Onset Of Cytokine Release Syndrome Research Articles

Phase I Study of PHE885, a Fully Human BCMA-Directed CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma Manufactured in

Phase I Study of PHE885, a Fully Human BCMA-Directed CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma Manufactured in <2 Days Using the T-Charge TM Platform

CRP and ferritin in addition to the EASIX score predict CAR-T–related toxicity

AbstractThe Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T–related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.

New-Onset Severe Cytopenia After CAR-T Cell Therapy: Analysis of 76 Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia.

Although chimeric antigen receptor T (CAR-T) cell therapy has proven to be effective in treating relapsed or refractory B-cell hematological malignancies, severe hematological toxicities remain an intractable issue. This retrospective study assessed the characteristics and risk factors of new-onset severe cytopenia following CAR-T cell infusion in 76 patients with r/r acute lymphoblastic leukemia. The rates of new-onset severe cytopenia were high, including severe neutropenia (SN) (39/56, 70%), severe anemia (SA) (35/66, 53%), and severe thrombocytopenia (ST) (31/64, 48%). Comparatively, cohorts with higher cytokine release syndrome (CRS) grades had higher incidence of severe cytopenia with prolonged duration. Multivariable analyses showed that elevated maximum (max) lg D-dimer and delayed peak time of CRS are independent risk factors for SN recovery; increased max lg IL-10 and delayed CRS recovery are risk factors for SA; high max lg ferritin is a risk factor for ST; and longer period to CRS onset or CRS recovery and higher grade of CRS are risk factors for prolonged hematological toxicities. These observations led to the conclusion that profiles of CRS, including its duration, severity and serum markers are correlated to the incidence and recovery of new-onset severe cytopenia, prompting clinical intervention for post-CAR-T severe cytopenia.

Beyond Cytokine Storm: Optimizing Treatment Strategies to Target the Complex Interplay between CAR Mediated Inflammatory Response, Disseminated Intravascular Coagulation and Macrophage Activation Syndrome

Background: Cytokine release syndrome (CRS) is a well described, non-specific toxicity of CAR therapy caused by high-level immune activation. Generally, CRS starts within a week of CAR-T cell infusion, is typically self-limited, and mitigation strategies utilizing tocilizumab (anti-IL6 receptor antibody) and/or corticosteroids are rapidly effective. Despite initial improvement, delayed manifestations including disseminated intravascular coagulation (DIC) and macrophage activation syndrome (MAS) may occur in some for whom CAR mediated inflammatory responses continue to evolve. To improve upon the safety profile of CAR therapy, we report on our experience with DIC and MAS.Design: We report on the toxicity profile of the first 30 children and young adults with relapsed/refractory CD22+ ALL treated on our phase I dose escalation anti-CD22 CAR therapy. All had routine monitoring of cytokines, fibrinogen, D-Dimer, PT/INR, PTT and CBC. Following observations of clinically significant DIC, we prospectively evaluated markers of activated coagulation, including: thrombomodulin, E-selectin, s-VCAM, v-ICAM, P-selectin, prothrombin fragment 1 + 2, tissue factor, and PAI-1. Markers for MAS, including ferritin, triglycerides and soluble IL2R were monitored, as well as immunohistochemical staining for hemophagocytosis on the bone marrow aspirate/biopsy.Results: From December 2014 to July 2017, 30 patients with ALL were treated at 3 dose levels. CRS was seen in 24/30 (80%), which was grade 1-2 in all, except for one grade 4. Eight of 24 (33%) with CRS developed DIC, which was grade 2 (no bleeding) in 3 patients and grade 3 (with bleeding) in 5 patients. Bleeding complications were primarily mucosal and included diffuse alveolar hemorrhage, epistaxis, hematuria, subconjunctival hemorrhage and petechiae/purpura that appeared disproportionate to the platelet count and typically occurred after resolution of acute CRS. Correspondingly, morphologic evaluation revealed hypogranular/agranular platelets seen in 16 of 20 patients (confirmed by electron microscopy in one), of whom 7 had DIC, suggesting an acquired platelet function defect; such patients received higher transfusion support. In those with DIC, PT/INR/PTT and D-Dimer rose with onset of CRS. Fibrinogen, initially elevated with the onset of CRS, fell precipitously with resolution of fever. At the time of clinically evident DIC, in 8 of 12 evaluable subjects, P-selectin values rose at least 50%, on average 17.6 days after CAR-T infusion and in 11 of 12 evaluable subjects, endothelial markers rose and peaked 2 weeks after CAR-T infusion (mean 15.2 days). Treatment of DIC was primarily supportive; methylprednisolone, starting at 0.5-1 mg/kg was initiated in patients with active bleeding, and continued q6-8 hours until stabilization. Resolution of DIC typically coincided with decrease in ferritin, suggesting an inflammatory mediated coagulopathy. Accordingly, patients with DIC also had statistically significantly higher ferritin (median 361,585 v 14,349, p<0.0001) IFN-g, IL-1b, IL-6, IL-8, IL-10 and MIP-1a (p<0.01 for all) than in those without DIC, mimicking elevations seen in MAS. Further supporting the link to MAS, 3 of 4 patients with DIC had soluble IL2R levels > 5-fold x the upper limit of normal at 2 weeks post CAR therapy. Additionally, one patient with DIC had active hemophagocytosis at the 1 month evaluation (Figure), which in the constellation of hepatic transaminitis, cytopenias and hyperferritinemia led to a diagnosis of MAS. Treatment with single agent anakinra, an IL-1 receptor antagonist, initiated as a steroid-sparing agent, was well tolerated and led to full resolution of hemophagocytosis; importantly, it did not impede ongoing CAR response, with clearance of all minimal residual disease from the one month to the two-month restaging time point.Conclusion: An intricate relationship exists between the initial inflammatory CRS, and later complications of DIC and MAS potentially induced by CAR T related inflammation. Although steroids and supportive care measures may stabilize DIC, cytokine profiles, which include elevated IL-1b, can assist when choosing targeted, steroid-sparing therapies such as anakinra. Future directions will include exploring the link between inflammation, DIC, and MAS and optimizing targeted anti-inflammatory strategies earlier in the treatment course to prevent serious complications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pharmacokinetics and Pharmacodynamics of Tocilizumab for the Management of Cytokine Release Syndrome (CRS) in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Treated with CAR T-Cell Therapy, CTL019

Background: ELIANA (NCT02435849) is a pivotal multicenter study to test the efficacy of CTL019 (tisagenlecleucel; anti-CD19 CAR-T) in children and young adult patients (pts) with relapsed/refractory B-ALL. Tocilizumab (toci) has been used for the management of moderate/severe (grade 3/4) CRS in ≈ 38% of pts treated with CTL019 (Buechner J et al, EHA 2017) at the same doses used in approved non-oncologic pediatric indications (<30 kg received 12 mg/kg and ≥30 kg received 8 mg/kg [800 mg max dose]). CRS onset generally occurred at a median of 3 days (range 1-22 days) after CTL019 infusion, requiring administration of 1-3 doses of toci in some patients per the Penn CRS treatment algorithm. Toci is a humanized mAb that binds to and blocks IL-6 receptor (IL-6R) signaling. The pharmacokinetics (PK) and pharmacodynamics (PD) of toci in pediatric B-ALL patients with CAR-associated CRS has not previously been described.Objectives: To characterize the PK/PD of toci for the management of CRS following CTL019 infusion in B-ALL in the ELIANA study. To describe the impact of toci on CTL019 cellular kinetics and expansion.Methods: Pharmacokinetics of toci and pharmacodynamics of soluble IL-6R (sIL-6R) concentrations (conc) were determined from serum and quantified using validated assays to provide mechanistic support for the use of toci in the management of CRS in B-ALL. Maximum toci conc (Cmax) was derived using non-compartmental methods and compared with levels in approved indications. sIL-6R, proinflammatory cytokines and time to CRS resolution were characterized to describe the pharmacodynamic effects of toci. Summary statistics and graphical analyses of CTL019 exposure by number of toci doses were performed for patients that responded to CTL019 infusion to describe the impact of toci on CTL019 expansion and persistence.Results: A total of 28 out of 58 pts with CRS received their first dose of toci at a median of 5 days (range 1-18) after CRS onset. 17 pts received 1 IV dose of toci; 8 pts 2 doses; 3 pts 3 doses. First dose of toci ranged from 6.9 to 12 mg/kg; second dose of toci ranged from 8 to 12 mg/kg. Following the first and second dose of toci, the mean Cmax (SD) were ≈ 111 (30.6) µg/mL and 265 (376) µg/mL, respectively (Table 1). Individual patient PK/PD concentration-time profiles in B-ALL, show increased sIL-6R after the first toci dose that remained elevated following the second dose (Figure 2). The median time to CRS resolution (including fever resolution) was 5 days (range, 2-29 days) after toci administration. CRS onset coincided with CTL019 expansion, and was followed by a peak in serum cytokines, including IL-6. Maximal expansion of the CTL019 transgene (determined by qPCR) was 159% higher in patients treated with toci (n=14) compared with patients that did not receive toci (n=28) demonstrating tocilizumab does not negatively impact expansion (Figure 3).Conclusions: Toci administration resulted in resolution of CRS symptoms within a median of 5 days after administration. Notably, levels of toci achieved in B-ALL were similar to levels published in pediatric non-oncologic indications [tocilizumab label], resulting in concentration- and time-dependent increases in sIL-6R. CTL019 transgene expanded and persisted following tocilizumab administration. Together these data support the use of toci for the management of CRS, showing the compound to be 1) pharmacologically active, 2) able to achieve levels consistent with those achieved in other disorders in spite of CRS and 3) able to be given without impairing CTL019 expansion. [Display omitted] DisclosuresLee:Novartis Pharmaceuticals Corporation: Other: Post-Doctoral Fellow; The State University of New Jersey: Other: Post doctoral fellow. Bittencourt:Novartis Pharmaceuticals Corporation: Consultancy; Amgen Inc.: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel Grant. Rives:Novartis Pharmaceuticals Corporation: Consultancy; Jazz Pharmaceutical: Other: Travel expenses; Shire: Consultancy. Boyer:Novartis Pharmaceuticals Corporation: Honoraria. Pulsipher:Adaptive: Other: Advisory board 6/17; CSL Behring: Other: advisory board Feb 2017; Jazz Pharmaceuticals: Other: advisory board, education; Chimerix: Other: Advisory board Dec 2015; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Jaitner:Novartis Pharma AG: Employment. Yi:Novartis Pharmaceuticals Corporation: Employment. Lund:Novartis Pharmaceuticals Corporation: Employment. Leung:Novartis Pharmaceuticals Corporation: Employment. Awasthi:Novartis Pharmaceuticals Corporation: Employment. Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties. Mueller:Novartis Pharmaceuticals Corporation: Employment.

Preliminary Safety Profile of the CD19-Directed Defined Composition CAR T Cell Product JCAR017 in Relapsed/Refractory Aggressive B-NHL Patients: Potential for Outpatient Administration

Preliminary Safety Profile of the CD19-Directed Defined Composition CAR T Cell Product JCAR017 in Relapsed/Refractory Aggressive B-NHL Patients: Potential for Outpatient Administration

Biomarkers for Predicting Toxicity and Response in Adult Acute Lymphoblastic Leukemia (ALL) Patients Treated with Blinatumomab

Introduction: Blinatumomab is a bispecific T-cell engaging monoclonal antibody, linking CD19+ B-cells with CD3+ T-cells. Blinatumomab has shown pronounced clinical benefit in relapsed/refractory (R/R) B-ALL patients. A common toxicity is cytokine release syndrome (CRS), which includes a constellation of symptoms related to systemic inflammatory response. No available conclusive data suggests that cytokine elevation predicts response to therapy, neurotoxicity, or severity of CRS. C-reactive protein (CRP) is currently used as a surrogate for IL-6 bioactivity. To this end, we sought to determine if there is an association between CRP and ferritin levels and development of CRS, neurotoxicity, and response in patients receiving blinatumomab.Methods: This IRB approved, single-center, retrospective study at Memorial Sloan Kettering Cancer Center included adult patients with R/R B-ALL treated with blinatumomab between 1/1/11 and 12/31/16. Patients without appropriate follow up were excluded. Patients were identified via electronic medical records and an internal pharmacy database. CRS was graded using the criteria outlined by Lee et al (Lee DW, et al. Blood. 2014 Jul 10;124(2):188-95). Continuous variables were summarized with medians, interquartile ranges (IQR: 25th and 75th percentiles), or ranges. Categorical variables were summarized with frequencies and percentages. Comparisons between groups were evaluated using the Wilcoxon rank sum test or Fisher's exact test for continuous and categorical variables, respectively. Maximum change in CRP or ferritin was calculated for each patient as the difference between peak value and baseline value of each respective biomarker.Results: A total of 25 patients were included. Median age was 51.7 years, with a predominant female population (56%). Eight patients (32%) had extramedullary disease at baseline; 12 patients (48%) had >50% bone marrow blasts at the time of treatment with blinatumomab. 14 patients (56%) experienced CRS during cycle 1, with ten grade 1 events and four grade 2 events. Among 11 patients who started cycle 2, two patients experienced CRS, one grade 1 and one grade 2 event. In cycle 1, median time to onset of CRS was one day (range, 0-9). Median baseline CRP was 0.94 mg/dl (range, 0.05-33.3), and days to peak CRP was two days (range, 0 - 13). Median peak CRP was significantly increased (p=0.001) in patients with CRS (20.6, IQR 17.1-31.9) compared to patients without CRS (5.2, IQR 1.7-12.0). In addition, median absolute peak ferritin level and incremental change in ferritin from baseline in cycle 1 significantly correlated to CRS (p=0.03 and 0.023, respectively). The presence of >50% blasts at pretreatment was not associated with increased incidence of CRS. Neurotoxicity was documented in six patients (24%) during cycle 1, with a median onset of nine days from the start of therapy (range, 1-23). Patients with neurotoxicity had a significantly shorter time to peak CRP, with a median of two vs. three days (p=0.031). Baseline and peak ferritin level in cycle 1 were significantly increased in patients with neurotoxicity (p=0.044 and 0.026, respectively). Eleven patients (44%) achieved a complete response and 14 patients (56%) had refractory disease. Responders were found to have significantly lower baseline CRP (p=0.008) and lower baseline ferritin values (p=0.03). No grade 4 or 5 CRS was observed and no patient discontinued therapy due to CRS.Conclusion: Our data shows there is an association between changes in biomarkers (CRP and ferritin) and development of CRS, and suggests frequent monitoring of these biomarkers may be useful in predicting patients at risk for CRS and neurotoxicity, possibly leading to earlier intervention. Considering the infrequent CRS events documented in cycle 2, our results raise the question of the required admission for patients in cycle 2. Due to a small sample size and retrospective nature of this study, these findings need to be examined prospectively to confirm the association of these biomarkers with blinatumomab-associated toxicities and inform monitoring guidelines. [Display omitted] DisclosuresHorvat:Agios: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Park:Amgen: Consultancy.

Neurological Consequences of Cytokine Release Syndrome Following Subcutaneous Recombinant IL-15 and Haploidentical Donor Natural Killer Cell Therapy for Advanced Acute Myeloid Leukemia

Abstract Cytokine Release Syndrome (CRS) is associated with elevated cytokine levels, macrophage activation, and IL-6 production after antibody or cell-based immunotherapy. We have observed over 200 patients with no CRS following adoptively transferred haploidentical donor natural killer (haplo-NK) cell products after lymphodepleting chemotherapy plus IL-2; and achieved complete remission in 30-50% of patients with refractory AML. To promote NK cell expansion without stimulation of Treg that may compromise NK function, we tested the substitution of IL-2 with the NCI manufactured rIL-15. Using the same lymphodepleting preparative regimen (Fludarabine 25 mg/m2IV for 5 days and Cyclophosphamide 60 mg/kg IV for 2 days) we infused CD3- and CD19-depleted haplo-NK incubated overnight with rIL-15 (10 ng/mL) prior to infusion. Two cohorts received rIL-15; either intravenously x 12 daily doses (at the Phase I MTD of 0.75 mcg/kg) or subcutaneously x 10 doses (5 days on, 2 days off, 5 days on at 2 mcg/kg SQ, the MTD when used as monotherapy in solid tumor patients). CRS was defined by modified CRS grading criteria (Lee et al. Blood, 2014). Results: Forty patients with relapsed/refractory AML were treated with haplo-NK plus IV rIL-15 (n=24) or SQ rIL-15 (n=16). Patients received an average of 11.6 IV doses [9-12, 96% of planned doses] or 7.5 SQ doses [1-10, 75% of planned doses]. Dosing was stopped for toxicity. No CRS events were observed after IV dosing. However, after SQ dosing, 9 of 16 patients [56%] had grade 1-4 CRS; [4 (25%) with grade 3-4 CRS) (Table 1). The median time from NK infusion to onset of CRS was 8 days [2-44]. Six of the 9 CRS patients (66%) had neurological events. Neurological toxicities included grade 1-2 encephalopathy (n=2), intracranial hemorrhage (ICH) (n=2, grade 1 and grade 5), and grade 4 seizures (n=2). One additional event (a patient with a fall resulting in ICH due to pre-existing gait abnormality) without evidence of CRS was not considered as IL-15 associated neurotoxicity CRS. Symptoms resolved in 4 of 5 patients who received treatment for neurologic CRS (3 received both steroids and Tocilizumab, 1 received steroids only, 1 patient did not require treatment as symptoms resolved with stopping IL-15). Non-neurologic toxicity included hypoxia (n=2) and hypotension (n=3). No significant correlations were found between development of CRS and absolute lymphocyte or monocyte count, presence or absence of haplo-NK expansion at day 14, number of rIL-15 doses received, or disease burden at baseline as measured by blast percentage in bone marrow. In the IV rIL-15 cohort, only 2 of 14 patients at the MTD (14%) cleared leukemia and underwent transplantation. In contrast, 8 of 16 patients (50%, P=0.04) in the SQ rIL-15 cohort achieved CR (n=7) or CRp (n=1), with 6 patients proceeding to alloHCT consolidation. CRS did not limit the clinical benefit in the SQ cohort as 4 of 9 [44%] patients with CRS achieved CR/PR compared to 4 of 7 [57%] patients without CRS. Pharmacokinetic data showed slower clearance of rIL-15 in SQ compared to IV dosing, as shown by higher trough levels prior to dose 2 (501 vs. 233 pg/mL, p Download : Download high-res image (163KB) Download : Download full-size image Disclosures Bachanova: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: 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; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller: Celegene: Consultancy; Oxis Biotech: Consultancy; Fate Therapeutics: Consultancy, Research Funding.

Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL).

2507 Background: C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 can eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. The tissue cross reactivity and whole genome membrane proteome array studies further confirmed the specificity of C-CAR039. Methods: GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system. Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen. Results: As of 1/31/2021, 28 patients were infused and 25 (DLBCL, n = 22; PMBCL, n = 1; tFL, n = 1; FL, n = 1) were evaluable for safety and efficacy at dose ranges of 1.0 x 106 to 5.0x106 CAR-T cells/kg. The median age was 54 (range, 28-71) years, median number of prior lines of therapy was 3 (range, 1–5), 76% (19/25) of patients were in Ann Arbor Stage III/IV, and 80% (20/25) were refractory to their last treatment. 5 patients (20%) received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. Of the 25 patients, 24 (96%) experienced CRS, 23 (92%) were grade 1 or 2, 1 patient was grade 3. Median time to onset of CRS was 3 days (range, 0-10), with median duration of 4 days (range, 1-25). 2 patients had a grade 1 ICANS. Grade≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 88%, 40%, 16% and 0% of patients, respectively. The best overall response rate was 92%, complete response (CR) rate was 84% and median time to response was 1.0 month (range, 0.9-1.2). With a median follow-up of 5.3 months, 76% remained in CR. Kaplan Meyer estimation of PFS at 6 months was 87.3% (95% CI, 71.2 to 100.0). Median duration of response has not been reached. Furthermore, C-CAR039 showed an encouraging cellular kinetic profile. In 25 evaluable patients, the median Tmax was 11 day, the median Cmax was 139,497 copies/mg gDNA, and the median AUC0̃28DAY of 1,673,844 day*copies/μg gDNA. Conclusions: C-CAR039 demonstrated a favorable safety profile and promising efficacy in this early clinical trial in patients with r/r B-NHL that might allow it to differentiate from existing therapies. The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR-T and peer therapies. These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response. Clinical trial information: NCT04317885 , NCT04655677 , NCT04696432 , NCT04693676 .

Characterization of cytokine release syndrome (CRS) following treatment with tebentafusp in patients (pts) with previously treated (2L+) metastatic uveal melanoma (mUM).

9531 Background: Cytokine-mediated adverse events (AEs) are commonly reported in pts treated with T cell engaging therapies. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells, has shown an overall survival benefit for pts with untreated mUM in a Ph3 trial (NCT03070392). Here we reviewed the incidence, kinetics, and outcome of CRS in tebe-treated pts on the IMCgp100-102 trial of 2L+ pts with mUM (NCT02570308). Methods: 127 HLA-A*02:01+ 2L+ mUM pts were treated with tebe at the RP2D of 68mcg following intra-patient dose escalation of 20 mcg dose 1 and 30 mcg dose 2. Pts were monitored overnight to allow management of hypotension and other cytokine-related AEs. Because the rate of severe CRS was low in Ph1, prophylactic corticosteroids, antihistamines or acetaminophen were not mandated. CRS was evaluated post-hoc according to ASTCT Consensus Grading criteria [1]. Circulating cytokines in serum were measured before and at 8hr and 12-24hr after dosing for the 1st, 3rd and 4th doses (n=105). This analysis was conducted on the primary analysis snapshot dated 04Jun20. Results: The most frequent treatment-related AEs that were likely cytokine-mediated included fever (80%), chills (64%), nausea (59%), hypotension (41%) and hypoxia (4%). In a post-hoc review using ASTCT criteria, 86% of pts (n=109) had any grade CRS. The majority of these 109 pts had either grade (G) 1 (n=42; 33%) or G2 (n=62; 49%), with few G3 (n=4; 3.1%), one G4 (0.8%), and no deaths. Onset of CRS began within 24 hours of administration and G≥2 hypotension or hypoxia typically resolved within 2 days of onset. Most CRS events occurred after the first 3 doses with a marked reduction in the frequency and severity of CRS thereafter; G3-4 CRS was limited to first two doses. Only 2 pts discontinued tebe due to CRS (1 G3 and 1 G4). Treatment of G≥2 CRS included iv fluids (n=45), iv steroids (n=18), oxygen (n=8), and vasopressor use (n=2). No pts received tocilizumab. Tebe induced a transient increase in peripheral cytokines, including IFNγ, IL-10, IL-6 and TNFα, within hours of tebe dosing, which were several fold higher in pts with CRS compared to pts without CRS. Higher levels of TNFα trended with severity of CRS. Conclusions: CRS, a common AE observed with all T cell engaging therapies, was frequently observed within 24 hours of initial tebe treatment. Most CRS events were mild or moderate in severity even without the use of prophylactic premedications, were reversible with standard management strategies, decreased in frequency and severity with subsequent doses, and rarely led to treatment discontinuation. Pts with CRS tended to have greater increases in serum cytokines, consistent with tebe’s proposed mechanism of action. [1] Lee, DW et al. Biol Blood Marrow Transplant 2019. Clinical trial information: NCT02570308.

Safety and efficacy of a novel anti-CD20 chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) patients after failing CD19 CAR-T therapy.

2508 Background: Relapse due to loss of the CD19 targeted epitope presents a therapeutic challenge of CD19 CAR-T therapy. These patients universally have a poor outcome and the unmet medical need is high. CD20 is a proven therapeutic target for B-NHL, supported by approved and widely used monoclonal antibody therapy. C-CAR066 is a novel 2nd generation chimeric antigen receptor T (CAR-T) therapy targeting CD20 antigen. Preclinical studies suggest that C-CAR066 has superior anti-tumor activity compared to CAR-Ts derived from scFVs of Leu16, Rituximab and Obinutuzumab and anti-CD19 BBZ CAR with FMC63. Methods: A phase I clinical trial (NCT04036019) was conducted to evaluate the safety and efficacy of C-CAR066 in subjects with r/r B-NHL who were previously treated with anti-CD19 CAR-T therapy. Patients (≥ 18 years) with r/r DLBCL, r/r FL or r/r MCL, ECOG &lt; 2 were eligible. GMP manufacture of C-CAR066 was in a serum free and fully closed semi-automatic system. A 3-day cyclophosphamide plus fludarabine regimen was followed by a single infusion of C-CAR066. Bridging therapy was allowed. Results: As of Jan 31, 2021, 7 patients (6 DLBCL, 1 tFL) were enrolled and infused with C-CAR066 at dose ranges of 2.0 x 106 to 4.8x106 CAR-T cells/kg. The manufacturing success rate was 100%. The median age was 51 (range, 41-62) years, and 42.9% (3/7) patients were male. The median number of prior lines of therapy was 5 (range, 2-6). One patient (14.3%) underwent autologous stem cell transplant (ASCT) and one patient received bridging therapy. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. All 7 patients experienced CRS and most (85.7%) were grade 1 or 2. One patient had grade 4 CRS and recovered after treatment with tocilizumab and corticosteroids. Median time to onset of CRS was 5 days (range, 1-9), with median duration of 4 days (range, 2-17). There were no episodes of ICANS. Grade ≥3 neutropenia, anemia, thrombocytopenia, and infections were reported in 57.1%, 42.9%, 28.6%, and 14.3% of patients, respectively. At a median follow-up of 7.8 months, the best overall response rate was 100%, with 71.4% (5/7) achieving complete response (CR). Median time to response was 1.0 month (range, 0.9-2.7). Median time to CR was 2.7 months (range, 0.9-2.8). By the cutoff date, 3 patients (2 PR, 1 CR) had disease progression. Median duration of response was not reached. Conclusions: C-CAR066 has shown a favorable safety profile and promising efficacy in patients with r/r B-NHL following failure of CD19 CAR-T therapy. These results show that C-CAR066 has a different mechanism of action compared to anti-CD-19 CAR-T therapy and could provide a solution to address the unmet medical need in B-NHL patients that have failed anti-CD19 CAR-T therapy. Clinical trial information: NCT04036019.

Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma

Preemptive administration of tocilizumab (toci) to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy may reduce rates of serious CRS but conversely may worsen neurotoxicity or risk of infections. Optimal toci administration strategies for patients with relapsed/refractory multiple myeloma (RRMM) receiving B cell maturation antigen (BCMA)-directed CAR-T therapies have not been evaluated. The objective of this study was to identify whether shorter time-to-toci intervals (hours between first fever attributed to CRS and first dose of toci) have any impact on therapy-related toxicities or clinical outcomes among patients with RRMM receiving BCMA-directed CAR-T therapies. We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. We divided patients based on the administration of toci and median time-to-toci interval into early-toci (time-to-toci ≤50th percentile), late-toci (time-to-toci >50th percentile), and no-toci (no toci received) groups. We compared the early-toci and late-toci groups with regard to patient characteristics, weight-based CAR-T toxicities, selected toxicities (CRS, neurotoxicity, macrophage activation syndrome, or infections), and clinical outcomes. Of 50 analyzed patients with a median follow-up of 15.3 months, 76% (n=38) received ≥1 dose of toci (range, 1 to 3) and were classified into early-toci (time-to-toci ≤12 hours) or late-toci (time-to-toci >12 hours) groups. The 2 groups (n=19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 versus 3.80×106 cells/kg, P < 0.01). Peak CRS grades (range, 0 to 2) using American Society for Transplantation and Cellular Therapy consensus criteria, neurotoxicity rates, and rates of severe infections were similar between groups; however, the median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the late-toci group. The median progression-free survival was 35.7 months in the early-toci group and 13.2 months in the late-toci group. While limited by small sample size and known confounders such as CAR-T cell dose, our analysis suggests that preemptive toci strategies for CRS management with BCMA-directed CAR-T therapy-specifically, toci administration within 12 hours of the first fever attributed to CRS-do not appear to increase rates of therapy-related toxicities or compromise efficacy. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM.

487 - Patterns of Tocilizumab Use Among Myeloma Patients Receiving BCMA-Directed Therapies: Effect on Day 30 Outcomes

INTRODUCTION Tocilizumab (toci) is often used to manage cytokine release syndrome (CRS) associated with chimeric antigen receptor T-cell (CAR-T) and T-cell engager (TCE) therapies, including therapies targeting B-cell maturation antigen (BCMA) in relapsed/refractory multiple myeloma (RRMM). Whether CRS development or early time-to-toci (defined as initial tocilizumab within 12 hours of CRS onset) impact 30-day outcomes is unknown. We performed a retrospective analysis of adult RRMM patients at our institution who received anti-BCMA CAR-T or TCE therapy. METHODS We reviewed all RRMM patients who received CAR-T/TCE therapy between 7/1/2017 and 6/30/2020. Time-to-CRS was defined as the first temperature ≥ 38°C without clear alternate etiology. CRS resolution was defined as the first timepoint marking defervescence lasting ≥ 24 hours or hospital discharge, whichever was sooner. For patients who developed CRS, we recorded initial and peak CRS grades using consensus criteria (Lee 2019), relevant biomarkers, time of first toci administration, and usage of corticosteroids/anakinra. We also recorded neurotoxicity, persistent neutropenia, and macrophage activation syndrome (MAS)-like features. Patients were categorized into three groups: no toci, early time-to-toci (first dose ≤ 12 hours of CRS onset), and late time-to-toci (first dose > 12 hours of CRS onset). We used logistic regression to predict objective response (≥ partial response [PR] at 30 days, IMWG criteria) and linear regression to predict CRS duration, with covariates including CAR-T/TCE product identity, time-to-CRS, and time-to-toci. RESULTS Of the 70 RRMM patients, 14 (20%) received TCE therapy and 56 (80%) received CAR-T therapies; 60 (87%) experienced CRS and 50 (72%) received toci (Figure 1). Of note, 24 patients also received dexamethasone and 11 patients received anakinra while hospitalized. Development of CRS was strongly associated with achievement of ≥ PR by Day 30 (odds ratio [OR] 13.8, 95% confidence interval [CI] 1.6-118). Patients who achieved a ≥ PR at Day 30 had shorter time-to-CRS intervals compared to non-responders (median 11.4 vs 26 hours, p=0.03). Among patients who developed CRS, time-to-CRS Of the 50 patients who received toci, 24 (48%) had early time-to-toci (≤ 12 hours) while 26 (52%) had late time-to-toci. Thirty-day response rates were similar between groups (71% early vs 69% late, p=1.0). Among the 48 patients with CRS lasting > 12 hours, receiving toci within 12 hours of CRS onset was associated with shorter total CRS duration (median 45 hours vs 56 hours, p=0.04). Patients who developed MAS-like features and/or neurotoxicity had somewhat lower time-to-toci intervals compared to patients who developed neither (MAS patients median time-to-toci 11.8 hours vs 16.9 hours, p = 0.59; neurotoxicity patients time to toci 12 hours vs 18.3 hours, p=0.15); however, these differences were not significant. CONCLUSION In RRMM patients receiving CAR-T/TCE therapy, the development of CRS is associated with achieving ≥ PR at Day 30. Furthermore, responders develop CRS earlier than non-responders. Among patients who develop CRS, early time-to-toci is associated with proportionately shorter CRS duration and does not appear to affect short-term responses, or development of MAS or neurotoxicity. Limitations of our analysis include its retrospective nature with heterogeneity between products and provider decision-making. Our results suggest that early time-to-toci may shorten CRS duration and potentially length of hospitalization. These hypothesis-generating findings warrant validation with longer follow-up. Additionally, prospective protocols implementing early or pre-emptive toci administration, similar to a published approach in lymphoma patients (Gardner 2019), warrant consideration in the RRMM population as well. Download : Download high-res image (329KB) Download : Download full-size image Disclosures Wolf: Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martin: Seattle Genetics: Research Funding; AMGEN: Research Funding; GSK: Consultancy; Sanofi: Research Funding; Janssen: Research Funding. Wong: Janssen: Research Funding; Amgen: Consultancy; Bristol Myers Squibb: Research Funding; Roche: Research Funding; GSK: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fortis: Research Funding. Shah: BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. OffLabel Disclosure: tocilizumab is an IL-6 receptor antagonist that is currently indicated and FDA approved for: Rheumatoid Arthritis (RA) Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease- Modifying Anti-Rheumatic Drugs (DMARDs). Giant Cell Arteritis (GCA) Adult patients with giant cell arteritis. Polyarticular Juvenile Idiopathic Arthritis (PJIA) Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis. Systemic Juvenile Idiopathic Arthritis (SJIA) Patients 2 years of age and older with active systemic juvenile idiopathic arthritis. Cytokine Release Syndrome (CRS) Adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.

Peripheral eosinophil counts predict efficacy of anti-CD19 CAR-T cell therapy against B-lineage non-Hodgkin lymphoma.

Rationale: The onset of cytokine release syndrome (CRS) and in vivo persistence of anti-CD19 chimeric antigen receptor T (CAR-T) cells after infusion correlate with clinical responsiveness. However, there are no known baseline biomarkers that can predict the prognosis of patients with B-lineage non-Hodgkin lymphoma (B-NHL). The aim of this study was to identify blood cell populations associated with beneficial outcomes in B-NHL patients administered CAR-T cell immunotherapies.Methods: We enumerated peripheral blood and CAR-T cells by retrospectively analyzing three CAR-T cell trials involving 65 B-NHL patients. We used a preclinical model to elucidate the eosinophil mechanism in CAR-T cell therapy.Results: During an observation period up to 30 mo, B-NHL patients with higher baseline eosinophil counts had higher objective response rates than those with low eosinophil counts. Higher baseline eosinophil counts were also significantly associated with durable progression-free survival (PFS). The predictive significance of baseline eosinophil counts was validated in two independent cohorts. A preclinical model showed that eosinophil depletion impairs the intratumoral infiltration of transferred CAR-T cells and reduces CAR-T cell antitumor efficacy.Conclusion: The results of this study suggest that peripheral eosinophils could serve as stratification biomarkers and a recruitment machinery to facilitate anti-CD19 CAR-T cell therapy in B-NHL patients.

Idecabtagene Vicleucel (ide-cel, bb2121) Responses Are Characterized By Early and Temporally Consistent Activation and Expansion of CAR T Cells with a T Effector Phenotype

Idecabtagene Vicleucel (ide-cel, bb2121) Responses Are Characterized By Early and Temporally Consistent Activation and Expansion of CAR T Cells with a T Effector Phenotype

Anti-CD19 CAR T-Cell (CNCT19) Infusion Following HDT/ASCT Is Safe and Effective in Patients with Relapsed/Refractory Large B-Cell Lymphoma

Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell is a promising therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma. 29~37% of patients can achieve sustained complete remission (CR) after anti-CD19 CAR T-cell infusion, which means that approximately two-thirds of patients will eventually progress and have extremely poor survival. We conducted a pilot study to explore the safety and efficacy of CNCT19 (a second-generation anti-CD19 CAR T-cell) cellular immunotherapy in conjunction with high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT). The preliminary results of the first 6 patients had been reported at the 61st ASH Meeting (Liu et al., 784a). Here we reported the updated enrollment, safety, efficacy, and follow-up of this study. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with large B-cell lymphoma refractory to primary or salvage therapy were eligible for this study. All patients must have received rituximab and anthracycline-containing treatment during their prior therapy. Conditioning regimen included GBC/M (gemcitabine, busulfan, and cyclophosphamide/melphalan) and BEAM (carmustine, etoposide, cytarabine, and melphalan, administered in one patient), and CNCT19 was infused on day +2, +3 or +4 following autologous stem-cell infusion. Results: Between January 2018 and May 2020, 13 patients were enrolled. The median age was 48 years (range, 29~ 64 years), and there were 7 males. Diagnosis of lymphoma subtypes included diffuse large B-cell lymphoma (n=10), high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangement (n=1), primary mediastinal large B-cell lymphoma (n=1) and transformed follicular lymphoma (n=1). The patients received a median of 3 (range, 2~4) lines of prior therapy and 76.9% had disease that was resistant to last-line therapy. The median dose of infused stem cells was 2.54×106 per kilogram of body weight (range, 1.77~8.7×106) and the median dose of infused CNCT19 cells was 2×106 per kilogram of body weight (range, 1.7~4×106). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT criteria. After CNCT19 infusion, 92.3% of patients experienced grade 1 CRS, and no one experienced grade 2 or higher CRS. The median time after CNCT19 infusion until the onset of CRS was 1.5 days (range, 0~3), and the median time until resolution was 8 days (range, 6~10). Seven patients (53.8%) received tocilizumab and two patients (15.3%) received glucocorticoids for the management of CRS. ICANS occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved after glucocorticoids treatment. The median times to neutrophil and platelet engraftment were 11 days (range, 8~32) and 17 days (range, 8~265), respectively. Ten patients were followed up for 3 or more months and evaluable for response. Eight of 10 patients achieved complete remission (CR), and the best overall response rate (ORR) and CR rate were both 80%. With a median follow-up of 11 months (range, 3~31) after CNCT19 infusion, the CR rate at 3 months and 6 months were 70% and 62.5%, respectively. Median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated proportion of PFS and OS at 12 months was 66.7% and 77.1%, respectively. Conclusion: CNCT19 infusion following HDT/ASCT could be safely administered in R/R large B-cell lymphoma patients. More patients achieved sustained remission compared with those who received anti-CD19 CAR T-cell therapy alone. The preliminary results of this pilot study support further investigation of the combination of CAR T cellular immunotherapy with HDT/ASCT. Disclosures Lv: Juventas Cell Therapy Ltd.: Current Employment.

Outcomes of Treatment with the Chimeric Antigen Receptor (CAR) T Cell Therapy Lisocabtagene Maraleucel (liso-cel) in the Nonuniversity Setting: Initial Results from the Outreach Study

Outcomes of Treatment with the Chimeric Antigen Receptor (CAR) T Cell Therapy Lisocabtagene Maraleucel (liso-cel) in the Nonuniversity Setting: Initial Results from the Outreach Study

Characterization of Cytokine Release Syndrome in the KarMMa Study of Idecabtagene Vicleucel (ide-cel, bb2121) for Relapsed and Refractory Multiple Myeloma

Characterization of Cytokine Release Syndrome in the KarMMa Study of Idecabtagene Vicleucel (ide-cel, bb2121) for Relapsed and Refractory Multiple Myeloma

Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)

Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma

CARTITUDE-1: Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy, in Relapsed/Refractory Multiple Myeloma