High Rate of Cytokine Release Syndrome-Related Coagulopathy with Low Incidence of Bleeding and Thrombosis in Patients Treated with B-Cell Maturation Antigen (BCMA)-Targeted Chimeric Antigen Receptor T-Cells (CAR-T)

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.

Real-time interleukin-6 (IL-6) kinetics predict cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy for Relapsed/Refractory B-cell malignancies

Clonal Hematopoiesis Is Associated with Severe Cytokine Release Syndrome in Patients Treated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Utilization of Investigations for Neurotoxicity in CD19 and BCMA CART Recipients

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Treatment Profile of CAR-T Cell Therapy Induced Cytokine Release Syndrome and Neurotoxicity: Insights from Real-World Evidence

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy

BCMA CAR T-cell expansion dynamics and toxicity after idecabtagene vicleucel and ciltacabtagene autoleucel for multiple myeloma

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

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

Use of Baseline Inflammatory Markers to Predict Toxicities Among Relapsed/Refractory Multiple Myeloma Patients Receiving Ambulatory Teclistamab and Talquetamab

CAR-T Cell Subsets and Immune Repertoire Are Associated with Immune-Related Adverse Events and Efficacy after CD19 CAR T-Cell Therapy in B Cell Lymphoma

An Endothelial Activation and Stress Index (EASIX) Based Predictive Model for Neurotoxicity and Cytokine Release Syndrome (CRS) after B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM)

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

7532 Background: CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells achieve high response rates in patients (pts) with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL), but are limited by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pivotal trial data suggested distinct toxicity risks across CD19 CAR T-cell products, but differences in pt and disease characteristics may have confounded these observations. Thus, we assessed the independent impact of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in 136 pts with R/R aggressive NHL. Methods: We retrospectively analyzed aggressive NHL pts treated at our institutions with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy. Axicel and tisacel pts were treated off trial using commercial products. JCAR014 (defined-composition 4-1BB-costimulated CD19 CAR T cells) was administered in all pts at the dose of 2x106/kg on a phase I/II clinical trial (NCT01865617). CRS and ICANS were graded according to the ASTCT criteria and CTCAE 4.03, respectively. We used multivariable proportional odds logistic regression to model CRS and ICANS grade. Results: The CAR T-cell product was axicel, tisacel, or JCAR014 in 50%, 28%, and 22% of pts, respectively. Compared to axicel pts, we observed higher preLD LDH levels in tisacel and JCAR014 pts, and lower preLD albumin with tisacel (p < 0.001) with comparable age and hematopoietic cell transplantation comorbidity (HCT-CI) indexes across CAR T-cell products. Higher day-28 overall response rate by Lugano criteria was observed after axicel (71%) compared to tisacel (56%) and JCAR014 (53%). Adjusting for age, HCT-CI, preLD LDH, preLD albumin, CAR T-cell product type was associated with CRS severity (tisacel versus [vs] axicel, OR = 0.45, p = 0.05; JCAR014 vs axicel, OR = 0.29, p = 0.005;). Age had limited or no impact on CRS severity (OR 95%CI, 0.97-1.02), while the effect of HCT-CI was undetermined (OR 95%CI, 0.85-1.27). In a multivariable model including the same covariates as above, CAR T-cell product type (tisacel vs axicel, OR =.14, p <.001; JCAR014 vs axicel, OR = 0.31, p = 0.009), preLD LDH (OR, 3.96 per log10 increase; p = 0.04) and age (OR per 10-year increase, 1.32; p =.06) were associated with ICANS severity. Interaction effect testing suggested effect modification of age by the CAR T-cell product type (tisacel/JCAR014 versus axicel, p = 0.06); using a multivariable model including this interaction term, the predicted probabilities of grade ≥3 ICANS in a 70 year-old after axicel, tisacel, and JCAR014 were 40%, 6%, and 8%, respectively. Conclusions: CAR T-cell product type independently impacts CRS and ICANS severity in NHL pts. Our findings provide key insights to guide patient and CAR T-cell product selection.