Rates Of Cytokine Release Syndrome Research Articles

Evaluation of cytokine release syndrome (CRS) in patients with relapsed or refractory multiple myeloma (RRMM) receiving step-up priming doses and longer dosing intervals of elranatamab: MagnetisMM-9.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (>1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]

Patterns of CRS with teclistamab in relapsed/refractory multiple myeloma with or without prior T-cell redirection therapy

AbstractTeclistamab (Tec) is a first-in-class BCMA × CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the 2 cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n = 10) compared with cohort 2 (80%, n = 36; P = .0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a fourfold increase in the incidence of CRS (95% confidence interval, 1.40-14.90; P = .0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.

Cladribine and Cyclophosphamide Lymphodepletion Prior to Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma

Introduction : Chemotherapy-based lymphodepletion (LD) with fludarabine and cyclophosphamide (Flu/Cy) is a standard preparatory step for chimeric antigen T-cell (CAR T) therapy and its importance for optimal CAR T expansion and efficacy is well-established. An international Flu shortage required our center and others to utilize alternative agents for LD or risk interruption in patient therapy. When unable to utilize Flu as part of the LD regimen for patients with relapsed/refractory large B-cell lymphoma (RR LBCL) that required CD19-directed CAR T as a standard of care therapy, our center adopted a standard operating procedure to substitute Flu with Cladribine (Clad), an alternate purine analogue with similar chemical structure, as part of Clad/Cy LD prior to axicabtagene ciloleucel (axi-cel). Here we report outcomes in these patients. Methods : We performed a retrospective, single-center analysis of consecutive RR LBCL patients who received Clad/Cy LD prior to axi-cel at Moffitt Cancer Center between 8/2022 and 1/2023, and compared outcomes to a historical cohort, consisting of 144 Flu/Cy axi-cel LBCL patients treated between 11/2017 and 2/2021. The Clad/Cy LD regimen, given as standard care, maintained Cy at 500 mg/m 2 and substituted Flu 30 mg/m 2 with Clad 5 mg/m 2/day with both agents given on Days -5, -4, and -3. For efficacy we compared best overall response (BOR) at 90 days and progression-free survival (PFS) comparing the two LD regimens. For safety we compared the rates of cytokine release syndrome (CRS) and neurotoxicity as graded by ASTCT criteria. We also performed correlative analyses exploring absolute lymphocyte count (ALC) kinetics, axi-cel expansion by quantitative PCR, and changes in the cytokine milieu as assessed by the enzyme-linked immunosorbent Ella™ system (Bio-Techne, Oxford, UK) at serial time points following infusion. Results : 23 patients received Clad/Cy LD followed by axi-cel for R/R DLBCL. Baseline characteristics of the study cohort based on LD are shown in the Table. Compared to the historical cohort, Clad/Cy patients received axi-cel after fewer lines of treatment (median 2 [range, 1-3] vs 2 [range, 1-7]; Rank-Sum test p<0.01) and had a greater proportion of relapsed (not refractory) disease (52% vs 22%, p<0.01). The 90-day BOR did not differ between the Clad/Cy and Flu/Cy groups (79% vs 84%; P=0.54) with a similar distribution of complete (22% vs 24%) and partial responders (57% vs 60%). With a median follow-up of 4.6 (95% CI, 3.2-6.2) months for Clad/Cy and 24.2 (95% CI, 21.5-25.8) months for Flu/Cy cohorts, PFS was similar (Figure 1B, Log-Rank p=0.84). Rates of CRS grade ≥ 2 were higher in the Clad/Cy cohort (70% vs 44%; p=0.02), but no CRS grade ≥ 3 was observed in the Clad/Cy compared to 13 (9%) of Flu/Cy patients, including three grade 5 events. Neurotoxicity ≥ grade 2 (44% vs 43%; p=0.77) and peak C-reactive protein levels (15 vs Flu/Cy 12; p=0.3) did not differ for the Clad/Cy and Flu/Cy cohorts. Both regimens had comparable peak axi-cel copy numbers (Clad/Cy 7.9 × 10 6 vs Flu/Cy 5.1 × 10 6 copies/µg). Clad/Cy resulted in a predictable decrease in the ALC from Day -5 to Day 0, but a less profound degree of lymphopenia on Day 0 (0.04 vs 0.02; p<0.01) with ALC 0 achieved later (Day +2 [IQR, +1 to +4] vs Day +1 [IQR, -1 to +2] for Flu/Cy). The median magnitude of change of cytokine levels (Delta = Day -5 - Day 0 concentration) differed between Clad/Cy and Flu/Cy for all tested analytes except IL-6 (3.4 vs 4.6 pg/mL for Flu/Cy; p=0.29). Clad/Cy resulted in greater increases in IL-2 (0.5 vs 0.2 for Flu/Cy; p=0.01) and GM-CSF (2.0 vs 0.9 for Flu/Cy; p=0.03), whereas Flu/Cy had higher IL-15 (31.4 vs 16.8 for Clad/Cy; p<0.01). Interestingly, IFN-γ tended to increase in Clad/Cy and to decrease in Flu/Cy (1.2 vs 0.0; p=0.01). Conclusions : Clad/Cy LD is feasible for axi-cel conditioning in the treatment of RR LBCL. Although it resulted in less profound LD on the day of CAR T infusion, a later ALC nadir, and a different cytokine milieu compared to Flu/Cy, it was associated with similar peak axi-cel expansion and, at short term follow-up, there appears to be similar initial efficacy and toxicity. Future analyses focusing on response durability and long-term toxicities such as infections and post-CAR T cytopenias are warranted.

Flat Dose Intravenous Immunoglobulin Primary Infection Prophylaxis in Multiple Myeloma Patients on Bispecific Antibody Therapy: Vanderbilt Experience

BACKGROUND Bispecific antibodies (BsAbs) are novel immunotherapeutic agents with prolific anti-multiple myeloma (MM) efficacy in highly relapsed/refractory disease (RRMM). They have been associated with profound and prolonged hypogammaglobinemia which represents a unique challenge regarding increased risk of serious (sometimes fatal) infections. Though IVIG has historically been dosed at 0.4g/kg for secondary prophylaxis, there is still uncertainty in optimal timing, schedule and frequency of supplementation in MM patients. At Vanderbilt University Medical Center, we have adopted a flat dose 10g IVIG prophylaxis schedule, which on average delivers ~36% of historical, weight-based dosing. At present, expert recommendations advise IVIG replacement every 4 weeks in recipients of BsAb starting the second month of therapy and continuing until the end of therapy or until serum IgG levels reach > 400 mg/dL, whichever is longer ( Mohan M et al. Br J Haematol.2023;00:1-11). Considering that MM BsAbs are currently used with continued dosing schedule, adoption and anticipated new BsAb approvals are increasing, IVIG has previously been on national/global shortage (occasionally unavailable), IVIG replacement during hypogammaglobulinemia represents a crucial aspect of adequate infection prophylaxis in MM, we explored the impact of our institutional 10g IVIG prophylaxis on infection rates in RRMM patients receiving BsAbs. Prior studies with comparable BsAbs reported Grade (G) ≥3 infection rate of 32-45% and 18%, in anti-BCMA and anti-GPRC5D BsAbs, respectively. In these trials, overall, 14-53% of patients received IVIG prophylaxis. METHODS We performed a retrospective review using electronic medical record of RRMM patients receiving anti-BCMA or anti-GPRC5D BsAbs from Jan 2019 to Dec 2022, either on clinical trials or as a standard of care at our institution. The inclusion criteria were minimum of two months of BsAb therapy, and the use of at least one month of monthly IVIG prophylaxis for serum IgG < 400 mg/dL. All patients were also on baseline valacyclovir, trimethoprim-sulfamethoxazole and levofloxacin prophylaxis. Routine disease and treatment specifics as well as infection rates and grades were collected. Infections were defined as mild (infections treated outpatient), moderate (required hospital admission) or severe (hospital admission with intensive care unit level of care), next to also being graded by CTCAE v5 with the rest of hematologic and non-hematologic adverse events (AEs). RESULTS A total of 30 patients with RRMM were identified. Table 1 illustrates the demographic and disease specifics: 79% received a median (range) of 4 (2-7) lines of prior therapy, over half were penta-class exposed, 27% were triple and quad refractory, 67% received a prior autologous stem cell transplant and 17% underwent prior treatment with BCMA targeting CAR-T therapy. All except 2 patients received BsAb therapy on clinical trials. Anti-GPRC5D BsAb was used to treat 60% of patients, while the rest (40%) received anti-BCMA BsAb, all of which were given for a median of 27 (12-45) months (Table 1). Overall, 30% of patients had one infectious episode, while 43% had ≥2. Viral infections (57%) were twice as common as bacterial (30%) (Table 2). Infections were mild in 60%, moderate in 23%, and severe in 6.6% of patients. We observed 27% rate of G ≥3 infectious complications. Patients had a median (range) IgG at diagnosis of 1284(196-5431), and 499(210-2246) at the time of onset of first infection (IgG values at the start of BsAb therapy, at first and at ≥2 infections are outlined in Table 2). The rate of G ≥3 neutropenia and lymphopenia was 6.6% and 30% respectively. There were 2 (6.6%) sepsis related deaths, one each with anti-BCMA and anti-GPRC5D BsAbs. Table 2 also describes severity and the rates of cytokine release syndrome and neurotoxicity. CONCLUSIONS We observed relatively lower rate of severe or ≥ G3 infectious events with 10g flat IVIG dosing schedule. While our results represent a small, single-institutional cohort of predominantly anti-GPRC5D treated RRMM patients and require prospective validation in a randomized (IVIG 10g vs 0.4g/kg body weight) fashion, they demonstrate feasibility of reduced level dosing of a critical resource such as IVIG, in the fast expanding, national/global BsAb-based MM armamentarium.

Permissive Cardiotoxicity As a Guiding Principle to CAR-T Therapy with Reduced Ejection Fraction Heart Failure

Introduction: Pivotal CAR-T registrational trials for the six CAR-T therapies currently FDA approved have excluded those with heart failure (HF), defined either by low ejection fraction (EF) or clinical symptoms of HF (NYHA functional classification). This has created a real-world dilemma for clinicians desiring to treat this patient population. There is concern that those with HF may not tolerate the physiologic and hemodynamic stressors associated with cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) and thus have increased risk of severe morbidity or death. The emerging concept of permissive cardiotoxicity seeks to allow for an acceptable level of cardiac toxicity to allow for treatment with highly efficacious but potentially cardiac toxic treatments like CAR-T therapy. To that end, in this study, we provide our real-world, single-institution experience with CAR-T therapy in patients with medically optimized HF with reduced EF (HFrEF) prior to date of apheresis. Methods: This was a retrospective review of 168 (100 B-cell lymphoma and 68 multiple myeloma) CAR-T therapy patients, with 20 (12%) identified with HFrEF of ≤50% prior to apheresis by two-dimensional transthoracic echocardiogram as part of the standard CAR-T screening process and without clinical symptoms of HF at time of apheresis. 19/20 patients received standard of care CAR-T products. This study was conducted following IRB approval. Statistical analysis was done using R version 4.2.3. Kaplan-Meier curves were used to calculate progression free survival(PFS) and overall survival(OS). Results: Twenty patients with HFrEF prior to CAR-T infusion were identified with median EF of 44.1% (range 25-50%) (see Table 1, Baseline Characteristics). The median age was 63.5 (37-82) years-old, predominately male gender (80%), Caucasian (70%), with ECOG of 1 (95%), and 10 patients (50%) received axicabtagene ciloleucel (axi-cel). Most patients received CAR-T for B-cell lymphoma (80%). Cardiac history included 5 (25%) with previous CAD, 1 (5%) with previous PAD, and 4 (20%) with history of atrial fibrillation/flutter. Cardio-Oncology was consulted prior to CAR-T therapy in 10 (50%) and 12 (60%) were optimized on goal-directed therapy (GDT). CKD was pre-existing in 4 (20%) patients. Where measured, all patients had a pre-CAR-T troponin within normal institutional limits (<0.05ng/mL). NT-BNP at baseline was only measured in 6 (30%) patients with a median value of 110pg/mL (49-3200, upper limit of normal 125pg/mL). Longitudinal strain prior to CAR-T was measured in 5 (25%) patients with median value of -16% (-19 to -10%, <-17% normal). There were no cases of grade ≥3 CRS with 3 (15%) grade 1 and 12 (60%) grade 2 CRS (see Table 1, Safety Outcomes). There were 4 (20%) with grade 3 ICANS, although most patients 12 (60%) did not experience ICANS. Compared to ZUMA-1, the 10 patients receiving axi-cel did not have significantly higher rates of CRS or ICANS. Tocilizumab was administered in 15 (75%) of patients and steroids given in 10 (50%) of patients. Following CAR-T infusion, 11 (55%) of patients required ICU admission, no patients required vasopressors, 6 (30%) experienced an AKI, 2 (10%) had LFT abnormalities, 4 (20%) had an arrhythmia, and 5 (25%) had further decline in EF with recovery occurring in most cases where measured. Only 2 (10%) of patients had an HF exacerbation within 30 days of CAR-T infusion. PFS and OS were 11.3 and 26 months, respectively. Conclusion: Given that all registrational CAR-T trials excluded HF, notable reservation exists among clinicians in the use of CAR-T therapy in patients with a history of HF and particularly HFrEF. In our institutional experience of 20 patients with good performance status and medically optimized on GDT, we demonstrate that CAR-T therapy can be given safely with rates of CRS and ICANS similar to that expected in the non-HF population. Additionally, while ICU utilization was high, the incidence of arrhythmias, renal or hepatic toxicity as indicators of end organ dysfunction, non-recovering EF decline, and heart failure exacerbation following CAR-T infusion were quite low. It is thus our practice to consider CAR-T therapy on a case by case basis in those with a history of HFrEF. The key to success being maximal cardiac optimization achieved through early engagement of our Cardio-Oncology colleagues based upon the concept of permissive cardiotoxicity.

An Economic Model to Estimate Costs of Cytokine Release Syndrome and Neurological Events Among Patients Treated with CAR T Cell Therapies for Relapsed or Refractory Follicular Lymphoma

Background: CAR T cell therapies have exhibited promising clinical responses in populations that are traditionally challenging to treat. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are 2 CAR T cell therapies now available in the United States (US) for the treatment of R/R follicular lymphoma (FL) after 2 or more lines of systemic therapy. Lisocabtagene maraleucel (liso-cel) is currently being investigated in clinical trials for the treatment of patients with R/R second-line high-risk and third line or later FL. As observed in other approved indications, the improved response and survival rates from the introduction of CAR T cell therapies are typically accompanied by the potential for AEs, such as cytokine release syndrome (CRS) and neurological events (NEs). However, the rates and severity of these AEs tend to vary across CAR T cell therapies. Understanding the economic implications of these 3 CAR T cell therapies and their associated AEs is crucial for informed decision-making and to underscore key economic and safety differences across the 3 CAR T cell therapies. The primary objective of this analysis was to estimate the average per-patient weighted costs of CRS and NEs for a patient with R/R FL treated with a CAR T cell therapy (liso-cel, axi-cel, or tisa-cel) based on clinical trial rates. Secondary objectives included estimates for (1) the opportunity cost of treating with axi-cel or tisa-cel versus liso-cel and (2) the additional number of patients eligible for treatment with liso-cel based on a hypothetical sample of 100 treated patients. Methods: An economic model was developed using data from the TRANSCEND FL (NCT04245839; n = 130), ZUMA-5 (NCT03105336; n = 124), and ELARA (NCT03568461; n = 97) studies. CRS and NE rates reported in the FL studies were incorporated in a decision analytic economic model to estimate costs from a health care system perspective in 2023 US dollars. Microcosting analysis data from the TRANSCEND FL study were used as CRS and NE cost inputs; the model assumed that CRS and NE management costs across CAR T cell therapies would not differ. The analysis used a Monte Carlo simulation approach to address uncertainty surrounding the clinical and economic data. The model output was a weighted average that represented cost for the average treated patient, including those with and without CRS and/or NEs. The average per-patient total cost difference between CAR T cell therapies was used to estimate the number of additional patients who could be treated with liso-cel versus axi-cel or tisa-cel. Results: Rates of CRS grade 1‒2/≥ 3 were 56.9/0.8% for liso-cel, 71.8%/6.5% for axi-cel, and 48.5%/0.0% for tisa-cel. Rates of NE grade 1‒2/≥ 3 were 13.1%/2.3% for liso-cel, 41.1%/ 15.3% for axi-cel, and 34.0%/ 3.1% for tisa-cel. The overall per-patient weighted average costs for CRS and NEs were estimated to be $20,626 for liso-cel, $44,096 for axi-cel, and $26,460 for tisa-cel (Figure). The per-patient weighted average cost per CRS event was $14,631 for liso-cel, $21,299 for axi-cel, and $12,456 for tisa-cel. The per-patient weighted average cost per NE was $5994, $22,797, and $14,004 for liso-cel, axi-cel, and tisa-cel, respectively. Total per-patient cost differences for liso-cel compared with axi-cel and tisa-cel were −$23,470 and −$5835, respectively. The resulting opportunity costs from treating 100 patients with liso-cel instead of axi-cel and tisa-cel would allow for the treatment of an additional 5.2 and 1.3 patients, respectively. Conclusions: This economic analysis revealed lower overall per-patient weighted average costs associated with liso-cel compared with axi-cel and tisa-cel, primarily due to lower CRS and NE rates versus axi-cel and lower NE rates versus tisa-cel. In comparison with axi-cel and tisa-cel, liso-cel demonstrated robust economic and clinical value, with lower rates of CRS and/or NEs associated with substantial cost savings per AE event.

Axicabtagene Ciloleucel in Patients Aged 75 and Older: A Retrospective Cohort Study

Background The treatment of older patients with relapsed/refractory (R/R) aggressive non-Hodgkin B-cell lymphomas (NHL) remains a significant clinical challenge. Chimeric antigen receptor T-cell (CAR-T) therapy represents a potentially curative option, but elderly patients remain underrepresented in relevant clinical trials, and less is known about the safety of CAR-T among patients older than 75 years. Toxicities including cytokine release syndrome (CRS), neurotoxicity (ICANS), arrhythmias, renal failure, and cytopenias may pose higher risk in elderly patients with comorbidities and decreased physiologic reserve compared to younger CAR-T recipients. We sought to characterize outcomes and toxicities of axicabtagene ciloleucel (axi-cel) in a cohort of patients aged ≥ 75 years. Methods This was a retrospective analysis of consecutive patients aged ≥ 75 years with R/R NHL who received axi-cel at New York-Presbyterian/Weill Cornell Medical Center. Data collected included patient characteristics and outcomes including response rates, event-free and overall survival, rates of CRS, ICANS, arrhythmias and severe cytopenias, and length of hospital stay. CRS and ICANS severity were graded following the ASTCT consensus criteria. Cytopenias were graded as per NCI-CTCAE v5.0. Event free survival (EFS) was defined as time to disease progression or death. Results We identified 15 patients with a median age of 78 (range 75-87) years; 6 (40%) were ≥ 80 years of age. 14 patients had a diagnosis of large B-cell lymphoma and 1 had multiply relapsed follicular lymphoma. Ten patients (67%) had received 3 or more prior lines of therapy. Additional baseline characteristics are summarized in Table 1. Among 10 patients (67%) who developed CRS of any grade, only 1 (7%) experienced grade ≥3 CRS; this CRS event was fatal. Five (33%) patients developed ICANS with only 1 patient (7%) developing grade ≥3 ICANS. Two (13%) patients and 10 (67%) patients developed grades 3 and 4 cytopenias within 30 days of infusion, respectively. Four (27%) patients required blood or platelet transfusions within 100 days of infusion. Febrile neutropenia was seen in 8 (53%) patients, and 8 patients had culture or PCR-verified bacterial (33%), viral (40%), or fungal (7%) infections. Only 1 (7%) patient developed a new abnormality on EKG within 30 days of infusion (right ventricular conduction delay). Median length of inpatient stay was 17 days (range 13-35), and 2 (13%) required re-hospitalization within 100 days of infusion. Overall and complete response rates at 100 days post-infusion were 13 (86%) and 11 (73%), respectively. At one year, overall and event-free survival were 72.2% (95% CI: 54.4-99.6%) and 53.3% (95% CI: 33.2%-85.6%), respectively. The median overall survival was 30.8 months with a median follow-up of 21.4 months. One patient experienced treatment-related mortality due to CRS, and 5 (33%) had subsequent disease relapse. Conclusion These results suggest that axi-cel is an effective and well-tolerated treatment for patients age ≥ 75 with R/R NHL. Only 1/15 patients developed grade ≥3 CRS or ICANS which is comparable to reported rates of toxicities in younger patients. Although multiple studies have identified cytopenias and cardiac arrhythmias as major CAR-T toxicities, a minority of our cohort required transfusions, and none developed life-threatening arrhythmias. OS and EFS were also comparable to real-world experience seen in younger patients. This study may be limited by the selection of a relatively fit population of elderly patients; however, the median Karnofsky Performance Score was 80 and ranged as low as 60. Overall, these findings show that axi-cel may be an appropriate strategy for relapsed aggressive NHL in carefully selected patients in their eighth and even ninth decades of life.

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 Profile of Brexucabtagene Autoleucel (brexu-cel; CD19-directed CAR T-cell therapy) in Adult Patients (pts) with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from a Multicenter Real-World Outcomes Study

Introduction: In October 2021, the FDA approved brexu-cel for the treatment of adults ≥ 18 years old with R/R B-ALL. Following this approval, a consortium of cancer centers was formed across the US to investigate outcomes following commercial brexu-cel use for adults with R/R B-ALL. One area of interest is the toxicity profile of brexu-cel when given in the real-world context, including the respective incidences and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). Methods: Eligible pts included adults ≥ 18 years old who received commercial brexu-cel starting in October 2021 onward at a participating center in the US (N = 25). Retrospective patient data were collected across participating institutions, with the most recent data lock occurring on June 30, 2023. Criteria from the ASTCT were used to grade CRS and ICANS severity. Statistical methods included the use of medians and simple ratios for descriptive outcomes; univariate logistic regression models were used to assess the association of various factors with the probability of CRS and ICANS, and Cox regression was used to examine the association of each with the hazards of mortality and failure for event-free survival (EFS; earliest of progression, relapse, or death). Results: Key demographics and toxicities are described in Tables 1 and 2 (respectively). Of the 152 pts infused with brexu-cel, 82% (N = 125) developed CRS and 56% (N = 85) developed ICANS. CRS and ICANS did NOT develop in 12% (N = 19). Twenty percent of all pts (N = 31) required ICU-level care for management of CAR-related toxicities, with a median LOS in ICU of 4 days (range 1-79). In univariate models, grade 3+ ICANS was most likely to occur in pts with active disease (≥ 5% marrow blasts and/or EMD) at the time of apheresis (OR 2.63, 1.28-5.38, p = 0.008); a numerical increase for grade 3+ CRS (OR 2.35, 0.69-8, p = 0.17) was seen in pts with active disease at apheresis. Therapies received for these CAR-related toxicities included steroids, tocilizumab (toci), and anakinra (Table 2). Among pts who received steroids (N = 94), 37% (N = 34) achieved a sufficient response to the first steroid trial and did not require subsequent therapies; otherwise, toxicities improved with the first steroid course but later worsened in 16% (N = 15); the first trial of steroids was not effective but improved when further steroids were given in 31% (N = 29); there were no responses to any doses of steroids in 10% (N = 9). In pts receiving toci (N = 103), 31% (N = 32) achieved a sufficient response to the first dose and did not require any further therapy; toxicities improved with the first dose but later worsened in 31% (N = 32); the first dose was ineffective but improvement was seen with subsequent doses in 21% (N = 22); 9% (N = 9) did not respond at all to toci. The rate of death within day +28 was 6% (N = 9), and the respective causes were typically multifactorial: CRS was implicated in 3 cases, ICANS in 3, infection in 5, disease relapse/progression in 2, and HLH in 1 case. In total, uncontrolled ICANS was implicated in the death of 6 pts (between day +9 to day +106). HLH was reported in 6 pts: in most cases, this was a biochemical diagnosis, and it either overlapped with concurrent CRS or infection or occurred following CRS/ICANS. The most common infections between day 0 and day +28 included bacteremia in 8% of pts (N = 12), fungal infections in 4% (N = 6), pneumonia in 3% (N = 5), and CMV infections in 3% (N = 4). The fungal infections included 4 instances of invasive sinopulmonary infections (2 due to aspergillus; 2 due to mucormycosis) and 2 cases of candidemia. With both CRS and ICANS treated as a time-varying covariate, the development of grade 3+ CRS was associated with a higher hazard of death (HR 2.38, 1.00-5.66, p = 0.05); grade 3+ ICANS was not associated with a demonstrably higher risk of death (HR 1.11, 0.60-2.05, p = 0.74). The HR of EFS failure for Grade 3+ CRS was 1.81 (0.87-3.79, p = 0.12) and for grade 3+ ICANS HR = 0.93 (0.56-1.53, p = 0.77). Conclusions: In this real-world study of toxicities from brexu-cel use for adults with R/R B-ALL, we observed CRS and ICANS in the majority of pts, and no new safety signals were observed. Rates of severe CRS and ICANS were more common with active disease. Interestingly, though CRS-related mortality was rare, grade 3+ CRS was associated with a higher risk of death. Efforts to identify mechanisms and mitigable risk factors for these toxicities are warranted.

A Phase II Trial of Prophylactic Anakinra to Prevent Neurotoxicity in Patients Receiving Anti-CD19 CAR T-Cell Therapy for Relapsed or Refractory Lymphoma: Final Results from Cohort 2

Background: Whilst tocilizumab is effective in the management of chimeric antigen receptor T-cell (CAR-T) associated cytokine release syndrome (CRS), there are no targeted therapies for immune effector cell-associated neurotoxicity syndrome (ICANS). Rates of severe (≥ grade 3) ICANS remain high with axicabtagene (axi-cel) and brexucabtagene (brexu-cel) at > 30%. Preclinical models have shown that anakinra, an IL-1 receptor antagonist, reduced CAR-mediated immune toxicities without affecting efficacy. Based on these data, we conducted a phase 2 trial of prophylactic anakinra in patients receiving commercial anti-CD19 CAR-T for r/r B-cell lymphoma (NCT04148430). The study had sequential enrollment in 2 independent cohorts. We recently reported results from cohort 1 in which patients received subcutaneous (SC) anakinra from day 2 until at least day 10 post-CAR infusion and showed that prophylactic anakinra reduced the rate of severe ICANS to 9.7% (Park, Nat Med, 2023). Herein, we report results from cohort 2 of the study where we utilized anakinra as a complete prophylactic strategy. Methods: Adult patients with a diagnosis of r/r large B-cell lymphoma (LBCL), high-grade B-cell lymphoma (HGBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) receiving commercial anti-CD19 CAR-T were enrolled. Patients received SC anakinra 100 mg daily from day 0 for at least 7 d. The frequency of anakinra could be increased up to 100 mg every 6 h, and the duration beyond 7 d for persistent or progressive CRS and ICANS. Tocilizumab and steroid use were allowed for the management of persistent or progressive CRS and ICANS. A baseline and day 5 lumbar puncture were performed for CSF analysis. The primary endpoint was the rate of severe ICANS, graded per the ASTCT criteria. Secondary endpoints included rates of severe CRS, all grade CRS and ICANS, overall response rate (ORR), survival outcomes, and serum and CSF biomarker levels. Results: 37 patients were screened, 31 enrolled, and 30 treated (LBCL=13, HGBCL=6, FL=6, MCL=5). 1 enrolled patient did not proceed with treatment due to COVID-19 infection. The median age of the cohort was 65yrs (range: 24 - 81yrs) and patients received axi-cel (19 pts; 63%), brexu-cel (5 pts; 17%), lisocabtagene (4 pts; 13%) and tisagenlecleucel (2 pts; 7%). Patients received a median 3 prior lines of therapy (range: 1 - 7); 22 (73%) were refractory to their immediate prior therapy; 17 (57%) received bridging therapy and 3 (10%) had active CNS disease at CAR infusion. Pretherapy tumor burden as measured by the median sum of the products of diameters was 1638mm 2 (range: 0 - 21,570mm 2). All patients started anakinra on day 0. Anakinra administration was increased in 24 patients (80%) during CRS; it was increased to a maximum of 100mg q12h in 1 patient and 100mg q6h in 23 patients. The median duration of anakinra administration was 9.5 d (IQR 8 - 13). No patient stopped anakinra due to an adverse event. A total of 3 patients (10%) experienced severe ICANS, all of which were grade 3 only. 9 patients (30%) experienced any grade ICANS (Fig 1A). The median time to ICANS onset was 6.5 d (range: 4 - 10 d). All-grade CRS occurred in 24 patients (80%). Most CRS events were grade 1 or 2 except for 3 grade 3 events (10%) (Fig 1A). Of the 24 patients who received CD28-containing CARs (axi-cel and brexu-cel), all-grade and severe ICANS rate was 29% and 12.5%, respectively (Fig 1B). In the 3 patients with active CNS disease, there was 1 grade 2, and 1 grade 3 ICANS event. 23 patients (77%) received tocilizumab and 18 (60%) received steroids for CRS and/or ICANS. The median follow-up was 5.8mo. The best ORR by day 100 was 83% (95% CI 65-94%) with a CR rate of 73% (95% CI 54-89%). The estimated progression-free and overall survival at 6mo was 72% (95% CI 50-93%) and 81% (95% CI 66-86%), respectively. Conclusion: Early use of prophylactic anakinra was safe, feasible and reduced the rate of severe ICANS without affecting efficacy in adult patients receiving anti-CD19 CAR-T for r/r B-cell lymphoma. Rates of severe ICANS were very similar between cohorts 1 and 2; at 9.7% and 10% in the entire cohorts, respectively, and 11% and 12.5% in patients treated with CD28-containing CARs, respectively. The risk-adapted dosing of anakinra likely contributed to the low rates of severe ICANS in this study. Detailed comparison of results from cohort 1, analysis of the anakinra dose-relationship on efficacy, and serum and CSF biomarkers will be presented at the meeting.

Clinical Outcomes with Prophylactic Corticosteroid Use for Axicabtagene Ciloleucel (axi-cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): A Multicenter Analysis

Introduction: In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in R/R LBCL, 11% and 31% of patients (pts) experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic evenets), respectively. To minimize the toxicities seen with axi-cel, a safety management cohort, Cohort 6 (N=40), was added to evaluate whether prophylactic (ppx) corticosteroids (CS) could decrease grade ≥ 3 CRS or ICANS. The 2-year update of ZUMA-1 Cohort 6 showed no grade ≥3 CRS and 15% grade ≥3 ICANS without any difference in objective response rate (ORR) or complete response rate (CR) when compared to cohorts 1+2 (Oluwole Blood 2022). The FDA had previously approved an update to the prescribing information for axi-cel to include use of ppx CS across all approved indications in January 2022. However, ppx CS is not a mandatory standard treatment and we sought to establish the clinical outcomes in the real-world practice. Methods: To assess the clinical outcomes of pts receiving ppx CS, we conducted a multicenter retrospective analysis of pts with R/R LBCL who were treated with axi-cel since the FDA approval of ppx CS in January 2022. Baseline characteristics, toxicities, and efficacy were compared between the no ppx and ppx CS groups. CRS and ICANS were graded based on ASTCT 2019 guidelines. Event-free survival (EFS) was defined as time from axi-cel infusion to progression, re-treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death due to any cause. Results: A total of 66 pts at 5 centers received axi-cel between Jan 31, 2022, and June 20, 2023. Thirty-five (52%) pts received ppx CS, with a median age of 63 years (26-85 years). By histology, 75% (n=50) of the pts had DLBCL, 13.6% (n=9) had high grade B-cell lymphoma (HGBL), 9.1% (n=6) had transformed follicular lymphoma (TFL) and 1.5% (n=1) primary mediastinal LBCL (PMBCL). 59% of the pts (n=37) had IPI >2 and 66% (n=43) had stage III/IV disease. The baseline characteristics at the time of apheresis are shown in Table 1 and were comparable between the 2 groups, except for more HGBL, fewer prior lines of therapy and longer median time from apheresis to axi-cel infusion in the ppx CS group. Among the entire cohort, only 37% (n=25) met ZUMA-1 eligibility criteria at the time of lymphodepletion, and 67% (n=44) needed bridging therapy. Any grade CRS occurred in 88% (n=58) of the pts, with grade ≥2 CRS in 38% (n=25). Any grade ICANS occurred in 55% (n=37) of the pts, with grade ≥2 ICANS in 41% (n=27). Any grade ICANS was significantly lower in the ppx CS group than the no ppx group (45.7% vs 65.5%). The rates of any grade CRS, grade ≥2 CRS, grade ≥2 ICANS, the median time to CRS onset, ICANS onset, CRS duration, and ICANS duration were comparable between the 2 groups. Tocilizumab and steroids use was similar between two groups with a trend towards less ICU admission in patients in the ppx CS group. Overall, 14 (21%) pts developed infectious complications within 30 days of axi-cel infusion. The day 30 ORR was 84% and was comparable between the 2 groups (77% in the ppx group vs 93% in the no ppx group). The CR was 45.7% in ppx CS group compared to 65.5% in no ppx group. At a median follow up of 219 days (27-1178), 37 (56.1%) pts had progressed and 25 (37.9%) pts had died. The number of days to progress was significantly lower in the ppx CS arm. The median EFS and OS were not significant between the 2 groups. Conclusions: This multicenter retrospective study showed that the efficacy of treatment with axi-cel in R/R LBCL did not decrease with the use of ppx CS. No significant differences in efficacy or CAR-T-associated toxicities were noted in the 2 groups, potentially due to selective use with patients at presumed higher risk of severe CRS and ICANS. A larger dataset and longer follow-up is needed for risk-stratified analysis and the study is ongoing.

Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel: Efficacy and Toxicity in a Real-World Setting

CD19 CAR-T therapy has revolutionized the management of high-risk and relapsed/refractory (R/R) large B-cell lymphoma (LBCL) but remains limited by significant toxicities leading to morbidity/mortality and high resource utilization. Single-arm studies have suggested differences in efficacy and toxicity across FDA-approved CD19 CAR-T products. A matching-adjusted indirect treatment comparison showed comparable efficacy and more favorable safety with lisocabtagene maraleucel (liso-cel) compared to axicabtagene ciloleucel (axi-cel), but was limited to clinical trial patients (pts) and suffered from an absence of patient-level data (Maloney, J Hematol Oncol, 2021). In the absence of randomized clinical trial data, adjusted comparative analyses using pt-level data are critically needed to guide product choice. Therefore, we retrospectively evaluated the impact of CAR-T product type on the outcomes of 129 LBCL pts receiving liso-cel or axi-cel per standard of care. All LBCL pts treated at our center with liso-cel or axi-cel outside of a clinical trial between 1/2018 and 5/2023 were included. Best response was determined within 3 months of CAR-T infusion by PET-CT imaging per Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS) were graded using ASTCT criteria. Of 129 total pts, 37% (n=48) and 63% (n=81) received liso-cel and axi-cel, respectively. Seven pts received out-of-specification liso-cel on an expanded access protocol. Pts who received liso-cel were older (median 67 vs 62 years, p=.003). Other baseline characteristics, including male sex (liso-cel vs axi-cel: 63% vs 69%, p=.4), HCT-CI score (1.0 vs 1.0, p=.6), pre-lymphodepletion (LD) LDH (178 vs 214 U/L, p=.14) and ALC (0.65 vs 0.60 x 10³/µL, p=.3), largest lesion diameter (3.1 vs 3.0 cm, p=.4), and extranodal disease (56% vs 56%, p>.9) were similar. The vein-to-vein time (time from leukapheresis to CAR-T infusion) was longer for liso-cel: median, 35 vs 27 days (p<.001). After liso-cel, the total inpt duration was shorter (median, 5 vs 14 days, p<.001) and fewer pts had ≥2 admissions (8.3% vs 22%, p=0.043). In pts with measurable disease prior to LD (n=113), we observed comparable efficacy with liso-cel vs axi-cel: ORR, 82% vs 77% (p=.5); CR, 56% vs 51% (p=.8). After a median follow-up of 17.7 months, we observed comparable 1-year outcomes with liso-cel vs axi-cel: duration of response (DOR), 56% vs 61% (p=.7); progression-free survival (PFS), 47% vs 47% (p=.99; Figure); and overall survival (OS), 69% vs 60% (p=.39). In pts evaluable for toxicity assessment (n=129), liso-cel was associated with lower rates of CRS and ICANS compared to axi-cel: any grade CRS, 62% vs 88% (p=.001); ICANS any grade, 32% vs 56% (p=.010); days with fever, median 2 vs 5 days (p<.001). Grade 3-4 CRS, 2.1% vs 9.9% (p=.2) or grade 3-4 ICANS, 23% vs 19% (p=0.5) were similar. We measured lower peak serum inflammatory markers after liso-cel: CRP, 58 vs 114 mg/L (p<.001); ferritin, 622 vs 1,315 ng/mL (p=0.007); IL-6, 55 vs 204 pg/mL (p=.010); and D-dimer, 1.4 vs 2.4 mg/L (p=.017). The incidence of infectious complications after liso-cel vs axi-cel was as follows: bacteremia: 6% vs 9% (p=.7); CMV viremia: 13% vs 6.2% (p=.3). Post-infusion median nadir cytopenias were less severe after liso-cel: ANC, 0.32 vs 0.04 x 10³/µL (p<.001); Plt, 69 vs 35 x 10³/µL (p=.003); and Hgb, 8.9 vs 8.2 g/dL (p<.001). Fewer pts developed severe neutropenia after liso-cel: 72% vs 93% (p=0.002). In multivariable analysis including pre-LD LDH and ALC, largest lesion diameter, age and HCT-CI score, we could not confirm an independent impact of the product type on CR, PFS, or OS ( Table). However, axi-cel remained independently associated with a higher odds of any grade CRS (adjusted OR [aOR] 4.56, 95% CI 1.65-13.5, p=.004) and any grade ICANS (aOR 3.44, 95% CI 1.42-8.85, p=.008). Our analysis of CD19 CAR-T therapy for R/R LBCL in the non-trial setting showed similar rates of durable responses following liso-cel and axi-cel. Pts who received liso-cel were older, with otherwise comparable baseline characteristics. Although liso-cel was associated with less toxicity, its vein-to-vein time was longer. In multivariable analyses, pre-LD LDH and largest lesion diameter were the only factors independently associated with response outcomes. We conclude that liso-cel is a robust alternative to other CD19 CAR-T products in older and frailer LBCL pts.

Phase 2 Study of Anakinra to Prevent CRS and Neurotoxicity after Treatment with Lisocabtagene Maraleucel: Planned Interim Analysis

BACKGROUND CD19 chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape for patients (pts) with relapsed/refractory B-cell malignancies, but they remain limited by significant toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). While a more favorable toxicity profile had been reported with lisocabtagene maraleucel (liso-cel), based on our real-world experience CRS and ICANS are still observed in 70% and 30% of pts, respectively (Portuguese et al., ASH abstract #172978). Data from our group (Gazeau, TCT, 2023) and others (Strati, Blood, 2023; Park, Nat Med, 2023) suggested the recombinant interleukin-1 receptor antagonist anakinra may successfully prevent and treat CRS and ICANS. Thus, we conducted a phase 2 investigator-initiated clinical trial of anakinra to prevent CRS and ICANS after liso-cel (NCT04359784). We report here our planned interim analysis (n = 15). METHODS Adults ≥18 years of age with Karnofsky performance status ≥60% and B-cell non-Hodgkin lymphoma receiving liso-cel per the FDA label were eligible for this study. Anakinra was administered at 200 mg/day SC from day 0 through day +13 after liso-cel infusion, with the first dose administered approximately 2-4 hours prior to liso-cel infusion. CRS and ICANS severity were assessed per 2019 ASTCT criteria. The primary endpoint was the absence of any grade CRS assessed using the Bayesian optimal phase 2 design.The primary endpoint was not met if ≥6 of the first 15 pts developed any grade CRS. RESULTS Nineteen pts were screened for the study and 15 pts were enrolled. All 15 pts received liso-cel and all doses of SC anakinra. All pts were evaluable for toxicity assessment; 12 pts were evaluable for disease response assessment at day +28 (n = 3, no measurable disease prior to lymphodepletion [LD]). Pt and disease characteristics are shown in Table 1. Eleven pts (73%) had diffuse large B-cell lymphoma, 3 (20%) had active CNS involvement, and 5 (33%) had bulky disease (≥5 cm). Median pre-LD serum ferritin and C-reactive protein (CRP) were 153 ng/mL (IQR, 129-231) and 6.8 (IQR, 1.5-17.2), respectively. All 15 pts received anakinra as planned without dose adjustment or interruption. There were no injection-site reactions or AEs attributed to anakinra. Two pts developed infections during anakinra treatment and were both due to mild Clostridium difficile colitis requiring oral antibiotics. Eight pts (53%) developed any grade CRS, including 1 (7%) case of grade 3 CRS. Four pts (27%) developed any grade ICANS, including 3 (20%) with grade 3 (Figure 1). Median CRS onset and duration were 2 and 2.5 days, respectively, and median ICANS onset and duration were 6 and 9 days, respectively. Three pts (20%) required tocilizumab (range, 0-1 doses), 4 (50%) required dexamethasone (median total dose, 5 mg; range, 0-200 mg), and 1 (12%) required high-dose methylprednisolone. The best overall response rate (ORR) by Lugano criteria was 67% (complete response, n = 5 [42%]). Study pts were retrospectively compared to pts who received liso-cel per standard of care off trial without prophylactic anakinra at our center (n = 42). Despite higher median pre-LD CRP and IL-6 levels, the incidence of CRS was lower in anakinra-treated compared to anakinra-untreated pts (53% vs. 69%, respectively) with comparable median duration of CRS (2.5 vs. 3 days, respectively). The incidence and duration of ICANS were similar (27% vs. 28%; median 9 vs. 8 days, respectively), as was the incidence and duration of hospitalization (67% vs. 74%, median 9.5 vs. 10 days, respectively). Based on Locally Estimated Scatterplot Smoothing (LOESS) estimates, time from liso-cel infusion to CRP normalization was faster in patients receiving anakinra (9 days) compared to those receiving liso-cel alone (14 days). CONCLUSION Low-dose SC anakinra prophylaxis during liso-cel treatment was very well tolerated with preserved anti-tumor efficacy. While our primary endpoint was not reached at our planned interim analysis, we observed lower CRS rates and faster resolution of CRS in comparison to a real-world cohort of pts receiving liso-cel without prophylactic anakinra. To further enhance the preventative effects of anakinra, we plan to change the administration route from SC to intravenous, and to allow anakinra dose uptitration for the last 10 participants in the study.

Patterns of Cytokine Release Syndrome with Teclistamab in Relapsed/Refractory Multiple Myeloma with or without Prior T-Cell Redirection Therapy

Introduction: Numerous therapeutic options with novel mechanisms of actions are currently available for treating patients with relapsed/refractory multiple myeloma (RRMM). Teclistamab (Tec) is a first-in-class BCMA X CD3 bispecific T-cell engager antibody that was recently approved for patients with RRMM who have received at least 4 lines of therapy (LOT). In the landmark MajesTEC-1 study, cytokine release syndrome (CRS) with Tec was reported at a rate of 72% (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022); however, patients who were previously treated with T-cell redirection therapies (TCRT) were excluded from the study [TCRT: chimeric antigen receptor (CAR) T-cells and/or other bispecific antibodies]. Given this knowledge gap, we investigated whether prior TCRT exposure impacts CRS rates with Tec in a real-world setting. Methods: Our institutional plasma cell disorders database was queried to identify RRMM patients who received commercial Tec from November 2022 to July 2023. Patients who completed the Tec step-up dosing phase (first step-up, second step-up and first full doses) were divided into two cohorts based on prior TCRT exposure before treatment with Tec (prior TCRT exposure: cohort 1 and no prior TCRT exposure: cohort 2). Data collection included patient demographics, disease characteristics, prior LOT, and rates/grades of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). The Chi-square/Fisher exact test was used to compare differences in CRS rates between the two cohorts. Univariate and multivariate logistic regression analyses were performed to assess impact of prior TCRT exposure on CRS rates with Tec. The results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). For cohort 1, the Mann-Whitney U-test was used to compare the median time elapsed from the last prior TCRT dose until the first Tec step-up dose between patients who developed CRS with Tec compared to those who did not. All statistical analyses were performed using SPSS software (version 29). Results: 50 patients (cohort 1: 25 and cohort 2: 25) were included in the final analysis. Baseline characteristics were comparable between the two cohorts except for prior LOT, where patients in cohort 1 represented a more heavily pretreated population (Table 1). The CRS rates were significantly lower in cohort 1 (40%, n=10) compared to cohort 2 (76%, n=19, p=0.02; Figure 1). CRS grades 1 and 2 occurred in 32% (n=8) and 8% (n=2) of patients in cohort 1 and 48% (n=12) and 28% (n=7) of patients in cohort 2, respectively (p=0.40). Among the CRS events, 60% (6/10) and 68% (13/19) occurred following the first Tec step-up dose in cohorts 1 and 2, respectively. In univariate logistic regression analysis, no prior exposure to a TCRT was associated with about a 5-fold increase in the incidence of CRS with Tec (OR= 4.8, 95% CI: 1.5-17.1.2, p=0.02). After adjusting for age, extramedullary disease (EMD) and elevated LDH levels, the impact of prior exposure to TCRT remained significant with an OR of 4.5 (95% CI: 1.3-18.6, p=0.01). In cohort 1 (prior TCRT exposure), the median time elapsed between the last TCRT dose and the first Tec step-up dose was 321.5 days (range: 50-808 days) in patients who developed CRS with Tec compared to 265 days (range: 41-1617 days) in those who did not (p=0.90). Conclusion: In our study, prior exposure to a TCRT was associated with a significantly lower incidence of CRS during the Tec step-up dosing phase, which may be suggestive of T-cell exhaustion. This observation will allow for optimization of CRS prophylactic strategies for RRMM patients receiving Tec treatment.

Pooled Analysis on Bispecific Antibody-Related Toxicities in Multiple Myeloma

Background: Multiple myeloma (MM) is a hematologic malignancy caused by the uncontrolled proliferation of malignant plasma cells in the bone marrow. Bispecific antibodies (BsAbs) are a new novel class of drugs currently assessed in the setting of relapsed/refractory MM (RRMM), with impressive outcomes. BsAbs are designed to direct against specific antigenic epitopes on the surface of malignant plasma cells, with two main categories: B-cell maturation antigen (BCMA) or other (non-BCMA) antigens which include G-protein coupled receptor family C group 5 member D (GPRC5D) and Fc Receptor-Like 5 (FcRH5). Methods: We conducted a pooled analysis of the available literature on BsAbs reported in the form of abstract or full peer-reviewed publications, published until June 2023, using PubMed, Scopus, Google Scholar and Embase databases. BsAbs were classified into two groups: BCMA and non-BCMA-directed agents. Studies on BsAbs used in combination with other plasma-cell directed agents, and studies reporting outcomes of patients who had prior exposure of other BsAbs were excluded. BsAb included in our study were the following: Teclistamab, Elranatamab, REGN-5458, AMG420, AMG701, CC-93269, TNB-383B, Linvoseltamab, Talquetamab, and Cevostamab. We collected safety data including cytokine release syndrome (CRS), neurotoxicity, infections rates and hematologic toxicities. We used T-test statistics to determine significance (p-value<0.05) and comparisons between the BCMA and non-BCMA groups. Results: A total of 1926 patients with RRMM treated with BsAbs were included in this analysis. Among them, 1288 (66.7%) received a BCMA-directed BsAbs, while 638 (33.1%) received a non-BCMA-directed bsAb. Patient baseline characteristics including prior lines of therapy (LOT), and refractoriness status were comparable between the two groups. The median age of the entire cohort was 63 years and had a median of 5 prior LOT. Median follow-up duration was 5.35 and 5.6 months for the patients treated with BCMA agents and non-BCMA agents, respectively. CRS was reported in 59.6% of all patients, infections in 50%, neutropenia in 41.86%, anemia in 37.32%, and lymphopenia in 36.41%. For grade 3-4 adverse events (AEs), the percentages were as follows: CRS 22.9%, infections 21.46%, neutropenia 38.12%, and anemia 25.37%. Non-BCMA-targeting BsAbs showed no significant difference in all grade and type hematologic toxicities (neutropenia, anemia, lymphopenia, leukopenia, and thrombocytopenia combined) compared to BCMA-targeting BsAbs (p=0.57). However, a significant difference was observed when comparing BCMA-targeting to non-BCMA-targeting BsAbs in terms of combined grade 3-4 hematologic toxicity (p=0.0002). In addition, the group of patients who received BCMA-targeting BsAbs had significantly worse hypogammaglobulinemia compared to patients treated with non-BCMA BsAbs (p=0.006). The overall CRS rate (all grades) was significantly higher in non-BCMA BsAbs (p<0.0001), however, both groups experienced similar grade 3-4 CRS rates. Neurotoxicity rates were also similar between the two groups (p=0.067). Conclusion: The use of BsAbs in MM has demonstrated remarkable efficacy; however, these have been linked to a unique adverse event profile. Our results showed that non-BCMA bsAb were associated less hematotoxicity (combined grade 3-4 events and hypogammaglobulinemia), whereas BCMA bsAb were associated with less CRS rates. This is important information for treatment selection and mitigation strategy development aiming to optimize patient outcomes.

A Phase I Clinical Trial of Fully Human Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed or Refractory Lymphoid Malignancies

Background: Chimeric antigen receptor (CAR) T-cells have revolutionized the standard of care for numerous lymphoid malignancies but continue to present challenges related to toxicity, long-term efficacy, cost, and accessibility. Novel CAR-T cell constructs hold promise for improving desired outcomes. CD19 CAR-T cells with fully humanized chimeric antigen receptors have demonstrated excellent preclinical activity and the potential for lower rates of cytokine release syndrome (CRS) and severe immune effector associated neurotoxicity syndrome (ICANS). To evaluate safety, we conducted a phase 1 clinical trial evaluating fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain against relapsed or refractory (R/R) CD19-positive lymphoid malignancies, utilizing a single lymphodepletion regimen and local CAR-T cell manufacturing using the Prodigy® Device. Methods: We designed a parallel-group phase I trial with two clinical groups. Group A enrolled subjects with relapsed and refractory CD19+ lymphomas and chronic lymphocytic leukemia (CLL), while Group B comprised patients with acute lymphoblastic leukemia/lymphoma (ALL). The primary endpoint was safety and toxicity assessment, along with the identification of the recommended phase 2 dose in each clinical group. Secondary endpoints included efficacy evaluation. Dose escalation in each group followed a “3 + 3” phase I study design, with three dose levels: 5e5 CAR-T cells/kg, 1e6 CAR-T cells/kg, and 2e6 CAR-T cells/kg. Lymphodepletion consisted of cyclophosphamide 60mg/kg on day -6 and Fludarabine 25mg/m2/day on days -5 to -3. Dose-limiting toxicities included prolonged CRS grade 3 or higher, ICANS grade ≥ 3, and grade ≥ 3 non hematologic toxicities with the exception of self-limited (<7 days) laboratory abnormalities without associated symptoms or clinical consequences. Results: As of 7/1/2023, a total of 13 patients were enrolled in Group A (NHL), and two patients were enrolled in Group B (B-ALL). Three patients in Group A withdrew consent or were withdrawn at the investigator's discretion due to new comorbid conditions before cell collection. Additionally, three patients were unable to receive CAR-T cell infusions due to disease progression, including two with Burkitt lymphoma. Among the remaining patients, 7 in NHL and 2 in B-ALL, received CART cells. The average age was 59 (range: 40-73), and 2 patients were female. In the NHL group, diseases treated included CLL (3), mantle cell lymphoma (2), follicular lymphoma (1), and Waldenstrom's (1). The median number of prior treatments was 4 (range: 3-10). CAR-T cell product manufacturing was successful in all patients to achieve the target dose, with a mean transduction efficiency of 43.8% (29.7% - 54.6%). One potential dose-limiting toxicity, nodular regenerative hyperplasia of the liver, considered possibly related to CAR-T cells, was observed in the NHL group at the 1e6 cells/kg dose level, leading to an expansion of this dose level. Other observed toxicities were as expected and manageable. Six patients experienced CRS, with grades 1-2 in the NHL group. Both patients in the B-ALL arm experienced CRS, one grade 1 and one grade e, with observed severity congruent with known disease burden before receiving CAR-T cells. Two cases of CRS required no intervention, while the remaining cases received tocilizumab (n=4), steroids (n=2), and/or anakinra (n1). There were three occurrences of ICANS, two in Group A and one in Group B. Treatments included corticosteroids (n=3) and anakinra (n=2). Among the 7 NHL patients evaluable for response, 2 achieved complete remission (follicular, mantel cell), three had a partial response (CLL), and one exhibited stable disease (Waldenstrom's). Two NHL patients (CLL and Mantel Cell) had subsequent disease progression. One B-ALL patient evaluable for response achieved a CR but experienced disease progression at one year and subsequently died. Discussion: In this parallel-group phase 1 study, fully human Hu19-CD841BBZ CAR-T cells with a 4-1BB costimulatory domain were successfully manufactured in all patients undergoing leukapheresis. Human CAR-T cells demonstrated preliminary safety and clinical activity in the setting of heavily pre-treated patients with R/R B cell malignancies. A platform of point-of-care manufacture permits access to novel CAR-T cell products, and may facilitate the development of novel immune effector cell products.

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.

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.