Severe Cytokine Release Syndrome Research Articles

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project

The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR Tcell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR Tcells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. Although this exploratory study was limited by unadjusted cross-study comparisons, it independently reproduced known risk factors for CAR Tcell toxicity. Findings provide stakeholders in the CAR Tcell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.

Sequential assessment of cardiac function after CART therapy in accordance with the grade of CRS

Abstract Introduction As Chimeric Antigen Receptor T-cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the potential involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but no prospective study has reported the time course of cardiac dysfunction. Moreover, the relationship between the severity of CRS and cardiac dysfunction after CAR-T therapy remains unclear. Purpose The objectives of this study are to prospectively examine the sequential changes in cardiac markers overtime after CAR-T therapy and to clarify the association between the grade of CRS and cardiac markers. Methods In this prospective observational study, 30 DLBCL patients who underwent CAR-T therapy from July 2020 to March 2022 were enrolled. Before and after the treatment, the level of cardiac biomarkers and echocardiographic index were sequentially collected. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely low-CRS group (CRS <2) and high-CRS group (CRS ≥2). Cardiac biomarkers and echocardiographic parameters were further analyzed in both groups. Results The average age of participants was 59.6 years, and 9 patients (30%) were female. The average duration of DLBCL was 2.7 years. The CRS showed its peak severity on day 3. The number of patients in low- and high-CRS group was 13 and 17, respectively and tocilizumab was administrated for 46% and 71% of the patients in low- and high-CRS group, respectively. At the baseline before CAR-T therapy, there were no significant differences in cardiac parameters between the two groups. During the follow-up, sequential measurements of cardiac biomarkers revealed that high-CRS group showed significantly higher NT-proBNP level compared to that of low-CRS group (NT-proBNP; 90pg/ml vs. 623pg/ml, p=0.0001, respectively) and both had their peak on day 3, whereas troponin T level did not show any differences. Likewise, sequential measurements of echocardiographic parameters revealed that high-CRS group showed significantly increased E/A compared to low-CRS group on day 7 (E/A; 0.77 vs. 0.90, p=0.021, respectively), but not in the later phase. The parameters for systolic function including GLS and EF and parameters for diastolic function such as E/e' and LAVI did not alter among the two groups throughout the follow-up. Conclusion In the patients who underwent CAR-T therapy for DLBCL, the elevation of NT-proBNP level and increase in E/A was transiently observed within a week and correlated with the severity of CRS. Funding Acknowledgement Type of funding sources: None.

CT-169 Cytokine Release Syndrome After Peripheral Blood Haploidentical Stem Cell Transplantation With Post-Transplant Cyclophosphamide: Time of Onset Matters

The use of post-transplant cyclophosphamide (PT-Cy) has favored haploidentical hematopoietic stem cell transplantation (haplo-HSCT) when an HLA-matched donor is not available or when an urgent transplant is needed. Although a high percentage of patients receiving PT-Cy haplo-HSCT develop cytokine release syndrome (CRS) after infusion, it only seems to affect prognosis in the reduced proportion of patients that develop severe CRS. Literature regarding the clinical impact of this complication is scarce. The aim of our study is to analyze new CRS characteristics and their prognostic implication on both transplant-related mortality (TRM) and overall survival (OS). From the cohort of 637 patients who underwent allo-HSCT at our center between January 2012 and December 2020, 150 patients who received PT-Cy haplo-TPH were selected for this retrospective analysis. Regarding CRS analysis, 16 patients were excluded due to the impossibility to distinguish between infectious and CRS fever. Median follow-up was 18 months (37 months for alive patients). Most patients (86%) developed CRS. The cohort was divided into two groups: patients who developed early-onset CRS (≤24h after infusion, 50%) and those with late-onset CRS or no CRS. Patients who developed early-onset CRS had a significant increase in first-year TRM (31% vs 15%, log-rank p=0.014) as well as lower first-year OS (60% vs 79%, log-rank p=0.008). Multivariate analysis of first-year TRM identified the following independent prognostic factors: SOS (HR 9.24, p<0.001), aGvHD grade ≥3 (HR 6.89, p<0.001), early-onset CRS (HR 3.09, p=0.007) and patient age at transplantation (HR 1.05 per year increment, p=0.002). Several risk factors were associated with developing early-onset CRS in a multivariate analysis: modified Baltimore haplo-HSCT platform (HR 7.54, p<0.001), active disease at transplantation (HR 2.94, p=0.015) and increased infused CD3+ cells (HR 1.05 per 107/kg increment, p=0.002). Graft-cryopreservation would be a protective factor (HR 0.14, p=0.005). We propose the definition of early-onset CRS as the one that is developed within 24h after haplo-HSCT infusion. Patients who develop early-onset CRS have a higher TRM and lower OS. However, this is a single-center retrospective study and further studies will be required in order to confirm these findings.

The risk factors and early predictive model of hematotoxicity after CD19 chimeric antigen receptor T cell therapy.

Hematotoxicity is the most common long-term adverse event after chimeric antigen receptor T cell (CAR-T) therapy. Here, a total of 71 patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma (LBCL) were used to develop an early hematotoxicity predictive model and verify the accuracy of this model. The incidences of early hematotoxicity at 3 month following CAR-T infusion in B-ALL and LBCL were 45.5% and 38.5%, respectively. Multivariate analyses revealed that the severity of cytokine release syndrome (CRS) was an independent risk factor affecting early hematotoxicity. The analysis between the peak cytokine levels and early hematotoxicity suggested that tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were closely associated with early hematotoxicity. Then, an early predictive model of hematotoxicity was constructed based on the peak contents of TNF-α and CRP. This model could diagnose early hematotoxicity with positive predictive values of 87.7% and 85.0% in training and validation cohorts, respectively. Lastly, we constructed the nomogram for clinical practice to predict the risk of early hematotoxicity, which performed well compared with the observed probability. This early predictive model is instrumental in the risk stratification of CAR-T recipients with hematotoxicity and early intervention for high-risk patients.

CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies

Immunotherapy utilizing chimeric antigen receptor T cell (CAR-T) therapy holds promise for hematologic malignancies, however, response rates and associated immune-related adverse effects widely vary among patients. Here we show, by comparing diversity and composition of the gut microbiome during different CAR-T therapeutic phases in the clinical trial ChiCTR1800017404, that the gut flora characteristically differs among patients and according to treatment stages, and might also reflect patient response to therapy in relapsed/refractory multiple myeloma (MM; n = 43), acute lympholastic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). We observe significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we find that patients with severe cytokine release syndrome present with higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, which is reproducible in an independent cohort of 38 MM patients. This study has important implications for understanding the biological role of the microbiome in CAR-T treatment responsiveness of hematologic malignancy patients, and may guide therapeutic intervention to increase efficacy. The success rate of CAR-T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here we show that therapeutic response in MM, ALL and NHL, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

Cytopenia after chimeric antigen receptor T cell immunotherapy in relapsed or refractory lymphoma.

BackgroundPatients with relapsed or refractory (R/R) lymphomas have benefited from chimeric antigen receptor (CAR)-T-cell therapy. However, this treatment is linked to a high frequency of adverse events (AEs), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. There has been increasing interest in hematological toxicity in recent years, as it can result in additional complications, such as infection or hemorrhage, which remain intractable.MethodsWe conducted a retrospective, single-institution study to evaluate the patterns and outcomes of cytopenia following CAR-T-cell infusion and potential associated factors.ResultsOverall, 133 patients with R/R lymphoma who received CAR-T-cell therapy from June, 2017 to April, 2022 were included in this analysis. Severe neutropenia, anemia and thrombocytopenia occurred frequently (71, 30 and 41%, respectively) after CAR-T-cell infusion. A total of 98% of severe neutropenia and all severe thrombocytopenia cases occurred in the early phase. Early severe cytopenia was associated with CRS incidence and severity, as well as peak inflammatory factor (IL-6, C-reactive protein (CRP), and ferritin) levels. In multivariate analysis, prior hematopoietic stem cell transplantation (HSCT), baseline hemoglobin (HB), and lymphodepleting chemotherapy were independent adverse factors associated with early severe cytopenia. In addition, 18% and 35% of patients had late neutrophil- and platelet (PLT)-related toxicity, respectively. In multivariate analysis, lower baseline PLT count was an independent factor associated with late thrombocytopenia. More severe cytopenia was associated with higher infection rates and poorer survival.ConclusionsThis research indicates that improved selection of patients and management of CRS may help to decrease the severity of cytopenias and associated AEs and improve survival following CAR-T-cell therapy.Clinical Trial Registration https://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Autologous Anti-CD19 CAR T-Cells immunotherapy in relapsed/refractory acute lymphoblastic leukemia patients. A systematic review and meta-analysis

Introduction: Acute Lymphoblastic Leukemia (ALL) is the most prevalent malignancy in children; however, when the neoplasm becomes refractory/relapses (R/R) the cure possibilities are practically null. Objectives: To analyze the Anti-CD19 Chimeric Antigen Receptors (CAR) T-Cells immunotherapy efficacy in the treatment of R/R ALL, providing evidence about the efficacy and safety of the therapy for the analyzed group. Methods: The study consisted of a systematic review and meta-analysis based on the analysis of indexed articles. The searches were carried out with the terms: “acute lymphoblastic leukemia”, “CAR T”, and “CD19-specific chimeric antigen receptor”. Results: Only 18 of the 94 articles obtained initially met the inclusion criteria and were selected for review, totaling 637 patients. Thus, it was observed in the responses that approximately 81% of the patients achieved a Complete Response; 7% did not respond; the neoplasm relapsed in 17% of the cases; and 6.1% of the patients died. The main side effects found were Cytokine Release Syndrome (CRS), Severe Cytokine Release Syndrome, and Neurotoxicity, present in 36.3%, 29%, and 24% of patients, respectively. Conclusion: Anti-CD19 CAR T-Cells immunotherapy is an effective therapy, capable of producing high rates of complete remission in R/R ALL treatment.

The correlation factors and prognostic significance of coagulation disorders after chimeric antigen receptor T cell therapy in hematological malignancies: a cohort study.

BackgroundAlong with cytokine release syndrome (CRS) and neurotoxicity, coagulation disorder is a common early complication of chimeric antigen receptor (CAR)-T cell therapy. However, the mechanisms and prognostic significance of CAR-T-related coagulation disorders are not fully known. This study explored the possible correlation factors and prognostic significance of coagulation disorders after CAR-T cell infusion in patients with relapsed/refractory hematological malignancies.MethodsThis cohort study included 56 patients with relapsed/refractory hematological malignancies who were treated with CAR-T cells between April 2017 and February 2022. The median follow-up was 26.8 months. Coagulation disorders were defined as the abnormality in at least one coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer. The correlation factors of coagulation disorders were analyzed using Wilcoxon rank-sum test, Fisher’s exact test, paired t-test and Spearman correlation coefficient. The prognostic significance of coagulation disorders was analyzed using Kaplan-Meier method and stepwise multivariate Cox regression model.ResultsThe incidence of coagulation disorders was 59% within 1 month of CAR-T cell infusion. PT prolongation, APTT prolongation, TT prolongation, and D-dimer increase peaked at a median of 6–9 days, and fibrinogen decreased to its lowest value at a median of 12 days. Coagulation disorders in patients with severe CRS were more significant (P<0.001). Abnormality of coagulation parameters was closely related to cytokines, CAR-T cells, liver function parameters, and von Willebrand Factor (VWF) in both peak level and peak time (P<0.05). Statistical analysis showed that coagulation disorders were associated with higher initial response rates (TT, P=0.006; D-dimer, P=0.010) and also longer progression‐free survival (PFS) (PT, P=0.017; APTT, P=0.018; TT, P=0.001; Fibrinogen, P=0.003; D-dimer, P<0.001) in CAR-T therapy, with TT prolongation (HR =0.279, 95% CI: 0.099–0.782, P=0.015) and D-dimer increase (HR =0.218, 95% CI: 0.087–0.548, P=0.001) independent predictors for PFS.ConclusionsThe protection of liver and endothelial cells may reduce CAR-T-related coagulation disorders. Further, coagulation disorders occurring within 1 month of CAR-T cell infusion can serve as a new predictor for prognosis in patients with hematological malignancies.

Humanized CD19-directed CAR-T Cell Therapy in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia With CNSL or Neurological Comorbidity.

Chimeric antigen receptor T cell (CAR-T) therapy has breakthrough potential for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). However, because of the risk for neurotoxicity, trials usually exclude patients with central nervous system leukemia (CNSL) or active neurological comorbidities (NC). Here, we evaluated the efficacy and neurotoxicity of humanized CD19-directed CAR-T therapy for R/R ALL with CNSL or NC. Of 12 enrolled patients, 4 had CNSL with bone marrow (BM) or testicular recurrence, 3 had BM relapses with NC, and 5 had BM relapse without NC. Bridging chemotherapy was performed for high tumor burden before CAR-T therapy. Patients with CNSL or BM relapse with NC or without NC experienced 100% complete remission. Tumor burden reduction did not occur in 1 patient with NC, who developed grade 5 neurotoxicity before BM assessment, and one patient with CNSL developed leukoencephalopathy. Severe cytokine release syndrome and neurotoxicity developed in 0% with CNSL, 33.3% with BM relapse and NC, and 0% without NC. CAR-T cells expanded in the cerebrospinal fluid (CSF) of all patients with no difference among CNSL, BM with NC, or no NC (respective median percentages among lymphocyte: 33.7%, 48.2% and 34.5%, P=0.899; respective median concentrations: 0.82, 2.21, and 0.46/μL, P=0.719). Median CSF CAR-T cell duration was 5.5 (3–9) months with CNSL and 3 (2–3) months without CNSL (P=0.031). CAR-T can be given safely and effectively to pediatric patients with R/R ALL with CNSL or NC who have near-normal neurological status. High tumor burden may confer increased risk for severe neurotoxicity.

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients

Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin’s lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined P=0.021 and undefined versus undefined P=0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months P < 0.0001 and undefined versus 2.0months P<0.001). While severe CRS was also an independent prognostic factor but associated with inferior PFS and OS. The 2-year OS and PFS for patients with grade 3 CRS were significantly shorter than those with grade 0-2 CRS (4.1 months versus undefined P<0.0001 and 1.7 months versus undefined P=0.0002). This study indicated that CD19/CD22 dual-targeted CAR-T therapy under a decitabine-containing lymphodepletion regimen may be a safe, potent effective approach to R/R DLBCL patients.

A Computational Model of Cytokine Release Syndrome during CAR T-cell Therapy.

Cytokine release syndrome (CRS) is a lethal adverse event in chimeric antigen receptor (CAR) T-cell therapy, hindering this promising therapy for cancers, such as B-cell acute lymphoblastic leukemia (B-ALL). Clinical management of CRS requires a better understanding of its underlying mechanisms. In this study, a computational model of CRS during CAR T-cell therapy is built to depict how the cellular interactions among CAR T-cells, B-ALL cells, and bystander monocytes, as well as the accompanying molecular interactions among various inflammatory cytokines, influence the severity of CRS. The model successfully defines the factors related to severe CRS and studied the effects of immunomodulatory therapy on CRS. The use of the model is also demonstrated as a precision medicine tool to optimize the treatment scheme, including personalized choice of CAR T-cell products and control of switchable CAR T-cell activity, for a more efficient and safer immunotherapy. This new computational oncology model can serve as a precision medicine tool to guide the clinical management of CRS during CAR T cell therapy.

The impact of race, ethnicity, and obesity on CAR T-cell therapy outcomes

AbstractCancer outcomes with chemotherapy are inferior in patients of minority racial/ethnic groups and those with obesity. Chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for relapsed/refractory hematologic malignancies, but whether its benefits extend commensurately to racial/ethnic minorities and patients with obesity is poorly understood. With a primary focus on patients with B-cell acute lymphoblastic leukemia (B-ALL), we retrospectively evaluated the impact of demographics and obesity on CAR T-cell therapy outcomes in adult and pediatric patients with hematologic malignancies treated with CAR T-cell therapy across 5 phase 1 clinical trials at the National Cancer Institute from 2012 to 2021. Among 139 B-ALL CAR T-cell infusions, 28.8% of patients were Hispanic, 3.6% were Black, and 29.5% were overweight/obese. No significant associations were found between race, ethnicity, or body mass index (BMI) and complete remission rates, neurotoxicity, or overall survival. Hispanic patients were more likely to experience severe cytokine release syndrome compared with White non-Hispanic patients even after adjusting for leukemia disease burden and age (odds ratio, 4.5; P = .001). A descriptive analysis of patients with multiple myeloma (n = 24) and non-Hodgkin lymphoma (n = 23) displayed a similar pattern to the B-ALL cohort. Our findings suggest CAR T-cell therapy may provide substantial benefit across a range of demographics characteristics, including for those populations who are at higher risk for chemotherapy resistance and relapse. However, toxicity profiles may vary. Therefore, efforts to improve access to CAR therapy for underrepresented populations and elucidate mechanisms of differential toxicity among demographic groups should be prioritized.

CD123-directed allogeneic chimeric-antigen receptor T-cell therapy (CAR-T) in blastic plasmacytoid dendritic cell neoplasm (BPDCN): Clinicopathological insights

PurposeBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy associated with overexpression of CD123. Allogeneic chimeric antigen receptor T cells (CAR-T) directed against CD123 in BPDCN have been studied in clinical trials. We performed post-mortem analysis of a patient treated with anti-CD123 CAR-T to elucidate cause of death, development of cytokine release syndrome (CRS), and tissue distribution of UCART123 cells. MethodsA post-mortem multidisciplinary clinicopathologic analysis was performed with digital droplet polymerase chain reaction of isolated blood and tissue ribonucleic acid (RNA) to evaluate tissue distribution of infused CAR-T. Multiparameter flow cytometry for detection of CAR-T was used for whole blood samples. Cytokine levels in plasma were measured using multiplex bead assay. Gene expression profiling on isolated RNA was performed using semi-custom Nanostring immune gene panel and RNA-sequence method. RNA in situ hybridization was performed using CAR-specific probe. ResultsThe patient developed severe clinical CRS refractory to corticosteroids, tocilizumab, and lymphodepletion. Despite significant reduction in BPDCN lesions, the patient passed away on day 9 of CAR-T. Autopsy results show that following lymphodepletion and UCART123 administration, the patient remained severely lymphopenic with few UCART123 cells detected, predominantly localized to spleen. ConclusionsNo definitive cause of death was determined, but we hypothesized that the patient may have succumbed to CAR-T-mediated cardiopulmonary toxicity. UCART123 cells displayed low overall distribution, with predominance in immune organs and tissues. Mechanism of CRS development is still poorly understood in patients receiving CAR-T therapy. Future directions in the field developing CD123-targeted agents in BPDCN are discussed.

The impact of tocilizumab treatment for cytokine release syndrome on the incidence of early blood stream infections after peripheral blood haploidentical hematopoietic cell transplantation

Cytokine release syndrome (CRS) is a potentially fatal systemic inflammatory response that can occur in patients undergoing peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT). Severe CRS has previously been associated with increased infection risk. IL-6 inhibitors, such as tocilizumab, are useful in moderate to severe CRS, but their effect on infection risk has not been established in this setting. We examined the effect of tocilizumab on blood stream infections (BSIs) in the early post-transplant period in 235 patients who underwent haplo-HCT from 2013 to 2020. Mild CRS was associated with a lower incidence of BSI than severe CRS (OR 0.31, 95% CI 0.13–0.74). In the tocilizumab group, 31% of patients had positive blood cultures versus 14% in the non-tocilizumab group (OR 1.61, 95% CI 0.30–8.60, p = 0.58). However, when controlling for CRS grade, tocilizumab was not independently associated with increased rates of BSIs, suggesting it does not further increase infection risk.

Patient preferences for treatment in relapsed/refractory diffuse large B-cell lymphoma: a discrete choice experiment

Aim: We quantified patient preferences for second-line diffuse large B-cell lymphoma therapies, including attributes of chimeric antigen receptor (CAR) T-cell therapy. Materials & methods: Using a discrete choice experiment, we surveyed 224 diffuse large B-cell lymphoma patients from the USA and Europe. Patients chose between two treatment options defined by six attributes with predefined levels for overall survival, adverse events (severe cytokine-release syndrome, severe neurological toxicities, severe infection) and time to return to pre-treatment functioning. Results: Increasing the probability of 1-year survival was most important to patients, followed by avoiding risks of cytokine-release syndrome and neurological toxicities. Respondents required a 13-14 percentage point increased 1-year survival probability to accept risks of treatment-associated adverse events. Conclusion: Patients prioritize survival and will accept certain adverse event risks to gain survival improvements.

Best Treatment Option for Patients With Refractory Aggressive B-Cell Lymphoma in the CAR-T Cell Era: Real-World Evidence From GELTAMO/GETH Spanish Groups.

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4–6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44–0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31–0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria.

Towards Remote Continuous Monitoring of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a noninfec-tious systemic inflammatory response syndrome condition and a principle severe adverse event common in oncology patients treated with immunotherapies. Accurate monitoring and timely prediction of CRS severity remain a challenge. This study presents an XGBoost-based machine learning algorithm for forecasting CRS severity (no CRS, mild- and severe-CRS classes) in the 24 hours following the time of prediction utilizing the common vital signs and Glasgow coma scale (GCS) questionnaire inputs. The CRS algorithm was developed and evaluated on a cohort of patients (n=1,139) surgically treated for neoplasm with no ICD9 codes for infection or sepsis during a collective 9,892 patient-days of monitoring in ICU settings. Different models were trained with unique feature sets to mimic practical monitoring environments where different types of data availability will exist. The CRS models that incorporated all time series features up to the prediction time showcased a micro-average area under curve (AUC) statistic for the receiver operating characteristic curve (ROC) of 0.94 for the 3 classes of CRS grades. Models developed on a second cohort requiring data within the 24 hours preceding prediction time showcased a relatively lower 0.88 micro-average AUROC as these models did not benefit from implicit information in the data availability. Systematic removal of blood pressure and/or GCS inputs revealed significant decreases (p<0.05) in model performances that confirm the importance of such features for CRS prediction. Accurate CRS prediction and timely intervention can reverse CRS adverse events and maximize the benefit of immunotherapies in oncology patients.

Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. Here, we present a case of bone marrow (BM) failure in a 57-year old man with DLBCL-type Richter transformation receiving tisagenlecleucel in a standard-of-care setting. His clinical course was notable for underlying BM infiltration, severe cytokine release syndrome, and multiple infectious complications in the setting of prolonged, profound neutropenia. Cytokine profiling revealed a signature consistent with acquired aplastic anemia - including downregulation of CD40-L and EGF. Flow cytometric analyses demonstrated migration of CAR T-cells to the BM, as well as peripheral blood expansion of both CAR and non-CAR bearing CD8+CD57+ T-cells, an immunophenotype linked to oligoclonality in aplastic anemia. From single-cell level transcriptomics, this cytotoxic T-cell population was characterized by T-cell receptor Vβ oligoclonal expansion and post-CAR clonal drift. Gene expression profiling revealed upregulation of exhaustion markers on (CAR) T-cells and decreased expression of genes involved in STAT signalling and inflammatory response. In conclusion, this case highlights the complex nature of CAR-T-related hematological toxicity and introduces oligoclonal (CAR) T-cell expansion as a potential contributing pathophysiologic mechanism.

S262: THE COBALT-LYM STUDY OF CTX130: A PHASE 1 DOSE ESCALATION STUDY OF CD70-TARGETED ALLOGENEIC CRISPR-CAS9–ENGINEERED CAR T CELLS IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) T-CELL MALIGNANCIES

Background: Overall survival (OS) in a subset of patients (pts) with T-cell lymphoma (TCL) has improved with front-line combination chemotherapy; however, R/R TCL pts continue to have very limited treatment options. For pts with R/R peripheral (PTCL) and transformed cutaneous TCL (CTCL), median OS is 1-2.5 and <5 yrs, respectively. Adapting autologous chimeric antigen receptor (CAR) T cell therapy for TCL continues to be challenging due to poor function of donor T cells, fratricide effect, and risk of infusing transduced malignant CAR T cells into pts. CTX130TM is a first-in-class, CD70-targeting allogeneic (allo) CAR T therapy that may allow for CAR T therapy in pts whose own T cells are not ideal to manufacture auto CAR T cells. CD70 is a co-stimulatory protein with temporally limited expression on activated lymphocytes and is highly expressed in many TCLs. CTX130 is modified with CRISPR/Cas9-editing to eliminate expression of: 1) T-cell receptor (TCR) by TCR alpha constant disruption, 2) major histocompatibility complex class I expression by β2-microglobulin disruption, and 3) CD70 to mitigate fratricide and enhance performance. Aims: Investigate safety and efficacy of CTX130 in pts with R/R TCL. Methods: COBALTTM-LYM (NCT04502446) is an open-label, multicenter, global study evaluating the safety and efficacy of CTX130 in pts ≥18 y with CD70+ (≥10% by immunohistochemistry) R/R TCL (PTCL or CTCL). Pts with PTCL and CTCL must have received ≥1 or ≥2 prior lines of systemic therapy, respectively. Pts received lymphodepleting chemotherapy (LDC) with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 for 3 days, followed by CTX130. Pts were treated with CTX130 at doses from 3x107 (dose level [DL]1) to 9x108 (DL4) CAR+ T cells. Pts could receive a second course of CTX130 if response was not achieved but had experienced clinical benefit or disease progression. The primary endpoint is safety (incidence of dose limiting toxicities [DLTs]). Key secondary endpoints include overall response rate (ORR, by Lugano and ISCL criteria for PTCL and CTCL, respectively), disease control rate (DCR; ≥stable disease [SD]), duration of response and OS. Results: As of 6 Dec, 2021, 17 pts with TCL were enrolled; 15 received CTX130, were evaluable for a Day 28 assessment and are included in the analysis. Among the pts who received CTX130, median age was 67 y, 7 pts had PTCL, and 8 pts had CTCL. Median CD70 expression was 90% (range, 20-100%). Median follow up was 3.1 months. At DL ≥3, ORR was 71%, CR rate was 29% and DCR was 100% (Table). Responses were observed in PTCL (75% ORR at DL≥3) and CTCL (67% ORR at DL≥3) and across disease compartments. CTX130 had an acceptable safety profile across all DLs. There were no instances of graft versus host disease, tumor lysis syndrome, hemophagocytic lymphohistiocytosis, or infusion reactions with LDC or CTX130. There were no DLTs, no Grade (Gr) ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS); Gr 1-2 CRS and ICANS were 47% and 20%. There was no increase in frequency or severity of CRS in pts who received second infusions of CTX130. 1 pt (7%) experienced a Gr ≥3 infection. There was a sudden death in 1 pt with William’s syndrome in the context of a lung infection. Image:Summary/Conclusion: We have observed clinically meaningful responses, including CRs with CTX130, the first CAR T directed against the novel target, CD70. CTX130 has an acceptable safety profile in pts with heavily pretreated R/R TCL and will be investigated further in an expansion phase of the study.

P1438: PROCALCITONIN IS ELEVATED IN SEVERE INFECTIONS AFTER CD19 CAR-T IN R/R B-NHL AND ENABLES DISCRIMINATION OF EARLY INFECTIONS FROM CRS – PARTICULARLY IN COMBINATION WITH THE CAR-HEMATOTOX SCORE

Background: Infections substantially contribute to the toxicity burden of CD19 CAR-T and represent the most common cause of non-relapse mortality. Determining if an episode of fever represents the onset of infection or cytokine release syndrome (CRS) remains a major clinical challenge. Most patients thus receive broad-spectrum antibiotics, which can confer resistance and may negatively influence the microbiome. Aims: We sought to characterize dynamic changes in serum inflammatory markers for infection vs. CRS and to develop clinical tools that discriminate for severe infections. Methods: Early infection events (day 0-30) and day-by-day CRS dynamics were characterized in 62 patients treated with CD19 CAR-T for relapsed/refractory B-NHL in a real-world setting (23 Axi-cel, 30 Tisa-cel, 9 KTE-X19). Severe infections were defined as requiring i.v. anti-infectives and/or hospitalization in the presence of microbiologic evidence or distinct clinical signs of infection; CRS was graded according to ASTCT criteria. Serum inflammatory markers (CRP, interleukin-6, procalcitonin) were recorded daily, and the baseline CAR-HEMATOTOX score (Rejeski et al Blood 2021) was assessed for each patient. Cumulative incidence curves were calculated as time-to-event-analysis for CRS 1°, ≥2° and severe infections. Index events were defined per patient for each toxicity category (= day of event). Inflammatory markers were tested using binary logistic regression for severe infections vs. CRS index events. Discriminatory thresholds were determined by optimizing the Youden J statistic. Results: The cumulative 30-day incidence of CRS 1°, CRS ≥2° and severe infections was 47%, 43%, and 25% respectively. Tocilizumab was applied in the majority of CRS patients (1°: 90%, ≥2°: 100%). We did not find a significant correlation between CRS grade and severe infections (G2 = 0.13, p = n.s.). Median onset of CRS and infection was 3 and 8 days, respectively. The majority of events occurred in the setting of coincident severe neutropenia (ANC <500/µl). Inflammatory markers were assessed both relative to CAR-T transfusion and the respective index event. CRS ≥2° was characterized by higher day 0-21 levels of interleukin-6 compared to CRS 0-1° (p<0.001). On the other hand, patients with severe infections exhibited both higher baseline inflammation (reflected by higher CRP levels on days 0-3), and higher peak procalcitonin levels (p<0.001) compared to CRS controls. These trends were particularly evident on the day of the index event (Fig. 1). Procalcitonin was significantly elevated for severe infections vs. CRS controls (median 1.6 vs. 0.3 µg/l, p<0.001), and an optimal discriminatory threshold of 1.4 µg/l was established. An elevated baseline CAR-HEMATOTOX was noted for patients with severe infections (median 5 vs. 2, p=0.002). By incorporating index-event procalcitonin levels with the score, the discriminatory capacity for severe infection events was improved. On ROC analysis, the ‘HT10 score’ (addition of 10 points to the patient-specific CAR-HEMATOTOX in case procalcitonin ≥1.4 µg/l on event day) exhibited superior discrimination for severe infections (AUC 0.92, p<0.0001, sens. 80%, spec. 89%). Image:Summary/Conclusion: CRS and infections are characterized by distinct patterns of inflammation after CD19 CAR-T (CRS: high IL-6; Infections: high procalcitonin). The high discriminatory capacity of the HT10 score for infections emphasizes the utility of procalcitonin in routine inflammatory panels. If validated prospectively, the score will enable more patient-individual decisions on antibiotic use.