Rates Of Cytokine Release Syndrome Research Articles

PF305 ANALYSES OF CYTOKINE RELEASE SYNDROME AND NEUROTOXICITY BY AGE AND LYMPHODEPLETING CHEMOTHERAPY USE IN ADULTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA TREATED WITH TISAGENLECLEUCEL

Background:Autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy tisagenlecleucel has demonstrated efficacy with a favorable risk/benefit profile in adults with relapsed or refractory diffuse large B‐cell lymphoma (r/r DLBCL) in the phase 2 JULIET trial. CAR T‐cell therapy is associated with unique toxicities, e.g., cytokine release syndrome (CRS) and neurotoxicity (NT), that require specialized management. It is important to understand how patient (pt) characteristics (e.g., age) and prior lymphodepleting (LD) chemotherapy regimens could inform risk and management of CRS and NT.Aims:This JULIET post‐hoc analysis aims to understand unique safety profiles associated with CAR T‐cell therapy in adults with r/r DLBCL treated with tisagenlecleucel, stratified by age or LD chemotherapy use.Methods:CRS and NT events observed in JULIET were graded with approaches common to CAR T‐cell therapy (CRS: Penn, Lee; NT: Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR‐T Related Encephalopathy Syndrome [mCRES]). Penn grades were reported per trial protocol; other grades were obtained via expert consensus grading (ASH2018 Schuster #4190; Maziarz #4183). Four medical experts independently re‐graded CRS using the Lee scale while blinded to original Penn grades, and graded NT using CTCAE and mCRES. Experts discussed grading assessments and reconciled disagreements at live meetings. Per the investigational charter, in cases that could not be reconciled, the most conservative final assessment of any reviewer determined final grading for any individual case.This analysis stratified JULIET pts who received tisagenlecleucel by age at screening (<65 or ≥65 years old [yo]) or LD chemotherapy use before infusion and type (fludarabine+cyclophosphamide [FC], bendamustine [B], or no LD therapy [permitted if white blood cell count ≤1,000 cells/μL ≥1wk pre‐infusion]). Demographics, disease characteristics, medical history, and CRS and NT grades were summarized and compared among subgroups.Results:Of 111 JULIET pts infused with tisagenlecleucel as of Dec 8, 2017, 86 were <65yo and 25 were ≥65yo. Overall, pts were similar in demographics and medical history, except that more pts aged <65yo received prior HSCT (<65 vs ≥65yo: 55.8% vs 24.0%, p < 0.01). The rates of any CRS grade (Lee: 59.3% vs 48.0%; Penn: 60.5% vs 48.0%), and grade ≥3 (Lee: 19.8% vs 8.0%; Penn: 22.1% vs 20.0%) were similar between age subgroups (Table 1). Among 64 pts with CRS per Penn (<65yo n = 52; ≥65yo n = 12), there were no differences in time to CRS onset, CRS duration, or proportions of pts with tocilizumab use. Overall, NT grades were similar between two subgroups with numerically higher rates in older pts: any grade (CTCAE: 43.0% vs 52.0%; mCRES: 14.0% vs 28.0%), grade ≥3 (CTCAE: 12.8% vs 20.0%; mCRES: 9.3% vs 24.0%). No grade 5 CRS or NT was observed in any JULIET pts. In stratification based on LD therapy (FC n = 81; B n = 22; no LD therapy n = 8), CRS and NT grades were similar across three subgroups (Table 1). Again, among CRS patients in LD therapy subgroups, no differences were observed regarding CRS characteristics and tocilizumab use.Summary/Conclusion:This JULIET post‐hoc analysis observed similar rates of CRS and NT grades using various grading approaches among pts aged <65 vs ≥65yo. In the only CAR T‐cell study for an approved product allowing different LD chemotherapies, no differences in safety were observed across LD regimens used in JULIET. These findings will inform clinical decision making in CAR T‐cell therapy use in r/r DLBCL.image

CD19 Directed Chimeric Antigen Receptor T Cell Therapy in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Introduction Chimeric antigen receptor (CAR) T-cells targeting CD19 have led to complete response (CR) rates of 70-90% in children and adults with refractory/relapsed B-cell acute lymphoblastic leukemia (ALL), which led to their FDA approval in 2017. However, different constructs have been used and the response rates vary among different studies. Toxicities in the form of cytokine release syndrome (CRS) and neurotoxicity remain a challenge. We conducted a systematic review and meta-analysis of all published and presented trials of anti-CD19 CAR T-cells in relapsed/refractory ALL. Objectives 1) To determine the efficacy of anti-CD19 CAR T-cells in ALL. 2) To describe the toxicities of anti-CD19 CAR T-cells in ALL. 3) To examine differences in efficacy and toxicity by age groups and construct type. Methods We searched MEDLINE and EMBASE and included studies that reported raw data on the outcomes of adults and children that were treated with anti-CD19 CAR T-cells for ALL. The random effects model was used to derive estimates of complete response (CR) and progression-free survival (PFS) at 1 year and toxicities. Secondary outcome was minimal residual disease (MRD) at 1 year. We planned subgroup analysis based on age (adults vs. children) and construct type. Results Of 1,139 potentially relevant references, 18 noncomparative trials were included with a total of 573 patients (309 adults and 264 children). Pooled CR was comparable between adults [84% (95 CI 80-86%)] and children [83% (95 CI 79-88%)], but varied by construct [86% (95 CI 82-90%) for 41BB co-stimulated CART cells vs 74% (95 CI 68-81%) for CD28 co-stimulated CART cells vs 86% (95 CI 80-91%) for fourth generation CART cells]. Pooled 1-year PFS was comparable for adults and children [53% (95 CI 31-74%) vs 56% (95 CI 50-65%)]. CRS rates were comparable among adults and children [76% (95 CI 71-81%) vs 72% (95% CI 68-77%)]. CRS was lower in CD28 compared to other constructs [47% (95 CI 41-53%) in CD28 vs 86% (95 CI 82-91%) in 41BB vs 76% (95 CI 69-83%) in fourth generation]. Neurotoxicity occurred more commonly in adults [44% (95 CI 35-54%) vs 17% (95 CI 12-22%)] and in those treated with 41BB compared to those treated with CD28 [34% (95 CI 27-40%) vs 14% (95% CI 9-20%)]. Pooled MRD negativity at 1 year was 77% (95 CI 71-82%) in adults and 82% (95 CI 77-87%) in children. CD28 construct led to lower MRD negativity [62% (95 CI 54-70%) vs 85% (95 CI 81-89%) in 41BB vs 81% (95 CI 69-93%) in fourth generation]. These data are summarized in Figure 1. Conclusions Pooled 1-year CR was 84%, pooled 1-year PFS was 57% and the efficacy of CAR T-cell therapy was comparable between adults and children. Analysis by construct type revealed differences in the efficacy and toxicity between different constructs with CD28 leading to lower efficacy and toxicity. This is the first study to systemically analyze the outcomes of anti-CD19 CAR T-cell therapy in ALL.

A U.S. Food and Drug Administration Age Based Pooled Analysis of Cytokine Release Syndrome and Neurotoxicity in Subjects with Relapsed/Refractory Lymphoma Treated with Chimeric Antigen Receptor (CAR) T Cell Therapy

Background: With recent FDA approvals of CAR T cell therapy for the treatment of relapsed/refractory aggressive B cell non-Hodgkin lymphoma, an increasing number of older adults will be treated with this therapy. An improved understanding of the safety of CAR T cell therapy in this population is important to inform clinical decision making for the treatment of older subjects.Methods: Data from two prospective single arm studies (n=214) of two approved CART cell products for the treatment of relapsed/refractory lymphoma were pooled and analyzed. Rates of cytokine release syndrome (CRS), as well as severity and treatment modalities (oxygen, vasopressor support, tocilizumab and steroids) were pooled and analyzed by age. Selected neuropsychiatric events were pooled and analyzed by age.Results: Age was balanced between the two studies. The median age of subjects was 58 years (range 22-76 years). Of the 214 total subjects, 24% were 65 years of age and older.CRS and neurotoxicity were evaluated in the subjects who received treatment with CAR T cell therapy. (Table 1).*Two studies employed different grading methods for CRS; Lee's criteria (Lee DW et al, Blood 2014) and U Penn criteria (Porter DL et al, Blood 2014)Conclusions: This exploratory analysis suggests overall similar rates of CRS and grade 2 and higher CRS in subjects less than 65 years as compared to 65 years of age and older. There appears to be an overall higher rate of encephalopathy and grade 3 and higher delirium/encephalopathy in adults 65 years and older compared to less than 65 years of age. The inclusion of greater numbers of patients ≥ 65 years of age in clinical trials will further inform clinicians about the safety and efficacy of CAR T cell therapy in older adults.Table 1: Adverse Events by Age in subjects treated with CART cell therapy [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Minimal Change in CAR T Cell Manufacturing Can Impact in Expansion and Side Effect of the CAR T Cell Therapy

Introduction: Chimeric antigen receptor (CAR)-modified T cells targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (rrALL). We previously reported a robust intent-to-treat product-manufacturing success rate of 100% in minimally selected, heavily pretreated patients with ALL in our Pediatric and young adult Leukemia Adoptive Therapy (PLAT)-02 phase 1 study (NCT02028455). Following completion of the Phase 1 study, a minimal change in CAR T cell manufacturing (henceforth referred to as SCRI-CAR19v2) was introduced with product infusion in 21 subjects.We sought to compare efficacy and toxicity of the subjects who received SCRI-CAR19v2 with those subjects enrolled on the Phase 1 portion of the trial (Gardner et al., Blood 2017).Methods: All subjects underwent apheresis, and CD4 and CD8 T cell subsets are selected immunomagnetically. SCRI-CAR19v2 manufacturing changes from the previously published phase 1 platform included no longer selecting cells in culture based of EGFRt expression and changing the manufacturer of the anti-CD3/CD28 bead stimulation. All patients received fludarabine/cyclophosphamide lymphodepletion (LD) followed by bedside thaw of CD4 and CD8 T cell products and infusion of each product at a 1:1 ratio for a total of 1x106 CAR-T cells/kg. Cytokine release syndrome (CRS) was graded according to Lee et al. and treated with our early intervention strategy of tocilizumab and dexamethasone for persistent, mild CRS.Results: Twenty-one subjects with CD19+ rrALL received SCRI-CAR19v2, with a median age of 13 years (range, 8-17 years), 10 subjects (47.6%) had a history of at least 1 prior allogeneic transplantation, with a range of 335 days from most recent transplantation before enrollment. The disease burden included 7 (33.3%) subjects having M3 bone marrow (BM), 5 (24%) having active CNS involvement at time of LD. Thirteen (62%) subjects had a high antigen burden (>15% CD19 antigen expressing cells in BM by flowcytometry prior to LD). CAR T cell products were released on all 21 subjects. 86% (18/21) of subjects had a documented minimal residual disease (MRD)-negative complete remission (CR) within 21 days following CAR-T cell therapy. The duration of functional CAR-T cell persistence, as measured by ongoing B-cell aplasia (BCA) was 61.1% at 1 year, compared to 20.6% for Phase 1 subjects (p=0.03). With a minimum of 1-year follow up (range 12-18 months), the 12-month event-free survival (EFS) and overall survival were 76% (95% CI 59-97) and 86% (95% CI 72-100), respectively; compared to 50.8% (95% CI, 36.9%-69.9%) and 69.5% (95%CI, 55.8%-86.5%) of phase 1(p=0.14 and 0.23, Figure 1). Of the 5 leukemic relapses, 1 lacked CD19 and 2 recurred as AML. Any grade CRS was seen in 71% (15/21) of infused subjects, with a maximum grade of 2. Although the grading scale from phase 1 to 2 was changed from CTCAE to Lee et al, there did not appear to be any differences in the rate of those requiring low dose vasopressors. Any grade neurotoxicity was seen in 67% (14/21) with grade ≥3 in 24% (5/21), which was similar to the phase 1, however, there was a single event of grade 5 cerebral edema, which had not previously been seen. Comparison of SCRI-CAR19v2 phenotype and functional attributes to SCRI-CAR19v1 revealed evidence of increased CD4 differentiation in the SCRI-CAR19v2 products (lower expression of CCR7, CD27, CD127, high expression of LAG-3 and TIM-3) while SCRI-CAR19v1 products showed a lower frequency of LAG-3, PD-1 and the percentage of cells secreting IFNg, suggesting a less activated phenotype.Conclusions:A small manufacturing change was associated with a more effector driven phenotype of the SCRI-CAR19v2 T cell product, which appears to result in longer CAR-T cell persistence (prolonged BCA). Although the overall rates of CRS and neurotoxicity appeared similar between the two groups, the single event of fatal cerebral edema invoked concern that it could be related to the more effector driven phenotype. Much of the discussion surrounding the toxicity profiles and long term persistence of CAR T cell products has focused on the construct itself, including the FcFv and co-stimulatory molecules. However here we show that a change in the manufacturing platform itself can have an impact on the in vivo performance of the CAR T cell product, potentially effecting both the toxicity profile and the ability to enhance long term persistance. [Display omitted] DisclosuresPulsipher:Amgen: Honoraria; CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding. Park:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jensen:Juno Therapeutics, Inc.: Consultancy, Patents & Royalties, Research Funding.

Blinatumomab Administered Concurrently with Oral Tyrosine Kinase Inhibitor Therapy Is a Well-Tolerated Consolidation Strategy and Eradicates Measurable Residual Disease in Adults with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Introduction: Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) to conventional chemotherapy regimens has improved outcomes for adult patients (pts) with (w/) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, the addition of chemotherapy to TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and mortality. As a result, we and others have investigated novel chemotherapy-sparing approaches for pts w/ Ph+ ALL. The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) has demonstrated single-agent activity in pts w/ B-ALL w/ minimal residual disease (MRD) or relapsed/refractory (R/R) ALL, including R/R Ph+ ALL (Martinelli et al., J Clin Oncol, 2017). In an effort to deepen responses, we have used BLIN concomitantly w/ commercially available TKIs as consolidation and re-induction therapy. Reported experience w/ BLIN+TKI is limited. Herein we describe the observed safety and efficacy of BLIN+TKI in pts w/ Ph+ ALL w/ varying disease burden at our institution.Methods: We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated Ph+ ALL receiving BLIN w/ concomitant, FDA-approved TKIs at Memorial Sloan Kettering Cancer Center (MSKCC) who began BLIN+TKI between March 2017 and April 2018. The primary objectives were to characterize the safety/toxicity profile and rates of MRD negativity by flow cytometry (FACS) and/or quantitative real-time PCR for BCR-ABL1 transcripts following consolidation (n=9) or re-induction (n=2) w/ BLIN+TKI.Results: Eleven pts (6F, 5M) were identified (Table 1). Median age at start of BLIN+TKI was 61.2 yrs (range, 27.7-76.9). Three pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). No pt had baseline hepatic dysfunction, central nervous system (CNS) or extramedullary (EM) disease prior to BLIN+TKI. All pts had documented CD19 expression on blasts prior to treatment. Ponatinib (PON) was the most commonly used TKI (n=7) followed by dasatinib (DAS, n=3), and nilotinib (NIL, n=1); one pt taking BLIN+PON briefly received BLIN+DAS during cycle 1. All pts were admitted for initiation of BLIN+TKI. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for pts w/ R/R ALL) in 10 pts and at 28 mcg/day IVCI in one pt (per flat dosing schedule described by Gökbuget et al., Blood, 2018).All 7 pts w/ MRD by FACS (n=5) and/or BCR-ABL1 PCR (n=7) prior to BLIN+TKI exhibited MRD negativity by FACS following 1 cycle of BLIN+TKI; 6 of these 7 pts achieved complete molecular response (CMR) by PCR following 1 cycle (n=5) or 2 cycles (n=1) of BLIN+TKI. All 6 remain in ongoing CMR at 1.8-15.1 months after initial achievement of CMR. Neither of the 2 pts w/ morphologic disease responded to BLIN+TKI and ultimately succumbed to their disease. The 2 pts who began BLIN+TKI in CMR have both maintained continuous CMR. Three pts have proceeded to 1st (n=2) or 2nd (n=1) alloHCT post-BLIN+TKI, without documented, relevant toxicities attributable to prior blinatumomab exposure. Median event-free and overall survival were not reached in this small group of pts, w/ median follow-up of 7.7 months among survivors (range, 3.2-16.0 months).Three pts developed grade 1 cytokine release syndrome (CRS). Notably, 2 of these pts had morphologic ALL at time of BLIN+TKI; none of these events warranted interruption of therapy or corticosteroids. No pts developed neurologic toxicity. Five pts exhibited transient transaminitis during BLIN+TKI; none reached recommended parameters to discontinue BLIN. Of these 5 pts, 4 were on concurrent PON. One pt required dose attenuation of PON; hepatic enzymes otherwise normalized w/o intervention.Conclusions: Our small series suggests that BLIN+TKI may be a safe and effective consolidation strategy for pts w/ MRD+ Ph+ ALL to achieve or sustain CMR, creating a platform for alloHCT or other post-remission therapy. Observed rates of CRS were higher and neurologic toxicity appeared lower (none documented) than in other studies of BLIN in pts w/ MRD (Gökbuget et al., Blood, 2018). Higher risk of transaminitis was noted in pts receiving BLIN+PON and warrants further observation, particularly as 28 mcg/day IVCI flat dosing is increasingly used for pts w/ MRD. Earlier incorporation of BLIN+TKI into treatment paradigms for Ph+ ALL may limit toxicity while deepening response and maintaining CMR. [Display omitted] DisclosuresKing:Genentech: Other: Advisory Board . Tallman:Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; Cellerant: Research Funding; ADC Therapeutics: Research Funding; AbbVie: Research Funding; AROG: Research Funding; BioSight: Other: Advisory board. Park:Pfizer: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Shire: Consultancy. Geyer:Dava Oncology: Honoraria.

JWCAR029 Is a CD19-Targeted CAR T Cell Product with Process and Quality Controls Delivered As a Flat Dose of CAR T Cell to Patients with NHL

Background:JWCAR029 is the first IND approved CD19-targeted CAR T cell product by China National Drug Administration (CNDA) containing 4-1BB as the co-stimulatory factor with highly reproducible process and quality control that allows flat dose of CAR T cell infusion. To date, a total of 22 lots have been manufactured and 18 subjects have been infused in the ongoing multicenter, Phase 1 trial (NCT03344367 and NCT03355859) evaluating the safety and efficacy of JWCAR029 in adult relapsed or refractory B-cell Non-Hodgkin lymphoma patients. The process and quality control strategy for JWCAR029 contributes to the low variability in drug product quality attributes.Methods:Manufacturing of JWCAR029 begins with patient derived autologous T cells obtain via apheresis. JWCAR029 drug products were analyzed for viability, potency, subtype of T cells, copy numbers of lentiviral vector, and cell health related attributes using cellometer related bioassays, flow cytometry, and real-time quantitative polymerase chain reaction system (qPCR), respectively.Results:Process and quality of JWCAR029 started with an automated wash and T cell purification that results in pure CD3+ populations (median 99.56%, Inter Quartile Range [IQR] 99.22-99.86%). CD3+ T cells were transduced with lentiviral vector expressing a CD19-directed CAR with a 4-1 BB/CD3ζ endodomain. CAR+ T cells were cultured to a target cell dose and then formulated / cryopreserved for infusion. To reduce between-lot variance, the cryopreserved drug product (CDP) was packaged at fixed volume with a tight range of viable cell concentrations (CD3+: median 40.25 × 10^6 cells/mL, IQR 31.10-69.13 × 10^6 cells/mL, N=22) and CD3+CAR+ cell concentrations (median 27.25 × 10^6 cells/mL, IQR 23.57-33.10 × 10^6 cells/mL, N=22). JWCAR029 does not use a fixed ratio of CD4+CAR+ cells/CD8+CAR+ cells in the final CDP (median 1.18, IQR 0.70-1.95, N=22).In the ongoing, multicenter, single arm, open-label and dose escalation Phase 1 trial, JWCAR029 was administered as a flat dose at dose level 1 (DL1) of 2.5 × 10^7 CAR+ T cells (6 subjects), at dose level 2 (DL2) of 5.0 × 10^7 CAR+ T cells (9 subjects), or dose level 3 (DL3) of 1.0 × 10^8 CAR+ T cells (3 subjects). After infusion, stable expansion of CD4+ and CD8+ CAR+ T cells were observed and peak value was appeared at day 11 to day 15 after administration. Low occurrence rate and manageable cytokine release syndrome (CRS) and neurotoxicity (NT) with high complete response (CR) rate were observed with emerging dose: response relationship. Detailed PK, clinical safety, and efficacy data of JWCAR029 will be presented separately.Conclusion:In order to employ standardized and high quality cell therapy methods in a Chinese multi-center trial, JWCAR029 was developed to provide a CD19-directed 4-1BB CAR T cell product with highly controlled manufacturing and quality processes enables administration in adult relapsed or refractory B-cell Non-Hodgkin lymphoma subjects. These control strategies in manufacturing and quality processes facilitated to the low rates of CRS and NT. DisclosuresHao:JW Therapeutics: Employment, Equity Ownership. Cheng:JW Therapeutics: Employment, Equity Ownership. Gao:JW Therapeutics: Employment, Equity Ownership. Liu:JW Therapeutics: Employment, Equity Ownership. Lam:JW Therapeutics: Consultancy. Yao:JW Therapeutics: Employment, Equity Ownership; WuXi AppTec: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Cytokine release syndrome and neurotoxicity after CD19 chimeric antigen receptor-modified (CAR-) T cell therapy.

Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

Abstract 960: Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL

Abstract JCAR017 is a CD19-directed 41BB chimeric antigen receptor (CAR) T cell product administered in a defined composition at a precise dose of CD8 and CD4 CAR T cells. JCAR017 manufacturing employs process controls that enable precise independent control of the infused dose of CD8 and CD4 cells. Preliminary safety data from JCAR017 administered in relapsed/refractory B cell non-Hodgkin lymphoma (NHL) demonstrated lower rates of cytokine release syndrome (CRS) and neurotoxicity (NT) compared to those reported for other CD19-directed CAR T cell therapies with heterogeneity in total infused dose and CD8 and CD4 composition. Multiple patient factors and blood biomarkers have been identified that correlate with JCAR017 CAR T cell in vivo expansion, antitumor activity, and toxicity (Heipel M et al. and Siddiqi T et al. ASH 2017). However, little is known regarding the contribution of CAR T cell product differentiation state to pharmacokinetics (PK), clinical outcome, or toxicity. Product characterization is executed on JCAR017 to define the CAR T cell memory phenotype composition and antigen-specific function. Product attributes were assessed for relationships with clinical response, safety, and PK through univariate, multivariate, and machine learning-based analyses. JCAR017 memory T cell composition demonstrated strong relationships with cytokine production profile observed following in vitro CD19 stimulation of the CAR T cell drug product. Specifically, products with elevated frequencies of CCR7+ central memory T cells exhibited increased production of IL-2 (Spearman ρ=0.55, P<0.0001), whereas patient drug product with increased frequencies of effector differentiated T cells demonstrated increased production of IFNγ (ρ=0.51, P<0.0001) and IL-13 (ρ=0.45, P<0.0001). The correlations between CAR T cell drug product memory phenotype and function translated to positive correlations between central memory subset composition and peak in vivo CAR T cell expansion (ρ=0.42, P=0.002) and progression-free survival (Kaplan-Meier survival estimate, P=0.0164). In addition, an increased frequency of a central memory subpopulation in drug product demonstrated relationships with CRS (P=0.0069) and severe NT (P=0.0014) events. The phenotype to functional links described above offer insights as to how specific memory subpopulations contribute to the complex CAR T cell mechanism of action. CAR T cell products with increased CCR7+ central memory composition demonstrated increased peak CAR T cell expansion and persistence, suggesting less differentiated CAR T cells contribute to PK and progression-free survival. These findings can be used to further define the next generation of gene-engineered T cell products (e.g., a fixed dose of CCR7+CAR+) that will decrease the dose-to-dose variability. Citation Format: Ryan P. Larson, Rachel Lower, Todd DeVries, Yue Jiang, Ronald J. Hause, Rich Getto, Brian Christin, Nathan K. Yee, Michael A. Bowen, Clinton Weber, Daniel Li, Tina Albertson, Claire Sutherland, Christopher G. Ramsborg. Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 960.

High durable CR rates and preliminary safety profile for JCAR017 in R/R aggressive b-NHL (TRANSCEND NHL 001 Study): A defined composition CD19-directed CAR T-cell product with potential for outpatient administration.

120 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Phase 1 pivotal trial of relapsed/refractory (R/R) B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Patients (pts) with R/R DLBCL NOS, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. The FULL dataset includes all pts in the DLBCL cohort (i.e. excludes MCL). The CORE dataset includes pts meeting inclusion for a planned pivotal DLBCL cohort (DLBCL NOS [ de novo or transformed from follicular lymphoma], ECOG 0-1, no prior allo-SCT). Results: As of July 7, 2017, 69 pts were treated in the DLBCL cohort and evaluable for safety. In the FULL dataset, 21 pts (30%) had cytokine release syndrome (CRS), with 1 serious CRS event (1%; Gr 4). Neurotoxicity (NT) at any grade developed in 14 (20%), including 10 (14%) with Gr 3-4 events. There were no Gr 5 CRS or NT events. Median time to onset of first CRS and NT was 5 days and 10 days, respectively, 13 (19%) received anti-cytokine therapy and only one required vasopressor support. In the CORE dataset (n = 49), similar rates of CRS and NT were shown. The majority of pts, 64% (44/69), had no CRS or NT, and median onset of CRS and NT were 5 and 11 days, respectively, suggesting outpatient delivery of JCAR017 may be feasible. In the DLBCL cohort, 68 pts were evaluable for efficacy; best overall response, 3-month, and 6-month response rates in the FULL dataset were 75% (51/68), 49% (27/55), and 40% (14/35), respectively; and, in the CORE dataset, were 84% (41/49), 65% (26/40), and 57% (13/23). The best overall, 3-month, and 6-month CR rates were 61% (30/49), 53% (21/40), and 52% (12/23), respectively, in the CORE dataset. Among 16 double/triple hit pts, best ORR was 81%, and 3-month CR rate was 60%. A trend toward improved response rate at 3 months was observed in pts treated at DL2 compared to DL1. Conclusions: At the symposium, we will report updated efficacy and the preliminary safety profile for JCAR017, which supports potential outpatient administration in R/R Aggressive B-NHL patients. Clinical trial information: NCT02631044.

Exposure-adjusted adverse events (AEs) comparing blinatumomab to standard of care (SOC) chemotherapy in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from a randomized phase III study.

7032 Background: Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown improved overall survival vs SOC in pts with r/r ALL in a randomized phase 3 study ( Haematologica 2016;101:S129). To better evaluate safety, we compared AEs of blin vs SOC after adjusting for varying treatment exposure times. Methods: Adults ≥ 18 yrs with r/r ALL (refractory, 1st relapse < 1 yr, ≥ 2 relapses or relapse after transplant) were randomized to receive blin or SOC (1 of 4 predefined regimens). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 µg/d on d1−7 in cycle 1, then 28 µg/d); up to 4 maintenance cycles (4 wks on/8 wks off) were allowed for ≤ 12 mo. Exposure-adjusted (exp-adj) event rates were calculated as no. of events*100/total exposure time (Table). Results: Median (range) no. of cycles were 1 (1−4) for SOC and 2 (1−9) for blin. The highest exp-adj rates (per 100 pt-yrs) were for pyrexia (507 SOC vs 376 blin), anemia (987 vs 229), thrombocytopenia (750 vs 126) and neutropenia (351 vs 121), all lower in blin. Febrile neutropenia (365 vs 93) and infections (1216 vs 436) were also both lower in blin (p < 0.0001). Exp-adj rates for neurologic events were 743 SOC vs 472 blin, with median time (range) to onset of 7 (1−43) d and 7 (1−190) d, respectively, and gr ≥ 3 cytokine release syndrome (CRS) rates were 0 SOC vs 10 blin. The most frequent AEs in both cycles 1 and 2 were pyrexia, nausea and anemia in both arms; CRS events decreased in the blin arm between cycles 1 and 2 (14% vs 2%). Most fatal AEs were related to infection in both arms. Conclusions: Here blin showed an AE profile consistent with that previously reported for r/r ALL, including similar rates of manageable CRS and neurologic events. Exp-adj AE rates were generally higher in SOC vs blin, including for cytopenias and infections. Clinical trial information: NCT02013167. [Table: see text]

Risk Factors for the Development of and Outcomes of Patients Who Develop Severe Cytokine Release Syndrome after Peripheral Blood Haploidentical Donor Transplant

Background:Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Following development of post-transplant cyclophosphamide (PTCy) regimens, the use of haploidentical hematopoietic cell transplantation (haplo-HCT) has expanded. While overall outcomes for haploidentical transplantation appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu. We recently described occurrence of severe cytokine release syndrome (CRS) after haplo-HCT. We further reported that severe CRS was associated with poor clinical outcomes, including transplant related mortality (TRM), overall survival (OS), and neutrophil engraftment (Abboud et al, BBMT, 2016). However, the factors predicting the occurrence of and long-term outcomes of patients who develop severe CRS after haplo-HCT is currently not known.Objective: To describe our clinical experience with CRS in an expanded cohort of haplo-HCT patients, its implication on clinical outcomes and elucidation of possible risk factors for the development of severe CRS.Patients and Methods: We performed a retrospective review of patients who had undergone peripheral blood T-Cell replete haplo-HCT with PTCy from July 2009 through March 2016 at our institution. A total of 137 patients were identified, 51% (74) were male, with a median age at transplant of 52 (19-73), a total of 40% (57) had active disease at the time of transplant. The most common diagnosis was AML (93 pts), followed by ALL (16 pts) and MDS (15 pts). Thirty-one percent (44 pts) had undergone prior transplant. In grading CRS, we used our approach modified from by Lee et al (Blood, 2014). Twenty-two patient, donor and disease characteristics were examined to identify predictors for the development of severe CRS.Results:One hundred and twenty-four (90%) of patients met criteria for CRS, and 26 (19%) suffered from severe (grade 3-4) CRS. Virtually all patients (99%) with CRS suffered from fevers. Patients with severe CRS had a significant delay in neutrophil (p < 0.0001) and platelet (p < 0.0001) engraftment compared to the patients who developed mild or no CRS (Figure 1A and 1B). Severe CRS was also associated with a high early transplant related mortality; the rate of death before post-transplant day 28 was 6.9 times higher for patients with grade 3-4 CRS compared with those with mild CRS (p < 0.0001, Figure 1C). Consistent with these findings, the development of severe CRS was associated with extremely poor survival. Median survival was 3 months for grade 3-4 CRS, 15 months for grade 1-2 CRS, and 13 months for no CRS. One-year OS was 4% for grade 3-4 CRS, 55% for grade 1-2 CRS, and 50% for no CRS (Figure 1D). There was no difference in the cumulative incidence of relapse, acute graft versus host disease, and chronic graft versus host disease (data not shown). A total of nine patients received Anti-IL-6 Therapy with tociluzimab (4 mg/kg of actual body weight), 4 of which suffered from severe CRS.In terms of predictive factors, the development of severe CRS was associated with disease risk index (p=0.037), HCT-CI score (p=0.005) and presence of a previous transplant (p=0.026) by univariate analysis. Risk and severity of CRS did not differ by age, ABO mismatch, age, CMV status of donor, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS among patients in remission or with active disease at the time of transplant.Conclusions: Severe CRS after peripheral blood haplo-HCT is associated with high early TRM, poor OS and delayed neutrophil and platelet engraftment. Furthermore, patients with high DRI, high HCT-CI and prior HCT are at a higher risk for the development of severe CRS after haplo-HCT. We have previously shown the safety and potential efficacy of using anti-IL-6 therapy in these patients. Our current results suggest potential benefit to targeting this pathway prophylactically in patients at high risk for the development of severe CRS. [Display omitted] [Display omitted] DisclosuresDiPersio:Incyte Corporation: Research Funding. Abboud:Gerson and Lehman Group: Consultancy; Merck: Research Funding; Teva: Research Funding, Speakers Bureau; Novartis: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Alexion: Honoraria; Baxalta: Honoraria; Pharmacyclics: Honoraria; Takeda: Honoraria; Cardinal: Honoraria. Fehniger:Affimed: Consultancy; Celgene: Research Funding; Fortress Biotech: Consultancy.

T-Cell Replete Peripheral Blood Haploidentical Donor Transplant Is Frequently Associated with Cytokine Release Syndrome Which Responds to Anti-IL-6 Therapy

Introduction: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Traditionally reserved for patients with an HLA-matched donor, advances in graft versus host disease (GVHD) prophylaxis utilizing post-transplant cyclophosphamide (PTCy) have expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). While overall outcomes for haplo-HCT appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu.The immediate post-transplant course in T cell replete haplo-HCT is often complicated by symptoms including fever, hypoxia, hypotension and organ dysfunction resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics such as CAR T-Cells. IL-6 is thought to be a key mediator of CRS in patients receiving novel T-cell engaging therapies, and tocilizumab has been used with success in this setting.Here we aim to describe the nature and incidence of CRS in haplo-HCT recipients, as well as its potential implications on clinical outcomes. Additionally, prospective analysis of cytokine profiles of haplo-HCT recipients and clinical responses to tocilizumab therapy are presented.Patients and Methods: We performed a retrospective review of patients who underwent haplo-HCT transplantation at our institution from July 2009 through April 2015. Patients were scored for symptoms of CRS based on established grading criteria (Lee et al, Blood 2014). Patients were stratified into three categories by grade of CRS experienced: none (grade 0), mild (grade 1-2) and severe (grade 3-4). Outcomes were assessed.A total of 84 patients were identified, 55% (46) were male, with a median age at transplant of 49 (19-73), and 49% (41) had active disease at the time of transplant. The most common diagnosis was AML (55 pts), followed by ALL (9 pts), MDS (5 pts) and NHL (2 pts). Among the patients, 26% (22 pts) had undergone prior transplant.In addition to the retrospective review, baseline and post- transplant cytokine levels were prospectively drawn in 10 patients who underwent haplo-HCT. A total of 7 additional patients who met criteria for CRS were treated prospectively with tocilizumab (dose: 4mg/kg-bw) and clinical responses were recorded. We recorded CRP levels in selected patients as part of clinical monitoring.Results: We found a high incidence, 85%, of CRS in our haplo-HCT patients. Among a total of 84 patients, 12 (14%) experienced severe CRS, 60 (72%) had mild CRS, and 12 (14%) patients had no evidence of CRS. The most common manifestations of severe CRS included: fever (100%), respiratory failure (75%), hypotension (83.3%), hepatic failure (25%) and renal failure (33.3%). The median maximum CRP (during post-transplant days 0 to 8) in all patients suffering from CRS was 155 mg/L.Of the twelve patients who suffered from severe CRS, nine (75%) died. Predicted median survival was 0.72 months for severe CRS, 12.7 months for patients with no CRS and was not reached for patients with mild CRS (fig 1). Rates of acute and chronic graft-versus-host disease did not differ by CRS status. The incidence of mild and severe CRS did not differ by ABO mismatch, age, CMV status, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS for patients in remission versus active disease at time of transplant. There were no differences in engraftment.Cytokine profiles in haplo-HCT recipients showed significant elevation in serum IL-6 levels, most significant in patients who suffered from severe CRS (fig 2). We administered tocilizumab to 7 patients with severe CRS symptoms early after haplo-HCT (median day of treatment was day +3) resulting in the resolution of their CRS symptoms within 48-72 hours. Over the same time period CRP levels dropped below 50% of the peak value.Summary:CRS is common after T-cell replete haplo-HCT and severe CRS is potentially associated with high risk of early mortality after transplant. Cytokine profiles suggest IL-6 is a key mediator of CRS in haplo-HCT patients. Tocilizumab appears to be an effective treatment for patients who develop severe CRS early after T-cell replete haplo-HCT. Future prospective studies are warranted in studying the role of tocilizumab in the treatment and potentially prevention of severe CRS in haplo-HCT patients. [Display omitted] [Display omitted] DisclosuresFehniger:Celgene: Research Funding. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Gerson Lehman Group: Consultancy.

Abstract A38: Phase I study of combination immunotherapy with agonistic CD40 monoclonal antibody (mAb) CP-870,893 (αCD40) and anti-CTLA-4 antibody tremelimumab (treme) in patients with metastatic melanoma

Abstract Purpose: Combining therapeutic activation of immune cells and checkpoint inhibition may improve response rates and overall survival in patients with metastatic melanoma. CP-870,893 (αCD40) is an agonistic fully human IgG2 mAb targeting the immune stimulatory molecule CD40. Treme is a fully human IgG2 mAb targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a negative co-stimulatory molecule found on T cells. Methods: Patients with histologically confirmed metastatic melanoma, measurable disease by RECIST 1.0, and no history of autoimmune diseases or previous treatments targeting CD40 or CTLA-4 were enrolled on a single-arm open-label dose escalation phase 1 study. αCD40 and treme were dosed i.v. every 3 weeks and 12 weeks, respectively , for a potential total of 16 doses of αCD40 and 4 doses of treme. Dose escalation followed a 3 + 3 strategy with alternating increases of αCD40 (range 0.1-0.2 mg/kg) and treme (range 6-15 mg/kg) in each cohort. Patient outcomes were scored using the Common Terminology Criteria for Adverse Events v3.0. Flow cytometric analysis of baseline blood samples was compared to samples obtained at least 3 weeks after the last dose of αCD40 and treme. Results were compared by paired t test. Results: Toxicity: Twenty-four patients were enrolled and treated at 4 different dose levels. Two patients were replaced per protocol due to rapid, symptomatic progression of disease; these patients were not evaluated for response but were included in toxicity analysis. Patients had received a median of 1 (range 0-5) prior treatments for metastatic disease prior to enrollment. Dose-limiting toxicities (DLT), considered to be likely due to treatment, were colitis (n=1) and hypophysitis (n=1) at 0.2mg/kg αCD40 and 15mg/kg treme and uveitis (n=1) at 0.2mg/kg αCD40 and 10mg/kg treme. Cytokine release syndrome (CRS), grade 1-2, occurring within 24 hours of CP administration, was the most common treatment-related toxicity occurring in 19 (79.2%) patients and typically involving chills and fever. CRS symptoms were controlled with standard supportive care in the chemotherapy infusion suite and with instructed use of antipyretics and antihistamines at home. All episodes of CRS resolved within 24 hours of αCD40 administration. The estimated maximum tolerated dose was 0.2 mg/kg of αCD40 and 10 mg/kg of treme. Outcomes: Overall objective response rate was 27.3% (best response): two patients (9.1%) had complete responses to treatment and four (18.2%) patients had partial responses. The median follow-up was 22 months with a median progression free survival of 2.5 months (95% CI: 2.0–3.1 months) and a median overall survival (OS) of 26.1 months (95% CI: 13.1–39.1 months). Two patients remain disease free for more than 18 months after study completion without further medical treatment. Correlative studies: Flow cytometric analysis of peripheral blood lymphocytes revealed changes in CD8+ T cell phenotypes. Double positive granzyme B+ and Ki-67+ cells increased from 0.56 ± 0.17% (mean ± standard error) for all CD8+ T cells at baseline to 1.01 ± 0.23% post-treatment (p=0.03). CD8+ T cells expressing both programmed cell death 1 and eomesodermin were also higher after treatment, increasing from 7.7 ± 1.1% to 10.4 ±1.8% (p= 0.04) of all CD8+ T cells. Conclusion: Combination therapy with αCD40 and treme was well-tolerated in patients with metastatic melanoma, with rates of CRS and other toxicity similar to previously reported rates for αCD40 or treme treatments alone. Overall objective response rate was 27.3%, with median OS of 26.1 months including two patients still disease-free. This antitumor activity, and biomarker evidence of immune activation, provides a rationale for expanded study. Citation Format: David L. Bajor, Rosemarie Mick, Matthew J. Riese, Richman P. Lee, Xiaowei Xu, Drew A. Torigian, Erietta Stelekati, Martha Sweeney, Brendan J. Sullivan, Lynn M. Schuchter, Ravi Amaravadi, E John Wherry, Robert H. Vonderheide. Phase I study of combination immunotherapy with agonistic CD40 monoclonal antibody (mAb) CP-870,893 (αCD40) and anti-CTLA-4 antibody tremelimumab (treme) in patients with metastatic melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A38.

Abstract CT137: Combination of agonistic CD40 monoclonal antibody CP-870,893 and anti-CTLA-4 antibody tremelimumab in patients with metastatic melanoma

Abstract Purpose: Combining immunostimulatory monoclonal (mAb) and checkpoint inhibition may improve response rates and overall survival in patients with metastatic melanoma. CP-870,893 is an agonistic fully human IgG2 mAb targeting the immune stimulatory molecule CD40 (αCD40). Tremelimumab (treme) is a fully human IgG2 mAb targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a negative co-stimulatory molecule found on T cells. Methods: Patients with metastatic melanoma were enrolled on a single-arm open-label phase I study. αCD40 and treme were dosed i.v. every 3 weeks and 12 weeks, respectively. Dose escalation followed a 3 + 3 strategy with alternating increases of αCD40 and treme in each cohort. Outcomes were scored using the Common Terminology Criteria for Adverse Events v3.0 and RECIST 1.0. Flow cytometric analysis of baseline blood samples was compared to samples obtained at least 3 weeks after the last dose of αCD40 and treme. Results: Toxicity: Twenty-four patients were enrolled and treated at 4 different dose levels. Two patients were replaced per protocol due to rapid, symptomatic progression of disease; these patients were not evaluated for response but were included in toxicity analysis. Dose-limiting toxicities (DLT), considered to be likely due to treatment, were colitis (n = 1) and hypophysitis (n = 1) and uveitis (n = 1). Cytokine release syndrome (CRS), grade 1-2, occurring within 24 hours of CP administration, was the most common treatment-related toxicity occurring in 19 (79.2%) patients. CRS symptoms were controlled with standard supportive care. All episodes of CRS resolved within 24 hours of αCD40 administration. The estimated maximum tolerated dose was 0.2 mg/kg of αCD40 and 10 mg/kg of treme. Outcomes: Overall objective response rate (ORR) was 27.3% (best response): two patients (9.1%) had complete responses to treatment and four (18.2%) patients had partial responses. The median follow-up was 22 months with a median progression free survival of 2.5 months and a median overall survival (OS) of 26.1 months. Correlative studies: Flow cytometric analysis of peripheral blood lymphocytes revealed changes in CD8+ T cell phenotypes. Double positive granzyme B+ and Ki-67+ cells increased from 0.56 ± 0.17% (mean ± standard error) for all CD8+ T cells at baseline to 1.01 ± 0.23% post-treatment (p = 0.03). CD8+ T cells expressing both programmed cell death 1 and eomesodermin were also higher after treatment, increasing from 7.7 ± 1.1% to 10.4 ±1.8% (p = 0.04) of all CD8+ T cells. Conclusion: Combination therapy with αCD40 and treme was well-tolerated in patients with metastatic melanoma, with rates of CRS and other toxicity similar to previously reported rates for αCD40 or treme treatments alone. Overall ORR was 27.3%, with median OS of 26.1 months. Given the tolerability, antitumor activity, and biomarker evidence of immune activation, expanded study of this combination should be pursued. Citation Format: David L. Bajor, Rosemarie Mick, Matthew J. Riese, Lee P. Richman, Xiaowei Xu, Drew A. Torigian, Erietta Stelekati, Martha Sweeney, Brendan Sullivan, Lynn M. Schuchter, Ravi Amaravadi, E. John Wherry, Robert H. Vonderheide. Combination of agonistic CD40 monoclonal antibody CP-870,893 and anti-CTLA-4 antibody tremelimumab in patients with metastatic melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT137. doi:10.1158/1538-7445.AM2015-CT137