Rates Of Cytokine Release Syndrome Research Articles

Cardiovascular Toxicities Associated with Bispecific T-Cell Engagers

Background: Bispecific T-cell engagers (BTEs) are a novel class of drugs used to treat hematological malignancies that link endogenous tumor antigens to CD3 on the T-cell receptor, priming circulating T-cells to effectively target tumor cells. Although chimeric antigen receptor T-cell therapies, a closely related class, have been associated with cardiovascular toxicity, little is known about the cardiovascular toxicity of BTEs. As early clinical trials may have been underpowered for the detection of cardiovascular adverse events (CVAEs), we conducted a large-scale post-marketing surveillance study to identify safety signals that may have been missed. Methods: Leveraging the US Food and Drug Administration's Adverse Events Reporting System (FAERS), we identified adverse event (AE) reports in patients who received BTEs from October 2014 to March 2023. Eligible therapies included Blinatumomab (CD3/CD19 bispecific antibody) and Teclistamab (CD3/BCMA bispecific antibody). The primary outcome of the study was the frequency and fatality rates of CVAEs associated with BTEs. CVAEs included bleeding, hypotension or shock, thromboembolic disease, heart failure, conduction abnormalities (including tachyarrhythmia, bradyarrhythmia, QT-prolongation, and premature contractions), myocarditis, pericarditis, sudden death, and vasculitis. Secondary outcomes included the frequency and fatality rates of cytokine release syndrome (CRS), neurotoxicity (seizures, altered mental status [AMS], speech disorders, gait disorders, and tremors), and infections. We used multivariable logistic regression models, adjusting for age, sex, and disease status, to calculate adjusted reporting odds ratios (RORs). RORs represent the likelihood of reporting a given AE with BTEs compared to reporting the same AE with all other drugs in the database. Mortality rates for each AE are also reported. Results: Overall, 1,181 cases were reported to FAERS for BTE-associated AEs. Among these, 148 (12.5%) involved CVAEs. The most common CVAEs (non-exclusive) were bleeding (70 events), hypotension or shock (56 events), thromboembolic disease (37 events), heart failure (23 events), and tachyarrhythmias (11 events). Less common CVAEs included myocarditis (3 events), pericarditis (1 event), sudden death (1 event), and vasculitis (1 event) (Figure 1A). Of these, BTEs as a class were disproportionately associated with shock or hypotension (ROR: 1.37 [95% CI: 1.03 to 1.80]). Blinatumomab was associated with disproportionately high rates of thromboembolic disease (ROR: 1.48 [95% CI: 1.05 to 2.08]), particularly disseminated intravascular coagulation (DIC; ROR: 4.67 [95% CI: 2.85 to 7.63]). Teclistamab was associated with disproportionately high rates of myocarditis (ROR: 35.79 [95% CI: 10.47 to 122.41]), QT prolongation (ROR: 9.85 [95% CI: 1.33 to 73.08]), and sudden death (ROR: 8.62 [95% CI: 1.16 to 63.99]). Compared to non-cardiovascular AEs, CVAEs were associated with a 92% relative increase in mortality (25.9% vs 50.7%; risk ratio: 1.92 [95% CI: 1.53 to 2.42]). Among CVAEs, the highest mortality rates were reported for heart failure (82.4%), myocarditis (66.7%), bleeding (61.5%), shock or hypotension (57.1%), thromboembolic disease (42.3%), and tachyarrhythmias (37.5%) (Figure 1B). Non-cardiovascular AEs such as neurotoxicity (322 events), infection (277 events), and CRS (190 events) were reported more frequently but had lower mortality rates (28.3%, 48.4%, and 40.0% respectively). Blinatumomab was associated with disproportionately high rates of CRS (ROR: 6.54 [95% CI: 5.41 to 7.92]) and neurotoxicity (ROR: 2.94 [95% CI: 2.56 to 3.39]). Neurotoxicity included AMS (ROR: 2.47 [95% CI: 2.01 to 3.04]), seizures (ROR: 2.81 [95% CI: 2.09 to 3.77]), speech disorders (ROR: 5.72 [95% CI: 4.16 to 7.85]), and tremors (ROR: 6.94 [95% CI: 5.15 to 9.34]). Teclistamab was associated with CRS (ROR: 134.35 [95% CI: 74.45 to 242.47]), infections (ROR: 6.83 [95% CI: 4.63 to 10.07]), and neurotoxicity (ROR: 2.75 [95% CI: 1.53 to 4.94]). Conclusion: In the first large-scale post-marketing surveillance study of BTEs, CVAEs were not uncommon and were more likely to be fatal compared to non-CVAE. Heart failure and myocarditis in particular may portend worse outcomes. These safety signals warrant clinical vigilance and further investigation of their mechanisms, optimal surveillance strategies, and treatment options.

Durable Efficacy and Manageable Safety in Patients Age ≥ 75 Years with Relapsed/Refractory Large B-Cell Lymphoma Treated with Tisagenlecleucel in the Real-World Setting

Background: Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR)-T cell therapy approved for the treatment of patients (pts) with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) who have received ≥2 lines of prior therapy. Previous analysis of the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showed high rates of durable response with progression-free survival (PFS), duration of response, and overall survival (OS) rates at 24 mo of 28%, 53%, and 44%, respectively, as well as similar efficacy outcomes among pts age ≥65 y as compared with pts age <65 y (Landsburg et al, ASH 2022). Although it has been shown that real-world pts treated with CAR-T cell therapy are older than those included in pivotal trials, limited data on CAR-T outcomes among pts age ≥75 y are available. Here, we report the first analysis of clinical outcomes in pts age ≥75 y with r/r LBCL treated with tisagenlecleucel in the real-world setting. Methods: Data were collected as a part of a noninterventional, prospective, longitudinal study using the CIBMTR cellular therapy registry. All pts were treated in the United States, Canada, or Israel. Efficacy outcomes analyzed included overall response rate (ORR), complete response rate (CRR), PFS, and OS. Key safety outcomes included the incidence and severity of adverse events, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Nominal P values are reported without adjusting for multiplicity. Results: As of May 4, 2023, 1375 pts had received tisagenlecleucel (infused set); 278 pts were age ≥75 y. Pts age ≥75 y had similar baseline characteristics compared with pts age <75 y (Eastern Cooperative Oncology Group 0-1, 85% in both populations; elevated lactate dehydrogenase [LDH], 47% in both populations), received similar lymphodepleting regimens, and received tisagenlecleucel in a similar number of days post relapse (81 d vs 85 d, respectively). Pts age ≥75 y had a lower frequency of prior autologous hematopoietic cell transplantation than pts age <75 y (12% vs 26%, respectively) (Figure). One hundred twenty-one pts age ≥75 y had comorbidities (121/278, 44%), including pulmonary disease (65/278, 23%), cardiac disease (60/278, 22%), and hepatic disease (21/278, 8%). Among 247 pts age ≥75 y who were evaluated for efficacy, the ORR (CR + partial response) was 64% (95% CI, 58.1-70.3) and CRR was 47% (95% CI, 41.0-53.8). ORR was similar in pts age <75 y (n=984; 60% [95% CI, 56.9-63.1]), as was CRR (46% [95% CI, 43.2-49.5]). With a median length of follow-up (infusion to data cutoff) of 30 mo, 24-mo PFS in pts age ≥75 y was 23% (95% CI, 16.7-30.1) compared with 28% in pts age <75 y (95% CI, 25.1-31.7). Twenty-four-mo OS in pts age ≥75 y was 39% (95% CI, 31.2-47.2) compared with 44% (95% CI, 40.1-47.8) in pts age <75 y (Figure). AE frequency in pts age ≥75 y (n=250) was comparable with pts age <75 y (n=1004), including the incidence of all-grade CRS (57% vs 60%, respectively; P=0.31) and grade 3/4 CRS (6% of each subgroup). Grade 5 CRS occurred in 2 pts age ≥75 y and 6 pts age <75 y. Tocilizumab was used to manage CRS in 66% of pts age ≥75 y compared with 56% of pts age <75. All-grade ICANS frequency in pts age ≥75 y was comparable with pts age <75 y (27% vs 22%, respectively; P=0.06). Grade 3/4 ICANS was experienced by 7% of each subgroup. Four pts age ≥75 y experienced grade 5 ICANS compared with 1 pt age <75 y. Median time to ICANS onset was similar in pts age ≥75 y (5 d, range 2.0-6.5) and pts age <75 y (5 d, range 3.0-8.0). Corticosteroids were used with similar frequency to manage ICANS in pts age ≥75 y (68%) compared with pts age <75 y (65%). Conclusions: In the first analysis of pts age ≥75 y, tisagenlecleucel demonstrated similar efficacy and rates of CRS and ICANS in pts with r/r LBCL age ≥75 y as compared with age <75 y. As few pts with r/r LBCL age ≥75 y received CAR-T cell therapy in clinical trials, real-world evidence for this age group is invaluable for guiding treatment decisions in this clinical setting, and supports consideration of tisagenlecleucel, a therapy that results in durable disease control in approximately one quarter of patients with a low risk of severe toxicity.

Safety of CAR-T Cell Therapy in Asymptomatic Patients with Positive Respiratory Viral Testing Prior to CAR-T Infusions

Introduction. Active infection is a contraindication to CAR T-cell infusion (CAR-T). Our standard institutional practice (SOP) is to perform a respiratory virus panel (RVP) prior to CAR-T infusion; however, the risk of toxicity after CAR-T in the context of an asymptomatic, incidentally noted respiratory viral infection (+RVP) during pre-CAR-T testing is unclear. We report our institutional experience for asymptomatic patients (pts) with PCR evidence of viral respiratory presence who subsequently received CAR-T. Methods. We retrospectively reviewed 306 pts with non-Hodgkin lymphomas who were treated at the Hospital of the University of Pennsylvania with commercial CAR-T products from 2018-2023. Per SOP, all pts had a PCR-based RVP test prior to lymphodepleting chemotherapy (LD); LD-CAR-T was delayed for at least 7 days for asymptomatic pts with +RVP. After 7 days, pts with continued +RVP can proceed to CAR-T if they remain asymptomatic. RVP included: adenovirus, non-SARS-CoV-2 coronavirus, human metapneumovirus, rhinovirus/enterovirus, influenza A/B, parainfluenza 1-4, respiratory syncytial virus A/B, with/without SARS-CoV-2. We selected pts who had a +RVP within 4 weeks of CAR-T and who were asymptomatic (without respiratory viral symptoms) at time of CAR-T infusion. Cytokine release syndrome (CRS) and neuro-toxicity domains defining immune effector cells (ICANS) were evaluated using ASTCT consensus grading. Any fever post-CAR-T without an alternative cause was considered CRS. Results . We identified 15 pts with +RVP who were asymptomatic at the time of CAR-T: 12 (80%) were male; median age 54 years (range 38-75); 10 (67%) had large B-cell lymphoma; 4 (27%) follicular lymphoma; 1 (7%) mantle cell lymphoma; ECOG performance status (PS) ≤1 in 14 (93%); lactate dehydrogenase (LDH) elevated in 5 (33%); 14 (93%) received bridging therapy. Overall, 11 pts (73%) had rhinovirus/enterovirus, 1 (7%) had SARS-CoV-2, 1 (7%) had non-SARS-CoV-2 coronavirus, 1 (7%) had adenovirus, and 1 (7%) had RSV A. Of these 15 pts with +RVP, 8 (53%) were asymptomatic at time of initial +RVP and 7 (47%) pts were symptomatic at time of +RVP. The median time of intial +RVP was 13 days before CAR-T; the median time of closest +RVP to CAR-T was 7 days prior to CAR-T. No patient who was asymptomatic with a +RVP developed symptoms between initial screening +RVP and CAR-T infusion. At the time of CAR-T infusion, all patients were asymptomatic and no patient required supplemental oxygen. CAR-T was administered outpatient in 9 pts (60%). Of 15 asymptomatic pts infused, 10 (67%) received tisagenlecleucel (tisa-cel), 2 (13%) axicabtagene ciloleucel (axi-cel), 2 (13%) lisocabtagene maraleucel (liso-cel), and 1 (7%) brexucabtagene autoleucel (brexu-cel). 8 of these 15 pts (53%) developed CRS (7 pts grades 1-2, one pt grade 3) and 4/15 (27%) ICANS (2 pts grades 1-2, 2 pts grades 3-4). Of the 8 patients who remained asymptomatic and received CAR-T, 6 (75%) received tisa-cel, 1 (13%) axi-cel and 1 (13%) liso-cel. 5 of these 8 pts (63%) developed CRS (all grades 1-2) and 1/8 (13%) ICANS (grade 2). Of the 7 patients whose symptoms resolved prior to CAR-T but had +RVP, 4 (57%) received tisa-cel, 1 (14%) axi-cel, 1 (14%) liso-cel, and 1 (14%) brexu-cel. 3 of these 7 pts (43%) developed CRS (2 pts grades 1-2, 1 pt grade 3) and 3/7 (43%) ICANS (1 pts grades 1-2, 2 pts grades 3-4). Discussion: In our experience, CAR-T in pts with PCR evidence of upper respiratory viral infection was generally safe in pts not requiring oxygen with a good PS who are asymptomatic or symptomatically resolved at time of CAR-T infusion. Rates of CRS and ICANS were comparable between asymptomatic pts and pts with resolved symptoms at time of CAR-T.

Real-World Evaluation of Teclistamab for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Teclistamab (TEC) is a bispecific BCMA-CD3 directed T-cell antibody (BsAb), recently approved by EMA and FDA. Approval was based on the MajesTEC-1 study showing high overall response rates (≥PR in 63.0%) in heavily pretreated patients with relapsed multiple myeloma (RRMM). Few reports have described Real-World experience despite that TEC can induce unique side effects including cytokine release syndrome (CRS), neurotoxicity (ICANS) and a high incidence of infection (MajesTEC-1: incidence 76.4%; ≥Gr3: 44.8%). Thus, we performed a Real-World analysis of TEC therapy from 7 International Myeloma Foundation (IMF) associated MM academic centers. Methods: Patients treated with standard-of-care TEC were included. Data was collected until 7/28/2023. Results: 103 pts were included; median age 63 (range 33-91y); 15 pts. (14.5%) >75 yrs; 56.5% were male, 71.8% Caucasian, 11.6% Hispanic, and 12.6% Asian. Pts received a median of 6 PLT (range 1-16); 75% were triple-class-refractory (n=41/52 (79%), 30/85 (35%) had high-risk cytogenetics/FISH and 32/80 (40%) had 1q21 gain. At least 57/76 (75%) of pts would not have been eligible for MajesTEC-1 (mostly from prior BCMA (n=28 CAR-T, n=14 ADC; n=3 BsAb; n=5 CAR-T+ADC). 14 pts had CrCl <30ml/min with 2 on HD. Median number of hospital days was 8 (n= 72) but 31 patients were treated entirely as outpatients (Mayo clinic (MN, AZ, FL)). CRS was seen in 52 (50.4%) (all grade 1: except 6 Gr2, 1 Gr4), generally resolved within 24 hrs and was managed with tocilizumab alone (n= 27) or dex alone (n=9) or dex+toci (n=12). CRS was more common with inpatient (56.9%) vs outpatient (35.4%) TEC Rx. CrCl <30 ml, did not appear to alter the incidence or severity of CRS (50%; 1 Gr4). ICANS was infrequent (n=5; 4.85%), 1 pt with Gr 4-Sz requiring HD-steroids and TEC discontinuation). Infections were common, seen in 54 (52.4%) of patients, the majority were viral URI or CMV reactivation (n=26; 3 pts receiving CMV Rx, 1 pt with CMV organ disease). IVIG was given in 43/67 (64%) pts. The overall response rate for evaluable patients (n=82) was 63%; (sCR/CR 14; VGPR 23; PR 15; MR 2, SD 14; PD 14). In evaluable pts treated with prior BCMA (n=43), the ORR was 53% (sCR/CR 4; VGPR 14; PR 5; 1 MR; SD 10; PD 9). The most common reason for treatment discontinuation was PD (26.2%). 14 pts have died by the time of data cut-off (7/28/23), with the most common cause of death being disease progression. Conclusions: In this Real-World evaluation of TEC, a high ORR was seen, similar to the MajesTEC-1 study. Responses were rapid and are expected to deepen over time (median f/u 5m). CRS rates were similar to MajesTEC-1 and no new toxicity signal was noted. The rates of infection appear low but may be related to short follow-up. Details regarding the incidence and types of infection and the global use of IVIG will be described. With longer follow-up, additional efficacy/toxicity data will be presented.

Toxicity and Efficacy Outcomes of Teclistamab in Patients with Relapsed-Refractory Multiple Myeloma (RRMM) Above the Age of 70 Years: A Multicenter Study

Introduction: Older patients (>70 years old) are often considered ineligible for intensive treatments including autologous stem cell transplant (ASCT) and chimeric antigen receptor T-cell (CAR-T) therapies, having a relatively poor performance status and concomitant comorbidities. Therefore, the interest in this age group has been shifted in utilization of novel therapies with a less toxic side effect profile and less risk for serious complications. Teclistamab is a novel B-cell maturation antigen (BCMA)-directed bispecific antibody that received approval for the treatment of patients with RRMM after ≥4 prior lines of therapy (LOT) based on the results of the MajesTEC-1 trial. In this retrospective study, we aimed to analyze real-world data on the efficacy and toxicity profile of teclistamab in a population of older RRMM patients, and compare them with younger individuals. Methods: Five US academic centers, part of the US Myeloma Innovations Research Collaborative (USMIRC) contributed data to this analysis. One hundred and two patients with RRMM who received teclistamab as of 7/1/2023 were included in this study. Baseline characteristics were outlined by descriptive analysis. Responses, including overall response rate (ORR) and compete response rate or better (≥CR) were assessed using the International Myeloma Working Group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. Statistical analysis was done with Chi-squared test and Kaplan-Meier method for progression-free survival (PFS) calculation. Results: Of the 102 patients included in this study, 33 (32%) were above the age of 70 years (older) with a median age of 75 (range 71-87) years. Disease characteristics of the older patient population were notable for 58% with high-risk cytogenetics as defined by presence of del(17p), t(4;14), t(14;16) and/or t(14;20), and 39% with extramedullary disease (EMD) prior to teclistamab initiation. Patients were heavily pretreated with a median of 6 (range 4-17) prior LOT; 58% had undergone prior ASCT and 97%, 58%, and 58% were triple, penta, and BCMA-directed therapy (BDT) refractory, respectively. Compared to patients with age <70 years (n=69), older patients were more likely to have a worse performance status (ECOG ≥2) (45% vs 26%, p=0.05); other baseline characteristics including high-risk cytogenetics, stage III (per revised international staging system) disease, extramedullary disease, triple, penta- and BDT-refractoriness status were comparable between the two groups (Table 1). Median follow-up time for the entire cohort was 3.2 months. Patients with age >70 years had a comparable ORR (70% vs 61%, p=0.37), and ≥CR (30% vs 28%, p=0.8) rates to those with younger age. In addition, the two subgroups had comparable median estimated PFS (5.4 vs 3.8 months, p=0.61) (Figure 1). Cytokine release syndrome (CRS) in most cases was grade 1-2, and CRS rates were similar between the older and younger patient groups (67% vs 64%, p=0.7). Likewise, most immune effector cell-associated neurotoxicity syndrome (ICANS) events were grade 1-2, and rates were comparable between the two groups (21% vs 11%, p=0.17, Table 1). Patients older than 70 years were more likely to have grade 3-4 thrombocytopenia within the first 90 days from teclistamab initiation (27% vs 12%, p=0.05), while the rest of grade 3-4 cytopenias were not different between the two cohorts. Infection rates (33% vs 26%, p=0.46) and hospital readmission rates (36% vs 23%, p=0.16) were comparable between the older and younger patients, respectively. Conclusions: This is the first and largest multicenter retrospective analysis characterizing a real-world cohort of patients who received teclistamab. Based on our results, older age (>70 years) does not appear to affect response outcomes or PFS. For the most part, the safety profile appears similar, however patients older than 70 years were more likely to develop grade 3-4 thrombocytopenia. Importantly, the infection rates were not significantly different between the two groups, further supporting the broad use of teclistamab in older patients with RRMM.

Adaptive Manufacturing of LV20.19 CAR T-Cells for Relapsed, Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by the presence of t(11;14) and bright CD20 expression. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL is limited by both relapse and high rates of Grade 3+ cytokine release syndrome (CRS) and ICANS with 15% and 31% patients (pts) experiencing such toxicities, respectively. To improve outcomes we utilized dual targeted lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T-cells with an adaptive manufacturing (MF) process to optimize the final CAR product as part of a Phase 1/2 clinical trial in R/R MCL. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report results of MCL pts from a fully enrolled Phase I safety run-in and Phase II efficacy cohort. The primary outcome for the Phase II cohort was day 90 complete response (CR) rate. The Phase II cohort utilized an adaptive 8/12 day MF process to enhance the percentages of T-SCM (stem cell-like memory) and T-CM (central memory) CAR T-cells in the final product by shortening culture time. CAR T-cells were harvested either on day 8 of MF or extended to a 12-day MF process depending on achieving target cell dose in culture. Fludarabine/cyclophosphamide lymphodepletion was started during MF to facilitate fresh infusion in eligible pts. Descriptive statistics were utilized for demographic data and the Kaplan Meier methodology for survival analysis. Results: In total 17 pts with R/R MCL received LV20.19 CAR T-cells (Phase 1=3 pts and Phase 2=14 patients). All pts achieved target cell dose. 13 pts received an 8-day product while 4 received a 12-day product. 14/17 pts received a fresh (non-cryopreserved) infusion. 8-day products were enriched for T-SCM/CM phenotype cells with significantly lower number of terminally differentiated effector memory (EMRA) T-cells in the CD4 compartment (p<0.05) than 12-day products. The median age was 63 (50-74 years) and 15 (88%) were cisgender male. The median number of lines of therapy was 4 (3-8). p53 deletions or mutation were present in 7 pts. Day 28 overall response rate (ORR) was 100%; CR rate=76% and partial response (PR) =24%. Initial ClonoSEQ MRD assay performed within the first 90 days of LV20.19 CAR T (n=13) was negative in 10 pts (77%). Among Phase II patients with day 90 results available (n=12) the ORR was 100%, CR rate=92% and PR rate=8% exceeding the Phase II efficacy threshold. Two pts have relapsed to date, +8 months and +2 years after infusion. There were two non-relapse mortality (NRM) events that occurred beyond day 28: gram negative rod sepsis & COVID19 infection resulting in a 1-year NRM rate of 12%. The 1-year progression free survival (PFS) was 77%, 1-year duration of response (DOR) was 92%, and 1-year overall survival (OS) of 84%. Median PFS/DOR/OS have not been met with median follow-up of 14 months of surviving pts (Figure 1). In terms of safety, 94% (n=16) experienced CRS, all grade 1-2. 18% (n=3) had ICANS in the first 28-days, 2 pts with Grade 3 toxicity. There were two pts with late (>day 28) episodes of Grade 1 neurological toxicity. Both pts had immense expansion of lymphocytes in the CSF (total nucleated cell count of 386/µLand 1005/µL) with CAR+ T cells present. Both received only a single dose of intrathecal hydrocortisone (no systemic steroids) with resolution of neurotoxicity within 24 hours of administration. Conclusions: Bispecific LV20.19 CAR T-cells with adaptive MF process is feasible, safe, and efficacious for R/R MCL with ORR 100%, no Grade 3+ CRS and low rates of Grade 3+ ICANS (12%). Adaptive MF enriched the final product with higher percentages of T-SCM/T-CM CAR cells and allowed most pts to receive CAR-T cells within 8 days of apheresis. Dual targeting of CD20 and CD19 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL.

Bridging Radiotherapy Prior to Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphomas: An ILROG Multi-Institutional Study

To report an ILROG multi-institutional analysis of bridging radiotherapy (BRT) prior to CD19-targeting chimeric antigen receptor T-cell (CAR T) therapy for relapsed/refractory aggressive B-cell lymphomas (BCL). Weretrospectively reviewed 115 patients (pts) with diffuse large BCL (n = 101, 88%), primary mediastinal BCL (n = 11, 10%), mantle cell lymphoma (n = 2, 2%), and T-cell/histiocyte rich large BCL (n = 1, 1%) who received BRT prior to commercial CAR T from 2018-2020 across 6 institutions. BRT toxicities were graded per CTCAE v5.0, cytokine release syndrome (CRS) per ASTCT, and immune effector cell-associated neurotoxicity syndrome (ICANS) per either ASTCT or CTCAE v5.0. Progression-free survival (PFS) and overall survival (OS), measured from CAR T infusion, were estimated using the Kaplan-Meier method. PFS was modeled using Cox regression with stepwise variable selection. BRTwas given prior to axicabtagene ciloleucel (axi-cel; n = 82, 71%), tisagenlecleucel (tisa-cel; n = 31, 27%), or brexucabtagene autoleucel (n = 2, 2%). Median age was 62 years with median of two prior lines of therapy. Most pts had advanced stage III/IV disease at leukapheresis (n = 87, 76%), elevated pre-leukapheresis LDH (n = 73, 63%), and bulky disease (n = 55, 50%) (1 lesion ≥7.5 cm). 78 pts (68%) had extranodal disease, 12 (10%) had central nervous system (CNS) involvement, and 36 (31%) had bone involvement. Systemic bridging therapy was given to 42 pts (37%). Median intervals from leukapheresis to BRT start and from BRT completion to CAR T infusion were 5 days (IQR -6, 11) and 12 days (IQR 9, 23), respectively. BRT was delivered to 163 total sites; most commonly the abdomen/pelvis (n = 58, 50%), head/neck (n = 34, 30%), thorax (n = 20, 17%), extremity/soft tissue (n = 20, 17%), and CNS (n = 13, 11%). Median biologically effective dose was 31.3 Gy (IQR 24, 39). Most common regimen was 30 Gy in 10 fractions (n = 27, 17%). 40 pts (35%) received comprehensive BRT (to all active lesions). There were no grade ≥3 BRT toxicities. Grade ≥3 CRS occurred in 9 pts (8%), including 8/82 (10%) after axi-cel and 1/31 (3%) after tisa-cel. Grade ≥3 ICANS occurred in 23 pts (20%), including 22/82 (27%) after axi-cel and 1/31 (3%) after tisa-cel. Median follow up was 26.9 months. 1- and 2-year OS rates were 60% and 49%. 1- and 2-year PFS rates were 41% and 35%. Comprehensive BRT associated with superior PFS (HR 0.34, 95% CI 0.19-0.62, p<0.001) in a multivariable model with age ≥60, ECOG ≥2, advanced stage, CNS disease, pre-leukapheresis LDH, and axi-cel. In this multi-institutional study, pts receiving BRT prior to CAR T therapy for BCL frequently had bulky disease yet experienced favorable PFS and OS. There were no serious toxicities attributable to BRT, and the rates of CRS and ICANS are comparable to those after CAR T alone. Comprehensive BRT associated with superior PFS.

Efficacy and Toxicity of CD19 Chimeric Antigen Receptor T Cell Therapy for Lymphoma in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis

The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I2 = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I2 = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I2 = 0%) and 5% (95% CI, 0% to 21%; I2 = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I2 = 68%) and 40% (95% CI, 3% to 85%; I2 = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.

Rates of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) from Center for International Blood and Marrow Transplant Research (CIBMTR) data on US subjects (SUBJ) with lymphoma following chimeric antigen receptor T cell therapy (CAR-T).

7528 Background: The engineered T-cell products axicabtagene ciloleucel (axi-cel) and brexucabtagene autoleucel (brexu-cel) are FDA approved for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), respectively. This study investigated real-world rates of CRS and ICANS following CAR-T. Methods: This study analyzed CIBMTR data of US SUBJ receiving axi-cel or brexu-cel for any indication from Oct 2020–Dec 2021 with ≥1 follow-up visit. CRS and ICANS were graded per American Society for Transplantation and Cellular Therapy consensus guidelines. Results: 927 SUBJ (median age, 63 y; men, 65%) from 87 centers were analyzed. Most received axi-cel (76%), 83% of whom had DLBCL or transformed follicular lymphoma (tFL); 24% received brexu-cel (MCL). Most SUBJ had Ann Arbor stage III/IV (63%), no active central nervous system disease (84%), and refractory disease at CAR-T infusion (66%). Among all 589 SUBJ with DLBCL/tFL who received axi-cel, 54% achieved complete response, 17% partial response, and 6% stable disease. 89/715 SUBJ with available data received treatment for CRS prevention, mostly tocilizumab alone (80% [71/89]) or in combination (3% [3/89]). Overall, 766 SUBJ (83%) developed CRS (grade ≥3, 64 [8%]; Table). Of the 89 SUBJ who received CRS prevention treatment, 78% developed CRS, with 3% (3/89) having grade ≥3. 77% of SUBJ with CRS received CRS treatment, 97% of whom received tocilizumab (alone or in combination [eg, with corticosteroids]). Most (64%) SUBJ with grade 1 CRS received treatment, 63% of whom received tocilizumab alone. ICANS occurred in 424/876 SUBJ with ICANS data (48%; Table), of whom 205 (48%) had grade ≥3. ICANS treatment was reported and administered to 86% of SUBJ with ICANS, 92% of whom received corticosteroids. Conclusions: CRS and ICANS incidence rates were consistent with previously published literature and highlight potential burdens of CAR-T. In addition, the treatment landscape for CRS is changing; SUBJ with grade 1 CRS often received treatment. These data will inform the design of future studies aimed at preventing and treating CAR-T toxicities. [Table: see text]

Safety and Efficacy of BCMA CAR-T Cell Therapy in Older Patients With Multiple Myeloma

Risks of B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy for patients with multiple myeloma (MM) include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, and infections. The efficacy and safety of BCMA CAR-T therapy in the geriatric setting, including complications such as falls and delirium, which may be more prevalent in older patients, have not been fully analyzed. We wanted to analyze the efficacy and safety of BCMA CAR-T therapy among older patients (age ≥70 at infusion) versus younger patients with MM. We analyzed all patients with MM who received any autologous BCMA CAR-T therapy over a 5-year period at our institution. Key endpoints included CRS, ICANS incidence, days to absolute neutrophil count (ANC) recovery, incidence of hypogammaglobulinemia (IgG < 400 mg/dL), infections within 6 months, progression-free survival (PFS), and overall survival (OS). Of 83 analyzed patients (age range 33-77), 22 (27%) were aged ≥70 at infusion. The older cohort had lower creatinine clearances (median 67.3 versus 91.9 mL/min, P < .001) and a higher proportion of patients with performance status ≥1 (59% versus 30%, P = .02) but were otherwise similar. Rates of any-grade CRS, any-grade ICANS, and days to ANC recovery were similar between groups. Rates of baseline hypogammaglobulinemia were 36% in older patients and 30% in younger patients (P = .60), whereas post-infusion hypogammaglobulinemia occurred in 82% versus 72%, respectively (P = .57). Infections occurred in 36% (n = 8) of the older cohort versus 52% (n = 32) of the younger cohort (P = .22). There were no statistically significant differences between the older and younger cohorts in terms of documented falls (9% versus 15%, P = .72) or non-ICANS delirium (5% versus 7%, P = 1.0). Median PFS was 13.1 months in older patients (95% confidence interval [CI], 9.2-not reached [NR]) versus 12.5 months in younger patients (95% CI 11.3-22.5, P = .42. Median OS was not reached in the older cohort (95% CI, NR-NR) versus 31.4 months in the younger cohort (95% CI, 24.8-NR) with P = .04. However, age ≥70 was not a significant predictor of OS after adjusting for high-risk cytogenetics, triple-class refractoriness, extramedullary disease, and bone marrow plasma cell burden. Although limited by small sample size and unmeasured confounders, our retrospective analysis did not demonstrate significant increases in CAR-T toxicity among older patients. This included toxicities associated with geriatric populations such as falls and delirium. Our paradoxical finding of borderline better OS among patients aged ≥70, which was not significant in regression modeling, may have been due to selection bias in favor of disproportionately healthy CAR-T candidates in the geriatric population. Overall, BCMA CAR-T remains a safe and effective option for older patients with MM.

Effect of Delayed Cell Infusion in Patients with Large B-Cell Lymphoma Treated with CAR T-Cell Therapy

Introduction: Lymphodepleting chemotherapy (LDC) is essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy and functions through multiple mechanisms, including elimination of sinks for homeostatic cytokines, such as interleukin [IL]-7 and IL-15. In clinical trials, LDC is typically given on the fifth through third day before cell infusion. However, in real-world practice, cell infusion may be delayed for multiple reasons, including clinical and logistical complications. It remains unclear whether delaying cell infusion impacts clinical outcomes and whether LDC should be repeated if cell infusion is delayed. Methods: We performed a retrospective cohort analysis of all patients with relapsed or refractory large B-cell lymphoma who received LDC with fludarabine and cyclophosphamide followed by standard of care axicabtagene ciloleucel (axi-cel) at the University of Texas MD Anderson Cancer Center between 1/2018 and 12/2021. For multivariate analyses, only factors significantly associated in univariate analysis were included. Results: Of 240 patients treated with axi-cel, 40 (16.7%) received delayed cell infusion with a median delay of 2 days (range 1-14 days). Reasons for delay included infections in 34 (85%) patients, disease-related procedures in 3 (7.5%) patients and logistical complications in 3 (7.5%) patients. On univariate analysis, baseline characteristics associated with infusion delay were extra-nodal sites > 1 (p = 0.034), high number of prior therapies (p = 0.015), low absolute monocyte count (p = 0.003), low hemoglobin concentration (p < 0.001), low platelet count (p = 0.009), high C-reactive protein (CRP; p < 0.001), high ferritin (p = 0.01) and high lactate dehydrogenase (LDH; p = 0.016) levels at the time of LDC initiation. On multivariate analysis, the association was maintained only for elevated CRP (odds ratio 1.009; 95% confidence interval [CI] 1.002-1.017; p = 0.009). When compared to patients who received cell infusion on-time, patients with delayed infusion had similar rates of cytokine release syndrome (CRS) of any grade (90% vs. 93.5%; p = 0.496), grade 3-4 CRS (12.5% vs. 8.0%; p = 0.542), immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade (65% vs. 64.5%; p = 0.952) and grade 3-4 ICANS (42.5% vs. 39.5%; p = 0.860), but exhibited a trend towards increased rate of grade 3-4 cytopenias at day 30 (74.3% vs. 58.0%; p = 0.09). Patients with delayed infusion had a significantly lower day 30 overall response rate (59.0% vs. 79.4%; p = 0.008) but similar complete response rate (43.6% vs. 54.3%; p = 0.293) to those with on-time infusion. After a median follow-up of 25.7 months (95% CI 22.6-28.8 months), patients with delayed infusion had significantly shorter median progression-free survival (PFS; 3.5 vs. 8.2 months; p = 0.002) and overall survival (OS; 7.8 vs. 26.4 months; p = 0.046) compared to those with on-time infusion. An association between extent of delay and survival was observed, with significantly shorter median PFS in patients who had delay of 2-5 days (1.8 vs. 8.2 months; p = 0.002) and >5 days (4.6 vs. 8.2 months; p = 0.040) but no significant difference in median PFS for patients with a delay of 1 day (5.4 vs. 8.2 months; p = 0.240) compared to those with on-time infusion (Figure). The association between delayed infusion and shorter PFS was maintained on multivariate analysis including age, International Prognostic Index score, LDH and CRP (hazard ratio 1.567; 95% CI 1.045-2.351; p = 0.03). When compared to patients with on-time infusion, patients with delayed infusion had lower serum IL-15 concentration (17.0 vs. 26.3 pg/mL) at time of cell infusion but comparable IL-7 concentration (16.4 vs 15.7 pg/mL). Conclusions: In real-world practice, cell infusion is delayed in more than 15% of patients, mostly due to infectious complications. In this single-center retrospective analysis, cell infusion delay was associated with higher rates of prolonged severe cytopenia and worse clinical outcomes, particularly if delay was longer than 1 day. Larger cohorts are needed to further characterize the impact of delayed cell infusion on treatment efficacy and determine whether biologically rational treatments directed at improving CAR T-cell function in these patients would be beneficial. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes for Patients with Relapsed or Refractory (R/R) Aggressive B-Cell Non-Hodgkin's Lymphoma (aBNHL) Treated with Commercial Tisagenlecleucel: Subgroup Analyses from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy that provides high rates of durable response, with a manageable safety profile, in adult patients with R/R diffuse large B-cell lymphoma (DLBCL). An overall response rate (ORR) of 53% and progression-free survival (PFS) rate of 33% at 24 months were observed in the pivotal Phase II trial, JULIET (NCT02445248) [Schuster et al. Lancet Oncol 2021; Jaeger et al. Blood 2020]. CIBMTR registry data revealed similar efficacy and a more favorable safety profile for patients with aBNHL treated with tisagenlecleucel in the commercial setting [Landsburg et al.Blood 2021]. The analyses presented here feature a larger cohort with longer follow-up, with outcomes analyzed by pre-infusion clinicopathologic and treatment characteristics. Methods: This non-interventional prospective study used data from the CIBMTR registry and included adult patients with R/R aBNHL in the USA, Canada, and Israel who received commercial tisagenlecleucel after August 30, 2017. Patients were stratified by eligibility for JULIET based on characteristics reported in the registry, such as disease histology, ECOG performance status (PS), comorbidities (recorded as pulmonary, cardiac, renal, or hepatic), and disease status at infusion. Outcomes were assessed in subgroups by reason for JULIET ineligibility, and by lactate dehydrogenase (LDH) level and lymphodepleting chemotherapy (LDC) regimen. LDH was taken as the last known value prior to LDC, or prior to infusion for patients who did not receive LDC. The safety and efficacy sets comprised patients who completed Day 100 safety and efficacy forms, respectively, including those who died prior to Day 100. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: As of May 4, 2022, data were collected from 1159 patients who received commercial tisagenlecleucel; the median manufacturing turnaround time was 26 days (IQR 24-30). Median age was 67.1 years, 61.2% were male, and 80% had DLBCL. There were 361 JULIET-eligible patients, 641 JULIET-ineligible patients, and 157 patients whose eligibility status could not be defined due to missing data. In the efficacy set (N=968), over a median follow-up of 23.2 months (range: 3.1-46.4), the ORR was 59.5% (Table 1). Month 24 outcomes were 28.4% for PFS, 52.6% for duration of response, and 43.6% for overall survival (OS). Patients with normal versus elevated LDH had improved efficacy outcomes (Table 2), while type of LDC regimen did not appear to impact efficacy (Table 2). Considering individual reasons for JULIET ineligibility, patients in morphologic complete response (CR) at infusion had higher ORR (87.3%) and 24-month PFS (46.3%) and OS (66.1%) than JULIET-eligible patients (Table 1). In patients with ECOG PS ≥2, as well as those with comorbidities (including pulmonary, cardiac, and hepatic disease), PFS was comparable with the JULIET-eligible population (Table 1). In the safety set (N=990), grade ≥3 CRS and ICANS occurred in 6.0% and 7.4% of patients, respectively. Compared with JULIET-eligible patients, rates of CRS and ICANS were lower for patients in morphologic CR at infusion, and higher among those with ECOG PS ≥2. Rates of grade ≥3 CRS were similar between patients with comorbidities and the JULIET-eligible population (Table 1). Conclusions: These analyses using data reported to the CIBMTR, with 1159 patients and >20 months' median follow-up, confirm that real-world outcomes with tisagenlecleucel are broadly similar to those observed in JULIET. Among all patients, normal LDH pre-infusion, but not LDC regimen received, was associated with significantly improved efficacy outcomes. Patients with comorbidities that would have rendered them ineligible for JULIET had similar efficacy outcomes to JULIET-eligible patients. Additionally, efficacy outcomes were similar in patients ineligible for JULIET due to ECOG PS ≥2, albeit with higher rates of grade ≥3 CRS and ICANS. A significantly higher response rate and trend towards improved survival outcomes were observed among patients in morphologic CR before infusion. These data suggest that tisagenlecleucel is appropriate therapy for several subsets of patients who would have been ineligible for JULIET. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Scholar-1 Refractoriness Criteria on the Efficacy of CAR-T Therapy in Aggressive B Cell Lymphoma, Compared with Non-Refractory Patients: A Real World Geltamo/Geth Study

Introduction. Chimeric antigen receptor (CAR) T-cell therapy is becoming the standard of care for patients with aggressive B cell lymphoma (ABCL), including diffuse large B-cell lymphoma (DLBCL) and high-grade B cell lymphoma (H-GBCL) pre-treated with 2 lines. We have recently reported real-world data in Spain, with efficacy results similar to those reported in the pivotal studies and other real-world experiences. It is known that patients with SCHOLAR-1 refractoriness criteria have a particularly poor prognosis with any treatment, so, the objective of this analysis is to evaluate the impact of SCHOLAR-1 refractoriness criteria on efficacy compared to non-refractory population. Methods This is a multicenter, retrospective, observational study that included all patients with relapsed or refractory (R/R) ABCL treated with CAR-T therapy in Spain and registered in the GELTAMO/GETH database (n=404). The main objective was to analyze efficacy in terms of response rates and survival for ABCL patients with or without SCHOLAR-1 criteria (primary refractoriness, refractoriness to last treatment, or early relapse after autologous stem-cell transplant [SCT]), comparing both commercial products axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel). Results From the 404 patients with ABCL registered, 20 were excluded due to absence of follow-up data and 31 for primary mediastinal lymphoma histology; finally, 353 patients were included for the primary analysis; 324 (91%) received the CAR-T cell infusion (164 axi-cel and 160 tisa-cel). Patient characteristics at infusion were balanced for both CAR-T products except for younger age (57 [23-79] vs 63 [23-79], p=0.02) and more patients with bulky disease (73 [46%] vs 43 [28%], p= 0.001) in the axi-cel group. With a median follow-up from infusion of 12.2 months (95%CI:11.3-13), median progression-free survival (PFS) was 3.3 months (95%CI: 2.4-4.2), and median overall survival (OS) was 15.2 months (95%CI: 10.7-19.7) for the whole infused cohort. For the infused patients 285 (88%) met at least one SCHOLAR-1 criteria (146 [52%] axi-cel y 139 [48%] tisa-cel) and 39 (11%) were non-refractory (18 [46%] axi-cel y 21 [54%] tisa-cel). There were no significant differences in patient characteristics between SCHOLAR-1 and non-refractory groups, except for a higher rate of bulky disease in the SCHOLAR-1 patients (39% vs 9%, p=0.001). Median OS was 12.3 months (95%CI: 9-15.6) and median PFS was 3.2 months (95%CI: 2.7-3.8) in the refractory group, whereas median OS and PFS were not reached (1 year-OS: 81%; 1 year-PFS: 54%) in the non-refractory group. In the SCHOLAR-1 group, comparing axi-cel and tisa-cel, 1 year-PFS was 42% and 25% (p=0.005) (Figure 1), and 1 year-OS was 60% and 39% (p=0.001), respectively. For non-refractory patients, 1 year-PFS was 87% and 77% (p=0.37) (Figure 1) and 1 year OS was 64% and 42% (p=0.35) for axi-cel and tisa-cel, respectively. In the multivariate analysis for the Sholar-1 cohort, factors independently influencing PFS were: CAR-T tisa-cel (HR 1.7 [CI:1.23-2.34, p=02001]), having received bridging therapy (HR 1.72 [CI: 1.08-1.27, p= 0.22], refractoriness to last treatment (HR 2.04 [CI: 1-17-3.55]), HCTCI ≥2 pre-infusion (HR 1.6 [CI: 1.19-2.29]), and for OS: CAR-T tisa-cel ( HR 1.74 [CI: 1.12-2.7, p= 0.012]), ECOG ≥2 pre-apheresis ( HR 2.4 [CI:1.11-5-47, p= 0.02]), previous auto-SCT ( HR 2.22 [CI:1.4-3.52, p= 0.001]). In terms of toxicity, 82% of patients had cytokine release syndrome (CRS) (6% ≥ grade 3), and 33% of patients had Immune effector cell-associated neurotoxicity syndrome (ICANS) (11% ≥ grade 3). Rates of CRS and ICANS were no different between refractory and non-refractory patients. CRS rate was 71% and 93% and CRS ≥ grade 3 rate was 4% and 8% (p=0.001) for tisa-cel and axi-cel respectively. ICANS rate was 16% and 50%, and ICANS ≥ grade 3 rate was 4% and 18% (p=0.001), respectively. Non-relapse mortality was 5% and 7% for tisa-cel and axi-cel respectively (p= 0.64). Conclusions: We conclude that SCHOLAR-1 refractoriness criteria influence notably the CAR-T cell therapy efficacy. In our experience, axi-cel showed better results in terms of efficacy than tisa-cel for this population, but also significantly more toxicity. Results for non-refractory patients are significantly better with both products, but the small sample size prevents reaching solid conclusions in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Intravenous Chimeric Antigen Receptor T-Cell Therapy in Adults with Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis

Introduction: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for non-Hodgkin's lymphoma. However, most CAR T-cell trials excluded primary central nervous system lymphoma (PCNSL) patients due to the neurotoxicity concern. This systematic review and meta-analysis aimed to explore the efficacy and safety of intravenous CAR T-cell therapy in PCNSL patients. Methods: We searched Pubmed, Scopus, Cochrane Library, and Embase for relevant articles from inception to June 26, 2022. We also hand-searched conference abstracts. The inclusion criteria for a study were: i) all participants being at least 16 years old; ii) at least 3 participants having PCNSL at the time of intravenous CAR T-cell infusion; and iii) reporting the rates of best complete response (BCR), best objective response (BOR), cytokine release syndrome (CRS), or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). We performed single-arm meta-analyses to quantitatively synthesize the outcomes using cumulative event rates (CERs) and 95% confidence intervals (95% CIs). Results: This review included 5 studies involving 35 participants. Intravenous CAR T-cell therapies included axicabtagene ciloleucel, tisagenlecleucel, obecabtagene autoleucel, lab manufactured anti-CD19, and sequential anti-CD19/22 CAR T-cell. The BCR and BOR were 56.0% (95% CI: 37.3-74.1%) and 66.9% (95% CI: 48.3-83.6%), respectively. The response rates were not significantly different among the costimulatory domains, including CD28, 4-1BB, and a combination of CD28 and 4-1BB. The rates of CRS, grade ≥ 3 CRS, ICANS, and grade ≥ 3 ICANS were 74.2% (95% CI: 55.7-89.6%), 0.6% (95% CI: 0-9.8%), 57.5% (95% CI: 31.3-82.0%), and 18.3% (95% CI: 5.4-35.0%). Subgroup analysis demonstrated that ICANS occurred more frequently in CAR T-cells with CD28 costimulatory domain (100%, 95% CI: 75.0-100%) than CAR T-cells with 4-1BB costimulatory domain (45.8% 95% CI: 24.8-67.5%). However, sICANS rates among costimulatory domains were not significantly different. Conclusion: The efficacy and safety profiles of intravenous CAR T-cell therapies in PCNSL patients are efficient and acceptable toxicity. Further studies should explore the effect of costimulatory domains on the side effects of CAR T-cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mosunetuzumab with Polatuzumab Vedotin Is Effective and Has a Manageable Safety Profile in Patients Aged

Background: Treatment decision-making for elderly DLBCL patients (pts) is challenging. Advancing age is associated with an increase in the incidence of comorbidity and vulnerability to treatment-related toxicities (Thieblemont & Coiffier. J Clin Oncol 2007). Mosunetuzumab (M) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Ab) that redirects T cells to eliminate malignant B cells. The Phase Ib/II GO40516 study (NCT03671018) is evaluating M in combination with the anti-CD79b antibody-drug conjugate polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). In the ongoing Phase II part of the study, M-Pola showed an acceptable safety profile with promising activity in pts with R/R B-NHL (Budde et al. ASH 2021). Here, we present a subgroup analysis of the efficacy and safety of M-Pola in pts aged <65 and ≥65 years with R/R aggressive B-NHL from the Phase Ib dose-escalation and Phase II dose-expansion cohorts. Methods: All pts in this analysis had DLBCL (including transformed follicular lymphoma and follicular lymphoma grade [Gr] IIIB), an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and ≥1 prior line of therapy, including an anti-CD20 Ab. Treatment cycles were 21 days. Pola (1.8mg/kg intravenous [IV] infusion) was given on Day (D)1 of Cycle (C)1-6. M (IV infusion) was given with step-up dosing during C1 to mitigate cytokine release syndrome (CRS), and the recommended Phase II dose was used in the Phase II dose-expansion cohort (1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3-8). Pts with stable disease or a partial response at the end of C8 could continue M for a total of 17 cycles, while pts with a complete response (CR) discontinued M after C8. In the Phase II expansion cohort, mandatory hospitalization was not required for M administration. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of March 15, 2021, with a median follow-up of 5.3 months (range: 0.7-23.7 months), 60 pts with R/R DLBCL had received M-Pola: 24 (40%) were aged <65 years and 36 (60%) were aged ≥65 years. At study entry, for pts aged ≥65 years, the median age was 73 years (range: 65-83), 53% had ECOG PS 1 and 8% had PS 2, 50% had International Prognostic Index 3-5, 81% had Ann Arbor stage III/IV disease, and 81% and 72% were refractory to a prior anti-CD20 Ab and to last prior therapy, respectively. There were more pts <65 years than pts ≥65 years with high lactate dehydrogenase (LDH; 63% vs 44%, respectively), with ≥3 prior lines of therapy (67% vs 56%), and refractory to CAR T-cell therapy (38% vs 25%; Table). Compared with younger pts, those aged ≥65 years had a numerically higher ORR (72% [95% CI: 55-86] vs 54% [95% CI: 33-75]) and CR rate (56% [95% CI: 38-72] vs 38% [95% CI: 19-59]). The rate of Gr 3-4 adverse events (AEs) was lower in pts ≥65 years than in those <65 years (39% vs 58%, respectively), with fewer neutropenia events occurring (14% vs 33%); the rate of serious AEs of any Gr was similar (39% vs 33%). Five pts ≥65 years discontinued M and/or Pola due to treatment-related AEs compared with one pt <65 years. The rate of CRS was comparable in pts aged ≥65 and <65 years (17% vs 21%), all CRS events were low-Gr (≥65 vs <65 years: Gr 1, 14% vs 21%; Gr 2, 3% vs 0%), and all CRS events resolved. Rates of serious AEs of infection were comparable in pts aged ≥65 and <65 years (11% vs 17%, respectively). Rates of peripheral neuropathy were 42% in pts aged ≥65 years vs 21% in pts aged <65 years, with most events Gr1-2 (≥65 vs <65 years: 1 vs 2 Gr 3 events). After the first M-Pola dose, pharmacodynamic changes in interferon-α and T-cell activation in peripheral blood were similar across age groups. Conclusions: M-Pola is effective and has a manageable safety profile in pts with heavily pretreated DLBCL, including older pts who may have more comorbidities and fewer treatment options, such as those who are poor candidates for CAR T-cell therapy. Numerically higher ORR and CR rates were seen in pts aged ≥65 years, although longer follow-up is required. Comparable rates of CRS and serious AEs were observed across age groups. Enrollment in the Phase II study with no mandatory hospitalization is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma

Background: New treatment options are needed for patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), especially those with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. In a retrospective cohort study of 114 patients with MCL who had PD while receiving ibrutinib, median OS upon ending ibrutinib treatment was 2.9 months (95% CI: 1.6-4.9; Martin et al. Blood 2016). The CD20xCD3 T-cell-engaging bispecific monoclonal antibody, glofitamab, has a novel 2:1 (CD20:CD3) configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Obinutuzumab pretreatment (Gpt) is given 7 days prior to the first dose of glofitamab to mitigate the risk of cytokine release syndrome (CRS). Phase I/II (NCT03075696) data for glofitamab monotherapy with step-up dosing (SUD) and Gpt (1000mg or 2000mg) have shown high response rates and manageable, mostly low-grade CRS in patients with R/R MCL, most of whom had prior BTKi therapy (Phillips et al. ASH 2021). Here, we report on the durability of response with glofitamab SUD in a larger cohort with additional follow up. Methods: All patients received Gpt 7 days before the first dose of glofitamab. Intravenous glofitamab SUD was given on Days (D) 8 (2.5mg) and 15 (10mg) of Cycle (C) 1, then at the target dose (16mg or 30mg after 1000mg Gpt; 30mg after 2000mg Gpt) from C2D1, every 3 weeks for up to 12 cycles. Response rates were assessed by Lugano criteria (Cheson et al. JCO 2014). Results: As of March 14, 2022, 37 patients had received glofitamab SUD after Gpt (1000mg Gpt, n=16; 2000mg Gpt, n=21). Median age was 72.0 years (range: 41-84), 73.0% of patients were male, 91.9% had Ann Arbor Stage III/IV disease and 32.4% had MCL IPI score ≥6 at study entry. Median prior lines of therapy was three (range: 1-5); 24 (64.9%) patients had prior BTKi therapy and seven (18.9%) had prior lenalidomide therapy. The majority of patients were refractory to their first line of therapy (62.2%; n=23) and/or their last prior therapy (73.0%; n=27). Median time since last therapy was 1.9 months (range: 0.1-107.5). After a median follow up of 8 months (range: 0-19), overall response rate (ORR) and complete response (CR) rates were 83.8% (31/37) and 73.0% (27/37), respectively, across both Gpt cohorts. In the 2000mg Gpt cohort, ORR and CR rates were 90.5% (19/21) and 81.0% (17/21), respectively. In the 1000mg Gpt cohort, ORR and CR rates were 75.0% (12/16) and 62.5% (10/16), respectively. Across both Gpt cohorts, median time to CR was 51 days. The majority of CRs (20/27; 74.1%) were ongoing at the data cut-off and an estimated 71.6% of patients with a CR remained in response at 9 months. Median duration of response was 12.6 months (95% CI: 10.0-NE) and median duration of CR was 10.0 months (95% CI: 4.9-NE). The two deaths that occurred after 10 months were due to COVID-19 (Figure). In safety-evaluable patients (n=37), the most common adverse events (AEs) were CRS (75.7%; by ASTCT criteria) and neutropenia (40.5%). CRS rates were lower in the 2000mg Gpt (14/21; 66.7%) vs the 1000mg Gpt (14/16; 87.5%) cohort. CRS events in the 2000mg Gpt cohort were all Grade (Gr) 1-3 (Gr 1, 33.3%; Gr 2, 23.8%; Gr 3, 9.5%), whereas there were two Gr 4 CRS events in the 1000mg Gpt cohort (Gr 1, 25.0%; Gr 2, 37.5%; Gr 3, 12.5%; Gr 4, 12.5%). All CRS events were manageable (17 patients received tocilizumab to manage CRS) and most resolved by data cut-off (one patient had ongoing CRS at the time of analysis). Neurologic AEs (NAEs) occurred in 19 patients (51.4%); all were Gr 1/2 except for one Gr 3 subdural hematoma in the 2000mg Gpt cohort. NAEs consistent with immune effector cell-associated neurotoxicity syndrome following glofitamab administration occurred in five patients (13.5%, all Gr 1/2 and nonserious). Tumor flare events occurred in five patients (13.5%, all Gr 1/2). No patients discontinued treatment due to AEs. Ten deaths were reported and considered unrelated to study treatment: PD, n=5; AEs, n=5 (COVID-19/pneumonia, n=4; cardiac arrest, n=1). Conclusions: Fixed-duration glofitamab monotherapy after Gpt (1000mg or 2000mg) induced high and durable CR rates, the majority of which were achieved early, in heavily pretreated patients with MCL, most of whom had prior BTKi therapy and thus a particularly poor prognosis. CRS events were manageable and mostly low grade. This is one of the largest datasets and longest follow-ups reported with a CD20xCD3 bispecific monoclonal antibody for patients with R/R MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Baseline CRP and Ferritin Identify Patients at High Risk of Poor Outcomes after Axicabtagene Ciloleucel Despite Corticosteroid Prophylaxis

Introduction: We and others have reported the role of cytokines and the tumor microenvironment on the development of severe grade >3 toxicities and CAR T resistance in recipients of CD19 targeted therapy. However, these analyses are not readily available outside of research settings. Early intervention and prophylactic strategies with cytokine blocking agents and/or steroids to mitigate severe toxicity have been explored. In a recent analysis of cohort 6 of the ZUMA-1 trial, investigators reported improved rates of severe toxicity with the prophylactic use of dexamethasone (Oluwole OO, Br J Haematol 2021). There is limited data on which patients benefit the most from such strategies. Methods: This is a study to evaluate factors associated with the development of severe immune mediated toxicities and treatment resistance in patients with R/R DLBCL treated with standard of care axicabtagene ciloleucel (axi-cel) at Moffitt Cancer Center. Baseline samples of CRP, LDH and ferritin were collected within one week prior to lymphodepleting chemotherapy. Cytokine analyses were performed as previously described (Faramand R, CCR 2020). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on ASTCT criteria. Patients were stratified into three risk groups based on baseline CRP and ferritin; low risk (CRP <4gm/dL and ferritin <400ng/dL), intermediate (not meeting criteria for high risk or low risk), and high risk (CRP >4gm/dL and ferritin >400ng/dL). During the study period, institutional clinical standards were revised to administer prophylactic corticosteroids consecutively to all patients meeting high risk criteria. Patient survival outcomes were compared using Kaplan-Meier curves and subsequent log-rank tests. Multivariable Cox proportional hazards regression model with adjustment for clinical covariates was used to estimate hazard ratios for survival outcomes. Results: 136 patients with R/R DLBCL treated with axi-cel (>2 lines of therapy) are included in this study. Baseline patient characteristics and outcomes are summarized in Table 1. Most patients developed CRS (n=126) with 10.3% developing severe (gr. >3) CRS. Eighty-three patients (61%) developed ICANS with 28% having severe gr. >3 toxicity. The median overall survival (OS) was 34.9 months with a median progression free survival (PFS) of 12.2 months. We previously reported association of baseline elevated IL6 levels with poor clinical outcomes. Baseline IL6 levels correlated (p<0.0001, Fig. 1A) with risk category based on CRP and ferritin. Rates of severe CRS (25.9 vs. 1.61%, p=0.001) and ICANS ( 51.9 vs. 16.1%, p=0.002) were significantly higher in the high-risk (HR) group in comparison to the low risk group. Median PFS was 3 months, 7.9 and not reached in the high, intermediate and low risk groups respectively (p=0.0001) (Fig. 1B). The median OS was significantly inferior in the HR group at 6.9 months compared to 14.9 months and not reached in the intermediate and low groups respectively (p<0.0001) (Fig. 1C). Based on the above risk stratification, ten additional patients met HR criteria and were treated with prophylactic dexamethasone for three days starting on the day of CAR T cell infusion. Although most patients (90%) developed CRS, none developed severe CRS in the prophylactic steroids group which compares favorably to 25.9% observed in historical HR patients who did not receive prophylactic steroids (p=0.16). Severe ICANS was lower (30%) in the prophylactic cohort as compared to 52% in historical HR patients (p=0.29). The median PFS and OS were 2.9 and 5.9 months respectively in recipients of prophylactic steroids. Discussion: We establish that baseline elevated levels of CRP and Ferritin are associated with severe toxicity, and significantly inferior PFS and OS. Patients in the low risk group have excellent outcomes in terms of toxicity and efficacy using standard treatment paradigms negating the need for steroid prophylaxis and may be considered for outpatient treatment. In this report, prophylactic steroids were only used in 10 patients meeting high risk criteria. While there were no cases of severe CRS, efficacy outcomes remained poor in this high-risk cohort despite steroid prophylaxis. High risk patients can be easily identified prior to treatment with CAR T using standard labs and are encouraged to enroll on clinical trials to improve outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Efficacy of BCMA-Targeted CAR-T Therapy in Geriatric Patients with Multiple Myeloma

Introduction: Risks of B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR-T) therapy for patients with multiple myeloma (MM) include cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS), and infections. Geriatric patients with MM are at higher risk of infections (Blimark 2015), and pre-existing comorbidities may complicate CRS and ICANS in older patients. While progression-free survival (PFS) was similar in older vs younger patients in the KarMMa trial of idecabtagene vicleucel (Berdeja 2020), BCMA CAR-T outcomes in the geriatric setting - including the risks of prolonged cytopenias, hypogammaglobulinemia, and infections - have not yet been analyzed. Methods: We analyzed all patients with MM who received any autologous BCMA CAR-T therapy from January 2017 - June 2022 at our institution. Key endpoints included CRS and ICANS incidence (American Society for Transplantation and Cellular Therapy criteria), days to absolute neutrophil count (ANC) recovery, incidence of hypogammaglobulinemia (IgG < 400 mg/dL), confirmed infections within 30 days of CAR-T infusion, response rates, time to measurable residual disease (MRD) negativity, PFS, and overall survival (OS). Characteristics were compared between older patients (age ≥70 at infusion) and younger patients using Fisher's & Kruskal-Wallis tests as appropriate. PFS and OS were compared using log-rank tests. Results: Of 77 analyzed patients (age range 33-77), 19 (25%) were aged ≥70. Gender, weight, performance status, years since diagnosis, presence of extramedullary disease, bone marrow plasma cell burden, high-risk cytogenetics, prior lines of therapy, and triple-class refractory status were similar between older and younger patients. Despite similar weights, older patients had lower Cockcroft-Gault creatinine clearances (median 69.2 vs 92.5 mL/min, p<0.001) and were more likely to receive reduced-dose fludarabine as part of lymphodepletion (53% vs 17%, p<0.01). Rates of any-grade CRS (79% vs 79%), rates of any-grade ICANS (11% vs 10%), and median days to ANC recovery (14.0 vs 13.5) were similar between older and younger patients. Rates of baseline hypogammaglobulinemia were 32% in older patients vs 28% in younger patients (p=0.77), while post-infusion hypogammaglobulinemia occurred in 84% vs 71%, respectively (p=0.36). Six infections occurred before Day +30, all in the younger cohort: rhinovirus (n=2), Staphylococcus epidermidis (n=2), CMV reactivation (n=1), and COVID-19 (n=1). There were two deaths before Day +100, both due to progressive MM in younger patients. Overall response rates (84% vs 90%) were similar between older and younger patients. Median PFS (Figure 1A) was not reached (NR) in older patients (95% CI 10.6-NR) vs 13.1 months in younger patients (95% CI 9.4-33.1), with p=0.19. Median OS (Figure 1B) was NR in older patients (95% CI NR-NR) vs 30.0 months (95% CI 24.8-NR) in younger patients, with p=0.05. Two-year survival probabilities were 93% vs 66%, respectively. Discussion: While limited by small sample size and unmeasured confounders, our retrospective analysis did not demonstrate significant increases in CAR-T toxicity among patients aged ≥70. Differences in rates of hypogammaglobulinemia between older and younger patients did not reach statistical significance. Fludarabine dose reductions during lymphodepletion (as expected with age-adjusted creatinine clearances) did not impair CAR-T efficacy among geriatric patients. Older patients paradoxically had a significantly better OS compared to younger patients, which may have been due to selection bias in favor of disproportionately healthy geriatric patients with regard to CAR-T candidacy. Overall, our data suggest that BCMA CAR-T is a safe and effective option for older patients with MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Results from a Phase 1/2 Study of Tandem, Bispecific Anti-CD20/Anti-CD19 (LV20.19) CAR T-Cells for Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with variable clinical course. The disease is characterized by presence of t(11;14) and bright CD20 expression. While frontline immunochemotherapy plus autologous hematopoietic cell transplant (HCT) has improved progression-free survival, invariably MCL patients (pts) relapse. Approved CD19 CAR T-cell therapy for relapsed/refractory (R/R) MCL provides durable disease control but is limited by high rates of Grade 3+ cytokine release syndrome (CRS) and neurological events with 15% and 31% of pts experiencing such toxicities. We hypothesized that bispecific, tandem, lentiviral CAR-T cell targeting both CD20 and CD19 B-cell antigens (LV20.19 CAR) with 4-1BB co-stimulatory signaling will improve clinical outcomes in R/R MCL and that expansion in IL7 and IL15 would produce less "exhausted” CAR product with more durable clinical activity. Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. We report below outcomes from a Phase 1/2 cohort of MCL pts. LV20.19 CAR T-cells were manufactured onsite in the CliniMACS Prodigy device with IL7+15 for cell expansion with goal of fresh infusion at varying lengths of manufacturing (8 vs 12 days). After safety run-in, we opened a 14 patient single stage Phase II arm with flexible 8/12-day manufacturing with fresh infusion for MCL pts. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method and differences between groups were evaluated via log-rank test. Results: To date, 10 MCL pts have received LV20.19 CAR T-cells at the specified dose of 2.5x10e6 cells/kg (Phase 1=3 pts and Phase 2=7 pts). 8 of 10 pts received 8-day manufactured CAR-T cells whereas two pts received a 12-day product in the Phase 1 cohort. Manufacturing was successful in 100% of pts and all received a fresh (non-cryopreserved) product. Median age was 62 years and median prior lines of therapy were 4 (range: 3-8). Three pts progressed after prior autologous HCT and 2 pts progressed after prior allogeneic HCT. Eight of 10 pts had progressed on a Bruton's Tyrosine Kinase inhibitor (BTKi) and 4 of these pts had additionally progressed on a non-covalent BTKi (pirtorbrutinib) administered on a clinical trial (Table 1). LV20.19 CAR T-cells produced in the CliniMACS Prodigy with IL-7/IL-15 had robust expansion with mean 5.4x10e8 CAR T-cells obtained on Day 7 of manufacturing. CAR T-cells from pts mostly consisted of central-memory and effector-memory phenotype T-cells with robust in-vivo expansion typically starting Day +4 after infusion. The Day 28 ORR was 100% (CR=60% and PR=40%). 7 of 9 pts with MRD assessed between Day 28-60 post CAR were negative. No patient has relapsed with a median follow-up of 18 months of among surviving pts. Regarding toxicity, all 10 pts (100%) had Grade 1-2 CRS (no grade 3+ events). Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 2 pts with one patient experiencing Grade 2 and the other Grade 3 toxicity. The patient with Grade 3 ICANS experienced a non-relapse mortality event due to gram negative sepsis after Day 28 evaluation. At 1-year the cumulative incidence of relapse and NRM were 0% and 10%, respectively while the 1-year PFS and OS were 90% each (Figure 1). Conclusions: Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R MCL with ORR 100%, no relapses with a median follow-up of >1.5 years, and no Grade 3+ CRS and low rates of Grade 3+ ICANS (10%). All pts on the Phase II arm had CAR T-cells manufactured on-site utilizing an 8-day platform with fresh CAR T-cell infusion and lymphodepletion starting during manufacturing. Dual targeting of CD19 and CD20 with CAR-T cells may improve outcomes in pts with relapsed, refractory MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Siltuximab for First-Line Treatment of Cytokine Release Syndrome: A Response to the National Shortage of Tocilizumab

Introduction Chimeric antigen receptor T (CAR T) cells targeting CD19 and BCMA are active in the treatment of B cell lymphoid malignancies. CAR T cell therapy can be complicated by cytokine release syndrome (CRS), a syndrome characterized by systemic inflammatory response, in which interleukin (IL) -6 plays a central role. Tocilizumab is a monoclonal antibody targeting the IL-6 receptor and is recommended for treatment of CRS. A national shortage of tocilizumab occurred in 2021. In order to conserve supply and continue providing CAR T cell therapy, our center replaced tocilizumab with siltuximab in our CRS management algorithm. Siltuximab is a monoclonal antibody that binds to IL-6 itself. We report the outcomes of patients treated with this "siltuximab-first” (SF) approach in comparison with patients treated with a "tocilizumab-first” (TF) based approach. Methods We conducted a retrospective review of patients treated with CAR T cells for lymphoma and multiple myeloma. Baseline characteristics and outcomes were collected from the transplant and cellular therapy database and medical records. CRS was graded according to the Lee scale and immune effector cell-associated neurotoxicity syndrome (ICANS) was graded according to the CAR T cell toxicity management grading system. At our center, anti-IL-6 therapy is utilized for grade 2 or greater CRS, or persistent grade 1 per provider discretion. The length of stay for CAR T hospitalization was measured from the day of CAR T cell infusion. Comparisons between groups were done using Fisher's exact test for nominal variables and Kruskal-Wallis rank sum test for continuous variables. All analyses were done using R and its packages. Results We identified 135 patients treated with CAR T cell therapy. Baseline characteristics are listed in Table 1. The majority of patients received treatment for relapsed or refractory B cell non Hodgkin lymphoma (NHL). CRS was observed in 95 (70.4%) patients, 44 (32.5%) had grade ≥ 2 CRS. Patients treated with the SF and TF protocols had comparable rates of CRS (SF = 67.5% vs. TF = 71.6%, p = 0.68) as well as grade ≥ 2 CRS (SF = 27.5% vs. TF = 33.3%, p = 0.54). Fifty one (37.8%) patients developed neurotoxicity, 23 (17%) grade ≥ 2, without differences between groups. Anti-IL-6 therapy was prescribed to 60 (44.4%) patients, without significant differences between groups (SF = 47.5% vs. TF = 43.2%, p = 0.71). The median number of doses of cytokine blocking agents was 1 (IQR 1 - 2), without a significant difference between groups. A larger proportion of patients with MM were treated using the SF CRS protocol (37.5% vs. 10.5%, p <0.001). Fourteen out of 19 patients (73.7%) treated with SF required only one dose of anti-IL-6 directed therapy, compared with 21/40 (51.2%) patients treated with TF. However, this difference did not reach statistical significance. Seven doses of tocilizumab were used in 5 patients during the period of SF protocol use, primarily due to persistent CRS after an initial dose of siltuximab or physician discretion. Thirty three patients (24.4%) received corticosteroids (inclusive of treatment of neurotoxicity), without differences in the proportions between groups (SF = 25.0% vs. TF= 24.2%, p = 1). Transfer to an intensive care unit (ICU) setting occurred in 14 (10.4%) cases, without significant differences between groups. Median length of stay (LOS) for the entire cohort was 10 days (IQR 7-14). Patients experiencing CRS had longer median LOS (12 vs. 7 days, p <0.001). The median LOS of patients with CRS requiring IL-6 blockade was 10.5 and 14 days for SF and TF, respectively (p = 0.09). Conclusions IL-6 blockade is an effective therapy for CRS. Adoption of a "siltuximab first” protocol in response to the national shortage of tocilizumab showed that the use of this agent is safe and feasible. We did not observe increased use of subsequent doses of anti-IL-6 therapy or steroids, and hospital resource utilization measures such as ICU transfer and LOS were comparable with tocilizumab - based protocols. The larger proportion of MM patients receiving the SF protocol can be attributed to timing of CAR T product approval and tocilizumab shortage. Differences in LOS are likely a result of population and time period differences. While prospective studies in larger numbers of patients may be needed, these results suggest siltuximab is a valid alternative for CRS management in CAR T cell patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal