grades of CRS by Day 28, rates of any grade CRS 48 hours post–CAR T infusion and grade ≥2 CRS by Day 28, and safety of ITA. Objective response rate and measurable residual disease will also be evaluated. This study will examine safety and efficacy of ITA for prevention of CD19 CAR T–induced CRS while monitoring for effects on tumor response.

Nowadays, chimeric antigen receptor (CAR) -T cell therapy has shown significant efficacy in treating hematological tumors, with an obvious increase in patient survival rates. However, with the widespread application of CAR-T, the incidence of CAR-T related adverse events has gradually increased, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and hemophagocytic lymphohistiocytosis (HLH). These complications may be life-threatening, so early diagnosis and intervention treatment are crucial for the prognosis of patients. In this review, we first comprehensively summarize the latest insights into the pathogenesis and clinical manifestations of CRS, ICANS, and HLH after CAR-T, with a focus on elaborating on the specific mechanisms and related pathways of the inflammatory storm caused by a large number of cytokines after CAR-T. We also discussed the established prevention and management strategies for the three complications mentioned above, and demonstrated the effectiveness of the treatment by introducing the therapeutic effects of various treatment methods in current clinical or preclinical trials. In addition, we provide a prospective perspective on the measures and modifications currently being studied to mitigate the toxicity associated with CAR-T cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Background: CAR-T cell therapy is cutting-edge immunotherapy for hematologic malignancies, and the pharmacist has a crucial role to play in its safe delivery. Aim: Through this review, the pharmacist's role in CAR-T therapy, ranging from protocol development to toxicity management, is evaluated with consideration of real-world evidence and the future direction. Methods: A Systematic literature review was conducted on PubMed, Embase, and Web of Science using searches for studies between 2017–2025. Relevance to pharmacist roles in CAR-T therapy informed study selection, synthesizing data on protocol management, product handling, and toxicity mitigation. Results: Pharmacists enable regulatory compliance, manage product logistics, and guide toxicity interventions, reducing adverse events by up to 40% in some settings. Case studies illustrate outpatient care (85% ambulatory care) and tocilizumab early start (90% severe CRS prevention). Complications are supply chain interruption and limited specialist roles (20% of centers). Conclusion: Pharmacists are the key to the success of CAR-T therapy, improving safety and outcomes. Dedicated positions and standardized training would be necessary to cope with emerging challenges, especially in outpatient and solid tumor settings.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

Chimeric Antigen Receptor T cells (CAR-T) are an outbreaking treatment option for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common specific toxicities, while severe neutropenia and infections are often observed as well. From March 2020, early G-CSF prophylaxis at day (D) two post-infusion was systematically proposed. We then compared patients treated before that date who did not receive G-CSF or who received late (after D5) G-CSF as control group. Patients administered with early G-CSF had similar duration of grade 4 neutropenia but significantly decreased incidence of febrile neutropenia (58% versus 81%, p = 0.018). Similar rate of toxicities was observed, including overall and grade 3-4 CRS (p = 0.93 and p = 0.28, respectively), and overall and grade 3-4 ICANS (p = 0.62 and p = 0.88, respectively). We observed no difference in the quality of CAR T-cells expansion (p = 0.79, %Cmax), nor in response rate (best ORR, 57.6% vs 61.8%, p = 0.93), nor survival even in a group of patients adjusted by a propensity score. In conclusion, early G-CSF administration was safe and effective in reducing febrile neutropenia without impact on toxicities nor on anti-lymphoma activity of CAR-T.

No abstract available

Introduction: Chimeric antigen receptor (CAR)-T cell therapy is limited in most cases to inpatient use due to risk of severe treatment-related toxicities. The two primary toxicities observed with CAR-T therapy, cytokine release syndrome (CRS) and neurotoxicity, are associated with increased circulating inflammatory cytokines such as IL-6 and IL-1. Targeting IL-6 with tocilizumab is effective for treating CRS but not neurotoxicity. Anakinra is an FDA-approved recombinant IL-1 receptor antagonist that competitively inhibits IL-1 receptor signaling and therefore blocks downstream production of inflammatory cytokines including IL-6. Leveraging support from Kite Pharma, we opened an investigator-initiated clinical trial (NCT04150913) with the hypothesis that anakinra could be administered prophylactically to prevent severe CRS and neurologic events (NE) in patients receiving axicabtagene ciloleucel (axi-cel). Here we report preliminary outcomes of this study. Study Design and Methods: This is a phase II single center, open-label study for patients ≥18 years old with relapsed or refractory large cell lymphoma. Patients must have progressed after ≥2 lines of systemic therapy but could not have CNS disease or have been previously treated with CAR-T therapy. Following leukapheresis and manufacturing, patients received 3 days of lymphodepleting chemotherapy (LDC, cyclophosphamide 500mg/m 2 and fludarabine 30 mg/m 2) and 200 mg of subcutaneously administered anakinra starting 4 hours prior to axi-cel infusion and daily thereafter for a total of 7 days. CRS and NE were graded based on the Lee 2013 criteria and the CTCAE 4.03 criteria, respectively, to enable direct comparison to the pivotal Zuma-1 cohorts. The primary endpoint is the rate and severity of NE within the first 30 days of infusion; secondary endpoints include the incidence and severity of CRS and disease response. CAR-T cell expansion, serum cytokines, and circulating biomarkers of toxicity were measured at baseline, day 3, 7, 14, 21, and 28 post CAR-T cell infusion. Results: Interim analysis of the first 6 patients demonstrated a median age of 68 (range 59-72). Patients included a diverse group of histologies including double-hit lymphoma (n=2), transformed indolent NHL (n=3), and DLBCL NOS (n=1). Two patients were considered primary refractory at time of enrollment. Pre-LDC baseline characteristics included a median SPD of 2819 mm 2 (range 1063-5802), median LDH of 415 (range 147-497) which were comparable to the pivotal ZUMA-1 cohorts. Baseline ferritin, CRP, SAA and IL-15 were similar to the pivotal ZUMA-1 cohorts. While low-grade CRS was observed in 5/6 patients, no patients experienced severe CRS and median onset occurred on day +8 (range 1-8). Four patients did not experience any NE, while two patients experienced grade 3 NE on days +6 till +9 (somnolence) and +12 (global aphasia only, for one day) respectively. With a median follow-up of 4 months, the day +28 overall response rate was 100% (4 CRs, 2 PRs), with 4/6 patients having an ongoing complete response at last disease assessment. One patient was re-infused at progression and remains in a CR 3 months from re-infusion. Responses were seen despite varying CAR-T peak level with most patients demonstrating expansion in the lower quartile of the historic ZUMA-1 cohort. Median post-infusion peak of CRP, ferritin, IL-2, GM-CSF, IFNγ, IL-10, IL-6 and SAA were lower than that observed in the pivotal ZUMA-1 cohorts. All patients remain alive at time of data analysis. Conclusions: With a limited number of patients analyzed thus far, anakinra appears to provide benefit to the toxicity profile of axi-cel, presenting reduced and/or delayed CRS and NE and a decrease in post-infusion inflammatory analytes, when compared to ZUMA-1 pivotal cohorts. No severe CRS was observed in this initial analysis and 2/6 patients experienced grade 3 NE (somnolence and global aphasia) after day 6. Despite CAR-T expansion in the lower quartile of that of ZUMA-1, we observed a 100% ORR with 4 patients remaining in CR at a median follow-up of 4 months. Additional subjects will be assessed to investigate the role of prophylactic anakinra in the management of CRS and NE, which has potential for making axi-cel treatment an outpatient therapy. Frigault: BMS: Consultancy; Editas: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Takeda: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Wehrli: CSL Behring: Patents & Royalties; Nestle: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Chou: Kite Pharma: Current Employment. Shen: Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Filosto: Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership ; Tusk Therapeutics: Patents & Royalties: or other intellecular property. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Maus: Agenus: Consultancy; Arcellx: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Atara: Consultancy; Bayer: Consultancy; BMS: Consultancy; Cabaletta Bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; In8bio (SAB): Consultancy; Intellia: Consultancy; GSK: Consultancy; Kite Pharma: Consultancy, Research Funding; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Novartis: Consultancy; Tmunity: Consultancy; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company.

No abstract available

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of malignancies, especially hematological tumors, but toxicities have tempered its success. The main impediments to the development of CAR-T cell therapies are the following: cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), tumor lysis syndrome (TLS), and on-target/off-tumor toxicity (OTOT). This review summarizes these side effects’ underlying mechanisms and manifestations over time. It provides potential prevention and treatment according to the consensus grading, stressing the significance of establishing strategies that anticipate, reduce, and navigate the beginning of these side effects. It is essential to fully comprehend the mechanisms underlying these toxicities to create efficient treatment and preventive approaches.

CAR‐T cell therapy is efficient in relapsed/refractory B‐cell lymphoma; yet, cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) remain major and potentially life‐threatening complications, which makes their prediction and prevention crucial. This international, retrospective study analyzed the predictive value of coagulation parameter dynamics for ICANS and CRS development in 265 B‐cell lymphoma patients at two tertiary‐care centers. Platelet counts, fibrinogen, PT, PTT, international normalized ratio, and D‐dimer, were recorded daily from pre‐lymphodepletion through 2 weeks post‐infusion. ICANS occurred in 34% of patients, with high‐grade events documented in 13%. Patients with ICANS had significantly lower median platelet (67 vs. 123 × 103/μL) and fibrinogen (263 vs. 379 mg/dL) levels than those without ICANS. During high‐grade ICANS days, fibrinogen and platelet levels were significantly reduced (p = 0.003 and p = 1.6 × 10−14, respectively). In > 75% of high‐grade ICANS cases, 1 day before its onset, platelet counts were < 100 × 109/L (median decrease: 11.6% versus 1.6% on other days; p = 0.001). Conversely, on the day preceding ICANS onset, higher fibrinogen concentrations were observed, with median values of 448 mg/dL in the ICANS group versus 376 mg/dL in the non‐ICANS group (p = 0.03). These findings suggest that platelet and fibrinogen dynamics could be early indicators of ICANS development in lymphoma patients.

Background: Whilst highly effective, CD19 CAR T cells have significant toxicities in the form of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is related to T cell expansion and is characterised by elevated concentrations of cytokines such as IL-6, TNFa, IFNg and others. IL-1 has been associated with neurotoxicity and anakinra an IL-1 receptor antagonist (IL-1 RA) reduces CRS mortality in mice. There is a lack of appropriate animal models to study the treatment and prevention of CRS, and most reported use immunodeficient xenografts. CLL is associated with a tumor supportive microenvironment and T cells exhibit multiple functional defects and features of exhaustion which contribute to reduced CAR T cell efficacy. These defects are closely recapitulated in Em-TCL1 (TCL1) mice, and induced in healthy mice by adoptive transfer (AT) of murine CLL splenocytes. We aimed to demonstrate the effect of pre-treatment of leukemic mice with the BTK inhibitors (BTKi) ibrutinib and acalabrutinib on CAR T cell function in CLL. Methods: Immunocompetent C57BL/6 mice (WT) received AT of pooled TCL1 cells from fully leukemic TCL1 mice from the same background. Selected groups were treated with either acalabrutinib or ibrutinib continuously via drinking water dissolved in vehicle for 3 weeks. Syngeneic donor CAR T cells were derived from pooled spleens from WT mice or WT mice with CLL by AT, treated with acalabrutinib (acalaCAR) or ibrutinib (ibrCAR) or left untreated (CLL CAR). Splenocytes were enriched for CD3+ with magnetic beads then activated with CD3/CD28 Dynabeads (Thermofisher) and r-IL2 (Roche). They were transduced with retroviral supernatant from MSGV-1D3-28Z-1.3mut (CD19-CD28) and cultured and expanded for 4 days before injection. All mice were given 100mg/kg IP cyclophosphamide on D-1 and on D0 1-2x106 CAR+ T cells pooled by pre-treatment group or untransduced T cells intravenously. Mice were bled every week starting D+7 from CAR T cells to assess CLL load, CAR/T cell subsets and groups were culled when they got sick or when peripheral blood (PB) CLL>70%. Previous experiments have demonstrated peak CAR expansion in this model at D+7, so at this time point plasma was prepared and stored at -80°C and cytokines were measured using electrochemiluminescent sandwich immunoassay (Mesoscale) and ELISA kit for mouse IL-1Ra (Thermofisher). Results: Mice with CLL treated with BTKi have significantly reduced spleen size and cell counts although the spleen remains highly infiltrated with CD5+CD19+ B cells. When these spleens are harvested and used to make syngeneic CAR T cells they lead to a more favorable phenotype with increased naïve and memory T cells and improved ex-vivo expansion compared to using spleens from mice with untreated CLL. At D+7 all mice which had received WT derived CAR T cells, but not in any other group appeared acutely distressed (hunched, limited mobility, poor motor response, hyperventilating) suggestive of CRS and most were pre-emptively culled due to our pre-defined end points. Two surviving mice rapidly returned to a highly active state with no clinical abnormalities within 12 hours. All WT CAR treated mice had high proportions of CD3+CAR+ cells (8-42%) with no normal B cells in the PB and the culled mice had normal sized spleens that were free from CLL and normal B cells, as was the bone marrow. Cytokine analysis reveals significantly higher concentrations of IL-6, TNFa, IFNg, MCP-1 and IL-1 RA in WT CAR treated mice in the PB, but not of IL-1b, IL-2, IL-10, IL-15, GM-CSF and MIP-1. All other mice responded to CAR T cells without becoming sick and mice receiving untransduced T cells needed to be culled by week 8 due to progressive disease. Now at week 20, a long-term survival analysis is ongoing and will be updated. Conclusions: In this model, T cell dysfunction induced by CLL is reflected in defects in CAR T function compared to T cells from WT healthy mice. Pre-treatment of mice with acalabrutinib and ibrutinib repairs T cell function, improves ex vivo expansion and T cell subsets of CAR T cells derived from mice with CLL, but notably did not lead to increased production of cytokines associated with CRS or ICANS. We therefore report here a clinically relevant model of CRS in CLL of immunocompetent mice in which novel treatment approaches can be investigated and its impact on the host immune response examined. Sanderson: Kite/Gilead: Honoraria. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

BACKGROUND AIMS With the increasing application of chimeric antigen receptor (CAR)-T cell therapy in various malignancies, an extra toxicity profile has been revealed, including a severe complication resembling hemophagocytic lymphohistiocytosis (HLH), which is usually disguised by severe cytokine release syndrome (CRS). METHODS In a clinical trial in whom 99 patients received B-cell maturation antigen CAR-T cells, we identified 20 (20.20%) cases of CAR-T cell-associated HLH (carHLH), most of whom possessed a background of severe CRS (grade ≥3). The overlapping features of carHLH and severe CRS attracted us to further explore the differences between them. RESULTS We showed that carHLH can be distinguished by extreme elevation of interferon-γ, granzyme B, interleukin-1RA and interleukin-10, which can be informative in developing prevention and management strategies of this toxicity. Moreover, we developed a predictive model of carHLH with a mean area under the curve of 0.81 ± 0.07, incorporating serum lactate dehydrogenase at day 6 post-CRS and serum fibrinogen at day 3 post-CRS. CONCLUSIONS The incidence of carHLH in CAR-T recipients might be relatively higher than we previously thought. relatively higher than we previously. A cytokine network distinguished from CRS is responsible for carHLH. And corresponding cytokine-directed therapies, especially targeting IL-10, are worth trying.

BACKGROUND CD19 chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of patients with relapsed/refractory B-cell malignancies. Yet it remains limited by potentially life-threatening toxicities such as CRS and ICANS. The risk of CRS and ICANS restricts the use of CD19 CAR T-cell therapy to large academic centers and leads to high healthcare resource utilization. Current toxicity prevention strategies have shown limited efficacy to date (prophylactic steroids with axi-cel: CRS, 80%; ICANS, 60%; Oluwole, BJH, 2021; early intervention with brexu-cel: CRS, 89%; ICANS, 60%; Shah, The Lancet, 2021). Our group has shown that endothelial activation and dysfunction are associated with the development of CRS and ICANS, suggesting a key role of increased vascular permeability and blood-brain barrier damage in their pathogenesis (Hay, Blood, 2017). Type-I interferons (IFN-alpha and beta) are major regulators of CD73 expression by endothelial cells, an enzyme critical to the maintenance of endothelial integrity. CD73 breaks down extracellular pro-inflammatory ATP into anti-inflammatory adenosine. In addition, extracellular ATP has been shown to be a major and early driver of systemic inflammation upstream from IL-6 production (Cauwels, Cell Death Dis, 2014), which is associated with severe CRS and ICANS. Preclinical models have demonstrated that IFN-beta-1a treatment is associated with reduced capillary and blood-brain barrier permeability via upregulation of CD73 expression (Floris, J Neuroimmunol, 2002; Kraus., Ann Neurol, 2004; Niemela, Eur J Immunol, 2008). In humans, two recombinant IFN-beta-1a therapies are FDA-approved for the treatment of multiple sclerosis. IFN-beta-1a given intravenously (IV) maximizes the drug's bioavailability and its protective effects on the endothelium. In a study of patients with ARDS, IV IFN-beta-1a (FP-1201 and FP-1201-lyo) was safe and induced CD73 expression (Bellingan, Lancet Respir Med 2014). Given the known effects of IFN-beta-1a on preserving endothelial function and blood-brain barrier integrity, we hypothesize that IV IFN-beta-1a (FP-1201) may prevent CRS and ICANS following CD19 CAR T-cell therapy ( Figure 1A). Since higher rates of severe CRS and ICANS have been reported after axi-cel and brexu-cel, which contain CD28-costimulatory domains, we will restrict the inclusion criteria to patients treated with these products to analyze a population with a higher unmet need and a more homogeneous risk of CRS/ICANS. STUDY DESIGN AND METHODS Objectives and endpoints: Primary objective: To evaluate the safety and feasibility of FP-1201 in patients undergoing treatment with axi-cel or brexu-cel with two co-primary endpoints: i) to estimate the incidence of dose-limiting toxicity rates within the first 14 days following the last administration of FP-1201; ii) to study the type, frequency, and severity of adverse events according to the NCI CTCAE v5.0 from the first administration of FP-1201 and until day +28 after CAR T-cell infusion Secondary objectives: i) To decrease the incidence and severity of ICANS; ii) to decrease the incidence and severity of CRS; iii) to decrease corticosteroid usage; iv) to evaluate the effect of FP-1201 on anti-tumor efficacy Exploratory objectives: To characterize the in vivo effects of FP-1201 on endothelial function, the systemic cytokine milieu, and CAR T-cell function Key inclusion criteria: Adults ≥18 years of age with Karnofsky performance status ≥60% and B-cell non-Hodgkin lymphoma eligible for treatment with axi-cel or brexu-cel Key exclusion criteria: Known hypersensitivity to IFN-beta or major organ dysfunction FP-1201 administration: The FDA-approved IFN-beta-1a Rebif® will be formulated for IV administration (FP-1201). Participants will receive FP-1201 at one of four dose levels detailed in Figure 1B. Statistical design and sample size: We will use a Bayesian Optimal Interval Design to guide the FP-1201 dose escalation. We will plan to treat up to 24 participants. SUMMARY This is a phase I/II study of IV IFN-beta-1a in preventing CRS and ICANS following axi-cel and brexu-cel. The aim is to demonstrate safety and efficacy and to investigate the biologic mechanisms of IFN-beta-1a in preventing endothelial dysfunction.Additional preclinical and preliminary clinical data will be presented at the meeting. This study is registered on clinicaltrials.gov as NCT05936229.

Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects.

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new form of immunotherapy for the treatment of hematologic malignancies. The two primary toxicities associated with CAR T-cell therapy include cytokine release syndrome (CRS) and neurotoxicity (NT). CRS is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids. While CAR-T cell therapy-associated NT is a well-described clinical phenomenon, its pathophysiology remains inadequately understood; treatments and preventive strategies remain elusive. Animal models and clinical trial experience suggest the centrality of monocytes, endothelial dysfunction, and the blood brain barrier in the development of CAR T-cell associated NT. Here we report what is known from pre-clinical models, clinical trials, and histopathologic studies regarding the pathophysiology of NT, predictors of its incidence, and potential targets for the treatment and prevention of NT.

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed B-cell lymphomas treatment. Its use is complicated by cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) resulting in heightened healthcare resource utilization through increased patient morbidity, hospitalization, and intensive care unit (ICU) transfers. The prevention of CRS and ICANS is the goal to facilitate improved patient safety and efficient resource allocation following CAR-T. In April 2024, our institution adopted a quality improvement (QI) initiative utilizing primary prophylactic anakinra 100 mg administered intravenously (IV) daily for 7 days starting on the day of infusion to mitigate CRS and ICANS. Through emerging evidence, we hypothesized prophylactic anakinra may reduce CRS and ICANS without compromising CAR-T efficacy. However, this practice of prophylactic anakinra remains off-label and its impact on our patient population remains unknown. Methods: This observational, single-center retrospective cohort QI analysis evaluated consecutive B-cell lymphoma patients treated with axicabtagene ciloleucel (axi-cel) or brexucabtagene autoleucel (brexu-cel) anti-CD19 CAR-T therapy the year before (March 1, 2023 to March 31, 2024) and the year after (April 1, 2024 to April 30, 2025) the implementation of anakinra prophylaxis. Outcome measures included incidence and severity of CRS and ICANS, ICU admissions, medications for CRS and ICANS, infection rates, hematologic toxicities, and supportive care resource utilization. The objective is to evaluate the clinical and resource impact of our prophylactic anakinra QI strategy. Results: A total of 20 patients without anakinra prophylaxis (median age 62 years; axi-cel, n=16; brexu-cel, n=4; large B-cell lymphoma (LBCL), 80%) and 25 patients with anakinra prophylaxis (median age 62 years; axi-cel, n=23; brexu-cel, n=2; LBCL, 72%) were analyzed. Severe (grade ≥3) CRS was absent in both groups; severe (grade ≥3) ICANS occurred in 20% without prophylaxis and 0% with prophylaxis. All-grade ICANS was reduced from 65% to 40% with prophylaxis. ICU admission occurred in 15% (n=3), exclusively in the non-prophylaxis group for severe ICANS. Treatment anakinra (i.e., 100 mg IV every 6 hours) was required in 60% patients without prophylaxis (median 31 [interquartile range (IQR) 20-39] doses) and 88% patients with prophylaxis (median 25 [IQR 20-36] doses). Tocilizumab use was decreased from 65% to 32% with anakinra prophylaxis, both groups requiring a median of 1 dose. Dexamethasone use was decreased from 100% in non-prophylaxis to 88% in prophylaxis group, with a median total cumulative dose of 115 (IQR 68-265) and 95 (IQR 45-173) mg, respectively. Infection rates were lower with prophylaxis from 70% to 40%. Day 30 incidences of anemia (grade ≥2) were 50% and 25%; neutropenia (grade ≥3) were 25% and 8%; and thrombocytopenia (grade ≥2) were 65% and 40% in non-prophylaxis and prophylaxis groups, respectively. At day 30, ongoing blood transfusions were required in 20% (n=4) and 8% (n=2); and ongoing granulocyte-colony stimulating factor use were required in 65% (n=13) and 36% (n=8) in non-prophylaxis and prophylaxis groups, respectively. Day 90 overall disease response rates were comparable between groups. Accounting for all CRS and ICANS medication expenses, the addition of prophylactic anakinra was estimated to increase drug costs by $171 (Canadian dollars) per patient. Conclusions: This QI initiative suggests prophylactic anakinra enhances patient safety by reducing severe ICANS and treatment-related toxicities, while improving healthcare efficiency through fewer ICU admissions and decreased reliance on high-cost therapies such as tocilizumab. Although introducing prophylactic anakinra adds a modest upfront medication cost, these expenses may be offset by downstream savings from decreased healthcare resource utilization. By mitigating severe toxicities and lowering the need for emergent interventions, anakinra prophylaxis may facilitate safer transitions to outpatient CAR-T therapy delivery. Given its favorable safety profile and minimal cost impact, prophylactic anakinra represents a scalable, cost-effective approach that could support the broader implementation of outpatient CAR-T therapy delivery models. Prospective validation is warranted to confirm these findings, to identify ideal dosing and evaluate their applicability across health systems.

Purpose CD19 chimeric antigen receptor T (CAR-T) cell therapy has shown promise in treating relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), but cytokine release syndrome (CRS) remains a significant side effect. Methods This retrospective cohort study investigated the use of tocilizumab for managing CAR-T-related CRS in 45 R/R B-ALL patients. Results Of these, 17 patients received tocilizumab, resulting in a significant reduction in the duration of grade 3 CRS compared to those who did not receive the drug. Additionally, 10 patients showed decreased cytokine levels.Importantly, tocilizumab did not impair CAR-T cell expansion or efficacy, nor did it increase the incidence of adverse events. Conclusion These findings suggest that tocilizumab may be an effective and safe strategy for mitigating CAR-T-related CRS in R/R B-ALL patients, potentially improving patient outcomes and survival.

No abstract available

Immune checkpoint inhibitors have dramatically improved the prognosis of NSCLC. However, various immune-related adverse events (irAEs) have been reported. Cytokine release syndrome (CRS) is an irAE that is occasionally severe and life-threatening. CRS is a major irAE of the chimeric antigen receptor T-cell therapy and a rare irAE for anti–programmed cell death protein-1 and programmed death-ligand 1 therapy. Therefore, reports of CRS were rare in NSCLC, but after approval of anti–programmed cell death protein-1 and anti–programmed death-ligand 1 plus anti–CTLA-4 antibodies, reports of CRS are increasing. We, here, report two cases of successful tocilizumab treatment for steroid pulse–refractory CRS in chemotherapy with durvalumab plus tremelimumab for NSCLC.

Background Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for hematological malignancies but is associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Tocilizumab, an IL-6 receptor antibody, is the standard for CRS management but can paradoxically increase circulating IL-6. A phase 2 study (Narkhede et al, ASH 2024) demonstrated the efficacy of siltuximab, a direct IL-6 antibody, for CRS/ICANS. Here, we compare results from the siltuximab trial to a contemporaneous cohort of real-world patients treated with tocilizumab at the same institution under identical eligibility criteria. Methods We analyzed two independent cohorts. The siltuximab group included patients from a prospective phase 2 trial (NCT04975555). The tocilizumab group was a retrospective cohort of patients treated at the same institution (Nov 19-Jun 23) outside the trial in a real-world setting. Primary endpoint of the prospective trial was response rate to anti-IL-6 therapy for CRS, which was compared to the retrospective cohort utilizing Fisher's exact test. Non-response was defined as requiring >2 doses of anti-IL-6 therapy, escalation of grade of CRS after 2 doses, or persistence of any grade CRS after 14 days from initial treatment. Secondary endpoints included time to response (TTR: time from completion of first anti-IL-6 infusion to time of first recorded normal vital sign persisting for 24 hours indicating resolution of CRS), CRS relapses and incidence of ICANS after anti-IL-6 therapy. A propensity score matching (PSM) was done for disease type, age, ferritin, LDH, CRP, bridging therapy, and costimulatory domain to compare response rates. The TTR distributions were analyzed utilizing the Mann-Whitney U test and as time to event endpoint with Peto-Peto modification of the Gehan-Wilcoxon test to account for heavy early distribution of events. Results The siltuximab (n=20) and tocilizumab (n=55) groups were compared. Baseline characteristics (siltuximab vs. tocilizumab, respectively) included median age [59 (38-79) vs. 64 (35-80) years]; disease subtypes [LBCL (15 vs 28), FL (2 vs 4), MCL (1 vs. 6), MM (2 vs 13)]; and co-stim domain [4-1BB (5 vs 28), CD28 (15 vs 27)]. Baseline mean (±SD) biomarkers were: CRP (21.20 ± 33.37 vs. 33.48 ± 69.75), LDH (238.20 ± 168.40 vs. 250.96 ± 266.69), and ferritin (379.75±393.38 vs. 552.22±489.60). For the primary endpoint analyzed for patients who developed CRS and received anti-IL-6 therapy, 15/19 pts (79%) in siltuximab group responded compared to 37/51 pts (73%) (p=0.79). One pt in siltuximab group did not develop CRS and 4 pts in tocilizumab group had CRS resolution prior to tocilizumab infusion. Median TTR was substantially shorter with siltuximab (1 hour, 12 minutes [Range 00:01–104:06) compared tocilizumab (6 hours, 14 minutes [Range 00:32–101:52) with p-value 0.0204. CRS relapse rates were similar between groups (tocilizumab 12/55, 22%, siltuximab 4/19, 21%). The incidence of grade 3/4 ICANS after anti-IL-6 therapy was also similar with tocilizumab (13/51, 25%) or siltuximab (4/20, 20%). PSM matched all variables other than ferritin and costimulatory domain and included 15 patients in each cohort. A higher proportion of patients treated with siltuximab (12/15, 80%) responded to treatment compared to those treated with tocilizumab (8/15, 53%), however the difference was not statistically significant (p=0.13, 95%CI 0.049, 1.361). Conclusion Siltuximab was associated with a higher rate of CRS resolution compared to tocilizumab, although this difference did not reach statistical significance, potentially due to limited sample size. However, siltuximab had nearly five times faster time to CRS resolution compared to tocilizumab with no notable differences observed in CRS relapse rates or the incidence of higher grade ICANS rates when anti-IL-6 therapy was administered after onset of CRS. Our limitations include our small prospective sample size and the use of a retrospective comparator group, with one cohort treated under a clinical trial protocol and the other reflecting real-world practice. These findings, along with promising results from a prospective trial, suggest siltuximab is a good option for CRS management. By directly targeting IL-6, siltuximab may accelerate recovery, and these preliminary data support the need for a prospective, randomized trial to evaluate its superiority for CRS response and time to resolution.

Background: Post-transplant cyclophosphamide (PTCy)-based allogeneic hematopoietic stem cell transplantation (alloHCT) is frequently associated with cytokine release syndrome (CRS). While tocilizumab is effective in managing CRS, its downstream impact on transplant outcomes, particularly graft-versus-host disease (GVHD), remains incompletely understood. Tocilizumab is also an established treatment for acute GVHD and modulates T-cell activity, which may interact with PTCy's immunologic effects. We investigated the impact of tocilizumab use for CRS on transplant outcomes in this setting. Methods: We conducted a retrospective study of adult patients undergoing PTCy-based alloHCT at our institution between January 2014 and December 2023. Patients who developed CRS were stratified by the receipt of tocilizumab (toci group vs. non-toci group). To control for confounding, we performed 1:1 propensity score matching based on age, disease, HLA match, stem cell source, conditioning intensity, and CRS onset. Engraftment, non-relapse mortality (NRM), and GVHD were analyzed using competing risk models. A p-value ≤ 0.05 was considered statistically significant. Results: 346 patients underwent alloHCT with PTCy, with AML (n=135), MDS (n=64), NHL (n=52), Hodgkin lymphoma (n=21) being the most common primary diagnoses. Among these 346 patients who received PTCy, 190 (55%) developed CRS, with a median onset of 2 days, median duration of 3 days, and an average maximum temperature (Tmax) of 102.8°F. Patients with HLA-mismatched donors were more likely to develop CRS than those who received HLA-matched allografts (p<0.001). Unexplained encephalopathy, possibly related to CRS, occurred in 36 patients (19%). A total of 46 patients (24.2%) received tocilizumab for CRS, 5 of whom received more than 1 dose. Six patients required escalation to ICU-level care for hypotension or hypoxia. Compared with those who did not receive tocilizumab, these patients were more likely to have HLA-mismatched donors (98% vs. 81%), receive peripheral blood stem cells (93% vs. 71%), experience earlier CRS onset (median 1 vs. 2 days after transplant), have high-grade CRS (Grade ≥2: 37% vs. 22%), and develop encephalopathy (26% vs. 18%) subsequently. After propensity score matching, 40 patients were included in each group. The two cohorts were well balanced by age, gender, disease type, remission status, performance status, HLA matching, stem cell source, conditioning intensity, and CRS onset day. Both groups had similar incidence of high-grade CRS (Grade ≥2: 32% vs. 31%), though the toci group experienced a significantly shorter CRS duration (median 3 vs. 4 days, p=0.005). Neutrophil engraftment was significantly delayed in the toci group (median 19 vs. 17 days, p = 0.01), while platelet engraftment was comparable (median 32 vs. 29 days). Bacterial infections within 100 days post-transplant were significantly more common in the toci group (65% vs. 28%). Tocilizumab use was associated with a significantly lower incidence of Grade II–IV acute GVHD (100-day incidence: 46% vs. 69%; HR 0.56, 95% CI 0.32–1.00, p = 0.05), although rates of Grade III–IV acute GVHD were similar. Notably, patients in the toci group had a significantly lower 2-year incidence of moderate-to-severe chronic GVHD (6.2% vs. 35%; HR 0.13, 95% CI 0.03–0.56, p < 0.01) and of any chronic GVHD (12% vs. 51%; HR 0.17, 95% CI 0.06–0.49, p < 0.01). There were no significant differences in non-relapse mortality, relapse-free survival, GVHD-free/relapse-free survival (GRFS), or overall survival (OS) between the two groups. Conclusion: In patients undergoing PTCy-based alloHCT, early administration of tocilizumab for CRS is associated with a shorter CRS duration and significant reductions in both acute and chronic GVHD. However, it is also linked to delayed neutrophil engraftment and a higher risk of early bacterial infections. Tocilizumab represents a valuable therapeutic strategy for CRS management in this context, but its use warrants close monitoring of infection.

Teclistamab, a T ‐ cell redirecting bispecific antibody (BsAb) targeting B ‐ cell maturation antigen (BCMA), has marked activity in heavily pretreated multiple myeloma (MM) patients (overall response rate: 63.0%; at least very good partial response [ ≥ VGPR]: 59.4%; median progression ‐ free survival [PFS]: 11.3 months). 1,2 Teclistamab treatment induces T ‐ cell activation and production of proinflammatory cytokines such as interleukin ‐ 6 (IL ‐ 6). 3 This increase in cytokines frequently results in a systemic inflammatory response syndrome (cytokine ‐ release syndrome [CRS]), characterized by fever, and in more severe cases also hypotension and hypoxia. 1,2,4,5 CRS mitigation strategies include step ‐ up dosing and pre-medication with steroids and antihistamines. The incidence of CRS in teclistamab ‐ treated patients was

BACKGROUND This study aimed to identify specific biomarkers in oncology patients experiencing immune-related cytokine release syndrome (irCRS)-like symptoms during immune checkpoint inhibitor (ICI) therapy, including severe cases like hemophagocytic lymphohistiocytosis (irHLH), and to distinguish these from sepsis. A secondary objective was to retrospectively analyze the efficacy of tocilizumab (TCZ) in treating corticosteroid (CS)-refractory high-grade irCRS. PATIENTS AND METHODS A cohort of 35 patients presenting with irCRS-like symptoms was studied, including 9 with irHLH-like manifestations and 8 with sepsis. Immune profiling was performed using 48 mass cytometry markers, along with an analysis of 45 serum biomarkers, including 27 cytokines and 18 additional markers from the HScore. Twelve patients with high-grade irCRS refractory to CS were treated with TCZ. RESULTS 24 biomarkers significantly distinguished between irHLH and Grade 3 irCRS (P=0.0027-0.0455). Hepatocyte growth factor (HGF) and ferritin had superior predictive values compared to the traditional HScore, both with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. CXCL9 differentiated irHLH from Grade 3 irCRS and predicted the need for TCZ treatment intensification (PPV=90%, NPV=100%). Additional biomarkers, including leukocyte count, neutrophils, ferritin, IL-6, IL-7, EGF, fibrinogen, and GM-CSF, discriminated sepsis from high-grade irCRS (PPV=75-80%, NPV=100%). Elevated frequencies of CXCR5+ or CCR4+ CD8 memory cells, CD38+ intermediate monocytes, and CD62L+ neutrophils were observed in high-grade irCRS compared to sepsis. All 12 patients with high-grade irCRS refractory to CS treated with TCZ experienced complete resolution. CONCLUSIONS This study highlights the importance of specific immunologic biomarkers in determining irCRS severity, predicting outcomes, and distinguishing between irHLH, irCRS, and sepsis. It also demonstrates the efficacy of TCZ in managing high-grade irCRS, underscoring the need for personalized therapeutic strategies based on these biomarkers.

This article summarizes key review findings that supported the approval of tocilizumab for treatment of severe or life‐threatening CAR T cell‐induced cytokine release syndrome.

, fibrinogen, and lymphocyte count, suggests that tocilizumab may play a therapeutic role in the management of severe COVID-19 cases.

No abstract available

The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding.

Patients treated with CAR-T and experiencing cytokine release syndrome (CRS) are often exposed to tocilizumab (anti IL6R). After the administration, IL-6 peaks in serum determinations and looses its predictive power to associate with severity of CRS. This study aimed to explore the role of Serum Amyloid A (SAA) as a potential biomarker for monitoring early toxicities, particularly in patients treated with CAR-T cells. The analysis included 34 consecutive patients treated with CAR-T therapy at our institution from May 2023 to June 2024. SAA levels were measured at multiple time points: before lymphodepletion, immediately before CAR-T infusion, and every other day up to day 14 post-infusion. Additional acute phase proteins (APPs), including C-reactive protein (CRP), interleukin-6 (IL6), interleukin-2 receptor (IL2R), procalcitonin, ferritin, soluble suppression of tumorigenicity 2 (SST-2), and soluble urokinase plasminogen activator receptor (SUPAR), were also assessed at these intervals. The study found that median baseline SAA levels were elevated above the upper limit of normal and exhibited wave-shaped kinetics post-CAR-T infusion, peaking on day 4 and declining thereafter. SAA levels were significantly higher before lymphodepletion compared to day 14 levels. When comparing early responders to non-responders, non-responders showed higher median SAA levels before lymphodepletion and at the day 4 peak. SAA may therefore mark tumor-associated inflammation also in this context. SAA levels were significantly higher in patients experiencing CRS of any grade, with a clear correlation between elevated SAA and CRS severity. However, no such correlation was found for immune effector cell-associated neurotoxicity syndrome (ICANS). Strong associations were also observed between SAA and other APPs, particularly CRP, procalcitonin, ferritin, SST2, and SUPAR, with moderate trends observed for IL6 and IL2R. In a focused analysis on patients previously exposed to tocilizumab, SAA emerged as the best-performing APP in identifying patients at risk of clinically relevant (grade 2 or higher) CRS, with a ROC analysis yielding an AUC of 0.86, being superior to CRP, IL6. IL2R, procalcitonin, and ferritin. A cut-off of 70 mg/L for SAA was identified, offering a sensitivity of 87% and specificity of 83% in distinguishing patients with grade 2-4 CRS. SAA is a valuable biomarker for assessing inflammation and CRS in CAR-T treated patients, particularly in those previously treated with tocilizumab, where traditional markers like IL6 may be less reliable. SAA measurement could guide clinical monitoring and intervention strategies, especially in settings where early detection of severe CRS is critical. Further research is recommended to confirm these findings and explore the broader applicability of SAA in CAR-T therapy.

PURPOSE To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC (P < .001), but persistence was not different (P = .73). Event-free and overall survival were worse in the HTBC (P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively (P = .18). CONCLUSION Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.

Background: Cytokine release syndrome (CRS) is one of the most common adverse effects of T-cell engaging bispecific antibodies (T-BsAbs) during the step-up dosing (SUD) phase of treatment. Previous studies demonstrated that a single prophylactic tocilizumab (Toci) dose of 8 mg/kg mitigated the incidence CRS events. Herein, we evaluated the efficacy of a low Toci dose (Toci-lo) of 4 mg/kg for CRS prophylaxis during the SUD phase. Methods: The study included relapsed/refractory multiple myeloma patients, treated with T-BsAbs and received prophylactic Toci-lo (cohort 1) administered prior to the first SUD only. A historical patient cohort that did not receive Toci prophylaxis was identified (cohort 2) for comparison. The CRS rates were compared between the two cohorts using the Fisher’s exact/Chi-square test. Univariate/multivariate logistic regression analysis was performed to estimate the odds of CRS events with Toci-lo prophylaxis. Results: A total of ninety patients were included in the final analysis (56 in cohort 1 and 34 in cohort 2). CRS rate was significantly lower in cohort 1 (21%, 95% CI:10.7–37.8%) compared to cohort 2 (55%, 95% CI: 38.0–70.8%; p=0.009). Grade 2 CRS rates were 2% and 21% in cohorts 1 and 2, respectively (p=0.0041). Based on multivariate logistic regression, Toci-low was associated with a significant reduction in CRS rates (OR: 0.2, 95% CI: 0.06–0.65; adjusted p=0.01). Conclusion: Based on our findings, prophylactic Toci-lo proved to be effective in reducing CRS events during the SUD phase of treatment with T-BsAbs. The implementation of this prophylactic strategy in clinical practice might minimize healthcare expenditures.

e13622 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized treatment of hematologic malignancies; however, severe toxicities like cytokine release syndrome (CRS) remain a limitation to broader utilization. Using a large dataset of patients treated with CAR-T, we developed a machine learning (ML) model leveraging multi-model patient characteristics to predict the risk of CRS onset with clinically meaningful lead times. Methods: A prospectively maintained dataset of CAR-T patients treated at Mayo Clinic was used. Baseline disease/patients characteristics, labs, ECG, echocardiogram, and vital signs (including data from remote patient monitoring program) were collected. A 24-hour rolling window was used to generate daily averages, maximum, minimum, and deltas for each parameter. ECG and echocardiogram data were forward-imputed; vital signs and labs were not imputed. Each day-post-infusion served as a potential event (CRS onset vs. no CRS). A gradient boosting classifier was trained and tested on a subset of patients (n = 351) using 1,000 bootstrap iterations, evaluating 24-, 48-, and 72-hour lead times. Shapley-based feature importance guided simplification to an 11-feature model, externally validated on an independent cohort (n = 51). Models’ performance assessed using the area under the receiver operating characteristic curve (AUC). Results: A total of 402 patients treated with CAR-T were examined. Median age was 64 years and 36% were female. Primary diagnosis was B-cell lymphoma (n = 240) or multiple myeloma (n = 162). A total of 226,332 vital sign measurements and 372,871 lab values, as well as ECG and echocardiogram data, were collected for 30 days post-infusion. Overall, 79.8% of patients experienced CRS within 30 days. The full ML model demonstrated AUCs of 0.90 (95% CI 0.86–0.93), 0.83 (95% CI 0.77–0.88), and 0.82 (95% CI 0.77–0.87) for 24-, 48-, and 72-hour predictions of CRS, respectively. Including “day of CRS onset post CAR-T” as a feature improved the 72-hour AUC to 0.87 (95% CI 0.83–0.90). A model restricted to vital signs alone showed AUCs of 0.88, 0.75, and 0.71 for 24-, 48-, and 72-hour horizons. An 11-feature model—focusing on temperature, blood pressure, fibrinogen, CRP, serum sodium level, QRS interval, and lymphocyte counts—maintained high accuracy at 24 hours (AUC 0.90, 95% CI 0.86–0.93) and was validated externally using an independent dataset with an AUC of 0.92. Conclusions: Our ML model provides a reliable approach for predicting if/when CRS will occur, with up to three days of lead time before clinical manifestation, offering an opportunity for proactive management. The robust performance of a parsimonious 11-feature model supports practical adoption across clinical settings and real-time risk stratification to enhance patient safety. Prospective validation and integration into clinical workflows will be critical to translating these findings into practice.

Background: Epcoritamab (epcor) is a subcutaneously administered bispecific antibody (bsAb) targeting CD3xCD20 approved for the treatment of both patients (pts) with 3L+ large B-cell lymphoma (LBCL) and 3L+ follicular lymphoma (FL) as monotherapy and is being further developed in other B-cell malignancies. Cytokine release syndrome (CRS) is the most common toxicity of bsAbs, including epcor. The diagnosis of CRS requires fever, with higher-grade events including hypotension, hypoxia, and/or organ dysfunction, which can be life-threatening. A predictive CRS model was developed for another CD3xCD20 bsAb, glofitamab (Gritti G et al. Blood Adv. 2024); however, it had suboptimal performance when applied to epcor LBCL data. This highlights the need for improved models to accurately identify pts at low risk for developing severe CRS to facilitate outpatient dosing. Methods: EPCORE™ NHL-1 (NCT03625037) is a multicohort, single-arm, phase 2 trial; the LBCL expansion cohort enrolled 157 adult pts with relapsed or refractory CD20+ LBCL, including diffuse LBCL (DLBCL) (n=139), high-grade B-cell lymphoma (n=9), Primary mediastinal B-cell lymphoma (n=4), and FL grade (G) 3B (n=5). Pts received SC epcor with 2 step-up doses: priming (0.16 mg) and intermediate (0.8 mg), followed by 48 mg full doses in 28-d Cycles (C): QW, C1-3; Q2W, C4-9; Q4W, C≥10 until progressive disease or unacceptable toxicity. Pts received CRS prophylaxis with steroids (predominantly prednisone), acetaminophen, and diphenhydramine in C1. ORR/CR rates by IRC were 63/40% (Thieblemont et al, EHA 2024). CRS was the most reported AE (51% all G [32% G1, 16% G2, 3% G3]) and most frequently occurred after the first full dose of epcor (C1 day [D] 15). Multiple logistic regression with 10-fold cross-validation and clinical interpretation were used to develop an epcor-specific model with risk scoring to identify factors predictive of developing G2+ CRS after the first full dose of epcor (C1D15). Potential factors included baseline characteristics (age, performance status, medical history, prior treatment, and disease burden) and laboratory data. Performance of the glofitamab 5-factor CRS model was assessed by applying the model to the epcor data in C1 and evaluating the negative predictive value (NPV) and the statistical significance of the model variables. Results: The epcor model development included a total of 147 pts with relapsed or refractory LBCL who received the first full dose (C1D15), of which 24 (16%) pts had G2+ CRS following that dose. A 3-factor model was identified using the following characteristics: (1) prior CAR T use (Yes vs No; odds ratio [OR] 0.11; P=0.0042); (2) extranodal disease (Yes vs No; OR 3.89; P=0.0420); and (3) baseline total metabolic tumor volume (TMTV) (≥80 mL vs <80 mL; OR 2.66; P=0.0659). A risk score (range, −2.2 to 2.4) assigns pts with a score of <1 as “low risk.” Of the 70 pts assigned as low risk by the model, 68 did not have G2+ CRS after the first full dose of epcor (NPV of 97%). The recall of the model was 92%. Validation of the model with other external datasets is planned. Previous studies have reported the glofitamab 5-factor CRS model to have an NPV of 97%; however, it did not perform well for predicting G2+ CRS for the epcor LBCL cohort. The resulting NPV was 80% and all factor P-values were >0.5. Conclusions: The epcor predictive 3-factor model uses baseline characteristics that can be calculated from local pretreatment assessments: prior CAR T, extranodal disease, and TMTV. This model was developed prior to the implementation of EPCORE NHL-1 C1 optimization measures (dexamethasone and fluids), which have further reduced the rates and severity of CRS in pts with LBCL. The model yielded an NPV of 97%, which could still be useful in identifying those already at lower risk of G2+ CRS, irrespective of the choice of steroids. The availability of TMTV may vary based on the clinical setting; however, as TMTV emerges as an important prognostic factor in LBCL, it is expected to become more readily available (Vercellino et al, Blood 2020). Once validated, adoption of this epcor-specific prediction model may support clinicians to tailor CRS monitoring, improving patient outcomes and resource utilization.

Background: Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation. CRS can be triggered non-specifically by T-cell engaging therapies. Risk factors for CRS are expected to be disease-specific and prediction of an individual patient's CRS risk is not currently possible. Glofitamab is a T-cell engaging bispecific antibody targeting CD20 and CD3 with a novel 2:1 format that has shown promising efficacy with a manageable safety profile in NP30179 (NCT03075696), an ongoing Phase I/II dose finding study evaluating glofitamab in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). While CRS is observed with glofitamab, cases typically occur with grade 1/2 severity (per ASTCT, Lee et al 2019) with most occurrences confined to the first cycle of therapy. Data from NP30179 were used to develop a model to predict the occurrence of Grade ≥ 2 CRS after the first glofitamab dose to enable stratification of patients according to risk of CRS with possible future implications for intensity of monitoring for those at low risk. Methods: Glofitamab was administered intravenously over 4 to 8 hours as a fixed or step-up dosing regimen, as previously described (Hutchings, et al JCO 2021). Non-overlapping training and validation data sets were defined; the training data set included patients with aggressive (n=165) or indolent NHL (n=31) who received a first dose of 0.6-25 mg, and the model validation data set (n=51; 35 aggressive NHL) included patients who received a 2.5mg first dose. The primary outcome was defined as Grade ≥2 CRS in the week after the first glofitamab dose, and included 65 events (n=58 training, n=7 validation). In the training data set we evaluated the association between the dose, putative risk factors (including demographics, medical history, disease characteristic variables, baseline laboratory values) and the occurrence of CRS. Univariate and multivariate models were applied in a stratified cross-validation setting to assess the most predictive and stable combination of risk factors. Baseline and on-treatment cytokine levels were analyzed via ELISA in a subset of patients (n=89). Results: The temporal pattern of CRS occurrences revealed that the vast majority of first CRS events occur after the first dose of glofitamab. To predict the occurrence of Grade ≥ 2 CRS after the first glofitamab dose, a multivariate model was developed to include glofitamab first dose and a combined risk score, termed the "CRS risk score" (CRSRS), which is the weighted sum of binarized risk factor values at baseline (Figure). The predictive ability was tested in the validation data set in which the incidence of Grade ≥ 2 CRS was 14% (7/51). A low risk group (CRSRS <5.0) was identified to be 60% of the test cohort with patients within this group having only 5% chance (Negative Predictive Value=0.95, SE=0.03) of experiencing a Grade ≥2 CRS. Induction of cytokines, including IL-6 and TNFα, was observed upon treatment with glofitamab and peak magnitude of cytokine induction was associated with CRS incidence and severity. Cytokine induction was evident by end of glofitamab infusion and peak levels of TNFα were observed by mid-infusion. CRSRS and TNFα induction were evaluated together for the subset of patients with cytokine data available to determine whether risk classification incorporating both metrics could refine the risk stratification of patients. Early TNFα changes were layered on top of CRSRS (at the cutoff of 5.0) such that patients with less than 1.5-fold induction were classified as low risk, and patients with more than 8-fold induction were classified as high risk. In the training data set, this decision tree approach improved the performance of prediction compared to CRSRS alone. Conclusions: A model based on 8 baseline factors allowed an accurate classification of risk for Grade ≥2 CRS upon treatment with glofitamab. Addition of TNFα induction may improve the predictive value. The predictive performance was confirmed in a separate validation data set with additional analyses in independent cohorts ongoing. The CRSRS, alone or in combination with cytokine induction, represents a tool to predict the occurrence of Grade ≥2 CRS after the first glofitamab dose to enable stratification of patients according to risk of CRS with possible future implications for the intensity of monitoring for those at low risk. K.V.K. and A.B. have contributed equally. Belousov: F. Hoffmann-La Roche Ltd: Current Employment. Byrtek: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Kwan: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Li: Genentech, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Carlile: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. McCall: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nielsen: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Piccione: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Background Chimeric antigen receptor T-cell therapy–related severe cytokine release syndrome (sCRS) has seriously affected the life safety of patients. Objective To explore the influencing factors of sCRS in children with B-cell hematological malignancies and build a risk prediction model. Methods The study recruited 115 children with B-cell hematological malignancies who received CD19- and CD22-targeted chimeric antigen receptor T-cell therapy. A nomogram model was established based on symptomatic adverse events and highly accessible clinical variables. The model discrimination was evaluated by the area under the receiver operating characteristic curve. The calibration of our model was evaluated by the calibration curve and Hosmer-Lemeshow test. The bootstrap self-sampling method was used to internally validate. Results Thirty-seven percent of the children experienced sCRS. Indicators included in the nomogram were tumor burden before treatment, thrombocytopenia before pretreatment, and the mean value of generalized muscle weakness and headache scores. The results showed that the area under the receiver operating characteristic curve was 0.841, and the calibration curve showed that the probability of sCRS predicted by the nomogram was in good agreement with the actual probability of sCRS. The Hosmer-Lemeshow test indicated that the model fit the data well (χ2 = 5.759, P = .674). The concordance index (C-index) obtained by internal validation was 0.841 (0.770, 0.912). Conclusions The nomogram model constructed has a good degree of discrimination and calibration, which provides a more convenient and visual evaluation tool for identifying the sCRS. Implications for Practice Incorporation of patient-reported outcomes into risk prediction models enables early identification of sCRS.

Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.

Abstract The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable in vitro and in vivo models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models for enhanced non-clinical prediction of possible adverse events associated with immunomodulatory therapies. This platform shall in the future guide early non-clinical safety assessment of novel immune therapeutics thereby also reducing the costs of their development. Therefore, we review current opportunities and challenges associated with non-clinical in vitro and in vivo models for the safety assessment of CAR T cell therapy ranging from organ-on-chip models up to advanced biomarker screening.

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IO Simulator is a Quantitative Systems Pharmacology platform implementing a mechanistic model of solid tumor-immune system interactions and the action of standard immuno-oncology drugs. Using a tarlatamab case study, we demonstrate how IO Simulator predicts combination therapy efficacy and cytokine biomarkers, which can be statistically related to the risk of cytokine release syndrome (CRS). This allows patient stratification and identification of doses that maximize efficacy without a substantial increase in cytokine release.

Chimeric antigen receptor T (CAR T) cell therapy has improved outcomes in several hematological malignancies but is associated with immune and hematologic toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytosis-like syndrome (IEC-HS). Although diagnostic and grading criteria have been established, there is no consensus on the optimal use of prediction tools. This review describes the incidence of these toxicities and highlights the utility of available tools for predicting and risk-stratifying patients. These studies focus on clinical scores, immunoassays by analyzing CAR T-cell expansion and imaging biomarkers of tumor burden. Among the former, the EASIX score and its derivatives have been validated for predicting severe CRS and ICANS, whereas the CAR-HEMATOTOX score has been validated for predicting prolonged cytopenia. Emerging prediction models aim to integrate these domains to allow early intervention or de-escalation of immunosuppression therapy.

Chimeric antigen receptor T-cell (CAR-T)-related adverse events (CAR-AEs), such as immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS), can be life-threatening and may require high-dose steroids. Identifying patients at high risk for severe CAR-AEs in a simplified way is crucial for early therapeutic intervention. This retrospective study analyzed 44 patients treated with axicabtagene ciloleucel (Axi-cel) to identify predictive factors for severe CAR-AEs. We found that grade ≥ 3 ICANS, hemophagocytic syndrome, and ICU admission were associated with a greater need for high-dose steroids, which we defined as events associated with high-dose steroids (EHS). The incidence of EHS was significantly higher in patients who developed an initial fever (≥ 38.6 °C) within 24 h of CAR-T infusion (p < 0.001). Progression-free survival (PFS) was significantly shorter in patients with EHS compared to those without EHS (p < 0.001). Additionally, patients who developed a fever within 24 h and those with a peak fever of ≥ 38.6 °C both tended to have higher peak CAR-T counts compared to other patients. Our findings suggest that an initial fever (≥ 38.6 °C) within 24 h of Axi-cel infusion may predict severe CAR-AEs requiring high-dose steroids, and that EHS is associated with worse PFS.

Acute cytokine release syndromes are associated with some therapeutic antibodies in man, leading to a spectrum of clinical signs from nausea, chills and fever to more serious dose limiting hypotension and tachycardia. When anticipated this syndrome is typically manageable, however this adverse reaction recently became headline news when a massive and unexpected cytokine release syndrome occurred within a few hours of dosing six healthy volunteers with a therapeutic antibody, putting their lives at risk due to multiple organ failure. Preclinical studies did not predict this adverse event, emphasising the need to compare the relative potency of the product in man and the chosen toxicology species, so that additional margins of safety can be applied when conducting first in man (FIM) studies if there is uncertainty over the predictability of the toxicology species. In vitro human PBMC and whole blood cultures may be useful for predicting cytokine release. However since cytokine release arises through at least two distinct mechanisms, it should be emphasised that the utility of these in vitro methods needs to be established for each antibody product.

Purpose Tarlatamab, a bispecific T-cell engager, has generated favorable response and survival outcomes in relapsed small cell lung cancer (SCLC). Factors influencing tarlatamab-associated treatment outcomes and toxicity have yet to be established. We performed a multivariate analysis to identify biomarkers associated with cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) and integrated these variables into a novel risk stratification tool to identify patients at high risk of clinically significant toxicity. Patients and Methods Logistic and ordinal regression analyses evaluated the predictive value of variables contributing to the presence and severity, respectively, of CRS and ICANS in 115 patients with ES-SCLC receiving tarlatamab. Selected variables were then tuned using 5-fold cross-validation and incorporated into novel elastic net-based prediction models. Results Rates of observed CRS, ICANS, and dysgeusia were 46%, 28%, and 47%, respectively. ORR (overall response rate) and DCR (disease control rate) were 44% and 58.2%, while 6-month PFS (progression free survival) and OS (overall survival) rates were 30.4% and 54.9%, respectively. Excluding patients on tarlatamab <30 days, presence of dysgeusia was associated with a lower rate of disease progression (HR 0.44, p=0.00691) and death (HR 0.34, p=0.0145). The presence of, increased size and number of extracranial metastases as well as elevated baseline LDH were significantly associated with increased likelihood of CRS. Increased ECOG performance status, increased volume of brain metastases, development of CRS, and elevated baseline LDH were all associated with increased risk of developing ICANS. Our cross-validated risk model successfully predicted CRS grade [≥]2 and ICANS events with 90.9% and 75% sensitivity, respectively. Conclusions This exploratory analysis identified several predictive biomarkers of toxicity that successfully stratified low and high-risk populations as part of an internally validated novel risk scoring tool.

Chimeric antigen receptor (CAR)-T cell therapy is a genetically-modified cellular immunotherapy that has a current established role in the treatment of relapsed/refractory B-cell acute lymphoblastic leukaemia and diffuse large B-cell lymphoma, with emerging utility in a spectrum of other haematological and solid organ malignancies. It is associated with a number of characteristic toxicities, most notably cytokine release syndrome and neurotoxicity, for which laboratory testing can aid in the prediction of severity and in monitoring. Other toxicities, such as cytopenias/marrow hypoplasia, hypogammagloblinaemia and delayed immune reconstitution are recognised and require monitoring due to the implications for infection risk and prophylaxis. The detection or quantitation of circulating CAR-T can be clinically useful, and is achieved through both direct methods, if available, or indirect/surrogate methods. It is important that the laboratory is informed of the CAR-T therapy and target antigen whenever tissue is collected, both for response assessment and investigation of possible relapse, so that the expression of the relevant antigen can be assessed, in order to distinguish antigen-positive and -negative relapses. Finally, the measurement of circulating tumour DNA has an evolving role in the surveillance of malignancy, with evidence of its utility in the post-CAR-T setting, including predicting patients who will inevitably experience frank relapse, potentially allowing for pre-emptive therapy.

Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a highly effective treatment for hematological tumors. However, the associated adverse reaction, Cytokine Release Syndrome (CRS), poses a significant challenge. While numerous studies have investigated CRS biomarkers during CAR-T cell therapy, the ability to predict CRS risk prior to treatment initiation remains a crucial yet underexplored aspect. The primary purpose of this study was to address the issue of limited data, explore an alternative approach using public data to identify predictive markers for CRS risk assessment from RNA-Seq in pre-treatment patients data, and comprehend the inducible mechanisms underlying CRS. We integrated information from two public databases, the FDA Adverse Event Reporting System (FAERS) for adverse reaction reports of CAR-T cell therapy and the Cancer Genome Atlas (TCGA) for RNA-Seq data on corresponding hematological tumors. Candidate genes were screened by correlation analysis between Reported Odds Ratio (ROR) values and RNA-Seq gene expression levels, and then core factors were identified through stepwise analysis of pathway enrichment, cluster analysis, and protein interactions. Our analysis highlighted the correlation between CRS risk and pre-treatment T cell activation/ proliferation, identifying key genes (IFN-γ, IL1β, IL2, IL6, and IL10) as significant CRS indicators. This study offers a unique perspective on predicting CRS risk before CAR-T cell therapy, circumventing the challenges of scarce clinical data by leveraging analysis of public databases. It elucidates the crucial role of T cell activation/proliferation dynamics in CRS. The analytical methods and identified markers provide a reference for the research and clinical application of CAR-T cell therapy.

BACKGROUND Bispecific T-cell engaging antibodies (BsAbs) are novel agents used to treat B-cell non-Hodgkin lymphoma (B-NHL); these agents demonstrate a different toxicity profile compared with standard chemoimmunotherapy. OBJECTIVE To describe common adverse events (AEs) experienced by patients with B-NHL during BsAb treatment. METHODS MEDLINE, EMCARE, and EMBASE were searched for relevant studies. Prospective interventional clinical trials of CD20-CD3 BsAbs in late development reporting on safety data for B-NHL patients, published until March 2023, were included. RESULTS This search identified 1481 records; 28 met the inclusion criteria. Cytokine release syndrome (CRS), neutropenia, pyrexia, and anemia were the most commonly reported AEs. CRS primarily occurred during the first cycle of treatment and was mostly low grade; 14 publications (48%) reported a grade ≥3; however, these occurred in less than 10% of patients. Mitigation strategies included premedication with corticosteroids, antipyretics, and antihistamines; step-up dosing; and planned hospitalizations. Two articles reported common signs and symptoms of CRS, which included pyrexia (98% and 99%), chills (13% and 35%), tachycardia (27% and 28%), and hypotension (24% and 38%). Supportive management, tocilizumab, and corticosteroids were widely used (reported in 16/28 studies) for the treatment of CRS. Patient risk factors for CRS included high tumor burden, bone marrow infiltration, and circulating disease. CONCLUSIONS The AE profile of BsAbs requires specialized nurses, skilled in assessing patients for risk factors and recognizing signs and symptoms of AEs. IMPLICATIONS FOR PRACTICE Findings from this review will contribute to cancer nurses' knowledge of CD20-CD3 BsAbs for B-NHL, optimizing the quality and safety of patient care.

No abstract available

Background: Rituximab, an anti-CD20 monoclonal antibody, is crucial in treating certain lymphoproliferative disorders, but up to 77% of patients may experience infusion-related reactions. Diphenhydramine, a first-generation antihistamine, is considered the standard of care for rituximab premedication but poses safety concerns, especially in older adults. The use of second-generation antihistamines, loratadine and cetirizine, have gained interest due to their improved tolerability and safety. However, antihistamine prescribing varies substantially and the relative effectiveness of antihistamines in reducing rituximab infusion reactions has not been previously assessed. Certain patient-specific risk factors, such as patients with more advanced disease, may also be associated with infusion-related reactions. Consideration of these variables would be necessary to better characterize potential factors contributing to a patient's likelihood of experiencing an infusion reaction. Furthermore, despite generally having a longer duration of effect compared to first-generation antihistamines, it is not known whether taking an extra dose of second-generation antihistamine impacts the incidence infusion-related reactions. Examining different generations of antihistamines and how their dosing strategies compare in their ability to reduce rituximab infusion reactions may prove relevant to the provision of patient-centred care. Objective(s): To evaluate antihistamine premedication prescribing practices for rituximab patients and to assess the incidence, severity, and symptoms of infusion reactions between antihistamine generations. Methods: This is a retrospective chart review of 422 adult patients with B-cell malignancies who received first dose intravenous rituximab across four Alberta cancer sites over a 12-month period. Data on patient characteristics, premedications, and infusion reactions were collected. The severity of reaction was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) grading scale. Chi-square and Fisher Exact tests were used to examine associations of infusion reactions with patient-specific factors. A multivariate logistic regression analysis was conducted to identify whether known risk factors were associated with infusion reactions among the different antihistamine groups. Results: Three antihistamines were identified: diphenhydramine 50 mg, loratadine 10 mg, and cetirizine 10 mg. Among all eligible patients, 225 (53.3%) were given diphenhydramine, 160 (37.9%) received loratadine, and 37 (8.8%) got cetirizine. The overall incidence of infusion reactions was 27%. There was no significant difference in infusion reactions between first- and second- generation antihistamines (p=0.44). The incidence of reactions amongst patients who received one antihistamine dose (same day of infusion) was not different compared with patients given two separate doses (p=0.83). Approximately 91% of patients who experienced an infusion reaction were classified as grade 2 using the CTCAE grade scale. There were 251 total reported symptoms among the 115 patients who experienced infusion reactions. Chills/rigors (n=41) and throat irritation (n=28) were the two most prevalent symptom types. In terms of the spread of symptom types, 39.1% of patients experienced 1 symptom, 44.3% experienced 2-3 different symptoms and 16.5% experienced 4 or more symptom types. Age <65 was significantly associated with a higher risk of experiencing infusion reactions (OR = 2.0, 95% CI: 1.3-3.1, p=0.0031). This observation persisted even after accounting for other variables such as sex, staging of disease, other antihistamine premedication (i.e. histamine-2 receptor blockers, corticosteroid, acetaminophen), and diagnosis. Conclusions: In hemato-oncology patients receiving first-time rituximab, infusion reactions did not differ by antihistamine choice. Using one dose of less sedating second-generation antihistamines may improve patient safety without compromising clinical efficacy. By recognizing second-generation antihistamines as a safer and equally efficacious option for rituximab premedication, standard antihistamine prescribing practices should be re-evaluated with the goal of optimizing patient safety and medication burden.

Abstract Background In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose‐dense (DD) doxorubicin‐cyclophosphamide (AC)–paclitaxel regimen. Patients, Materials, and Methods In this prospective, single‐arm study, patients who completed four cycles of DD‐AC for stage I–III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3–4 HSRs. Results Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%–20.0%) patients had any‐grade HSRs, for a total of 22 (4.5%; 3.1%–6.4%) HSRs over 486 paclitaxel cycles. Any‐grade HSRs occurred in 1.6% (0.3%–5.0%), 6.5% (3.3%–11.3%), 7.4% (3.9%–12.5%), and 2.6% (0.7%–6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%–2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any‐grade HSRs occurred in 2.7% (3/111; 0.7%–6.8%) and 0.9% (1/109; 0.05%–4.3%) of patients in cycle 3 and 4, respectively. Conclusion Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose‐dense paclitaxel if HSRs are not observed during cycles 1 and 2. Implications for Practice Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care.

9584 Background: All immune therapies that rapidly activate T cells, including T cell engagers, can induce cytokine release syndrome (CRS). Tebentafusp (tebe), a T cell receptor bispecific (gp100 x CD3) can also induce skin adverse events (AEs), due to gp100+ cutaneous melanocytes. CRS and skin AEs may require management with short term corticosteroids, which may also be used as premedication for subsequent tebe doses. Here we report the first analysis of systemic corticosteroid use and correlation with efficacy from a Phase (Ph) 3 trial for any T cell engager. Methods: Post hoc analyses were performed on the tebe arm of the Ph3 [NCT03070392] study in previously untreated HLA-A*02:01+ metastatic uveal melanoma (mUM) (N = 245). Due to the low rate of severe AEs in Ph1 trials, prophylactic corticosteroids were not mandated. The association between overall survival (OS) and corticosteroid use (new start within 30 days of first tebe dose) was investigated using landmark analyses in the safety population. Multivariate analyses were adjusted for key patient characteristics and AEs of special interest: CRS, rash, and liver function test (LFT) elevation. Steroid type (hydrocortisone vs. others) and treatment duration (1 vs. > 1 day) were also investigated. Results: In the Ph3 trial, 64/245 (26%) patients received new systemic corticosteroid within 30 days after the first dose of tebe, mostly for treatment of AEs (56/64, 88%) or pre-medication due to previous AE (14/64, 22%). 25 of the 64 patients received corticosteroids only for a single day. The most frequent AEs (≥15%) were rash (18/64, 28%), CRS (15/64, 23%), and hypotension (12/64, 19%). In a logistic regression model, elevated baseline LDH, the dominant prognostic marker, was most strongly associated with use of corticosteroids (p = 0.01). In the multivariate analysis, corticosteroids were not associated with any significant OS difference (HR 1.41, 95% CI 0.83-2.4, p = 0.2) and this effect did not differ in patients with or without CRS, rash or LFT elevation (all interaction tests p > 0.2). There was no difference in OS according to corticosteroid type or whether administered for 1 vs > 1 day. Conclusions: This is the first analysis from a phase 3 trial of the impact of systemic corticosteroids on survival for a T cell engaging cancer therapy. The vast majority of tebe-treated patients (84%) either did not require corticosteroids (74%) or only received them on a single day (10%). The most frequent reason for corticosteroid use was an emergent AE, including CRS and rash. Corticosteroid use following the pre-specified AE guidelines was not associated with any significant impact on OS. Clinical trial information: NCT03070392.

9531 Background: Cytokine-mediated adverse events (AEs) are commonly reported in pts treated with T cell engaging therapies. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells, has shown an overall survival benefit for pts with untreated mUM in a Ph3 trial (NCT03070392). Here we reviewed the incidence, kinetics, and outcome of CRS in tebe-treated pts on the IMCgp100-102 trial of 2L+ pts with mUM (NCT02570308). Methods: 127 HLA-A*02:01+ 2L+ mUM pts were treated with tebe at the RP2D of 68mcg following intra-patient dose escalation of 20 mcg dose 1 and 30 mcg dose 2. Pts were monitored overnight to allow management of hypotension and other cytokine-related AEs. Because the rate of severe CRS was low in Ph1, prophylactic corticosteroids, antihistamines or acetaminophen were not mandated. CRS was evaluated post-hoc according to ASTCT Consensus Grading criteria [1]. Circulating cytokines in serum were measured before and at 8hr and 12-24hr after dosing for the 1st, 3rd and 4th doses (n=105). This analysis was conducted on the primary analysis snapshot dated 04Jun20. Results: The most frequent treatment-related AEs that were likely cytokine-mediated included fever (80%), chills (64%), nausea (59%), hypotension (41%) and hypoxia (4%). In a post-hoc review using ASTCT criteria, 86% of pts (n=109) had any grade CRS. The majority of these 109 pts had either grade (G) 1 (n=42; 33%) or G2 (n=62; 49%), with few G3 (n=4; 3.1%), one G4 (0.8%), and no deaths. Onset of CRS began within 24 hours of administration and G≥2 hypotension or hypoxia typically resolved within 2 days of onset. Most CRS events occurred after the first 3 doses with a marked reduction in the frequency and severity of CRS thereafter; G3-4 CRS was limited to first two doses. Only 2 pts discontinued tebe due to CRS (1 G3 and 1 G4). Treatment of G≥2 CRS included iv fluids (n=45), iv steroids (n=18), oxygen (n=8), and vasopressor use (n=2). No pts received tocilizumab. Tebe induced a transient increase in peripheral cytokines, including IFNγ, IL-10, IL-6 and TNFα, within hours of tebe dosing, which were several fold higher in pts with CRS compared to pts without CRS. Higher levels of TNFα trended with severity of CRS. Conclusions: CRS, a common AE observed with all T cell engaging therapies, was frequently observed within 24 hours of initial tebe treatment. Most CRS events were mild or moderate in severity even without the use of prophylactic premedications, were reversible with standard management strategies, decreased in frequency and severity with subsequent doses, and rarely led to treatment discontinuation. Pts with CRS tended to have greater increases in serum cytokines, consistent with tebe’s proposed mechanism of action. [1] Lee, DW et al. Biol Blood Marrow Transplant 2019. Clinical trial information: NCT02570308.

Background: Infusion reactions (IRs) are the most common adverse events (AEs) of infliximab (IFX) treatment in patients with inflammatory bowel disease (IBD). Prophylactic premedication (PM) with corticosteroids or antihistamines prior to IFX infusions has been used in clinical practice, but its efficacy is not known. The aim of this study was to assess the influence of steroid PM on IR incidence in pediatric patients with IBD receiving IFX. Methods: We performed a case–control study that included pediatric patients with IBD receiving IFX. Patients were divided into four subgroups according to the agent and PM they received: Remicade (original drug) + PM, and two biosimilars—Reshma +/− PM, and Flixabi—PM. At our site, until 2018, PM with steroids was used as a part of standard IFX infusion (PM+); however, since then, this method has no longer been administered (PM−). IRs were divided into mild/severe reactions. Differences between subgroups were assessed with the appropriate chi-square test. Multivariate logistic regression was used to assess associations between PM and IR incidence, correcting for co-medication usage. Results: There were 105 children (55 PM+, 44 male, mean age 15 years) included in the study who received 1276 infusions. There was no difference between the PM+ and PM− subgroups, either in incidence of IR (18.2% vs. 16.0% of patients, p > 0.05) or in percentage of infusions followed by IR (2.02% vs. 1.02% of infusions, p > 0.5). The OR of developing IR when using PM was 0.34, and the difference in IRs ratio in PM+ and PM− patients was not statistically significant (95% CI, 0.034–1.9). There were 11/18 (61.1%) severe IRs (anaphylactic shock) reported in all patients (both PM+ and PM−). Conclusion: At our site, the incidence of IR was low, and PM did not decrease the incidence of IR in pediatric patients with IBD receiving IFX. These results indicate that PM with steroids should not be a standard part of IFX infusion to prevent IR.

Aims:Pertuzumab plus trastuzumab and docetaxel is a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Infusion reaction represents one of the common side effects of anti-HER2 agents. There is no standard premedication to prevent infusion reactions, although antihistamines, acetaminophen, and/or corticosteroids are often used for this purpose. This study evaluated the ability of premedication to prevent induction reactions in patients receiving pertuzumab, trastuzumab, and docetaxel. Methods: This retrospective, single-institute study assessed infusion reactions in 72 women with HER2-positive early breast cancer who received pertuzumab, trastuzumab, and docetaxel between November 2018 and April 2021. Thirty-six patients received premedication consisting of oral acetaminophen prior to pertuzumab and trastuzumab administration and dexamethasone and D-chlorpheniramine maleate intravenously prior to docetaxel administration (previous regimen). Thirty-six patients received premedication consisting of acetaminophen, dexamethasone, and D-chlorpheniramine maleate sequentially prior to pertuzumab, trastuzumab, and docetaxel administration (current regimen). Results: The rates of infusion reaction after the initial injection were 55.6 and 16.7% in the previous and current regiment groups, respectively (p = 0.001). Trastuzumab more frequently caused infusion reactions than pertuzumab and docetaxel. Chills, vomiting, and nausea were the major symptoms of infusion reactions. Conclusion: Premedication featuring the upfront use of dexamethasone and D-chlorpheniramine maleate prior to the administration of anti-HER2 targeted agents significantly prevented infusion reactions.

Background Ublituximab is a glycoengineered monoclonal antibody that effectively reduces multiple sclerosis (MS) relapses but carries a significant risk of infusion-related reactions (IRRs), which is relatively higher than that reported for some other anti-CD20 agents. This study aims to characterize real-world IRRs associated with ublituximab and describe premedication practices across participating centers. Methods This multicenter retrospective study included ublituximab-treated MS patients identified from existing medical records (a convenience sample) at MS centers across the United States. Data on demographics, MS phenotype, premedication regimens, and IRRs were collected. Variables were summarized, and Fisher’s exact test was used to compare the occurrence and timing of IRRs across baseline and premedication categories. Also, associations between premedication strategies and IRRs were assessed by logistic regression. We conducted statistical analyses using JAMOVI (v2.5). p-values were adjusted for multiple comparisons. Results Among 89 patients with multiple sclerosis (PwMS) treated with ublituximab, 34.8% (n = 31) experienced IRRs. All patients received premedication, with the acetaminophen dose being the only component significantly associated with overall IRR occurrence (p = 0.006). Significant differences in reaction timing (immediate versus delayed) were observed across certain corticosteroid and antihistamine categories. All IRRs were mild to moderate in severity. Conclusion Approximately one-third (34.8%) of ublituximab-treated patients experienced IRRs, with varied timing and symptom patterns. No independent predictors of IRRs were identified. Importantly, all IRRs observed in this study were mild to moderate, suggesting that ublituximab infusions were generally well tolerated in this real-world cohort.