Cytokine release syndrome in solid tumors.

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

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

Pretransplant Clinical Factors Can be Used to Predict the Risk of Cytokine Release Syndrome after Haploidentical Peripheral Blood Transplantation

11067 Background: Cytokine release syndrome (CRS) is a potentially life-threatening complication commonly seen in patients receiving chimeric antigen receptor (CAR)-T cell therapy, allogeneic stem cell transplant, or immunotherapies. This study aims to evaluate the inpatient burden outcomes of CRS leading to hospitalization in patients diagnosed with cancer. Methods: Hospitalizations for cytokine release syndrome (CRS) were identified using ICD-10 coding from the 2020 National Inpatient Sample (NIS), the largest all-payer inpatient database in the US. Only CRS patients with a co-diagnosis of cancer (identified using the Clinical Classification Software (CCS) coding) were included in this study. The underlying severity of illness index was used to verify CRS grading. Sampling weights were applied to generate nationally representative estimates. Results: In 2020, there were 4,765 hospitalizations coded with CRS. 27.2% of these admissions had a co-diagnosis of cancer (n=1,295) and were included in the final analysis. The top co-diagnoses in the patients with CRS without cancer were COVID-19 infection and sepsis. Hematologic malignancies had the highest incidence amongst cancer types (75.7%), the distribution was as follows: 29.6% with diffuse large B-cell lymphoma, 19.9% with acute lymphoblastic leukemia, 12.8% with multiple myeloma, 12.2% with acute myeloid leukemia, and 7.7% with mantle cell lymphoma. The most common procedures in oncology patients hospitalized with CRS were CAR-T cell therapy (29.3%), chemotherapy (28.6%), stem cell transplant (8.5%), or Blinatumomab bispecific antibody (5.4%). 11.4% of patients with CRS received tocilizumab. Of those that received tocilizumab, 10% were CRS grade 2, 56.7% were grade 3, 33.3% were grade 4. 51.7% of tocilizumab was given in the first 48 hours of admission. A minority of CRS patients required critical care interventions: 12.0% requiring intubation, 5.8% requiring vasopressor support, and 2.7% received dialysis. Overall, 10.4% of all oncology admissions with CRS resulted in death during hospitalization (n=135). Of these deaths, 92.6% were in the extreme severity of illness and 63.0% were CRS grade 4. Those with CRS who died during hospitalization had a significantly longer length of stay (24.6 vs 13.6 days, p<0.001). The overall median hospital charges of a CRS-related admission were $531,692. Conclusions: This study represents the inpatient burden of CRS-related admissions in patients diagnosed with cancer. CRS admissions are commonly seen in patients with hematologic malignancies, those undergoing CAR-T cell or immunotherapies (bispecific antibodies). CRS poses a significant healthcare burden, with average hospital charges being greater than 0.5 million US dollars per admission. About 1 in 10 patients with CRS died during hospitalization with higher mortality likely with severe CRS grades and longer length of stay.

Severe Cytokine Release Syndrome Is a Fatal Complication after PBSC, but Not after BM Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Background: Adoptive cellular therapies (ACT) have met with significant success in hematologic malignancies. The number of ACT trials in solid tumors has been increasing, however data are limited on the overall safety and efficacy of ACT in this population. We aimed to conduct a systematic review and meta-analysis looking specifically at TCR and CAR-T in solid tumors and rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) relative to the current approved agents in hematologic malignancies. Methods: We conducted a systematic review of published studies/abstracts from January 2015 up to and including July 2021, selecting those that included ≥ 5 patients. Endpoints included rates and differences in CRS and ICANS. Response rates were evaluated. Statistical tests in the pooled data included χ2 and multivariable logistic regression. Results: This meta-analysis included a total of 1,250 patients [566 patients with solid tumors who had received ACT in phase I, II or I/II clinical trials; a comparison was made with five phase 2 clinical trials in hematologic malignancies used for the first FDA approvals of these agents (JULIET, ZUMA-1, ZUMA-2, TRANSCEND and KARMMA), encompassing 684 heme malignant patients]. Rates of CRS of any grade, CRS ≥ grade 3, ICANS of any grade, and ICANS ≥ grade 3 in solid tumors were 33.0%, 3.8%, 2.3% and 2.1%, respectively. Fever, hypotension, and hypoxia were experienced by 37.4%, 18.5%, and 8.5% of solid tumor patients, respectively. CRS, ICANS, fever and hypoxia in solid tumor patients did not differ by whether the ACT received was TCR or CAR T. Objective response (ORR = CR + PR) in patients with solid tumors was higher with TCR compared with CAR-T [odds ratio (OR) = 3.1, P=0.001] and with NY-ESO-1 than other targets (OR=2.0, P=0.031). Compared to hematologic patients treated with ACT, solid tumor patients treated with adoptive cellular therapies were significantly less likely to experience CRS of any grade (62.4% vs. 33.0%, P<0.001), CRS ≥ grade 3 (7.3% vs. 3.8%, P=0.043), fever (50.3% vs. 37.4%, P=0.001), hypoxia (34.1% vs. 8.5%, P<0.001) or hypotension (29.5% vs. 18.5%, P=0.006), ICANS of any grade (29.7% vs. 2.3%, P<0.001), or ICANS ≥ grade 3 (13.9% vs. 2.1%, P<0.001). However, objective response (20.1% vs. 75.4%, P<0.001) and clinical benefit (CBR = CR + PR + SD) (62.6% vs. 90.9%, P<0.001) rates for ACT were lower in patients with solid tumors than in patients with hematologic malignancies. Conclusions: CRS and ICANs were less prevalent in solid tumor cellular therapies. Based on this analysis, T-cell therapies in solid tumors are relatively safe, but further studies with larger populations and longer follow up are needed to address the role of these treatments in cancer. Citation Format: Mirella Nardo, Ji Y. Son, Goldy G. George, David S. Hong. Safety and efficacy of CAR T and TCR therapies in solid tumors: A systematic review and meta-analysis, including a comparison with five phase II trials in hematologic malignancies used for the first FDA approvals of these agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2764.

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

Severity of Cytokine Release Syndrome and Its Association with Infections after T Cell-Replete Haploidentical Related Donor Transplantation.

Estimation of the Resource Utilization and Costs of Cytokine Release Syndrome Observed in the Transcend-NHL Clinical Trial: A Micro-Costing Study

Antithymocyte globulin (ATG)/anti-T lymphocyte globulin (ATLG) aids graft-versus-host disease (GVHD) prophylaxis in HLA-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. This study aimed 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. This retrospective single-center analysis included consecutive recipients of allogeneic HSCT treated with ATG/ATLG as GVHD prophylaxis at the Medical University of Vienna between January 1, 2014, and August 15, 2021. Multivariate regression models were used to explore risk factors for CRS and its association with clinical outcomes (acute GVHD grade II-IV, clinically significant cytomegalovirus infection, nonrelapse mortality, and overall survival) at 6 months after HSCT. A total of 284 patients (median age, 54 years; interquartile range [IQR], 45 to 61 years; 120 females, 164 males) were included in the study. ATLG was used in 222 patients (78%); ATG, in 62 (22%). One hundred sixty-six patients (58%) developed CRS grade ≥1 during ATG/ATLG administration. CRS was mostly mild, with 92% of the cases CRS grade 1-2. Thirteen patients (5%) developed CRS grade 3, and 1 patient had CRS grade 4. No CRS-related death (grade 5) occurred. Patients with CRS showed a pronounced systemic inflammatory response as measured by inflammatory markers C-reactive protein, IL-6, and procalcitonin. In multivariate analysis, lymphoma as the underlying disease, high ATLG dose 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 compared with patients without CRS (24% versus 14%; P=.04). This effect remained statistically significant only for CRS grade 3-4 (subdistribution hazard ratio, 3.70; 95% confidence interval, 1.58 to 8.68; P < .01) after adjusting for relevant confounders. Other clinical outcome parameters were not affected by the occurrence of CRS. 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 an 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 IL-6 blockade, in this setting.

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

Lead-in Dose Optimization to Mitigate Cytokine Release Syndrome in AML and MDS Patients Treated with Flotetuzumab, a CD123 x CD3 Dart® Molecule for T-Cell Redirected Therapy

CD19 antigen: From tumor target to safety switch able to improve the safety profile of CAR T cell therapy

Higher Grade Cytokine Release Syndrome Is a Predictive Factor for Gvhd in Haploidentical Stem Cell Transplantation with Peripheral Blood Cell

Background: Chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (BiTE) therapies are T-cell engaging treatments with expanding indications in hematologic malignancies, particularly relapsed/refractory multiple myeloma (MM). BiTE agents are also under investigation for first line use and solid tumors. While their efficacy is established, immune-related adverse events (AEs), especially cytokine release syndrome (CRS) and downstream cardiovascular effects, pose clinical challenges. The cardiovascular sequelae of CRS remain under-characterized, with limited comparative data across therapies. Methods: The FDA Adverse Event Reporting System (FAERS) was queried for AEs linked to five MM-approved immunotherapies: idecabtagene vicleucel and ciltacabtagene autoleucel (CAR-Ts); teclistamab, talquetamab, and elranatamab (BiTEs). Reports were filtered by “plasma cell myeloma” and the AE term “cytokine release syndrome”. Disproportionality metrics including reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian information component were calculated for each drug and pooled by class. Significance was assessed via log(ROR) comparison. Results: Of 45,285 MM-related AEs, 1,379 (3.0%) were CRS. RORs were highest for idecabtagene (65.7; 55.9–76.9), followed by ciltacabtagene (11.1; 9.29–13.29). BiTE agents showed lower RORs: teclistamab (8.59; 7.42–9.95), talquetamab (6.93; 5.3–9.04), and elranatamab (6.15; 4.77–7.93). Pooled RORs demonstrated a ~3.9-fold higher CRS signal with CAR-Ts (29.9; 26.5–33.6) than BiTEs (7.71; 6.87–8.64; p &lt; 0.00001). Pooled Bayesian values further confirmed this disparity: CAR-T (3.73; 3.37–4.14) vs. BiTEs (2.52; 2.25–2.82). Conclusion: CAR-T therapies exhibit significantly higher CRS pharmacovigilance signals than BiTE agents in MM, suggesting higher cardiotoxic potential. These findings support CV risk stratification in treatment selection and underscore the need for prospective cardio-oncology registries to validate real-world toxicity patterns.