High-grade Cytokine Release Syndrome Research Articles

Abstract 9828: Active Surveillance of Cardiotoxicity with Cardiac Biomarkers During Chimeric Antigen Receptor T-Cell Therapy

Introduction: Chimeric Antigen receptor T- Cell (CAR-T) immunotherapy has been a breakthrough for various hematological malignancies. Cardiotoxicites such as heart failure, arrhythmia and acute coronary syndrome occur in approximately 1/3 of patients who develop cytokine release syndrome (CRS) following CAR-T. High grade CRS (Grade ≥ 2) and elevated troponin level are associated with increased risk of cardiotoxicity. It is unclear whether active cardiotoxicity surveillance with serial cardiac biomarker measurements during CAR-T would allow early detection of cardiotoxicity. Methods: This was retrospective cohort study involving patients diagnosed with non-Hodgkin lymphoma treated with CAR-T therapy (Axicabtagene ciloleucel- Yescarta, tisagenlecleucel- Kymriah, Brexucabtagene autoleucel- Tecartus). Baseline cardiac workup with electrocardiogram (ECG), transthoracic echocardiogram (TTE), troponin (Reference <0.03ng/mL), B-natriuretic peptide (BNP, <100pg/mL) were uniformly performed in all participants. Follow up ECG, Troponin and BNP were obtained at day 5 after CAR-T and at development of CRS Grade ≥2. When clinically indicated, cardiac MRI with gadolinium contrast was performed. Cardiac MRI diagnosis of myocarditis was based on Lake Louise Criteria. Results: A total of 47patients undergoing CAR-T therapy were studied. Baseline comorbidities were not predictive of CRS or cardiac events. There were 39 patients with low grade CRS (82.9%) and 8 patients (17.0%) with grade 2 CRS. Five patients had elevated troponin I levels (Grade 1 CRS - 3; Grade 2 CRS - 2). Cardiac MRIs were performed in three patients (two normal studies, one with mild myocarditis). Five patients (10.6%) had an adverse cardiac event (Myocarditis with heart failure - 1; new-onset atrial fibrillation - 3; Type 2 myocardial infarction -1). Conclusion: Adverse cardiac events are a relatively common occurrence in patients receiving CART therapy. Active surveillance for cardiotoxicity using cardiac biomarkers in CAR-T patients may play an adjunctive role in the early identification of adverse cardiac events. Larger studies are needed to adjudicate the use of such screening measures in these high-risk patients.

Abstract 10168: Association Between the Grade of Cytokine Release Syndrome and Cardiac Dysfunction After Chimeric Antigen Receptor T Cell Therapy for Diffuse Large B Cell Lymphoma Patients

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 involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but their association is not fully investigated. Therefore, we designed a prospective study to clarify the association between the grade of CRS and cardiac dysfunction in the DLBCL patients after CAR-T therapy. Methods: In this prospective study, 14 DLBCL patients who underwent CAR-T therapy from July 2020 to May 2021 were enrolled. Before and after CAR-T therapy, we collected the levels of troponin T (TnT) as a marker for myocardial damage, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) as markers for systolic function, and E/e’ and left atrial volume index (LAVI) as markers for diastolic function. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely the low-CRS Group (CRS<3) and the high-CRS Group (CRS≧3). The markers for cardiac injury and dysfunction were further analyzed in both groups. Results: Average age was 56.4 years and 7 patients (50%) were female. The number of patients in the low-CRS and high-CRS Group were 11 and 3, respectively. Before CAR-T therapy, there were no differences in cardiac function between the two groups. From the hyper-early phase of CAR-T therapy, the increase of TnT, E/e’ and LAVI from the baseline were significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.023, 0.039, and 0.024, respectively). Subsequently, the decrease of GLS from the baseline became significantly larger in the high-CRS Group compared to the low-CRS Group (P=0.049). These results indicated that cardiac dysfunction after CAR-T therapy occurred in the order of myocardial damage, diastolic dysfunction, and systolic dysfunction. Conclusion: We for the first time demonstrated the association between high-grade CRS and cardiac dysfunction after CAR-T therapy through a prospective study.

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

Background:Early Cytokine Release Syndrome (CRS) is a common complication following haploidentical stem cell transplantation (Haplo-HSCT) induced by the proliferation of alloreactive T-Cells. CRS is occurring more frequently in patients receiving peripheral blood stem cells (PBSC) comparatively to bone marrow transplant, however its impact on outcome, notably graft versus host disease (GVHD) remain unclear. The main objective was to evaluate the impact of severity of CRS on the risk of GVHD.Patients and Methods:This retrospective single-center study included patients who had received a first haplo-HSCT for hematological malignancies, with PBSC as graft source. All patients received either a reduced-intensity conditioning (RIC) based on thiotepa (5mg/kg), busulfan (260 mg/m²) and fludarabine (120 mg/m²) [TBF], or a non-myeloablative conditioning (NMAC) based on fludarabine (150 mg/m²), cyclophosphamide (29 mg/kg) and 2 Gy TBI [CyFluTBI]. GVHD prophylaxis was based on PT-Cy 50 mg/kg (day+3 and +4) and cyclosporine A plus mycophenolate mofetil starting at day+5. All patients were given GSCF from day+5 to neutrophil recovery.Results:241 consecutive patients were analyzed. One hundred patients (54%) had myeloid malignancies, and 111 (46%) had lymphoid malignancies. Most patients had intermediate or low risk DRI (n = 180, 75%) and HCT-CI was ≥ 3 for 159 patients (66%). Using ASTCT consensus criteria, 226 patients (94%) developed CRS, including 183 grade 1 and 43 grade ≥ 2. Transplantation and patient characteristics were not significantly different between patients with CRS grade 0-1 vs. ≥ 2, except for age. Indeed, patients with CRS grade ≥ 2 were significantly older than patients with CRS grade 0-1 (median 65 vs 60 yo respectively, p = 0.01).Patients with grade ≥ 2CRS had significantly higher cumulative incidence of day-100 grade II-IV acute GVHD (grade 0-1 vs. ≥ 2 : 28% and 44%, p = 0.028) and 4-year moderate to severe chronic GVHD (grade 0-1 vs. ≥ 2 : 16% and 30%, p = 0.024) compared to patients with grade 0-1 CRS (Figure 1). No difference in the cumulative incidence of relapse was observed between CRS groups (grade 0-1 vs. ≥ 2 : 22% and 21%, p = 0.802).By multivariate analysis, CRS grade ≥ 2 was the only factor associated with grade II-IV acute GVHD (HR = 1.99; 95%CI = [1.17-3.39], p = 0.011). CRS grade ≥ 2 was significantly associated with a higher risk of moderate to severe chronic GVHD (HR = 2.67; 95%CI = [1.36-5.21], p = 0.004) and poorer GVHD- and relapse-free survival (GRFS) (HR = 1.78 ; 95%CI = [1.19-2.67], p = 0.005). Progression free survival, overall survival and non-relapse mortality were not influenced by the severity of CRS.Conclusion:In the context of PBSC haplo-HSCT, the occurrence of grade ≥ 2 CRS following graft infusion is significantly associated with an increased risk of both acute and chronic GVHD. This may improve the early identification of patients with high risk of GVHD for whom specific enhanced GVHD prophylaxis should be investigated. [Display omitted] DisclosuresChabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

Easix Predicts Severe Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neuro-Toxicity Syndrome (ICANS) in Patients Receiving CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy

Background: Endothelial dysfunction underlies the two main complications of chimeric antigen receptor T (CAR-T) cell therapy, i.e. cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The purpose of this retrospective analysis was to evaluate and validate the Endothelial Activation and Stress Index (EASIX)) as predictor for CRS and ICANS in patients receiving CD19-directed CAR-T cells.Methods: In this retrospective study, the training cohort recruited 107 patients treated with CAR-T cells at the University Hospital Heidelberg (n=83) and Charité University Medicine Berlin (n=24) from Oct 1, 2018, to March 31, 2021. Patients from the validation cohort (n=93) received CAR-T cells within the ZUMA-1 trial (ClinicalTrials.gov number: NCT02348216).The training cohort included 37 and 34 patients with relapsed / refractory (r/r) large B-cell lymphoma (LBCL) treated with Axi-cel and Tisa-cel, respectively, 1 patient with acute lymphoblastic leukemia (ALL) treated with Tisa-cel, 2 patients with mantle cell lymphoma (MCL) treated with KTE-X19 on an early access program; and 5 patients with LBCL, 5 patients with MCL, 5 patients with chronic lymphocytic leukemia, 4 patients with follicular lymphoma, and 14 patients with ALL treated with the 3 rd generation CAR-T HD-CAR-1. Median age was 57 (20-81) years, 72% were male. The 93 patients of the validation cohort all had r/r LBCL and received Axi-Cel.EASIX and serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin and interleukin-8) were measured before start of lymphodepletion (EASIX-pre), and on days 0, 3, and 7 after CAR-T infusion. Primary endpoints were severe CRS and/or ICANS (grades 3-4).Results: Of the 107 patients of the training cohort, 61 patients (58%) developed CRS grades 1-4 and 24 patients (22%) developed ICANS grades 1-4. Higher grade CRS (grade ≥ 3) was seen in 6 patients (6%) with a median onset of 4 (0-14) days, while grade ≥ 3 ICANS occurred in 11 patients (11%; median onset 8 (4-17) days). EASIX values increased continuously from lymphodepletion to day 7 after CAR-T cell application (EASIX-pre 2.0 (0.5-76.6, interquartile range (IQR) 1.2/4.1); EASIX-d0 2.0 (0.3-91.5, IQR 1.2/4.2); EASIX-d3 2.4 (0.3-69.1, IQR 1.3/4.9) and EASIX-d7 2.7 (0.4-94.0, IQR 1.4/7.5)).In the validation cohort, Grade ≥ 3 CRS was observed in 10 patients (11%) and grade ≥ 3 ICANS in 28 patients (30%). Similar to the training cohort, EASIX values rose from lymphodepletion to day 3 after CAR-T cell application (EASIX-pre 1.8 (0.3-106.1, IQR 1.0/4.7); EASIX-d0 2.0 (0.3-120.4, IQR 1.1/4.1) and EASIX-d3 2.7 (0.3-57.9, IQR 1.7/6.2).In both cohorts, all EASIX values (pre, d0, d3, d7) were significantly higher in patients who developed either grade 3-4 CRS, ICANS or both (see Figure 1 for the training cohort).EASIX predicted grade 3-4 CRS and ICANS before lymphodepleting therapy (-pre), on day 0 and on day 3 in both cohorts: AUC EASIX-pre, training cohort 0.73 (0.62-0.85, p=0.002), validation cohort 0.76 (0.66-0.87, p<0.001). An optimized cut-off for EASIX-pre (1.86) identified in the training cohort associated with an odds ratio (OR) of 5.07 (1.82-14.10), p=0.002 in the validation cohort in multivariable binary logistic regression analysis including age, gender, diagnosis and disease stage.Serum endothelial stress markers did not predict the two complications when assessed before CAR-T infusion, but diagnostic markers were strongly associated with CRS and ICANS grade 3-4 on day+7.Conclusions: EASIX-pre is a validated predictor of severe complications after CAR-T therapy and may help to tailor safety monitoring measures according to the individual patient's needs.Data on patients from the ZUMA-1 trial were provided by Kite/Gilead. [Display omitted] DisclosuresPenack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Takeda: Research Funding; Incyte: Research Funding; Priothera: Consultancy; Shionogi: Consultancy; Omeros: Consultancy. Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees; Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; TolerogenixX: Current holder of individual stocks in a privately-held company; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; Novartis: Other: Travel grants, Research Funding. Müller-Tidow: Janssen: Consultancy, Research Funding; Pfizer: Research Funding; Bioline: Research Funding. Bullinger: Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Honoraria; Menarini: Consultancy; Sanofi: Honoraria; Novartis: Consultancy, Honoraria; Seattle Genetics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Hexal: Consultancy; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Dreger: Gilead Sciences: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

Adverse Events Following CAR T-Cell Therapy: A Single Institution Retrospective Analysis of Toxicities Following CAR T-Cell Therapy for Children and Young Adults with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: CAR T-cells have demonstrated remarkable ability to induce complete remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL). This success, however, is tempered by the toxicities associated with CAR T-cell therapy. Much has been published on cytokine release syndrome (CRS), but, to date, a comprehensive profile of specific end organ toxicities secondary to CAR T-cell therapy in the pediatric and young adult population is lacking.Methods: This retrospective, single center study, was performed to characterize the specific adverse events (AEs) experienced by pediatric and young adult patients during the first 30 days following CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events (CTCAE) were collected from all patients with r/r ALL treated on one of three phase I CAR T-cell trials (CD19, CD22, and CD1922) at the Pediatric Oncology Branch of the National Cancer Institute at the National Institutes of Health from 2012-2020. The primary objective was to determine the incidence of all severe AEs, defined as > grade (Gr) 3 AEs, overall and by organ system, attributed to research or disease. Secondary objectives were to stratify severe AEs based on development of CRS and CRS grade (using ASTCT CRS grading criteria). Descriptive statistics were reported along with comparisons of continuous parameters using Mann-Whitney and binomial parameters using Fischer's exact tests.Results: We reviewed AE data from 134 patients with r/r ALL receiving one of 3 unique CAR T-cell constructs (Table). The median age was 15.2 years (Interquartile range (IQR) 9.5-21.2). The median number of prior therapies was 5 (IQR 3-6) and 57% had received a prior hematopoietic stem cell transplant (HSCT).Amongst the 134 patients, a total of 1747 individual > Gr 3 AEs were experienced by 133 patients (99%) during the first 30 days following CAR infusion (Figure 1A). The median number of > Gr 3 AEs per patient was 10 (IQR 4.8-19).Cytopenias (including neutropenia, thrombocytopenia and anemia) comprised the vast majority of total > Gr 3 AEs (n=983, 56.3%). The most common severe (> Gr 3) AEs were thrombocytopenia (n=433, 24.8%), metabolic abnormalities (i.e. electrolyte derangements) (n=333, 19.1%), neutropenia (n=332, 19%), and anemia (n=218, 12.5%).With exclusion of cytopenias, 764 > Gr 3 AEs were experienced by 111 patients (83%), with a median of 4 (IQR 1-8.3) > Gr 3 AEs per patient. One grade 5 pulmonary AE occurred in the setting of acute respiratory distress syndrome (ARDS). Focusing on non-cytopenia AEs (Figure 1B), metabolic AEs made up 43.6% of AEs; hepatic toxicities (n=115, 15%), febrile neutropenia (n=114, 14.9%), and cardiovascular toxicities (n=59, 7.7%) were the next most frequent.Of the 134 patients, 104 (77.6%) developed CRS. All 30 patients without CRS had at least 1 > Gr 3 AE (median 6, IQR 3-11.3). In contrast, the median number of > Gr 3 AEs in those with CRS was 11.5 (IQR, 6-21.5), (p=0.0021). When stratified by CRS Gr 1-2 versus CRS Gr 3-4 (Figure 2), patients with higher-grade CRS also had a higher median number of > Gr 3 AEs per patient (p= 0.0017).Conclusions: Among 134 children and young adults with r/r ALL receiving phase I CAR T-cells, we found a high incidence (99%) of severe AEs, with a per patient median of 10 (IQR 4.8-19) > Gr 3 AEs. While the majority of > Gr 3 AEs were cytopenias, 17 different categories of AEs were experienced. The development and severity of CRS associated with an increase in the median number of severe AEs per patient. As phase I trials of CAR T-cell therapy expand, it is imperative to understand the full toxicity profile of these therapies. While the definition and refined grading of CRS has helped advance the field, there is a gap in knowledge regarding patient specific end-organ toxicities beyond CRS. Our data help establish a foundation for the full toxicity profile experienced by patients enrolling on phase I CAR T-cell trials. With an emerging role for earlier intervention for CRS, we anticipate that the toxicity burden will decrease. Next steps include characterizing the specific toxicities within each AE category, evaluating duration and time to resolution, distinguishing attribution to research versus disease and studying the impact of earlier use of tocilizumab on toxicity profile. Future directions will incorporate assessment of baseline organ function pre-CAR and its impact on development of post CAR severe AEs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment-Related Adverse Events of Chimeric Antigen Receptor T-Cell (CAR T) in Clinical Trials: A Systematic Review and Meta-Analysis.

Simple SummarySuccessful treatment of hematological malignancies with chimeric antigen receptors T (CAR-T) cells has led to much enthusiasm for the wide clinical usage and development of novel CAR-T therapies. However, it also challenges physicians and investigators to recognize and deal with treatment-associated toxicities. We conducted a systematic review and meta-analysis from 84 eligible study and a total of 2592 patients to identify the comprehensive incidences and severity of CRS and neurological symptoms (NS) as well as the potential differences in AEs across a variety of cancer types, CAR-T targets, and other factors, thereby offering a significant implication on its future application and research.Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24–36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23–37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.

Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma

BackgroundChimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown.MethodsFrom a large cohort of consecutive adult patients...

Cytokine Release Syndrome By T-cell-Redirecting Therapies: Can We Predict and Modulate Patient Risk?

T-cell-redirecting therapies are promising new therapeutic options in the field of cancer immunotherapy, but the development of these modalities is challenging. A commonly observed adverse event in patients treated with T-cell-redirecting therapies is cytokine release syndrome (CRS). Its clinical manifestation is a burden on patients, and continues to be a big hurdle in the clinical development of this class of therapeutics. We review different T-cell-redirecting therapies, discuss key factors related to cytokine release and potentially leading to CRS, and present clinical mitigation strategies applied for those modalities. We propose to dissect those risk factors into drug-target-disease-related factors and individual patient risk factors. Aiming to optimize the therapeutic intervention of these modalities, we illustrate how the knowledge on drug-target-disease-related factors, such as target expression, binding affinity, and target accessibility, can be leveraged in a model-based framework and highlight with case examples how modeling and simulation is applied to guide drug discovery and development. We draw attention to the current gaps in predicting the individual patient's risk towards a high-grade CRS, which requires further considerations of risk factors related, but not limited to, the patient's demographics, genetics, underlying pathologies, treatment history, and environmental exposures. The drug-target-disease-related factors together with the individual patient's risk factors can be regarded as the patient's propensity for developing CRS in response to therapy. As an outlook, we suggest implementing a risk scoring system combined with mechanistic modeling to enable the prediction of an individual patient's risk of CRS for a given therapeutic intervention.

A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.

125 Background: Prostate specific membrane antigen (PSMA) is a highly expressed tumor-associated antigen potentially amenable to chimeric antigen receptor-modified T (CAR-T) cell therapy for castration-resistant prostate cancer (CRPC). However, a primary challenge to the success of CAR-T therapy in CRPC is the immunosuppressive microenvironment, characterized by high levels of TGFβ. The immunosuppressive functions of TGFβ can be inhibited in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity. Methods: We conducted a first-in-human phase 1 clinical trial to evaluate the feasibility, safety and preliminary efficacy of PSMA-directed/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in patients with metastatic CRPC (NCT03089203). In a 3+3 dose-escalation design, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting (LD) chemotherapy. In Cohort 3, one patient received 1-3 x 108/m2 CART-PSMA-TGFβRdn cells following a LD chemotherapy regimen of cyclophosphamide and fludarabine (Cy/Flu). In Cohort -3, three patients received 1-3 x 107/m2 CART-PSMA-TGFβRdn cells following Cy/Flu. Patients underwent metastatic tumor biopsies at baseline and on day 10 following treatment. Quantitative PCR of CART-PSMA-TGFβRdn DNA was performed at serial timepoints to evaluate for CAR-T expansion and persistence in peripheral blood and trafficking to target tissues. Multiplex cytokine analysis assessed CART-PSMA-TGFβRdn bioactivity. Results: Ten patients received CART-PSMA-TGFβRdn therapy across dose-level cohorts. All CART-PSMA-TGFβRdn infusion products met target transduction efficiency. Evaluation of CAR-T cellular kinetics demonstrated dose-dependent peripheral blood T cell expansion, as well as tumor tissue trafficking in post-treatment tumor biopsies. At Cohort 2 and above, 5 of 7 treated patients developed grade ≥2 cytokine release syndrome (CRS). Marked increases in inflammatory cytokines (IL-6, IL-15, IL-2, IFNγ) correlated with high-grade CRS events. One grade 5 adverse event (sepsis) occurred in Cohort 3. PSA decline was observed in 6 of 10 patients (median decline -33.2%, range -11.6% to -98.3%), and PSA30 response occurred in 4 of 10 patients (including one patient achieving PSA &lt; 0.1 ng/mL). Conclusions: Adoptive cellular therapy with CART-PSMA-TGFβRdn is safe and feasible in patients with metastatic CRPC. A dose-dependent and lymphodepletion chemotherapy-dependent relationship was observed with CART-PSMA-TGFβRdn cell expansion, cytokine expression, CRS, and anti-tumor effect. Correlative cell trafficking and paired tumor Nanostring analyses will be presented. Future clinical investigations seek to enhance anti-tumor efficacy, while optimizing the therapeutic window. Clinical trial information: NCT03089203.

Low Utility of the H-Score and HLH-2004 Criteria to Identify Patients with Secondary Hemophagocytic Lymphohistiocytosis after CAR-T Cell Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction: Secondary hemophagocytic lymphohistiocytosis (HLH) is an aggressive life-threatening activation of the immune system triggered by an underlying condition. Use of chimeric antigen receptor therapy (CAR-T) to treat relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and development of secondary HLH. Application of HLH scoring systems such as the H-score or HLH-2004 criteria to identify CAR-T triggered HLH is not validated in this setting. Inability to promptly recognize the development of secondary HLH in CAR-T patients and to distinguish it from CRS may lead to delay in HLH specific therapy and increased mortality. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify possible patients with HLH post-CAR-T for R/R DLBCL. Methods: A single center retrospective analysis of 75 patients with R/R DLBCL following CAR-T was performed. Using a peak ferritin of 500 mcg/L or higher within 30 days of CAR-T administration, 43 out of 75 patients were identified at risk for HLH. The H-score and HLH-2004 criteria were applied retrospectively. Measurement of NK activity was not available for any patients and soluble IL2 was collected intermittently. The mean H-score was calculated, and two sample t-test performed to evaluate for a difference in the mean H-score between low versus high grade CRS, low versus high grade ICANS, as well as presence versus absence of cytopenias at days 30, 90 and 180. Low grade CRS/ICANS was defined as 1, and high grade as 2 or higher. CRS was graded per Lee 2014 criteria and ICANS per CTCAEv.4. The 43 patients were then subdivided by H-score threshold of 169 into H-score Low (&amp;lt; 169) and H-score High (≥ 169). The threshold of 169 was used given a prior validation study showing optimal sensitivity and specificity for identifying acquired HLH in adult patients with an H-score equal to or higher than 169. Both Progression Free Survival (PFS) and Overall Survival (OS) were defined as time from CAR-T infusion until an event of last follow up. Kaplan-Meier curves were produced to describe the distribution of PFS and OS between two subpopulations of low and high H-Score. Results: Median peak ferritin was 1571.8 mcg/L (range: 375 mcg/L - &amp;gt;50,000 mcg/L, table 1). Median H-score was 135 (range 61 -250). Four patients were treated with HLH directed therapy receiving steroids with either tocilizumab, siltuximab and/or anakinra. Of these 4 patients, only 2 met five HLH-2004 criteria. All 4 patients had H-scores above 169 (209, 211, 228 and 250). Of these 4 patients, one died from complications thought secondary to HLH. Fourteen patients (14/43, 32%) had an H-score &amp;gt;169. Ten patients did not require any HLH directed therapy and had no clinical evidence of HLH. The mean H-score was not different between patients with low vs high grade CRS (148.2 vs 141.8, p=0.7) or low vs high grade ICANS (145.9 vs 142.6, p=0.8). No statistical correlation was seen between H-score and cytopenias at any time point. There was no significant difference in PFS or OS between the H-score low vs high subgroups (p=0.7, p=0.1 respectively, figure 1 and 2). Patients with higher H-score tended to have longer length of hospitalization for CAR-T (Pearson correlation coefficient 0.289). Conclusions: In patients with R/R DLBCL post CAR-T, the use of either the H-score or application of HLH-2004 criteria had low utility in identifying possible HLH in patients who screened in based on peak ferritin within 30 days of CAR-T administration. While apparent differences between the H-score high and low categories may not reach statistical significance due to the small number of patients, our exploratory analysis does not support the use of H-Score to evaluate for HLH post-CAR-T. The immediate post-CAR-T period is characterized by a high inflammatory state, which likely results in high H-scores. Results from our study suggest a need for further characterization of HLH following CAR-T and the role for a CAR-T specific HLH scoring system to distinguish secondary HLH from CAR-T related inflammation in this specific patient population. Disclosures Hardy: American Gene Technologies: Other: DSMB Member; Kite/Gilead: Other: Advisory Board Member; Incyte Corporation: Other: Advisory Board Member.

Detecting 24 Kinds of Cytokines Via Flow Cytometry Aimplex Kit Is an Effective Way to Monitor CRS after CAR-T Cells Infusion

Introduction: Cytokine release syndrome (CRS) is a serious side effect of chimeric antigen receptor-T cell (CAR-T) therapy. Effective cytokine monitoring can provide support for early prevention and treatment. As more and more promising markers have been identified to be associated with CRS responses, traditional ELISA method is inapplicable because it's sample-consuming, low flexibility, and difficult to detect multiple cytokines simultaneously. Aimplex kit, a new high-throughput technique based on flow cytometry(FCM) and micro beads has been testified a effective way to monitor multiple cytokines in peripheral blood(PB) samples. If a new suitable cytokines panel is established to monitor the variation curve of multiple cytokines in patients' PBs post CAR-T therapy, study the relationship between clinical symptoms and the lab results, even build a cytokines database of CAR-T therapy, it would offer a promising support to prevent and handle CRS. On the other hand, by studying the relationship between cytokines and activated cells, we might investigate mechanisms of CRS and explore more related markers. Methods: A two tubes panel was designed to detect 24 cytokines, including IFN-γ/IL-1β/IL-2/IL-4/IL-5/IL-6/IL-8/IL-10/IL-12p70/IL-17A/IL-17F/IL-22/TNF-α/TNF-β, and sCD25/GM-CSF/IL-15/MCP-1/GranzymeB/Reg3A/ST2/TNFRSF1A/Elafin/MIP-1 alpha. 50 PB samples from complete response(CR) patients without CAR-T therapy were detested as normal controls to establish the normal values of 24 cytokines. 81 patients who infused CAR-T cell in Hebei Yanda Ludaopei Hospital from January to June 2020 were selected. Serum were collected on 0d, 4d, 7d, 11d, 15d, 20d and 30d after infusion, and 24 cytokines were detected by FCM Aimplex. Of which 31 patients were selected for methodological comparison between FCM and ELISA by detecting four routine cytokines, IL-6, IFN-γ, TNF-α and sCD25. 66 Patients were divided into 2 groups according to clinical manifestations, 60 patients without or mild CRS were classified as low grade CRS group, 6 patients with grade 2 or 3 CRS were classified as high grade CRS group. Results: The comparative test showed that a good relationship between the results of ELISA and Aimplex kit, showing similar time-cytokines variation curve of PBs after CAR-T treatment. The concentrations of IL-2, IL-10, IL-12p70, IL-17A, IL-17F, MCP-1, ST-2s, IL-5, IL-6 and IFN-γ were significantly higher in high CRS grade group. By comparing the proportion of CAR-T+, CD8+ and CD4+ T cells in CD3+ cells and the concentration of cytokines in PB specimens, there were obvious positive correlations between percentages of CAR-T+, CD8+ T cells and most cytokines, and negative correlation between proportion of CD4+ T cells and most cytokines. Conclusions: Detecting 24 kinds of cytokines by Aimplex kit is a promising method, which is time and specimens saving, and can cost-effectively reflect the cytokine situation in PBs from patients post-CAR-T treatment. Increasing the sample size and establishing a cytokines database will be helpful for monitoring, early prevention and control of side effects after CAR-T treatment. Disclosures No relevant conflicts of interest to declare.

Abstract 4231: Factors predictive of CAR T cell associated hemophagocytic lymphohistiocytosis (HLH)

Introduction: HLH is a T cell mediated inflammatory syndrome associated with immune activation and NK cell dysfunction. In the context of CAR T cells, HLH occurs in a subset of those with cytokine release syndrome (CRS), yet predisposing factors are not yet well established. Utilizing our ongoing phase I study of CD22/4-1BB CAR T cells in children and young adults with CD22+ B cell malignancies (NCT02315612), we evaluated patient and product characteristics to elucidate factors associated with HLH. Methods: We retrospectively reviewed multiple variables to identify correlates of HLH in those infused. Definitions for CRS and HLH are in Table 1. Multiple univariate analyses were performed to identify risk factors for HLH; variables with significance were incorporated into a multiple logistic regression model to predict those at risk of HLH-like CRS. Results: 52 of 60 (86.7%) treated subjects developed CRS; 21 (40.4%) of whom subsequently developed HLH. The following factors were associated with HLH: lower baseline blood and marrow NK% and higher CD3% cells; CD4/CD8 T cell selection (TCS) of the apheresis product (which increased CD3 and reduced NK cell populations); and higher IL18. Following infusion, distinct cytokine profiles and prolonged predominance of CD8 T cells distinguished those with HLH from those without it. Multiple logistic regression identified a) use of TCS, b) higher grade CRS and c) high baseline bone marrow T/NK ratio as most predictive of HLH; leading to a model with 75% sensitivity and 80% specificity. Conclusion: Our results provide novel insights into factors associated with CAR T cell related HLH and implicate preexisting T and NK cell populations, baseline cytokines, apheresis selection methodologies and CAR T cell expansion parameters in the pathophysiology. With a goal of earlier intervention to prevent HLH, the predictive model will be prospectively evaluated. Biologic correlative studies and assessment of generalizability in alternate CAR T cell constructs are planned. Citation Format: Daniel A. Lichtenstein, Seth M. Steinberg, Steven L. Highfill, Bonnie Yates, Ping Jin, Jianjian Jin, Sandhya Panch, Haneen Shalabi, David F. Stroncek, Terry J. Fry, Nirali N. Shah. Factors predictive of CAR T cell associated hemophagocytic lymphohistiocytosis (HLH) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4231.

Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies

AbstractAntigen-escape relapse has emerged as a major challenge for long-term disease control after CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. From March 2016 through January 2018, we conducted a pilot study in 89 patients who had refractory/relapsed B-cell malignancies, to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-specific, third-generation chimeric antigen receptor-engineered (CAR19/22) T cells. Among the 51 patients with acute lymphoblastic leukemia, the minimal residual disease-negative response rate was 96.0% (95% confidence interval [CI], 86.3-99.5). With a median follow-up of 16.7 months (range, 1.3-33.3), the median progression-free survival (PFS) was 13.6 months (95% CI, 6.5 to not reached [NR]), and the median overall survival (OS) was 31.0 months (95% CI, 10.6-NR). Among the 38 patients with non-Hodgkin lymphoma, the overall response rate was 72.2% (95% CI, 54.8-85.8), with a complete response rate of 50.0% (95% CI, 32.9-67.1). With a median follow-up of 14.4 months (range, 0.4-27.4), the median PFS was 9.9 months (95% CI, 3.3-NR), and the median OS was 18.0 months (95% CI, 6.1-NR). Antigen-loss relapse occurred in 1 patient during follow-up. High-grade cytokine release syndrome and neurotoxicity occurred in 22.4% and 1.12% patients, respectively. In all except 1, these effects were reversible. Our results indicated that sequential infusion of CAR19/22 T cell was safe and efficacious and may have reduced the rate of antigen-escape relapse in B-cell malignancies. This trial was registered at www.chictr.org.cn as #ChiCTR-OPN-16008526.

Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma

Peak Lymphocyte Count after CAR T Infusion Is a Clinically Accessible Test That Correlates with Clinical Response in Axicabtagene Ciloleucel Therapy for Lymphoma

Sequential CD19- and Bcma-Specific Chimeric Antigen Receptor T Cell Treatment for RRMM: Report from a Single Center Study

Background: Relapsed and/or refractory multiple myeloma (RRMM) has a very poor prognosis, especially for chinese patients with limited therapeutic options. Chimeric antigen receptor transduced T cells (CARTs) had been approved to be one of the rescue strategies for malignant B cell hematological tumors. CARTs targeting B-Cell Maturation Antigen (BCMA) were effective against RRMM in recent published clinical studies. CD19 is expressed by B cells before terminal differentiation into plasma cells and is associated with the enhancement of tumor-propagating and drug-resistance properties of myeloma. Thus, CD19 is also a potential therapeutic target. To our knowledge, we firstly designed the clinical study to evaluate the safety and efficacy of sequential infusion of CD19 and BCMA-Specific CARTs for RRMM patients (pts) (NCT 03196414). Our initial results showed this stragety had substantial anti-myeloma activity and well tolerated toxicities, which had been released at the 59th ASH meeting. Here, we will report the latest clinical data of a total of 28 RRMM patients receiving combined autologous CARTs infusion. Methods: Human T cells were collected from autologous peripheral blood mononuclear cells (PBSC). CART production was performed by the Unicar-Therapy Bio-medicine Technology Company (Shanghai, China). In this trial, RRMM pts firstly receive FC regimen as lymphodepleting conditioning , then were infused into CART-19 (1×107/kg on day 0) and CART-BCMA (total dose range: 2-6.8×107/kg) cells as split-dose infusions (40% on day 1 and 60% on day 2). After one month from CARTs infusion, some pts were adminstrated IMiDs for maintence therapy after hematopoietic recovery, including oral thalidomide 50mg/d or lenalidomide 10mg/d. This trial design and observation was seen in Blood,2017,130(Suppl.):506.The median follow-up time was 16 (3-28) months. Results: By January 2019, 28 pts were enrolled in this clinical trial. Among them, 23 (82.1%) pts were males and 5 (17.9%) pts were females. The median age was 57.5 (range: 42-69) years old. All pts were resistant to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), or both. These pts had received an average of 3 (2-8) lines of therapy prior to enrollment. The most common adverse event of CART therapy was acute cytokine release syndrome (CRS), which occurred in 28 pts (100%). 19 pts (67.9%) were evaluated grade 1-2 CRS. 7 pts (25.0%) were evaluated grade 3 CRS, and 2 pts (7.1%) were grade 4. High-grade CRS was associated with elevated levels of IL-6, IFNγ, IL-10 and CRP, especially IL-6 upgradation to thousands of times the baseline. Other toxicities within two weeks of CARTs infusion included fatigue (n=28; 100%), cytopenia (n=28; 100%), anemia (n=28; 100%), prolonged APTT (n=23; 82.1%), elevated creatinine (n=13; 46.4%), gastrointestinal reaction(n=9; 32.1%), elevated transaminase (n=9; 32.1%). Notably, one patient (CRS grade 4) developed grade 4 CRES who exhibited generalized seizure. But this life-threatening complication was quickly relieved after corticosteroids and sodium valproate administration. Two pts (7.1%) had HLH/MAS. No fatal or severe adverse events emerged after two weeks following the infusion. Chronic side effects included chronic diarrhea, hematocytopenia, mild infection, grade ≤2 bilirubin and/or transaminase elevation, hypogammaglobulinemia, etc. No treatment related mortality occurred in this group of pts. Among the 28 pts who completed the CARTs infusion, 27 pts were monitored at predetermined time points and one patient lost follow-up. The overall response rate was 92.6%, and 88.9% of the pts were above PR. 11 pts (40.7%) were CR or sCR, 8 pts (29.6%) were VGPR, 5 pts (18.5%) were PR and one (3.7%) was MR. The remaining 2 pts, one (3.7%) was evaluated as SD and another (3.7%) was PD. 4 pts died from myeloma progression during the follow-up. Of those pts, the median PFS was 8 months. The median OS was 16 months. Conclusions: Combined sequential administration of CART-19 and CART-BCMA cells can be manufactured from heavily-treated MM pts, and could elicit sustained remission for RRMM pts. Toxicities can be well tolerated. CARTs early expansion and persistence in vivo post infusion may be predictive of clinical outcome. How to prolong the survival time of CARTs in vivo is one of the subjects worth studying in the future. Disclosures No relevant conflicts of interest to declare.

Improvement in Cytokine Release Syndrome Management for the Treatment of AML Patients with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Molecule for T-Cell Redirected Therapy

Improvement in Cytokine Release Syndrome Management for the Treatment of AML Patients with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Molecule for T-Cell Redirected Therapy

Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells.

Tisagenlecleucel is a chimeric antigen receptor–T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half‐life, and terminal half‐life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or corticosteroids on the expansion rate was observed. This work represents the first mixed‐effect model‐based analysis of chimeric antigen receptor–T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on chimeric antigen receptor–T cell expansion.

Early and late hematologic toxicity following CD19 CAR-T cells.

Autologous T cells transduced with CD19-directed chimeric antigen receptors have recently been approved by several regulatory agencies for the treatment of relapsed and refractory leukemia and lymphoma, after demonstrating remarkable remission rate in advanced patients. The most common adverse events reported are cytokine-release syndrome (CRS), neurotoxicity, and hematologic toxicity. Here, we focus on early and late cytopenia occurring after CD19 CAR-T cells in 38 patients treated with CD19 CAR-T cells. Neutropenia, thrombocytopenia, and anemia occur frequently (94, 80, and 51%, respectively) after CAR-T cell infusion, and are associated with a biphasic nature, as in 93% of patients hematologic toxicity occurs after 21 days from cell infusion. Late hematologic toxicity was more common in patients with high grade CRS and in patients treated after a recent stem cell transplantation. Interestingly, since these events occur late after the lymphodepleting chemotherapy and after resolution of CRS, we found perturbations in SDF-1 levels to correlate with events of late neutropenia, likely associated with B-cell recovery.

Updated Phase 1 Results of Zuma-3: Kte-X19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Background Although ∼1/2 of adult patients (pts) with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes. The initial report of Phase (P) 1 of ZUMA-3, the P1/2 trial of KTE-X19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), demonstrated a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity (Shah et al. ASH 2017. #888). Here, we present updated ZUMA-3 P1 safety and efficacy data. Methods Adult pts (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow (BM) blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy. The primary endpoint for P1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the BM, and duration of remission. Safety analyses included all pts who received KTE-X19; pts with ≥ 2 months of follow-up were evaluated for efficacy. Results As of April 12, 2018, 35 pts have received KTE-X19 (median follow-up of 11 months [range, 2 −25 months]). Median age was 40 years (range, 18 – 69 years), 51% male, 66% ECOG 1, 37% prior blinatumomab, and 60% ≥ 3 prior lines of treatment. Median BM blast burden at Screening was 70% (range, 5 −100). Six, 14, and 15 pts received 2, 1, and 0.5 × 106 cells/kg doses, respectively. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%) pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 cytokine release syndrome (CRS) occurred in 9 pts (26%, median time to onset 5 days [range, 1 −15 days]); events resolved in all pts (excluding 2 with a Grade 5 event), and the median time to resolution was 11 days (range, 7 −42 days). There were 2 KTE-X19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to CRS at the 2 × 106 cells/kg dose. Grade ≥ 3 neurologic events occurred in 16 pts (46%, median time to onset 7 days [range, 4 −24 days]); neurologic events resolved in all pts (excluding 2 patients with unresolved events at death), with a median time to resolution of 17 days (range, 6 −53 days). Among the 32 pts evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60%–91%).CR or CRi was achieved by 23 pts (72%), and 1 pt (3%) had blast-free BM. Conclusion High remission rates were achieved by adult pts with R/R ALL, with ∼3/4 of pts achieving CR or CRi with undetectable MRD after a single dose of KTE-X19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-X19 offers clinical benefit for pts with otherwise limited treatment options.

Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia