High-grade Cytokine Release Syndrome Research Articles

Identification of cytokine release syndrome and indicators of severity in retrospective databases among patients receiving immunotherapy.

Cytokine release syndrome (CRS) can occur following cancer immunotherapies, but is most often mild and of limited duration. International Classification of Diseases (ICD)-10 codes allowing identification of CRS were introduced in 2020 but may be underutilized. We evaluated the performance of a published claims-based algorithm to detect CRS (any grade) and high-grade CRS (HG, grades 2-5), as well as identified indicators of HG CRS in retrospective data. Adults with low-grade and HG CRS during an encounter coinciding with administrations of blinatumomab or chimeric antigen receptor-T therapy were identified in three types of retrospective databases (hospital chargemaster data, electronic health records, and administrative claims). The algorithm's sensitivity in detecting any CRS and HG CRS was reported. A least absolute shrinkage and selection operator (LASSO) regression model was developed to identify indicators of HG CRS. Performance of the model was evaluated using area under the curve (AUC). The sensitivity of the algorithm to detect any grade CRS ranged between 77%-100% and between 8%-80% for HG CRS, depending on the type of database. The LASSO model identified hypotension, positive pressure (including mechanical ventilation), tocilizumab, and vasopressors as indicators of HG CRS. AUC varied between 60% and 75%. The algorithm accurately detected any grade CRS for over three-quarters of instances, but was not as reliable for HG CRS. Results varied based on database attributes. Hypotension, vasopressors, positive pressure, and tocilizumab were associated with HG CRS and may be methodologically helpful signals of CRS severity in retrospective data.

Abstract 4114505: Cardiovascular Adverse Events After Anti-BCMA CAR-T (Ide-Cel and Cilta-Cel) for Relapsed/ Refractory Multiple Myeloma

Introduction: Idecabtagene vicleucel (Ide-Cel) and ciltacabtagene autoleucel (Cilta-cel) are novel CAR-T therapies targeting B-cell maturation antigen (BCMA) and approved for relapsed and refractory multiple myeloma (RRMM). While cardiovascular adverse events (CVAE) are relatively common with CD-19 CAR-T, the incidence of CVAE in the real-world setting for anti-BCMA CAR-T in RRMM is largely unknown. This study aims to determine the incidence of CVAE and its associated risk factors in patients treated with ide-cel and cilta-cel. Method: This single-center retrospective cohort study evaluated RRMM patients treated with ide-cel and cilta-cel from May 2021 to December 2023. We assessed baseline cardiac and oncologic characteristics and clinical outcomes post-CAR-T. Cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome (ICANS) grading followed ASTCT consensus guidelines. Result: A total of 164 RRMM patients treated with ide-cel (N=109) or cilta-cel (N=55) with at least 6 months follow-up were included. The average age was 63 years, and 57% were male. Advanced RRMM stage (R-ISS III) was present in 17% with a median of 6 prior lines of therapy. CRS grade equal or greater than 2 occurred in 22%, and ICANS grade equal or greater than 3 in 6.7%. Twenty patients (12.2%) experienced CVAE, including atrial fibrillation (7.9%), non-sustained ventricular arrhythmia (3.0%), heart failure (3.7%), and cardiovascular death (0.6%). R-ISS III was associated with increased CVAE (52.9% vs. 11.5%; P=0.001). Patients with CVAE had higher baseline ferritin and CRP levels and a higher incidence of CRS grade ≥ 2 (60% vs. 16.7%; P<0.001) and ICANS grade ≥ 3 (20% vs 4.9%; P=0.001). Treatment with tocilizumab, steroids, or anakinra was more common in patients with CVAE. Conclusion: CVAE occurred relatively frequently following BCMA CAR-T therapy, with high-grade CRS identified as a consistent risk factor. Most CVAEs were manageable with appropriate supportive care, including careful observation and active treatment of CRS.

Prevalence of adverse events following bispecific antibody therapy in non-Hodgkin lymphoma: A meta-analysis.

e19008 Background: Bispecific antibodies (BsAb) have emerged as a new treatment modality for relapsed/refractory non-Hodgkin lymphomas (R/R NHL). They exert their effect by binding to CD3 on T-cells and CD19 or CD20 on lymphoma cells, activating the T-cell to exert cytotoxic effects against the tumor and normal B-cells. Treatment related adverse events (TRAE) include infections, cytokine release syndrome (CRS), neurotoxicity (ICANS). This meta-analysis was conducted to assess prevalence of TRAEs from prospective clinical trials that evaluated BsAb in R/R NHL. Methods: A systematic review was conducted through PubMed, Embase, Scopus, Web of Science, and Cochrane to identify BsAb clinical trials in NHL through October 2023. Eligible studies included phase I-III trials evaluating BsAb in any type of NHL, either as monotherapy or combination therapy irrespective of prior lines of treatment. Primary outcomes of interest include infection, neutropenia, CRS, and ICANS. All studies were weighted equally. Pooled prevalence estimates of TRAE were calculated using common and random effects models. Heterogeneity tests were performed using Cochran’s Q test. Subgroup analysis examined infection rates in monotherapy versus combination therapy cohorts. Results: After screening 1039 studies, 36 clinical trials with 2162 patients were included. The lymphoma subtypes were diffuse-large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. The BsAbs included mosunetuzumab (13 studies), epcoritamab (10 studies), blinatumomab (5 studies), glofitamab (5 studies), odronextamab (2 studies), and AFM11 (1 study). The median age of patients was 66 years, and patients had received a median of two prior lines of therapy. Median follow-up duration was 9.1 months. The prevalence of all-grade infections was 35% (95% CI: 0.33-0.38; I2 = 79%). For grade ≥3 infections, the prevalence was 16% (95% CI: 0.14-0.18, (I2 = 77%). There were higher rates of all-grade infections in the combination therapy cohort (41%, 95% CI: 0.36-0.47) compared with the monotherapy cohort (33%, 95% CI: 0.30-0.36). All-grade and grade ≥3 neutropenia occurred in 31% (95% CI: 0.29-0.34; I2 = 80%) and 22% (95% CI: 0.20-0.24, I2 = 61%) of patients. CRS was observed in 45% of patients (95% CI: 0.43-0.48, I2 = 85%). Grade ≥3 CRS occurred in only 2% of patients (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). ICANS occurred in 12% (95% CI: 0.10-0.14, I2 = 90%) while grade ≥3 ICANS was rare, at 3% (95% CI: 0.02-0.03, I2 = 0%, p = 0.99). Conclusions: BsAb is associated with nontrivial rates of infections and neutropenia. The rates of high grade CRS and ICANS are low. The heterogeneity of the findings could be attributed by an underreporting of TRAE and small sample sizes from various studies. These results highlight the need for vigilant practices to diagnose and treat infections early and consideration for antibacterial prophylaxis in this immunocompromised population.

Anticytokine Therapy and Corticosteroids for Cytokine Release Syndrome and for Neurotoxicity Following T-Cell Engager or CAR T-Cell Therapy

What Is the Issue? Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common toxicities secondary to T-cell engager or chimeric antigen receptor (CAR) T-cell therapy. The US FDA and Health Canada approved tocilizumab, an anti-interleukin-6 receptor antagonist, for the management of severe or life-threatening cases of CRS. Corticosteroids also play an important role in CRS management and are the mainstay of ICANS management. Decision-makers are interested in understanding the use of anticytokine drugs (i.e., tocilizumab, anakinra, siltuximab) and/or corticosteroids in the management of CRS and ICANS following T-cell engager or CAR T-cell therapy. What Did We Do? We identified and summarized the literature comparing the clinical effectiveness and safety of anticytokine therapy and/or corticosteroids with alternative care or treatment as usual for treating and preventing of CRS and ICANS. We also searched for evidence-based recommendations for the use of anticytokine therapy and/or corticosteroids to treat and prevent CRS and ICANS. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and February 26, 2024 for CRS; and between January 1, 2019 and March 4, 2024 for ICANS. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? This report presents evidence-based findings on 3 retrospective chart review studies, 2 prospective cohort studies, and 4 consensus guidelines. Limited and low-quality clinical evidence from studies with a high risk of bias suggested that early use of tocilizumab or corticosteroids, or prophylactic use of tocilizumab or anakinra may reduce the risk of a high-grade CRS without a negative impact on neurotoxicity or immunotherapy treatment outcomes. The included guidelines recommend the use of tocilizumab for treatment of higher-grade CRS, or for treatment of grade 1 CRS if symptoms persist for 3 days or more. Corticosteroids could be added in conjunction if there is no improvement or persistent symptoms after tocilizumab therapy. For the management of ICANS in the absence of concurrent CRS, supportive care is the preferred treatment option for grade 1 ICANS, while corticosteroids are recommended for the management of grade 2 to 4 ICANS. In the presence of concurrent CRS, guidelines recommend tocilizumab therapy as per management of CRS, and corticosteroids should be continued until improvement to grade 1. We did not identify any clinical evidence regarding the clinical efficacy and safety of anticytokine therapy and/or corticosteroids for treatment of CRS and ICANS compared with alternative treatment or treatment as usual. We also did not identify any guidelines for the use of prophylactic anticytokine therapy, corticosteroids, or both for the prevention of CRS and ICANS. What Does This Mean? Despite limited and low-quality evidence, the findings suggest some potential benefits of prophylactic or early use of anticytokine therapy and corticosteroids for the management of immunotherapy-related toxicities. Guidelines offer guidance on the management of CRS, ICANS and other less common toxicities related to immunotherapy based on the available low-quality evidence. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is limited and of low quality. To improve the certainty of findings, there is a need for more robust prospective clinical trials with larger sample sizes, and lower risk of bias.

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

Germline Determinants of Toxicity and Efficacy in Patients with Large B-Cell Lymphoma Treated with Anti-CD19 Autologous CAR T-Cell Therapy

Background. Increasing data have demonstrated that acquired genetic aberrations, including TP53 mutations in the tumor cells and clonal hematopoiesis, can impact the efficacy and/or toxicity of anti-CD19 autologous CAR T-cell therapy (CART) in patients with large B-cell lymphoma (LBCL). Recent data have suggested that germline genetic aberrations, including polymorphisms in CD19, ABCB1, MISP and CPVL (Strati P et al, Leukemia 2022) and deleterious germline variants in STXBP2, can also affect outcomes in these patients. However, a comprehensive analysis of germline determinants of response and toxicity after CART in this patient population has not yet been described. Methods. Genome-wide genotyping using the Illumina Genome Screening Array (GSAv2.0) was performed in 170 patients with relapsed or refractory LBCL treated with standard of care axicabtagene ciloleucel in third line and beyond. Response was assessed according to 2014 Lugano criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT criteria, and cytopenia according to CTCAE v5. Polygenic risk score (PRS) instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice. Risk of poor response and toxicity was estimated using logistic regression models with standardized PRS scores as a continuous variable adjusting for age at diagnosis, gender, and bridging therapy (yes/no). Exploratory genome-wide association study (GWAS) analyses were also performed. Results. The median age was 58 years, 116 (68%) were male, and 91 (54%) received bridging therapy. Interestingly, increasing PRS for baseline IL-6 levels was associated with decreased risk of CRS grade (G) 2-4 (β: -0.15, 95% CI: -0.30 to -0.013, p=0.030) and ICANS G3-4 (β: -0.21, 95% CI: -0.37 to -0.066, p=0.005). Similarly, increased genetically-predicted monocyte levels decreased risk of ICANS G3-4 (β: -0.16, 95% CI: -0.31 to -0.018, p=0.027). Baseline genetically-predicted monocyte levels were also associated with increased probability of a CR at D90 (β: 0.19, 95% CI: 0.041 to 0.34, p=0.011). For prolonged cytopenia (defined as G3-4 cytopenia ongoing at day 30), risk was increased with increasing PRS for reticulocyte levels (β: 0.29, 95% CI: 0.10 to 0.48, p=0.002). No genome-wide significant (p<5x10 -8) variants were identified in the exploratory GWAS analyses, however, several loci at p=10 -5 were located within/near potential biologically-relevant candidate genes. This included an association with prolonged cytopenia for rs111940551 located upstream of IKZF1, a regulator of lymphocyte differentiation, and serving as a putative expression quantitative trait loci (eQTL) for this gene. An intragenic variant identified for ICANS G3-4 (rs1149927) was in high linkage disequilibrium (D'=0.97) with a variant previously shown to be associated with brain morphology. Conclusion. PRS representing baseline levels of several key blood cell traits, particularly monocytes, and inflammatory markers may impact toxicities and efficacy of CART in patients with LBCL. The intriguing finding of an inverse association for IL-6 with both high-grade CRS and ICANS was unexpected and needs further investigation. Larger studies are warranted to confirm these observations and better understand how relevant germline genetic determinants may influence efficacy and toxicity after CART therapy. Elucidating such determinants may help in improving patient selection and in developing strategies to enhance the therapeutic index of CART.

Retrospective and Observational Study on CAR-T 19 Bridge Therapies in Pediatric, Adolescents and Young Adults

INTRODUCTION CAR-T therapy has revolutionized the treatment of B-ALL. The development of CAR-T therapy is a long and delicate process where once apheresis is done, a bridge period that least until CAR-T cells are infused starts. Meanwhile, the objective will be to maintain disease control, decrease tumor burden (TB) and prevent disease progression with no severe comorbidities by the administration of a bridge chemotherapy. That will decrease the risk of severe (grade 3-4 ASTCT) Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) with an improvement of event free survival. Nevertheless, there is no consensus nor standard guidelines about bridge chemotherapy type, especially in pediatric patients. In this way, the main objective of this study is to identify CAR-T outcomes in pediatric, adolescents and young adults (AYA) diagnosed of BCP-ALL based on bridge chemotherapy. MATHERIAL AND METHODS An observational, retrospective and non-interventional study of Spanish pediatric and AYA under 24 years old diagnosed with BCP-ALL treated with tisagenlecleucel that have been registered by the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy (GETH-TC) CAR-T clinical database from years 2017 to 2022. Data have been collected from nine centers members of GETH-TC CAR-T workgroup: La Paz University Hospital, Sant Joan de Déu University Hospital, Virgen del Rocío University Hospital, Niño Jesús Pediatric University Hospital, Gregorio Marañón General University Hospital, Vall d'Hebron University Hospital, Salamanca Clinic University Hospital, Germans Trials i Pujol University Hospital and Valencia Clinic Hospital. General, pre-CAR-T, CAR-T-related and post-CAR-T variables have been analysed from GET-TC CAR-T database, highlighting those related to bridge therapy and related outcomes. Bridging chemotherapy was analyzed considering whether the patients had received high (myelosuppression ≥7 days) or low (myelosuppression ≤7 days) intensity schemes, or in contrast, immunotherapy. Fisher's Exact Test for count data and Log Rank test for Overall Survival (OS), Relapse Free Survival (RFS) and Duration of Response (DOR). Variables with p<0.05 value have been considered of statistical significance. RESULTS Baseline characteristics of the 103 patients are summarized in Table 1. CRS after infusion was presented in 86 (83.5%) patients. Grade 3-4 was developed in 4/29 (13.8%) with low pre infusion TB in contrast to 18/55 (32.7%) with high TB (p=0.001). Complete remission (CR) was achieved 87 (85.3%) patients. All patients (100%) with a low TB were in CR VS 78.2% in the high TB arm (p=0.015). Otherwise, 91.9% of those patients that received low intensity bridge chemotherapy or immunotherapy were in CR VS 71% of those where high intensity bridge was administered (p=0.027). With a median of 23.75 months, OS at 12 months was 62.23% (CI95% 51.71-74.89). No statistical significance was found between bridge chemotherapy groups, although it was higher in low intensity and immunotherapy group (68.33% CI95% 55.41-84.27) VS (57.89% CI95% 40.43-82.89) (p=0.11). With a median of 9.26 months, RFS at 12 months was 41.7% (CI95% 31.71-54.85). No statistical significance was found between bridge chemotherapy groups, but was higher in low intensity group and immunotherapy (51.8% CI95% 39.45-68.01) VS (34.69% CI95% 18.59-64.74) (p=0.089). With a median of 8.28 months, DOR at 12 months was 41.7% (CI95% 31.71-54.85). No statistical significance was found between bridge chemotherapy groups, with an increasing tendency in low intensity group and immunotherapy (51.8% CI95% 39.45-68.01) VS (34.69% CI95% 18.59-64.74) (p=0.089). In the multivariate analysis, grade 3-4 CRS HR 8.7 (CI95% 0.82-92) (p = 0.072) and high TB HR 4.7 (CI95% 1.1-20) (p = 0.038) were related with a decreased OS. CONCLUSIONS Receiving low intensity bridge or immunotherapy is related with high rates of CR. In the same way, in this group of patients there is tendency to achieve higher OS, RFS and DOR. This is the reason because its use should be prioritized avoiding those of high intensity bridge chemotherapy. High TB is an important risk factor related with a poor response and high grade CRS development, so it is essential to reduce TB previous CAR-T infusion in order to improve outcomes and reduce toxicities.

Real World Experience with a Zuma -1 Cohort 4 Adopted Approach to CRS and Icans in CAR-T Recipients

Introduction: Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy approved for treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). The registrational phase I/II ZUMA-1 study Cohorts 1 and 4 addressed toxicity management in terms of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) whereby tocilizumab and corticosteroids were deployed earlier in Cohort 4.(1,2) Although Cohort 4 consisted of only 41 patients, it demonstrated that earlier intervention resulted in significantly fewer cases of grade ≥3 CRS (2%) and ICANS (17%) and a lower cumulative dose of steroids. Furthermore, efficacy as determined by overall response rate (ORR) and complete response (CR) did not appear to be negatively impacted by earlier use of tocilizumab and corticosteroids. However, given the small number of patients in Cohort 4, concern has remained that earlier intervention may have a deleterious impact on CAR-T cell expansion, persistence, and efficacy. During the COVID-19 pandemic, with overwhelmed Intensive Care Units (ICUs) across the country, we adopted a Cohort 4 guided approach to CAR-T toxicity management with the hope of decreasing the need for ICU level of care following CAR-T infusion. Herein, we present our single-institution, real-world experience since implementing an early intervention strategy with Cohort 4 and compare it with our previous Cohort 1 axi-cel recipients in terms of toxicity (CRS, ICANS, ICU utilization) and efficacy. Methods: 119 patients receiving axi-cel CAR-T therapy for R/R LBCL are included in this single-institution, retrospective study with 70 in Cohort 1 and 49 in Cohort 4. The transition from a Cohort 1 to Cohort 4 approach occurred in March 2021. Thus, for Cohort 1 the data cut-off was February 2021 and for Cohort 4 it was after April 2021. The COVID pandemic and the lack of the ICU capacity was the initial chief rationale for transitioning to Cohort 4. This study was conducted following IRB approval and in accordance with the Declaration of Helsinki. R version 1.3.1099 (R-studio) was used for all statistical modeling. All statistical tests were 2-sided and conducted at the 0.05 level of significance. Results: The median age was 62 (22-88) years-old, 35% female gender, 76% advanced stage III-IV disease, 22% with bulky ≥10cm disease, 71% with diagnosis of Diffuse LBCL, and 26% with more than three lines of previous therapy. The median follow-up time at analysis was 1.5 years. Laboratory parameters and comorbidities did not significantly differ between groups except for a higher incidence of renal insufficiency in the Cohort 4 group (28.6% vs 4.3%, p<0.001) (see Table 1). The median maximum grade CRS was significantly lower for Cohort 4 (2 vs 1, p<0.001) although the median grade of ICANS was not different. The utilization of tocilizumab and siltuximab was similar in both groups. The duration of steroid use was comparable in both; however, the total steroid use (dexamethasone equivalent) was notably lower in Cohort 4 (110 mg vs 190 mg, p=0.026). ICU admission following CAR-T infusion was much lower in Cohort 4 (16.3% vs 60%, p<0.001). Most patients (>80%) were discharged home after CAR-T therapy and did not need placement in a rehabilitation center or long-term facility. The ORR and ongoing responses were similar in both groups with nearly 90% achieving a response and 60% with an ongoing response. The cumulative incidence of relapse, PFS, and OS were not significantly different between the groups (see Figure 1). Conclusion: The use of an early toxicity intervention strategy based upon ZUMA-1 Cohort 4 in the real world results in significantly lower high-grade CRS, decreased cumulative steroid dose, and an 73% reduction in ICU utilization without significantly impacting efficacy in terms of incidence of relapse, PFS, or OS. Our real-world experience with the adoption of a Cohort 4 strategy suggests that patient morbidity may be greatly attenuated without compromising CAR-T therapy response. However, the need for longer follow-up to evaluate the impact early use of steroids has on CAR-T persistence and PFS at >5 years remains.

ATA3431: Allogeneic CD19/CD20 Bispecific CAR EBV T Cells for the Treatment of B-Cell Malignancies

BACKGROUND: Chimeric antigen receptor (CAR) therapy targeted against CD19 has yielded remarkable clinical responses in the treatment of relapsed/refractory B-cell malignancies, but about a third of patients ultimately relapse due to the loss or downregulation of CD19. Furthermore, technical and logistical challenges associated with autologous CAR T therapy limits access for a majority of eligible patients. To help address these challenges, we have developed an allogeneic bispecific tandem CAR directed against both CD19 and CD20 (ATA3431) built on our Epstein-Barr virus (EBV) T-cell platform. EBV T cells maintain expression of endogenous T-cell receptors that have inherently low alloreactivity due to their recognition of defined viral antigens. CAR EBV T cells have demonstrated a favorable safety profile with no associated evidence for graft-versus-host disease or high-grade cytokine release syndrome (Curran KJ, 2020). The bispecific tandem CAR design allows either CD19 or CD20 target antigen recognition to activate the CAR EBV T cell, with the goal of extending durability of response and limiting antigen escape. In clinical trials, autologous bispecific CAR T cells were shown to be efficacious and safe (Larson 2023, Shah 2020). Additionally, a 1XX mutated CD3ζ signaling domain and our optimized CAR EBV T-cell platform preserve a central memory phenotype, robust expansion, functional persistence, and potent antitumor activity of ATA3431. METHODS: We generated CD20/CD19 bispecific CAR EBV T cells containing a modified CD3ζ signaling domain 1XX using our EBV T-cell platform. As a benchmark comparator, we generated autologous CD20/CD19 bispecific CAR T cells using a 12-day process derived from OKT3/CD28-activated T cells. The final products were characterized via immunophenotyping and evaluated for in vitro and in vivo response to antigen expressing targets. RESULTS: CD20/CD19 bispecific CAR EBV T cells generated from multiple healthy donors demonstrated stable CAR expression, a high proportion of T-cell memory populations, and consistent HLA-independent killing of CD19 + and/or CD20 + tumor cells over repeated in vitrochallenges. ATA3431 mediated highly potent antitumor activity in an established disseminated tumor model of Burkitt's lymphoma and correlated with long-term in vivo persistence of CAR T cells without additional cytokine support. Moreover, ATA3431-treated animals showed superior tumor growth inhibition compared to animals treated with autologous CD20/CD19 bispecific benchmark CAR T cells. No treatment-related toxicities were observed in animals treated with ATA3431. CONCLUSIONS: Preclinical evaluations of ATA3431 show B-cell tumor growth inhibition without any treatment-related toxicities and thereby support advancing ATA3431 for clinical evaluation. Curran KJ, Sauter CS, Kernan CS, et al. Durable remission following “off-the-shelf” chimeric antigen receptor (CAR) T-cells in patients with relapse/refractory (R/R) B-cell malignancies. 2020 Transplantation & Cellular Therapy Meetings. Orlando. Larson SM, Walthers CM, Ji B, Ghafouri SN, et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma. Cancer Discov. 2023 Mar 1;13(3):580-597. doi: 10.1158/2159-8290.CD-22-0964. PMID: 36416874; PMCID: PMC9992104. Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020 Oct;26(10):1569-1575. doi: 10.1038/s41591-020-1081-3. Epub 2020 Oct 5. PMID: 33020647.

Cardiac events after standard of care idecabtagene vicleucel for relapsed and refractory multiple myeloma

AbstractIdecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)–targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell–associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited.

383 TAKOTSUBO SYNDROME AFTER CAR-T CELL INFUSION

Abstract Introduction The mechanisms of cardiotoxicity during CAR-T cell therapy remain unclear to this day. We present the case of a 63-year-old woman with diffuse large B-cell lymphoma, who underwent CAR-T cell therapy. Five days after the infusion, she developed takotsubo cardiomyopathy. This is one of the rare cases of CAR-T cell-induced takotsubo cardiomyopathy. Case Description a 63-year-old woman with a diffuse large B-cell lymphoma and without significant cardiovascular history was treated with CAR-T cell therapy. The patient had arterial hypertension, dyslipidemia and history of CAD in the family. Prior to CAR-T cell therapy, she underwent baseline cardiac evaluation with an echocardiogram which showed a normal biventricular function. Within 24 hours of the infusion of CAR-T cells, she developed grade I cytokine release syndrome (CRS) with high-grade fever and sinus tachycardia. On day four, she developed grade three immune effector cell associated neurological syndrome which was treated with tocilizumab and dexamethasone. On day five laboratory testing showed a disproportionate elevation of BNP compared to hs-TnI. An ECG reported diffuse new-onset T wave inversion in all the precordial leads and a prolonged QT interval, and an echocardiogram showed severely reduced left ventricular ejection fraction (EF = 30%) with evidence of apical ballooning and right ventricular systolic dysfunction. Coronary angiography showed significant stenosis of the middle segment of the circumflex artery, which poorly could explain the clinical presentation of the patient. Ventriculography was also performed, which confirmed the ultrasound findings. During the next 48 hours, ECG and left ventricular function improved along with a gradual reduction of BNP and hs-TnI. We concluded that takotsubo syndrome was the most likely diagnosis. The InterTAK score was 89, which corresponded to a probability of takotsubo of 99.4%. The patient's therapy was then optimized with an increase in the dosage of angiotensin receptor antagonists and beta blockers. One month after CAR-T cell infusion, echocardiography showed complete recovery of biventricular function and ECG completely normalized, together with the values of BNP and TnI-hs. Medical treatment was left unmodified. Conclusions the pathophysiology of left ventricular systolic dysfunction during CAR-T cell therapy is unclear, but the main hypotheses are IL-6 mediated myocardial depression during CRS, stress-induced or takotsubo cardiomyopathy, and direct toxicity from CAR-T cells. From the currently available data from retrospective studies, cardiovascular events strongly overlap with CRS and, particularly, with high-grade CRS. Therefore, there is a strong rationale for early treatment with tocilizumab as it has been postulated from retrospective data a lower risk of cardiovascular events with earlier administration of tocilizumab during CRS. Surveillance for cardiotoxicity in patients receiving CAR-T cell therapy is mandatory for prompt recognition and treatment of cardiovascular complications. Our understanding of CAR-T cell-induced cardiomyopathy is still limited, and data regarding predictive factors for persistent cardiac dysfunction are lacking. It is important to differentiate cardiovascular events related to CAR-T cell therapy from epiphenomenon of CRS and capillary leak, to allow for a broader assessment of cardiac events among future CAR T-cell trials.

Prolonged duration of lymphocyte deficiency, high-grade CRS, and ventilation are linked to fungal breakthrough in patients with hematologic malignancies 60 days after CAR-T infusion: A single center case-control study

BackgroundRisk 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 MethodsA 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. ResultCumulatively, 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. ConclusionThere 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.

Tocilizumab for the Management of Cytokine Release Syndrome after Haploidentical Hematopoietic Transplant with Post-Transplant Cyclophosphamide-Based GvHD Prophylaxis

Haploidentical hematopoietic cell transplant (HaploHCT) with post-transplant cyclophosphamide (PTCy) has expanded the donor pool and made HCT available to patients without a matched donor. Cytokine release syndrome (CRS) is a syndrome of systemic inflammation with massive cytokine release, originally described after chimeric antigen receptor T cell (CAR T) therapy, is a frequent complication early after HaploHCT. Severe CRS after HaploHCT has been associated with higher non-relapse mortality (NRM) and worse overall survival (OS). Currently, no standard guidelines exist for CRS management in HaploHCT patients other than general supportive measures. Here, we described the impact of tocilizumab, an interleukin-6 receptor inhibitor used to manage CRS in CAR T therapy setting, on clinical outcomes in patients who experienced CRS after HaploHCT. We retrospectively identified a case series of 120 patients who experienced CRS after undergoing HaploHCT with PTCy-based GvHD prophylaxis at City of Hope from 06/2019 to 06/2021; of whom 11 patients received tocilizumab for CRS management. We matched these patients in a 1:2 ratio with 21 patients with CRS post-Haplo-HCT who did not receive tocilizumab (based on age, primary diagnosis, conditioning regimen, and CRS grading), then analyzed and compared OS, disease-free survival (DFS), relapse rate (RR), NRM, cumulative incidence (CIN) of grade II-IV and III-IV acute GvHD, and chronic GvHD between the two groups by univariate analysis. P-values were 2 sided at a significance level of 0.05. Table 1 summarize patient and transplant characteristics. Median age of patients in tocilizumab (TOCI) and no-tocilizumab (NO-TOCI) cohorts were 64 years (range: 27-70) and 62 years (range: 20-76). HLA 6/12 mismatch was the most common in both cohorts (81.8% in TOCI and 66.7% in NO-TOCI). All patients received mobilized peripheral blood stem cells (PBSC) as graft source. Majority of patients received non-myeloablative or reduced intensity conditioning regimens (81.8% in TOCI and 76.2% in NO-TOCI). Grade 2 CRS was most common in both cohorts (72.2% in TOCI and 71.4% in NO-TOCI); and grade 3-4 CRS was documented in 1 patient (9.1%) in TOCI and 2 patients (9.5%) in NO-TOCI cohort. Tocilizumab doses were 4 mg/kg (n=2), or 8 mg/kg (n=9). All patients but one (90.9%) received one single dose of tocilizumab and 1 patient received 2 doses of tocilizumab at 8 mg/kg/dose. All tocilizumab doses were administered either on day +3 (45%) or day +4 (55%) post-HCT (the patient with 2 doses was counted towards day +3). No high-grade tocilizumab-related side effects were documented in those 11 patients. Day 28 CIN of neutrophil engraftment was lower in TOCI compared to NO-TOCI patients (54.5% vs 76.2%, 95% CI: 21-79 and 50-90%, P=0.07 - Figure 1a). At 12 months post HaploHCT, survival outcomes were similar with NRM of 18.2 and 19% (95% CI: 3-46% and 6-38%, P=0.92); and RR of 19.5 and 14.3% (95% CI: 3-49% and 3-33%, P=0.78) in TOCI and NO-TOCI cohorts, respectively. DFS and OS were not affected by tocilizumab administration (P=0.90 and P=0.98; respectively). Three patients in TOCI and 7 patients in NO-TOCI cohort died; their causes of death were not directly related to CRS. While CIN of day 100 grade II-IV (P=0.97) and grade III-IV acute GvHD (P=0.47) were not affected by tocilizumab administration, CIN of chronic GvHD was significantly higher in TOCI compared to NO-TOCI (60.6 vs 23.8%, 95% CI: 19-86% and 8-44%, P=0.05 - Figure 1b). In conclusion, our results indicates that tocilizumab used for CRS management after in HaploHCT setting with PTCy-based GvHD prophylaxis was well tolerated and had no effect on survival outcomes. However, our study showed a trend towards delayed neutrophil engraftment and a statistically significant higher incidence of chronic GvHD in patients who received tocilizumab. It is possible that tocilizumab may interfere with T cell expansion, which could impact PTCy-mediated elimination of alloreactive T cell clones and/or affect regulatory T cells function; both mechanisms could lead to higher incidence of chronic GvHD. Using this approach to mitigate CRS risk should be reserved to patients with high grade CRS where mortality is high. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Soluble Factors Correlated with High-Grade Cytokine Release Syndrome (CRS): A Comparison of Subcutaneous (SC) Versus Intravenous (IV) Delivery of Alnuctamab (ALNUC; BMS-986349; CC-93269) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Soluble Factors Correlated with High-Grade Cytokine Release Syndrome (CRS): A Comparison of Subcutaneous (SC) Versus Intravenous (IV) Delivery of Alnuctamab (ALNUC; BMS-986349; CC-93269) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody (Ab) that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), odronextamab demonstrated encouraging activity in pts with DLBCL receiving ≥2 prior lines of therapy (LOT). DLBCL pts treated with odronextamab at doses ≥80 mg had an ORR of 53% and a CR rate of 53%. Responses were durable with 88% probability of an ongoing response at 12 mos (Bannerji R. et al. Lancet Haematol. 2022). The R2PD for R/R DLBCL was determined as 160 mg weekly. Here, we present for the first time, results from a prespecified analysis of the 160 mg DLBCL cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS). Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with DLBCL who had relapsed or were refractory to ≥2 prior LOT including an anti-CD20 Ab and an alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen was 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 160 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 160 mg full dose on C2D1 (0.7/4/20 regimen). 160 mg weekly continued until the end of C4. After C4, maintenance treatment was 320 mg odronextamab every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria. Results As of April 20, 2022, 121 pts with DLBCL were evaluable for safety; 90 for efficacy. Median age 67 y (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 58% IPI score ≥3, median prior LOT 2 (range 2-8), and 56% were primary refractory. 65% were double refractory to anti-CD20 Ab and alkylator in any LOT. Median duration of study follow-up was 17.1 mos. ORR and CR rate by ICR were 53% (48/90) and 37% (33/90), respectively, and were consistent across high-risk subgroups and in the subgroup treated with the 0.7/4/20 step-up regimen. CRs were durable; median duration of CR was not reached (95% CI: 10.2 mos-not estimable) and the probability of an ongoing CR at 9 mos was 73%. TEAEs occurred in 117 (97%) pts, considered treatment related in 102 (84%). In the overall safety-evaluable population, the most common TEAEs (>30% all grades) were CRS (53%), pyrexia (41%), and anemia (34%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥3 CRS events were observed. Only Grades 1 and 2 CRS were observed in 35% and 13% of DLBCL pts, respectively. All CRS events resolved with supportive measures; 20% of pts received tocilizumab and none required vasopressors or mechanical ventilation for CRS management. ICANS was reported in only 2 pts (4%) following revisions to step-up dosing, and both were low grade; ICANS occurred in 6% of pts with the 1/20 regimen. Treatment-related Grade 5 AEs occurred in 2 pts (2%), and treatment-related AEs led to odronextamab discontinuation in 8 pts (7%). Conclusions In the first results from a pivotal Ph 2 trial, odronextamab demonstrated clinically meaningful efficacy, durable CRs, and manageable safety with only low grade ICANS reported with the 0.7/4/20 regimen. The results of this study confirm the preliminary odronextamab activity observed in ELM-1, and collectively show odronextamab efficacy both before and after CAR T therapy in hard-to-treat, highly aggressive R/R DLBCL, while at the same time demonstrating a manageable safety profile. The 0.7/4/20 odronextamab step-up dose regimen for C1 mitigates the risk of high-grade CRS, which has been observed consistently with other bispecifics and CAR T therapies and may present an important future option for the management of pts with R/R DLBCL. Updated safety and efficacy data will be presented.

Cell Product Differences on Incidence of Venous Thromboembolism in Patients Treated with CAR T-Cells for Aggressive B-Cell Lymphomas

Introduction Chimeric antigen receptor T (CAR T)-cell therapy has substantial activity in relapsed lymphoid malignancies. However, it is associated with important complications, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Venous thromboembolic events (VTEs) following CAR T-cells have been reported with variable incidence. Risk factors for the development of VTEs following CAR T-cell therapy are largely unknown, including whether the CAR T-cell construct is associated with increased VTEs. Methods We retrospectively evaluated patients treated at our institution who received CAR T-cell therapy for non-Hodgkin lymphoma between May 2018 and January 2022. Baseline characteristics and outcomes were collected. VTEs included deep venous thrombosis and pulmonary embolism. The cumulative incidence (CI) of VTE was calculated with death as competing risk and comparisons between groups were done with Gray test. Univariate comparisons of baseline parameters were performed with Fisher's exact test evaluating the following covariates: age (older or younger than 70 years), LDH and C-reactive protein levels, ECOG performance status, revised IPI, BMI, personal history of VTE, and stage. Due to the low number of VTEs, we did not attempt multivariate modeling based on baseline characteristics. All analyses were performed using R. This study was approved by our Institutional Review Board. Results We identified 95 patients treated with CAR T-cells between May 2018 and January 2022. The majority had diffuse large B-cell lymphoma (DLBCL) (88, 93%). Baseline characteristics are listed in Table 1. Prior history of VTE occurred in 16 patients and 27 received at least one dose of therapeutic or prophylactic anticoagulation post-CAR T infusion prior to developing VTE. Most patients had central venous access during their hospitalization for CAR T cell therapy (n = 91). A total of 56 patients received axicabtagene ciloleucel (58.9%), 30 patients received tisagenlecleucel (31.6%), 5 patients received brexucabtagene autoleucel (5.3%), and 4 received lisocabtagene maraleucel (4.2%). Post-CAR T VTE occurred in 13 patients (14%); median time to VTE (IQR) was 15 days (7-48), with a 100-day cumulative incidence of 12%. All VTEs were DVTs and the majority were PICC line-associated (10, 77%). The incidence of VTE was higher for patients treated with axicabtagene ciloleucel or brexucabtagene autoleucel in contrast to 41BB-containing constructs (16% vs. 3%, p = 0.03) (Figure 1). Among baseline characteristics, a prior history of VTE was associated with increased risk of subsequent VTE (39% vs. 13% without prior VTE, p = 0.04). The 100-day CI of VTE for patients with and without CRS were 15% and 4% (p = 0.09), while the 100-day CI of patients with and without ICANS were 18% and 7% (p = 0.09). Subgroup analysis of patients treated with CD3ζ/CD28 signaling showed that 100-day VTE CI was higher among patients with a prior history of VTE (33% vs. 12%, p = 0.03) and those with BMI of ≥ 30 (38% vs. 11%, p = 0.03). We did not observe an increased incidence of VTE in patients with baseline ECOG performance status ≥ 2, stage III/IV disease, elevated baseline lactate dehydrogenase or C-reactive protein. After a median follow up of 24 months (IQR 13-36), the median progression free survival (PFS) was 7 months (95% CI = 4-12) while the median overall survival (OS) was 14 months (95% CI = 11-19), there were no statistically significant differences in PFS or OS among patients with and without VTE. Conclusions VTEs are an emerging toxicity associated with CAR T cell therapy. We show that increased VTE incidence at 100 days is associated with the use of CD3ζ/CD28 CAR T-cells. This difference may correlate with differing degrees of systemic inflammatory response, as previous reports have detailed higher incidence of high-grade CRS with axicabtagene ciloleucel vs. tisagenlecleucel, and other construct-specific factors may further increase VTE risk in patients with established VTE risk factors (e.g. history of VTE and obesity). We also observed that a large proportion of post CAR T VTEs corresponded to line-associated DVTs. Taken together, these findings may help identify patients at increased risk of VTE after CAR T-cell therapy and potentially guide decisions on surveillance, choice of central access, or prophylactic anticoagulation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Bridging Therapy on Infectious Complications Post CAR T-Cell Therapy: The UT Southwestern Experience

Background: CAR T-cell therapy (CAR T) has become a powerful new tool in the treatment of relapsed/refractory (r/r) hematologic malignancies. Infections are well-recognized risks of CAR T. Bridging therapy is often employed to allow patients to reach successful infusion but may also further immunosuppress this already vulnerable group. This study aims to identify patterns of infections post-CAR T and the potential impact of bridging therapy. Methods: Medical records of patients who underwent apheresis for CAR T from 2018-2022 for r/r lymphomas or multiple myeloma (MM) at UT Southwestern were analyzed. Demographics, treatment characteristics and infection data were collected via retrospective chart review. Post-CAR T infections were identified by reviewing patient hospitalizations after CAR T infusion for infectious complications confirmed by positive diagnostic studies during admission. Infections were categorized as bacterial, viral, fungal, or multi-pathogenic. Time-to-infection was calculated from lymphodepletion (LD) date. Categorical variables were compared using Fisher's exact test. Continuous variables were compared using Mann-Whitney U test. Overall- and progression-free survival (OS and PFS) were calculated from CAR T infusion date, estimated by the Kaplan-Meier method, and compared using a log-rank test. Results: Data were collected on 75 total patients, 44 with lymphoma and 31 with MM, who underwent apheresis and 74 (98.7%) underwent CAR T. Baseline patient characteristics are shown in Table 1. All patients received standardized opportunistic infection (OI) prophylaxis and intravenous immunoglobulin (IVIG) and growth factor support based on institutional guidelines. Thirty-eight patients (51%) had a post-CAR T infection. Post-CAR T infections manifested at a median of 117 days (range: 12 - 1344 days) after LD. Patients who received bridging therapy had an earlier median incidence of post CAR T infections (92 vs 113 days post-LD, p = 0.03). Number of prior lines of therapy did not predict infection rates or time to infection. Time-to-infection did not vary by lymphoma versus MM or by cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity (ICANS) grade. MM patients had a numerically higher rate of viral infections (77% vs 41%) while lymphoma patients had a higher bacterial infection rate (65% vs 55%). A majority (58%) of these patients had infectious events between 31- and 100-days post lymphodepletion [Figure 2]. Infection rates were not significantly associated with tocilizumab or steroid usage during CAR T. In our cohort, 77% of patients received bridging. Bridging therapy was associated with a significantly higher neutropenic fever rate (73% vs 37%, p = 0.006), which persisted after adjusting for prior lines of therapy. All patients with neutropenic fever received broad-spectrum antibiotic coverage. In lymphoma patients, bridging therapy was associated with higher grades of CRS (p = 0.018). Being hospitalized for infection within 6 months (p=0.01) or receiving antibiotics in the month (p=0.02) prior to lymphodepletion, were associated with grade ≥3 CRS. One-year PFS and OS were 55% and 74% for the entire cohort. Four patients died due to infectious complications after successful CAR T infusion at a median of 163 days post infusion. Patients who had post-CAR T infections trended towards worse progression-free survival (1-year PFS 65% vs 46%, p = 0.1) and had similar OS (1-year OS 70% vs 77%, p = 0.75). Conclusions: Bridging therapy prior to CAR T may increase the risk of neutropenic fever and be associated with earlier infectious risk. Febrile neutropenia and high-grade CRS drive more intensive resource utilization, which may be mitigated with more intentional patient selection for bridging therapy.Our findings show that post-CAR T infections contribute to significant morbidity, and thus calls for personalizing bridging strategies, peri-CAR T OI prophylaxis and infection management. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Systematic Meta-Analysis of Cytokine Release Syndrome Incidence in B-Cell Maturation Antigen-Targeting Chimeric Antigen Receptor T-Cell Therapy and Bispecific Antibodies for Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: B-cell maturation antigen (BCMA)-targeting immunotherapies (eg, chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAb)) have achieved remarkable clinical responses in patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T cell activation and cytokine elevations leading to cytokine release syndrome (CRS), which could be life-threatening if presenting in high grades. This study utilized a meta-analysis approach to compare CRS profile in BCMA-targeting CAR-Ts vs. BsAbs in pts with RRMM. Methods: CRS profiles for BCMA-targeting CAR-T and BsAb therapies were compiled from publicly available data in published literature up to July 2022. The meta-analysis included 28 CAR-Ts, including 2 approved therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) and 8 investigational BsAb. The weighted proportion of all Grades, Grade 1-2, and Grade ≥3 CRS was estimated using fixed- and random-effects meta-analytic models. Between-study heterogeneity was evaluated using the heterogeneity index (I2) and P-value. Subgroup analyses were performed to assess the differences in CRS incidence and severity across CAR-T and BsAb and routes of BsAb administration (IV vs. SC). Dosing, priming/premedication (premeds) regimens, time to onset, duration of CRS, and CRS management were compared. Results: A total of 53 studies including 2092 RRMM pts treated with BCMA-targeting CAR-T and BsAb therapies were included in the analysis. The meta-analysis showed a significantly higher weighted proportion of CRS with CAR-T therapies vs. BsAb (all Grades 87% (95% CI: 80-93) vs. 67% (95% CI: 58-75), I2= 87%, P-value <0.01; and Grade ≥3 6% (95% CI: 3-9) vs. 0.2% (95% CI: 0.0-1.7), I2= 65%; P-value <0.01 (Figure 1). Average time to CRS onset was delayed (5 days vs. 1 day) and the median duration of CRS was longer (5 days vs. 2 days) after CAR-T compared to BsAb. Use of premeds (eg, corticosteroids, antihistamines, and antipyretics) was reported for 5 BsAb agents, while premeds were not used to reduce CRS severity with CAR-Ts. Tocilizumab and corticosteroids were used to manage CRS in 50% (325/649 pts; 12 studies) and 17% (87/525 pts; 9 studies) of patients, respectively, treated with CAR-T therapies, as compared to 31% (212/677 pts; 13 studies) and 16% (102/625 pts; 9 studies) of patients, respectively, treated with BsAb agents. Two BsAbs evaluated both IV and SC routes (Table 1). A higher incidence of CRS Grade 1-2 was found following SC compared to IV route of BsAb administration: 73% (95% CI: 62-83) vs. 58% (95% CI: 48-68) (I2=73%; P-value= 0.05), respectively. However, higher doses were evaluated with SC compared to IV routes. A higher incidence of CRS Grade ≥3 was observed with BsAb administered IV vs. SC: 0.9% (95% CI: 0.0-4%) vs. 0.0% (95% CI: 0.0-0.3%), respectively (I2= 49%; P-value = 0.05). CRS occurrence by dose number administered was reported for 3 BsAbs. Except for teclistamab, which reported CRS events in 4.8%, 2.4%, 1.2% and 3.6% of pts following the 4th, 5th, 6th, and later doses, respectively, the other 2 BsAbs (CC- 93269 and elranatamab) reported CRS episodes mostly following either the first or second dose, and rarely with the third or later doses. Conclusions: The current analysis showed BCMA CAR-T therapies to be associated with higher CRS incidence, higher rates of Grade ≥3 CRS, longer CRS duration, and more prevalent tocilizumab and steroid use for CRS management compared to BsAb, possibly due to a) higher cytokine production following CAR-T therapies and/or b) use of premedication and priming regimens with BsAb which may improve the CRS profile (Table 1). Despite evaluation of a higher dose range, the proportion of CRS Grades ≥3 was higher with BsAb dosed IV vs. SC suggesting that the SC route of administration may allow exploration of higher doses while reducing the incidence of high-grade CRS. This meta-analysis showed that different types of BCMA-targeting immunotherapies and administration routes could contribute to different CRS profiles. The analysis is limited to published literature, and biases due to missing data or different reporting approaches cannot be excluded (eg, several BsAbs reported CRS rates pooled across doses). The analysis will be updated upon availability of full publications with more granular data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells

Abstract Background: H3K27M-mutated DMGs are universally lethal central nervous system tumors that express high levels of the disialoganglioside GD2. IV administered GD2-CAR T cells (GD2-CART) regress DMG in preclinical models, and locoregionally delivered CARs demonstrate enhanced activity in xenograft models of brain tumors. Methods: NCT04196413 is a 3+3 Phase I dose escalation trial testing GD2-CART in patients with H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1: 1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART (10-30e6 GD2-CART) administered via Ommaya catheter without LD every 4-8 weeks for a maximum of 12 doses. We previously reported early results from 4 patients treated on DL1, which demonstrated clinical activity and manageable toxicity. Here we provide updated results for DL1 and DL2. Results: Thirteen subjects were enrolled and 11 treated [n=4 DL1 (3 DIPG/1 sDMG); n=9 DL2 (7 DIPG/2 sDMG)]. Two subjects were removed prior to treatment due to rapid progression. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade 4 cytokine release syndrome (CRS), successfully managed with tocilizumab, anakinra, and corticosteroids. CRS occurred earlier on DL2 vs. DL1 (Day 3 vs 7). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN), which was successfully managed with anakinra and, in some cases, CSF drainage and dexamethasone. No DLT due to TIAN has occurred. Ten patients have had adequate follow-up to assess benefit. Nine experienced radiographic and/or clinical benefit after IV infusion, and they received subsequent ICV GD2-CART infusions (median= 4 ICV infusions/pt, range 1-6). ICV infusions were not associated with high-grade CRS, although some subjects developed transient fever, headache, meningismus, nausea, and/or vomiting, and several subjects developed TIAN. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit at 11+, 9.5+, 8+ and 7+ months following enrollment. A 31-year-old with sDMG has experienced a near-complete (&amp;gt;95%) reduction in tumor volume and a 17-year-old with DIPG experienced a near-complete (&amp;gt;98%) reduction in volume of a pontine tumor. Conclusions: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with unacceptable rates of high-grade CRS at 3e6/kg. ICV GD2-CART without LD, administered following a previous course of IV GD2-CART with LD, has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD. Patients are eligible for up to 12 ICV infusions of GD2-CART administered every 4-6 weeks. Clinical benefit will be formally assessed using patient-reported outcomes. GD2-CART has the potential to transform therapy for patients with H3K27M+ DIPG/sDMG. Citation Format: Robbie G. Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Valentin Barsan, Rebecca Richards, Cynthia Campen, Agnes Reschke, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Ashley Jacobs, Karen Yamabe-Kwong, Lindsey Rasmussen, Esther Nie, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Snehit Prabhu, Katherine E. Warren, Tim Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Michelle Monje, Crystal L. Mackall. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells [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 CT001.

DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells

BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (>95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.