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We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)–targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices (CD), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline (CD = 0.89–0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs (CD = 0.56–0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response.

Supplementary Data Combined

Table S1: Detailed descriptions of all grade neurotoxicity; Table S2: Correlation between CAR T cell phenotype and neurotoxicity; Table S3: Correlation between CSF cytokines and CSF protein concentrations; Table S4: Definitions of CRS

Figure S1: Detailed time course of neurotoxicity for each patient; Figure S2: Serum cytokines in relation to tocilizumab and corticosteroid administration; Figure S3: Hematopoietic toxicity and coagulopathy in severe neurotoxicity; Figure S4: Angiopoietin 1 and 2 alterations in severe neurotoxicity

Aims Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient’s immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. Methods and results From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104–647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan–Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6–4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4–8.8) after adjusting for cancer burden. Conclusion Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

BACKGROUND: B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein–coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×10(6) CAR T cells. At the 450×10(6) CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×10(6) to 150×10(6) cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×10(6) to 150×10(6) cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×10(6) to 150×10(6) cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.)

Objectives To report the epidemiology, treatments, and outcomes of adult patients admitted to the ICU after cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Design Retrospective cohort study SETTING:: Nine centers across the U.S. part of the chimeric antigen receptor-ICU initiative. Patients Adult patients treated with chimeric antigen receptor T-cell therapy who required ICU admission between November 2017 and May 2019. Interventions Demographics, toxicities, specific interventions, and outcomes were collected. Results One-hundred five patients treated with axicabtagene ciloleucel required ICU admission for cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome during the study period. At the time of ICU admission, the majority of patients had grade 3-4 toxicities (66.7%); 15.2% had grade 3-4 cytokine release syndrome and 64% grade 3-4 immune effector cell-associated neurotoxicity syndrome. During ICU stay, cytokine release syndrome was observed in 77.1% patients and immune effector cell-associated neurotoxicity syndrome in 84.8% of patients; 61.9% patients experienced both toxicities. Seventy-nine percent of patients developed greater than or equal to grade 3 toxicities during ICU stay, however, need for vasopressors (18.1%), mechanical ventilation (10.5%), and dialysis (2.9%) was uncommon. Immune Effector Cell-Associated Encephalopathy score less than 3 (69.7%), seizures (20.2%), status epilepticus (5.7%), motor deficits (12.4%), and cerebral edema (7.9%) were more prevalent. ICU mortality was 8.6%, with only three deaths related to cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Median overall survival time was 10.4 months (95% CI, 6.64-not available mo). Toxicity grade or organ support had no impact on overall survival; higher cumulative corticosteroid doses were associated to decreased overall and progression-free survival. Conclusions This is the first study to describe a multicenter cohort of patients requiring ICU admission with cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy. Despite severe toxicities, organ support and in-hospital mortality were low in this patient population.

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.

Purpose A task force of experts from 11 United States (US) centers, sought to describe practices for managing chimeric antigen receptor (CAR) T-cell toxicity in the intensive care unit (ICU). Materials and methods Between June–July 2019, a survey was electronically distributed to 11 centers. The survey addressed: CAR products, toxicities, targeted treatments, management practices and interventions in the ICU. Results Most centers (82%) had experience with commercial and non-FDA approved CAR products. Criteria for ICU admission varied between centers for patients with Cytokine Release Syndrome (CRS) but were similar for Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS). Practices for vasopressor support, neurotoxicity and electroencephalogram monitoring, use of prophylactic anti-epileptic drugs and tocilizumab were comparable. In contrast, fluid resuscitation, respiratory support, methods of surveillance and management of cerebral edema, use of corticosteroid and other anti-cytokine therapies varied between centers. Conclusions This survey identified areas of investigation that could improve outcomes in CAR T-cell recipients such as fluid and vasopressor selection in CRS, management of respiratory failure, and less common complications such as hemophagocytic lymphohistiocytosis, infections and stroke. The variability in specific treatments for CAR T-cell toxicities, needs to be considered when designing future outcome studies of critically ill CAR T-cell patients.

Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

Introduction: Chimeric antigen receptor T cell (CAR-T) therapy harnesses a patient’s own immune system to target cancer. Cardiotoxicity occurs in up to 25% of patients treated with CAR-T. There are limited data characterizing the association between the development of cardiotoxicity after CAR-T and mortality among patients following CAR T cell therapy. Hypothesis: We hypothesized that cardiotoxicity following CAR-T treatment would be associated with a higher rate of mortality. Cardiotoxicity was a composite outcome defined as the development of heart failure, cardiogenic shock, or myocardial infarction. Methods: We included the first 202 adult patients entered into a multicenter registry receiving anti-CD 19 CAR-T for lymphoma or acute lymphoblastic leukemia (ALL). Of these, 108 died and 94 survived. Covariates included standard baseline cardiovascular and cancer parameters, the occurrence of cardiotoxicity and mortality. Results: Those that did and did not die after CAR-T were similar in age, sex, and pre-lymphodepletion chemotherapy regiment. Death after CAR-T was more common in patients with than without hypertension (66% vs. 47%, p=0.009) or ALL (66% vs. 48%, p=0.02), and less common with baseline coronary artery disease (25 vs. 56%, p=0.04). There was no difference in mean cytokine release syndrome (CRS) grade, rate of ≥2 CRS, or in the use of tocilizumab or steroids between those who did and did not die after CAR-T. During a mean follow-up of 372±284 days, 33 (16%) patients experienced cardiotoxicity. Patients with vs. without cardiotoxicity died more often (76% vs. 49%, OR 3.2, CI 1.4 - 7.6, p=0.005). In a Cox model adjusted for covariates identified in univariate analyses, occurrence of cardiotoxicity with CAR-T was independently associated with an increased risk of mortality (adjusted HR: 1.85, 95% CI: 1.17-2.92, p=0.009). Conclusions: CAR-T recipients who experience cardiotoxicity have higher mortality.

Cancer immunotherapy has entered a new era with the recent introduction of genetically engineered T-cells that express chimeric antigen receptors (CARs) capable of recognizing and destroying tumor cells. Several clinical trials in patients with relapsed or refractory B-cell malignancies have demonstrated complete remission rates ranging from 50% to 90%, with long-term data suggestive of a possible curative response. CAR T-cell therapy is currently under investigation for earlier use in these disease processes and in various other solid and liquid tumors. CAR T-cell therapy is associated with a unique postinfusion toxicity profile including cytokine-release syndrome and neurotoxicity. These toxicities are usually reversible but can be fatal, requiring close vigilance and prompt treatment often in an intensive care unit (ICU) setting. CAR T-cell therapy is currently restricted to designated centers possessing expertise in acute toxicity management, but wider use is likely if early therapeutic successes are replicated. As perioperative and critical care physicians, anesthesiologists may encounter such patients in the perioperative or ICU setting and should become familiar with this unique and novel therapeutic modality capable of causing extreme cardiovascular and respiratory compromise. This review will describe the immunobiology of CAR T-cells, their relevance to cancer treatment, clinical aspects of their therapeutic use in cancer chemotherapy, toxicities related to CAR T-cell use, and their therapeutic management.

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as ‘living drugs,’ their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.

Patients who develop chimeric antigen receptor (CAR) T-cell–related severe cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells ({"type":"clinical-trial","attrs":{"text":"NCT01044069","term_id":"NCT01044069"}}NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day −1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell–related toxicities.

Factors contributing to hematopoietic recovery following chimeric antigen receptor (CAR) T-cell therapy have not been well studied. In an analysis of 83 patients with hematologic malignancies treated with CAR T-cell therapy, we describe patterns of hematopoietic recovery and evaluate potentially associated factors. We included patients who received axicabtagene ciloleucel (n = 30) or tisagenlecleucel (n = 10) for B-cell lymphoma, CD19-28z CAR T therapy for B-cell acute lymphoblastic leukemia (NCT01044069; n = 37), or B-cell maturation antigen targeting CAR T cells for multiple myeloma (NCT03070327; n = 6). Patients treated with CAR T cells who had not progressed, died, or received additional chemotherapy had “recovered” (per definition in Materials and methods section) hemoglobin, platelet, neutrophil, and white blood cell counts at rates of 61%, 51%, 33%, and 28% at month 1 postinfusion and 93%, 90%, 80%, and 59% at month 3 postinfusion, respectively. Univariate analysis showed that increasing grade of immune effector cell–associated neurological syndrome (ICANS), baseline cytopenias, CAR construct, and higher peak C-reactive protein or ferritin levels were statistically significantly associated with a lower likelihood of complete count recovery at 1 month; a similar trend was seen for cytokine release syndrome (CRS). After adjustment for baseline cytopenia and CAR construct, grade ≥3 CRS or ICANS remained significantly associated with the absence of complete count recovery at 1 month. Higher levels of vascular endothelial growth factor and macrophage-derived chemokines, although not statistically significant, were seen patients without complete count recovery at 1 month. This remains to be studied further in larger prospective studies.

CD19-targeted chimeric antigen receptor (CAR) T cells have shown excellent activity against relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL). CAR T cell therapy is associated with early toxicities, including cytokine release syndrome and neurotoxicity. The incidence and severity of these toxicities has been associated in part with baseline disease and patient characteristics, which also may impact overall survival (OS) and progression-free survival (PFS). However, there are limited data on patient selection and how to better predict toxicities or outcomes. Indexes used in patients with DLBCL, such as the International Prognostic Index (IPI and age-adjusted IPI [aaIPI]) and in transplantation recipients, such as the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), have not been evaluated in this setting. Here we evaluated 4 indices— IPI, aaIPI, HCT-CI, and the Charlson Comorbidity Index (CCI)—and their associations with early CAR T cell related-toxicities and outcomes. We demonstrated an association between high-risk IPI or aaIPI and inferior PFS in patients with R/R DLBCL treated with CAR T cell therapy. We also found an association between aaIPI and IPI with OS and neurotoxicity, respectively. CCI was not associated with toxicities or outcomes, and owing to the small sample size, we could not draw a conclusion regarding associations with the HCT-CI. Both the IPI and aaIPI are widely used tools that can now provide better information to guide selection of patients who would best benefit from CD19 CAR T cell therapy.

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood–cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system–specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958–71. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899

Background: CD19 CAR T cells have demonstrated high response rates in patients (pts) with relapsed or refractory (R/R) lymphoma, but these therapies are associated with high rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), often requiring prolonged hospital stay including transfer to the intensive care unit (ICU). Real-world data and early and prophylactic corticosteroid trials with axicabtagene in R/R large cell lymphoma have reported lower rates of severe CRS to Methods: Adult pts with R/R large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) receiving commercially available CD19 CAR T cells were enrolled. Pts received anakinra 100mg subcutaneous every 12 hours starting either on day 2 of CAR T cell infusion or after 2 documented fevers of ≥38.5 prior to day 2, whichever was earlier. Anakinra was continued for a minimum of 10 days, and the dose could be increased to 100mg every 6 hours and continued beyond 10 days in the case of persistent or progressing CRS and ICANS. Pts received tocilizumab and/or corticosteroids after anakinra initiation for persistent or worsening CRS or ICANS. CRS and ICANS were assessed per the ASTCT consensus grading. Disease response was assessed per the Lugano criteria. The primary objective was to determine the rate of severe ICANS within the first 28 days of CAR T cell infusion. Secondary objectives included assessment of severe CRS, all grades of CRS and ICANS, disease response and serum and CSF cytokines. Results: A total of 31 pts (LBCL=27, MCL=4) were enrolled to the study. The median age of the pts at the time of T cell infusion was 62 (range, 30-77). CD19 CAR products included axicabtagene (23 pts; 74%), tisagenlecleucel (4 pts; 13%) and brexucabtagene (4 pts; 13%). 17 pts (55%) received bridging therapy prior to T cell infusion. All pts started anakinra at 100mg q12h; 25 pts started on day 2 and 6 pts prior to day 2 for grade 1 CRS. Anakinra dose was increased to 100mg q6h in 13 pts (42%). The median duration of anakinra administration was 10 days (range, 10-27). CRS of all grades was observed in 21 pts (68%) with severe CRS (grade 3-4) in 2 pts (6%) (1 with axicabtagene and 1 with brexucabtagene) (Table). Median CRS duration was 5.5 days (range, 1-21). ICANS of all grades was observed in 4 pts (13%), with severe ICANS in 2 pts (6%) (both grade 3; 1 with axicabtagene and 1 with brexucabtagene). No pt experienced grade 5 CRS or ICANS. Tocilizumab and corticosteroids were used in 9 pts (29%) and 6 pts (19%), respectively. Three pts (10%) required ICU transfer (2 with brexucabtagene and 1 with axicabtagene). In LBCL pts treated with axicabtagene (n=23), both severe CRS and ICANS were observed in 4% with tocilizumab and steroid use in 22% and 13%, respectively (Table). With a median follow-up of 104 days (range, 21-363), overall disease response rate at month 1 was 74% for all pts, with CR rate at 1 and 3 months of 58% and 52%, respectively. Conclusion: Early use of IL-1 receptor inhibitor anakinra appears to be safe and feasible, and reduces the rates of both severe CRS and ICANS with the comparable response rates in adult pts with R/R B-cell lymphoma receiving CD19 CAR T cells. The overall severe CRS and ICANS rates were 6% each with relatively low utilization of tocilizumab (29%) and corticosteroids (19%). In pts receiving axicabtagene, the rate of severe ICANS was 4%. A longer follow-up is needed to assess durability of remission, but the study provides strong support for continued investigation of IL-1 inhibition in prevention of severe ICANS. Further exploratory analysis is planned to address the impact of anakinra on changes in serum and CSF cytokines. Figure 1 Figure 1. Disclosures Park: BMS: Consultancy; Servier: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Autolus: Consultancy; PrecisionBio: Consultancy; Intellia: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Kura Oncology: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy. Sauter: Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Palomba: Juno: Patents & Royalties; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; Wolters Kluwer: Patents & Royalties; PCYC: Consultancy; Ceramedix: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; BeiGene: Consultancy; WindMIL: Honoraria; Rheos: Honoraria; Nektar: Honoraria; Priothera: Honoraria; Pluto: Honoraria. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Dahi: Gilead sciences: Membership on an entity's Board of Directors or advisory committees; Kite pharma: Membership on an entity's Board of Directors or advisory committees. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; McKinsey & Company: Consultancy. Batlevi: Kite Pharma: Consultancy; TouchIME: Honoraria; Seattle Genetics: Consultancy; Juno/Celgene: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Perales: Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Equilium: Honoraria; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Honoraria; Incyte: Honoraria, Other; Cidara: Honoraria; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Sellas Life Sciences: Honoraria; NexImmune: Honoraria; Omeros: Honoraria; Novartis: Honoraria, Other. Santomasso: Janssen: Consultancy; Legend: Consultancy; Kite/Gilead: Consultancy; Celgene/BMS: Consultancy; Incyte: Consultancy; In8bio: Consultancy. Sadelain: Juno Therapeutics: Patents & Royalties; NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Minerva Biotechnologies: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Ceramedix: Patents & Royalties; Atara Biotherapeutics: Patents & Royalties. Brentjens: BMS: Consultancy, Patents & Royalties, Research Funding; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; sanofi: Patents & Royalties; Caribou: Patents & Royalties. OffLabel Disclosure: Anakinra for prevention of CRS and ICANS associated with CD19 CAR

Introduction Cytokine release syndrome (CRS) and immune effector cells associated neurotoxicity syndrome (ICANS) are common CAR T cells toxicities. Various grading systems that attribute different grades of severity to symptoms are currently used, preventing comparisons of different products and possibly leading to management implications. Methods We included 53 patients (pts) with B acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T cells (NCT01044069) and 49 pts with diffuse large B cell lymphoma (DLBCL) who received axicabtagene ciloleucel (axi-cel, n=36) or tisagenlecleucel (tisa-cel, n=13) after FDA approval. CRS and ICANS were retrospectively graded according to the new ASTCT consensus grading system, for comparison with other available systems: Lee, Penn, Memorial Sloan Kettering Cancer Center, CARTOX and CTCAEv5.0 for CRS; CTCAEv4.03 and CARTOX for ICANS. We then used ASTCT grades to predict management according to current guidelines for DLBCL pts (axi-cel and tisa-cel insert packages, CARTOX and NCCN guidelines) and compare it to the actual treatment received at our center. Results According to the ASTCT grading, B-ALL pts had 87% CRS (28% grade ≥3), while DLBCL pts had 86% CRS (14% grade ≥3) with axi-cel, and 54% (no grade ≥3) with tisa-cel. B-ALL pts had 55% ICANS (45% grade ≥3), while DLBCL pts had 55% ICANS (33% grade ≥3) with axi-cel, and 15% with tisa-cel (no grade ≥3) (fig. 1). When comparing grading systems, agreement on CRS and ICANS diagnosis was found in 99% and 91% cases, respectively. However, when evaluating toxicities grade by grade, only 27% pts had the same grade in each system for CRS, and 55% for ICANS (fig. 2). When predicting management for DLBCL pts, we found some relevant differences across current guidelines (fig. 3). At our center 58% and 13% of patients with CRS received tocilizumab (toci) and steroids, respectively, similarly to what predicted according to axi-cel's, CARTOX and NCCN guidelines, but differently from tisa-cel's label (10% and 5%). For ICANS, while tisa-cel's label does not provide any recommendations, other guidelines-based predictions were mostly overlapping. Indications for treatment vary across current guidelines, which were developed on single products and different grading systems, thus, should not be universally applied. This discrepancy becomes particularly relevant for cases with discordant CRS/ICANS grades. As such, we gave toci to 66% pts upgraded to grade 3 by Penn (grade 2 by ASTCT), while they would receive both toci and steroids according to axi-cel/CARTOX/NCCN guidelines, but would not be treated according to tisa-cel's. Conclusions Different grading systems provide inconsistent CRS/ICANS scores. To avoid discrepancies in assessing and managing toxicities of different products, a unified grading should be used and paired management guidelines with product-specific indications should be developed.

Background Cytopenias are observed post-CAR T, yet there is minimal data delineating the pathobiology and trends thereof. We report the largest series to our knowledge thus far, of hematopoietic recovery post-CAR T and factors affecting this recovery. Methods We retrospectively reviewed 115 adult patients who received CAR T, at our center, for relapsed/refractory (R/R) B cell lymphomas after FDA approval, R/R B cell acute lymphoblastic leukemia (ALL, NCT01044069) and multiple myeloma (MM, NCT03070327). Blood counts were collected for 12 months or until censored for relapse, progression or initiation of chemotherapy/ conditioning for autologous or allogeneic stem cell transplantation (HCT)/ subsequent treatment with CAR T. Only patients with follow-up > 30 days were included. "Recovery" for the respective blood count was defined to signify absence of transfusions or risk of infections: hemoglobin > 8g/dL and platelets > 50,000/µL without transfusion support in 2 weeks and 1 week, respectively; absolute neutrophil count (ANC) > 1,000/µL and white cell count (WBC) > 3,000/µL without growth factor support in 2 weeks. "Complete countrecovery" refers to recovery per above criteria in all 4 counts. Results Eighty three patients were included (Figure 1). By 1 month (n = 83), hemoglobin, platelets, ANC and WBC recovery was noted in 61%, 51%, 33% and 28%, respectively. At 3 months (n = 41), these were 93%, 90%, 81% and 59%. Figure 2 shows recovery at subsequent months. Upon examination of potential variables in a univariate model, lack of recovery of hemoglobin, platelets, ANC and complete count recovery at 1 month was statistically significantly associated with type of CAR construct, higher grade (3-4 vs 1-2 vs none) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as well as a higher peak CRP and ferritin (data for complete count recovery in Figure 3). Additionally, lack of hemoglobin recovery at 1 month was associated with lymphodepletion using high dose cyclophosphamide (recovered vs no recovery in 58% vs 42%, p = 0.01) and diagnosis of ALL (65% vs 35%, p = 3 prior lines of therapy (78% vs 22%, p = 0.04). At 3 months, absence of complete count recovery was associated only with the CAR T construct utilized. We also performed a sensitivity analysis using data for all 115 patients and no significant difference in univariate analysis was seen. Conclusions Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months following CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients.

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)–targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices (CD), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline (CD = 0.89–0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs (CD = 0.56–0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response.

CD19-specific chimeric antigen receptor (CAR) T cell therapy is a promising treatment for hematological malignancies however is associated with neurotoxicity. Axicabtagene ciloleucel is approved to treat adult patients with relapsed or refractory large B-cell lymphoma. Here we describe the neurological features and encephalogram (EEG) patterns of patients with refractory lymphoma treated with axicabtagene ciloleucel at Memorial Sloan Kettering Cancer Center (MSKCC). We retrospectively analyzed the neurological features and EEG patterns of the first six patients with refractory lymphoma treated at MSKCC with axicabtagine ciloleucel between February and April 2018. All six patients developed neurotoxicity, with both diffuse encephalopathy and focal neurological features.None of the patients had pre-existing neurological conditions. All patients received prophylatic levetiracetam and had a long-term video EEG performed. Two patients developed neurological findings concerning for focal status epilepticus. One patient had rhythmic right arm movements followed by weakness and the EEG showed left lateralized rhythmic delta activity (LRDA) with sharp waves and attenuation possibly reflecting a post-ictal state. The second patient had right facial and bilateral eye twitching concerning for focal motor status epilepticus. The EEG showed diffuse dysfunction - rhythmic delta activity and triphasic waves. Both patients had clinical improvement with addition of fosphenytoin. The remaining four patients had EEGs showing diffuse cerebral dysfunction. Neuroimaging in all patients was unrevealing for acute or significant structural pathology. Most patients had resolving neurologic symptoms; one patient had prolonged paraparesis. CONCLUSIONS: Axicabtagene ciloleucel can lead to transient diffuse and focal neurological findings of varying severity including focal status epilepticus. EEG is useful in characterizing cerebral dysfunction however is limited in detecting epileptic events. In patients who develop clinical status epilepticus escalation of AEDs may be warranted despite EEG not fulfilling status epilepticus criteria. Further study is needed to determine whether AED escalation can optimize patient outcomes.

Objectives Chimeric antigen receptor T-cell therapy, a type of immune effector therapy for cancer, has demonstrated encouraging results in clinical trials for the treatment of patients with refractory hematologic malignancies. Nevertheless, there are toxicities specific to these treatments that, if not recognized and treated appropriately, can lead to multiple organ failure and death. This article is a comprehensive review of the available literature and provides, from a critical care perspective, recommendations by experienced intensivists in the care of critically ill adult chimeric antigen receptor T-cell patients. Data sources PubMed and Medline search of articles published from 2006 to date. Study selection Clinical studies, reviews, or guidelines were selected and reviewed by the authors. Data extraction Not available. Data synthesis Not available. Conclusions Until modifications in chimeric antigen receptor T-cell therapy decrease their toxicities, the intensivist will play a leading role in the management of critically ill chimeric antigen receptor T-cell patients. As this novel immunotherapeutic approach becomes widely available, all critical care clinicians need to be familiar with the recognition and management of complications associated with this treatment.

CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

Background We aimed to characterize institutional resources utilized (other than T cell collection and CAR T cell manufacturing and infusion) peri-chimeric antigen receptor-modified (CAR) T cells administration. Methods Adult patients treated on selected investigator-initiated clinical trials of CAR T cell therapy at Memorial Sloan Kettering Cancer Center were identified from the institutional database. Utilization data was collected from the start of admission for CAR T cell infusion through the end of the initial admission for infusion or through 30 days following initial CAR T cell infusion, whichever was longer. Descriptive statistics were used to analyze the data. Results Between 6/2007 to 4/2018, 106 pts (56 pts (53%) B-cell acute lymphoblastic leukemia (ALL), 37 (35%) chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (NHL), and 13 (12%) multiple myeloma (MM)) on 4 clinical trials receiving inpatient CAR T cell infusions. The median age was 53 yrs (range 22-77) with 65% male. The median length of stay for the admission during which CAR T cells was given was 23 days (range 4 -133), with ALL patients admitted longer (Figure 1). 43 (41%) spent at least one day in the intensive care unit (ICU), with a range of 0-43 days. Outpatient clinic visits through day 30 post CAR T cell infusion occurred in 57 (53%) patients. A total of 62,953 laboratory panels and 1,190 radiology studies done during the study time frame. Fourteen percent of the labs were complete blood counts, basic or comprehensive metabolic panels, or liver function tests. For the total population, ALL, CLL/NHL, MM, there were a median of 63.5 (range 13-368), 91.5 (21-368), 47 (13-167), and 51 (range 38-113) of these panels done per patient during the time frame, respectively. Among the radiology studies, 25% were CT scans, 10% MRIs, 7% PET scans, 5% ultrasounds, and 53% x-rays, with differences in patterns of use by disease type (Figure 2). Chemotherapy accounted for 328 units (0.8%) of the 41,331 units of medications given in this time frame. The median medication units per patient was 255 (range 35-2091), 423 (range 35-2091), 200 (range 41-1190), and 207 (range 90-666) for the total population, and the ALL, CLL/NHL, and MM pts, respectively. Thirty-two doses of tocilizumab were given to 25 patients (24%), with ALL pts receiving 23 of those doses (72%). Conclusion CAR T cell therapy utilizes many resources and can create challenges in institutional resource capacity. Identifying these resources will allow for better allocation and care delivery. Further refinement of CAR T cell products and improvements in CAR T cell-related toxicity management may permit safer delivery of this therapy and reduce costs per patient. Comparison with alternative therapies and analysis of resource utilization for the commercial CAR T cell products is warranted.

Background: CAR T therapy is FDA approved for specific relapsed/ refractory (R/R) B cell lymphomas and acute lymphoblastic leukemia (ALL), and clinical trials are ongoing for R/R multiple myeloma (MM). Cytopenias have been observed post-CAR T, yet there is minimal data delineating the pathobiology and trends. We report the largest series to our knowledge thus far, of hematological recovery and factors affecting count recovery after CAR T. Methods: We retrospectively reviewed adult patients who received CAR T for R/R B cell lymphomas after FDA approval and those treated for R/R B cell ALL (NCT01044069) and MM (NCT03070327) at our center. Blood counts were collected for up to 12 months or until censored for relapse, progression or initiation of chemotherapy/ conditioning for autologous or allogeneic stem cell transplantation (HCT)/ subsequent treatment with CAR T. Only patients with follow-up > 30 days were included. "Recovery" for the respective blood count was defined as hemoglobin > 8g/dL and platelets > 50,000/µL without transfusion support in 2 weeks and 1 week, respectively; absolute neutrophil count (ANC) > 1,000/µL and white cell count (WBC) > 3,000/µL without growth factor support in 2 weeks. "Normalization" was defined as normal range for the laboratory; hemoglobin > 11.2g/dL in women and 12.5g/dL in men, platelets > 160,000/µL, ANC > 1,500/µL and WBC > 3,000/µL without transfusion support as above. "Complete count recovery" refers to recovery per above criteria in all 4 counts. Categorical variables were compared using Fisher's exact test and continuous variables using the Wilcoxon rank-sum test. Results: Eighty three patients were included (Table 1). Using the noted nadir values, grade 1-2 and 3-4 anemia was seen in 22% and 78%, thrombocytopenia in 29% and 66%, neutropenia in 3% and 96% while leucopenia in 0% and 100%, respectively. During the follow-up, 66% patients received packed red cell transfusion, 52% received platelet transfusion and 62% received growth factor support. By 1 month (n=83), recovery of hemoglobin, platelets, ANC and WBC was noted in 61%, 51%, 33% and 28%, respectively. At 3 months (n=41), these respective percentages were 93%, 90%, 81% and 59%. All patients had recovered hemoglobin and platelet count by 4 months (n=17), and ANC by 9 months (n=14). By 3 months, normalization of hemoglobin, platelets, ANC and WBC was noted in 39%, 34%, 71%, and 39%, respectively. Upon examination of potential variables in a univariate model, lack of recovery of hemoglobin, platelets, ANC and complete counts recovery at 1 month was statistically significantly associated with type of CAR construct, higher grade (grade 3-4 vs grade 1-2 vs none) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as well as a higher peak CRP and ferritin (data for complete count recovery in Table 2). Additionally, lack of hemoglobin recovery at 1 month was associated with lymphodepletion using high dose cyclophosphamide (recovered vs no recovery in 58% vs 42%, p=0.01) and diagnosis of ALL (65% vs 35%, p = 3 prior lines of therapy (78% vs 22%, p = 0.04). At 3 months, absence of complete count recovery was associated only with the CAR T construct utilized. A multivariate logistic regression model resulted in wide confidence intervals due to small size of subgroups, hence leading to unreliable point estimates (data not shown). Conclusions: Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months post-CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients. The association of count recovery and CAR construct can be influenced by underlying diagnosis as specific CAR constructs were used for specific diagnosis. Since patients with no disease response were excluded and were censored at progression, these effects are less likely to be affected by disease response; however the association of depth of response could not be evaluated in this study. These results warrant future studies to understand underlying mechanisms of inadequate recovery. Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy. Sauter:Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Celgene: Consultancy; GSK: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy. Santomasso:Novartis: Consultancy; Kite/Gilead: Consultancy; Juno/Celgene: Consultancy. Palomba:Noble Insights: Consultancy; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen: Research Funding; Janssen: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Brentjens:Celgene: Consultancy; JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding. Park:Takeda: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy. Perales:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mailankody:Celgene: Research Funding; Juno: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria.

Introduction Chimeric Antigen Receptor (CAR) T cells are associated with unique toxicities, including cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS). Patients (pts) with severe CRS and ICANS exhibit hemodynamic instability and coagulopathy with evidence of endothelial activation and increased blood brain barrier permeability. Increases in inflammatory cytokines and biomarkers of endothelial activation in serum and CSF have been associated with severe CRS and ICANS. The EASIX (Endothelial Activation and Stress Index) score [lactate dehydrogenase (LDH) (U/L) × creatinine (mg/dl) / platelets (PLT) (109 cells/L)] correlates with severe fluid overload and survival in allogeneic transplant pts. Elevated LDH and low PLT levels have been associated with severe ICANS development, and high IL-6 levels are seen in severe CRS and ICANS. We hypothesized that the EASIX and a newly proposed version of it, the modified-EASIX (mEASIX), in which creatinine is replaced by CRP (mg/dL) as an easily available surrogate for IL6, would be associated with CRS and ICANS in CAR T cells pts. Methods We analyzed 2 different populations of adult CAR T cells pts treated at our institution: 1) B-cell acute lymphoblastic leukemia (B-ALL) pts treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) aggressive diffuse large B-cell lymphoma (DLBCL) pts treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval starting from 2018. EASIX and mEASIX scores were calculated for each patient daily from start of lymphodepletion conditioning to day +14. A log transformation using base 2 (log2) was applied to all EASIX/mEASIX variables to reduce skew. CRS and ICANS were graded according to the ASTCT grading system. Results 87 pts, B-ALL (n=53) and DLBCL (n=34), were analyzed. According to ASTCT grading, 83% (72/87) experienced CRS and 54% (47/87) developed ICANS, grade ≥3 in 23% (20/87) and 40% (35/87) of pts, respectively. When analyzed by disease, CRS and ICANS rates were 87% (46/53) and 55% (29/53) for B-ALL and 76% (26/34) and 53% (18/34) for DLBCL, respectively. CRS and ICANS were grade ≥3 in 28% (15/53) and 45% (24/53) of B-ALL pts and in 15% (5/34) and 32% (11/34) of DLBCL pts, respectively. Median time of onset of CRS after CAR T cell infusion was day +2 and median onset of ICANS was day +6 for the overall population and the subgroups. High EASIX and mEASIX scores at start of conditioning were both associated with development of any grade CRS [OR=1.81 (95% CI 1.09-3.36) p=0.038 and OR=1.94 (95% CI 1.32-3.38) p=0.005] and grade ≥3 CRS [OR=1.47 (95% CI 1.05-2.29) p=0.049 and OR=1.34 (95% CI 1.07-1.80) p=0.024], respectively (Table). Following CAR T cell infusion, high scores of both EASIX [OR=1.60 (95% CI 1.12-2.43) p=0.017] and mEASIX [OR=1.32 (95% CI 1.07-1.69) p=0.014] on day +1 were associated with development of grade ≥3 CRS. Moreover, both high EASIX [OR=1.43 (95% CI 1.08-1.96) p=0.018] and mEASIX [OR=1.29 (95% CI 1.07-1.60) p=0.010] scores on day +3 were associated with grade ≥3 ICANS. When analyzed by disease, results were confirmed for severe CRS and ICANS in B-ALL patients, while in the DLBCL group only mEASIX at start of conditioning and at day +1 was associated with development of any grade CRS. EASIX and mEASIX scores were not associated with response rates to CAR T cells therapy. Conclusions EASIX and mEASIX scores calculated at baseline (before lymphodepletion) are associated with development of CRS and severe CRS. Moreover, both high EASIX and mEASIX scores on day +1 and day +3 are associated with occurrence of grade ≥3 CRS and grade ≥3 ICANS, respectively. We conclude that EASIX and mEASIX, as markers of endothelial damage and inflammation, could be useful as early predictors in guiding treatment decisions before the onset of severe symptoms. Table Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy. Giralt:Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Kite: Consultancy. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy. Santomasso:Kite/Gilead: Consultancy; Juno/Celgene: Consultancy; Novartis: Consultancy. Sauter:GSK: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Perales:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.

The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients. We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger ( Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure). We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients ( Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system. Disclosures Batlevi: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giralt:Jazz Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Kite: Consultancy. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties. Santomasso:Kite/Gilead: Consultancy; Novartis: Consultancy; Juno/Celgene: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyte/Gilead: Research Funding; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Chimeric antigen receptor-modified (CAR) T cells have the potential to provide durable clinical benefit in patients with several relapsed or refractory hematologic malignancies. We aimed to characterize institutional resources utilized (other than T cell collection and CAR T cell manufacturing and infusion) around the time of CAR T cell administration. Methods: Adult patients treated on selected investigator-initiated clinical trials of CAR T cell therapy at Memorial Sloan Kettering Cancer Center were identified from the institutional database. Utilization data was collected from the start of admission for CAR T cell infusion through the end of the initial admission for infusion or through 30 days following initial CAR T cell infusion, whichever was longer. The data were sorted by disease type and into the categories of encounters, lab work, radiology, medications, and other diagnostic testing. Descriptive statistics were used to analyze the data. Results: We identified 106 patients on 4 clinical trials receiving inpatient CAR T cell infusions between 6/2007 to 4/2018, with 56 patients (53%) having B-cell acute lymphoblastic leukemia (ALL), 37 (35%) chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (NHL), and 13 (12%) multiple myeloma (MM). The median age was 53 years (range 22-77), 45 years (range 22-74), 64 years (range 35-77), and 58 years (range 43-68) for the total population, and the ALL, CLL/NHL, and MM groups, respectively, and 65%, 75%, 41%, and 31% were male, respectively. The median length of stay for the admission during which CAR T cells was given was 23 days (range 4 -133), with ALL patients admitted longer (Figure 1). Intensive care unit (ICU) days were limited with a range of 0-43 days, though 43 (41%) spent at least one day in the ICU. Of note, some protocols required infusion of the CAR T cells to be in the ICU. ICU admissions for ALL patients were than for other histologies longer (median 9 days vs 4 days). Outpatient clinic visits through day 30 post CAR T cell infusion occurred in 57 (53%) patients, with more of these in the CLL/NHL patients (median of 2 visits, range 1-4). As expected, laboratory and radiology studies accounted for a large portion of resource utilization with a total of 62,953 laboratory panels and 1,190 radiology studies done during the study time frame. Fourteen percent of the labs were complete blood counts, basic or comprehensive metabolic panels, or liver function tests. For the total population, ALL, CLL/NHL, MM, there were a median of 63.5 (range 13-368), 91.5 (21-368), 47 (13-167), and 51 (range 38-113) of these panels done per patient during the time frame, respectively. Blood cultures accounted for 1.3% of the total laboratory tests. Among the radiology studies, 25% were CT scans, 10% MRIs, 7% PET scans, 5% ultrasounds, and 53% x-rays, with differences in patterns of use by disease type (Figure 2). Cardiac testing (echocardiographs & electrocardiograms) was done in 104 (98%, total 634 tests). Electroencephalogram was performed in 18 patients (17%, total 18 tests). There were 173 bone marrow aspirations/biopsies in 88 patients (83%) and 71 lumbar punctures in 38 patients (36%), many of which were potentially done for disease assessment rather than toxicity management. Finally, 41,331 units of medications were given in this time frame, of which chemotherapy was 328 units (0.8%). The median medication units per patient was 255 (range 35-2091), 423 (range 35-2091), 200 (range 41-1190), and 207 (range 90-666) for the total population, and the ALL, CLL/NHL, and MM patients groups, respectively. Thirty-two doses of tocilizumab were given to 25 patients (24%), with ALL patients receiving 23 of those doses (72%). Conclusion: While providing potential clinical benefit, CAR T cell therapy utilizes resources across the therapeutic spectrum, and increasing use of this therapeutic modality can create challenges in institutional resource capacity. Identifying these resources will allow for better care delivery and allocation of funds. Further refinement of CAR T cell products and improvements in CAR T cell-related toxicity management may permit safer delivery of this therapy and reduce costs per patient. Additional analysis of resource utilization among patients treated with commercial CAR T cell products, as well as comparison with alternative therapies and cost-effectiveness analysis, is warranted. Disclosures Shah: Amgen: Research Funding; Janssen: Research Funding. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Shire: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Younes:Genentech: Research Funding; BMS: Honoraria, Research Funding; Pharmacyclics: Research Funding; Abbvie: Honoraria; Merck: Honoraria; Takeda: Honoraria; J&J: Research Funding; Incyte: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria; Roche: Honoraria, Research Funding; Curis: Research Funding; Astra Zeneca: Research Funding; Novartis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria. Geyer:Dava Oncology: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Mailankody:Physician Education Resource: Honoraria; Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Bach:Vizient: Other: Personal Fees; Hematology Oncology Pharmacy Assoc: Other: Personal Fees; Excellus Health Plan: Other: Personal Fees; Gilead: Other: Personal Fees; Foundation Medicine: Other: Personal Fees; JMP Securities: Other: Personal Fees; Janssen: Other: Personal Fees; Grail: Other: Personal Fees; American Society for Hospital Pharmacy: Other: Personal Fees; Kaiser Permanente: Research Funding; Third Rock Ventures: Other: Personal Fees; WebMD: Other: Personal Fees; Anthem: Other: Personal Fees; Goldman Sachs: Other: Personal Fees; Novartis: Other: Personal Fees; Defined Health: Other: Personal Fees.

Patients with relapsed/refractory MM (RRMM) rarely obtain durable remissions with available therapies. Clinical use of BCMA targeted CAR T cell therapy was first reported in 12/2015 for RRMM, and based on small numbers, preliminary results appear promising. Given that host immune anti-murine CAR responses have limited the efficacy of repeat dosing (Turtle C. Sci Trans Med 2016), our goal was to develop a human BCMA targeted CAR T cell vector for clinical translation. We screened a human B cell derived scFv phage display library containing 6x1010 scFvs with BCMA expressing NIH 3T3 cells, and validated results on human MM cell lines. 57 unique and diverse BCMA specific scFvs were identified containing light and heavy chain CDR's each covering 6 subfamilies, with HCDR3 length ranges from 5-18 amino acids. 17 scFvs met stringent specificity criteria, and a diverse set was cloned into CAR vectors with either a CD28 or a 4-1BB co-stimulatory domain. Donor T cells transduced with BCMA targeted CAR vectors that conveyed particularly desirable properties over multiple in vitro assays, including: cytotoxicity on human MM cell lines at low E:T ratios (>90% lysis, 1:1, 16h), robust proliferation after repeat antigen stimulation (up to 700 fold, stimulation q3-4d for 14d), and active cytokine profiling, were selected for in vivo studies using a marrow predominant human MM cell line model in NSG mice. A single IV injection of CAR T cells, either early (4d) or late (21d) after MM engraftment was evaluated. In both cases survival was increased when treated with BCMA targeted CAR T cells vs CD19 targeted CAR T cells (median OS at 60d NR vs 35d p10,000 fold) CAR T expansion at day 6, followed by contraction of CAR T cells after MM clearance, confirming the efficacy of the anti-BCMA scFv/4-1BB containing construct. Co-culture with primary cells from a range of normal tissues did not activate CAR T cells as noted by a lack of IFN release. Co-culture of 293 cells expressing this scFv with those expressing a library of other TNFRSF or Ig receptor members demonstrated specific binding to BCMA. GLP toxicity studies in mice showed no unexpected adverse events. We generated a retroviral construct for clinical use including a truncated epithelial growth factor receptor (EGFRt) elimination gene: EGFRt/hBCMA-41BBz. Clinical investigation of this construct is underway in a dose escalation, single institution trial. Enrollment is completed on 2/4 planned dose levels (DL). On DL1 pts received cyclophosphamide conditioning (3g/m2 x1) and 72x106 mean CAR+ T cells. On DL2 pts received lower dose cyclophosphamide/fludarabine (300/30 mg/m2 x3) and 137x106 mean CAR+ T cells. All pts screened for BCMA expression by IHC were eligible. High risk cytogenetics were present in 4/6 pts. Median prior lines of therapy was 7; all pts had IMiD, PI, high dose melphalan, and CD38 directed therapies. With a data cut off of 7/20/17, 6 pts are evaluable for safety. There were no DLT's. At DL1, grade 1 CRS, not requiring intervention, occurred in 1/3 pts. At DL2, grade 1/2 CRS occurred in 2/3 pts; both received IL6R directed Tocilizumab (Toci) with near immediate resolution. In these 2 pts time to onset of fever was a mean 2d, Tmax was 39.4-41.1 C, peak CRP was 25-27mg/dl, peak IL6 level pre and post Toci were 558-632 and 3375-9071 pg/ml, respectively. Additional serum cytokines increased >10 fold from baseline in both pts include: IFNg, GM CSF, Fractalkine, IL5, IL8, and IP10. Increases in ferritin were limited, and there were no cases of hypofibrinogenemia. There were no grade 3-5 CRS and no neurotoxicities or cerebral edema. No pts received steroids or Cetuximab. Median time to count recovery after neutropenia was 10d (range 6-15d). Objective responses by IMWG criteria after a single dose of CAR T cells were observed across both DLs. At DL1, of 3 pts, responses were 1 VGPR, 1 SD, and 1 pt treated with baseline Mspike 0.46, thus not evaluable by IMWG criteria, had >50% reduction in Mspike, and normalization of K/L ratio. At DL2, 2/2 pts had objective responses with 1 PR and 1 VGPR (baseline 95% marrow involvement); 1 pt is too early to evaluate. As we are employing a human CAR, the study was designed to allow for an optional second dose in pts that do not reach CR. We have treated 2 pts with a second dose, and longer follow up data is pending. Figure 1 Figure 1. Disclosures Smith: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. Almo: Cue Biopharma: Other: Founder, head of SABequity holder; Institute for Protein Innovation: Consultancy; AKIN GUMP STRAUSS HAUER & FELD LLP: Consultancy. Wang: Eureka Therapeutics Inc.: Employment, Equity Ownership. Xu: Eureka Therapeutics, Inc: Employment, Equity Ownership. Park: Amgen: Consultancy. Curran: Juno Therapeutics: Research Funding; Novartis: Consultancy. Dogan: Celgene: Consultancy; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liu: Eureka Therpeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.