Incidence Of Cytokine Release Syndrome Research Articles

Phase I Open-Label Single-Arm Study of Sscart-19 in Adult Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in China

Background: Although CAR-T therapy has shown amazing efficacy in the treatment of hematologic malignancies in recent years, it is also accompanied by high-frequency of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), especially in acute lymphoblastic leukemia patients. Therefore, it is not recommended to enroll patients with active CNS involvement in CAR-T therapy. ssCART-19 is an autologous CD19-specific chimeric antigen receptor T-cell with short hairpin RNA-IL-6 gene silencing element. ssCART-19 can simultaneously express CAR structure and IL-6 silencing element. CAR structure can recognize and bind CD19 positive tumor cells, enhance T cell amplification, and finally exert T cell killing activity, such as releasing cytokines and perforin. Post-transcriptional expression of short hairpin RNA-IL-6 gene silencing element can recognize mRNA of IL-6, inhibit the expression of endogenous IL-6 in CAR-T cells through RNA interference mechanism, and then reduce the stimulation or activation intensity of downstream immune cells (mainly monocytes), with the control of the overall release intensity of cytokines, it reduces the incidence of severe CRS and ICANS, at the end reduces the clinical risk of CAR-T therapy. Methods: The trial of ssCART-19 in adult patients with R/R B-cell ALL (NCT04825496) is a single-arm, open-label Phase 1 study conducted in China. Patients underwent leukapheresis to obtain T cells for ssCART-19 manufacturing. Patients received fractionated infusions split over 3 days (10%; 30%; 60%) after lymphodepleting chemotherapy (3 days fludarabine and cyclophosphamide). Adverse events (AEs) were graded according to CTCAE, v5.0; CRS and ICANS were graded according to ASTCT Consensus Grading. The overall response rate(ORR) of complete response (CR) and CR with incomplete hematological recovery (CRi) within 3 months, duration of remission, relapse-free survival, and OS were assessed as secondary endpoints. Results : ssCART-19 was administered at 3 doses levels (DL) of 1×10 6/kg, 5×10 6/kg, or 10×10 6/kg. As of June 30th 2023 data cutoff (the median follow-up 15.9 months), 13 patients enrolled and underwent leukapheresis, 12 patients were received ssCART-19 treatment, 5 patients in DL1, 6 patients in DL2, and 1 patients in DL3. ssCART-19 was manufactured using serum-free culture system and no manufacture failure was reported. All 12 patients diagnosed with B-cell ALL were relapsed (75.0%) and refractory (25.0%) to multiple lines of prior therapy (100.0% patients had received 2 or more therapies). Five patients (41.7%) had more than 50% blasts in the bone marrow. All 12 patients did not have DLT events within 28 days. The most common ssCART-19-related AEs were transient neutropenia (100.0%), lymphopenia (100.0%), leukopenia (100.0%), anaemia (100.0%) and thrombocytopenia (83.3%). Adverse events of special interest (AESI) were CRS and ICANS. Among the 12 patients, 9 patients (75.0%) developed CRS, and 3 patients (25.0%) were grade 3 CRS. Notably, none of the 12 patients were occurred ICANS. No death cases were reported due to CRS or ICANS. A 83.3% overall response rate was achieved in efficacy-evaluable patients (n=12), with 7 complete response (CR, 58.3%), and 3 CR with incomplete hematological recovery (CRi,25.0%). The median duration of remission, relapse-free survival and OS have not been reached. Among them, 6 patients were in ongoing remission for over 12 months. Notably, one of the 12 patients (S012) had central nervous system infiltration with grade 2 before ssCART-19 infusion(Figure 1). After ssCART-19 therapy, the patient had no ICANS and got continuous remission. Robust CAR T-cell expansion occurred in all patients with a median time to T max of 12.5 days (range 9-14d), and peak copy number (C max) of 52495 (194-348000) copies/μg DNA. Conclusions ： ssCART-19 CAR-T cell therapy can effectively reduce the incidence of severe CRS and ICANS, especially control the occurrence of ICANS. And ssCART-19 achieved a high rate of remission in adult patients with R/R B-cell ALL. The ORR within 3 months were 83.3%. And, ssCART-19 shows good clinical efficacy in the treatment of leukemia patients with central nervous system infiltration. Thus, with the combination of short hairpin RNA-IL-6 gene silencing element, ssCART-19 can greatly improve the safety of CAR-T therapy, especially in central nervous system infiltration patients.

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.

Efficacy of Chimeric Antigen Receptor T-Cell Therapy Is Not Impaired By Previous Bispecific Antibody Treatment in Patients with Large B-Cell Lymphoma

Introduction: Potential T-cell exhaustion after bispecific antibody (BsAb) treatment remains an open question, raising the theoretical concern that prior BsAb exposure could affect subsequent chimeric antigen receptor (CAR) T-cell efficacy. Clinical data on CAR T-cell outcomes after prior BsAb treatment in the setting of large B-cell lymphoma (LBCL) are scarce and highly awaited to better define treatment sequencing in relapsed/refractory (R/R) patients. Methods: We conducted a retrospective, international study including R/R LBCL patients treated with CD19-targeted CAR T-cells at 15 centers between July 2018 and January 2023 who had been exposed to BsAbs prior to apheresis. Then, we identified a control cohort from patients included in the DESCAR-T Registry (n=764). We carried out a 1:1 propensity score matching (PSM) to achieve balance between cohorts; 13 baseline covariates were included in the PSM. We compared response rates, survival outcomes and toxicity after CAR T-cell therapy, according to previous BsAb exposure. Results: We identified 47 LBCL patients who received BsAb therapy prior to CAR T-cell apheresis. Median age was 65 years (range 31-82), with a male predominance (66%), and median prior lines of therapy before BsAb were 2 (IQR 2-3) (Table). The BsAbs targeted CD20/CD3 (91%) or CD22/CD3 (9%), either in monotherapy (n=41, 87%) or in combination with other agents (n=6, 13%) (lenalidomide [n=2], polatuzumab [n=1], chemotherapy [n=2], missing [n=1]). The median time on BsAb treatment was 98 days (IQR 56-160) with a best overall (complete) response rate (ORR [CRR]) of 47% (19%). Median progression-free survival (PFS) and duration of response (DOR) were 3.1 months (95% CI 2.7-4.4 months) and 8.8 months (95% CI 2.2-NR), respectively. Cytokine release syndrome (CRS) occurred in 59% of patients (grade 3 in 4%). No neurologic toxicity (NT) was reported. In 26 (55%) patients, bispecific antibody was the last line before CAR T-cell therapy. Median washout between the last BsAb dose and lymphocyte apheresis for CAR T-cell manufacturing was 43 days (range 34-103 days). In terms of the subsequent CAR T-cell therapy, patients received axi-cel (n=22, 47%), tisa-cel (n=20, 43%) or liso-cel (n=5, 11%). Most patients developed CRS after infusion (79%, 6% grade >2), with a low rate of NT (23%, 2% grade >2). Neutropenia and thrombocytopenia grade >2 were reported in 66% and 45% of patients, respectively. Regarding efficacy, ORR after infusion was 83% (CR 43%). Median PFS and overall survival (OS) were 6.6 months (95% CI 2.6-not reached [NR]) and NR (95% CI 9.0-NR), respectively. The rate of overall (complete) response was similar between patients who had previously responded (CR or PR) or not (SD or PD) to BsAb therapy (82% [41%] vs 84% [44%], respectively, p=0.64). However, all 9 patients achieving CR after BsAb achieved subsequent response to CAR T-cells. Given the wide variability in the washout between last BsAb dose and lymphocyte apheresis, we evaluated the impact of this interval on CAR T-cell efficacy. The 6-month PFS and OS of patients previously exposed to BsAb within 45 days of lymphocyte apheresis was similar to patients who had a longer washout (59% vs 47% [p=0.25] and 83% vs 67% [p=0.21], respectively). In the second part of the analysis, we matched our cohort with a control group of CAR T-cell recipients not previously exposed to BsAbs. The final analysis included 2 sets of 42 patients with comparable characteristics. Median follow-up from CAR T-cell infusion was 11.5 months for the BsAb cohort (CI 95% 6.4-19.0 months) and 18.8 months for the control cohort (CI 95% 10.9-23.0 months). Patients with previous BsAb exposure showed a similar PFS (p=0.10, Figure) and OS (p=0.08) after CAR T-cell infusion in comparison to the control group. In terms of toxicity, there were no differences in the incidence of CRS (p=0.41) or NT (p=1.0) after infusion. Conclusions: Previous exposure to bispecific antibody treatment targeting different antigens does not have a negative impact on survival outcomes after CAR T-cell therapy. Lack of response to a previous BsAb does not predict for lower response rates after CAR T-cell infusion.

Phase 1/2 Study of Donor-Derived Anti-CD33 Chimeric Antigen Receptor Expressing T Cells (VCAR33) in Patients with Relapsed or Refractory Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

Background and Significance: Although allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative therapy for patients with high-risk acute myeloid leukemia (AML), relapse occurs in 30% to 40% of alloHCT recipients and is associated with a 2-year post-relapse survival rate of less than 20%. Chimeric antigen receptor (CAR) T cells targeting tumor-associated antigens have demonstrated efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia and other hematologic malignancies, but there is limited clinical experience with CAR T cell therapies for AML. Current challenges for autologous AML CAR T cell therapy include the inability to harvest adequate numbers of functional, undifferentiated T cells as CAR T cell starting material. In addition, the potential presence of AML blasts in an autologous cell collection can interfere with T cell proliferation and function during the manufacturing process. To circumvent these impediments in patients with R/R AML after alloHCT, VCAR33 represents a CD33-directed CAR T cell product generated from lymphocytes from each patient's prior allogeneic stem cell donor. CAR T cell manufacture from HLA-matched donors will likely not only eliminate delays and failures in production due to lymphopenia but also improve T cell function by using healthy starting material. CD33 is a preferential target for AML CAR T cell therapy as it is expressed on the majority (>80%) of AML blasts and because prior clinical experience with gemtuzumab ozogamicin (GO; tradename: Mylotarg TM) has demonstrated the safety and efficacy of targeting CD33. Study Design and Methods: Study NCTxxxxxxxx* is a multi-center phase 1/2 study evaluating the safety and preliminary efficacy of VCAR33, donor-derived allogeneic CAR T cells targeting CD33 (Figure 1). The CAR construct used for the manufacture of VCAR33 contains a lintuzumab-derived binding domain and a CD28 co-stimulatory domain. Key inclusion criteria include adult patients with relapsed or measurable residual disease positive (MRD+) AML after undergoing alloHCT with an 8/8 HLA-matched related or unrelated donor. Patients who have undergone alloHCT with trem-cel, a CD33-deleted allogeneic stem cell product intended to facilitate the post-HCT treatment with CD33-directed therapies by reducing on-target off-tumor hematotoxicity, may also participate. Patients will be assigned to one of two study arms based on their AML disease burden: Arm A for morphologic disease with ≥ 5% blasts in the bone marrow, or Arm B for MRD+ defined as < 5% blasts in the bone marrow with ≥ 0.1% CD33+ leukemia cells by flow cytometry. The patient's prior stem cell donor undergoes apheresis for collection of mononuclear cells, which are used as starting material for VCAR33 manufacturing. Patients will receive lymphodepletion on days -5 to -2 with fludarabine (total 120 mg/m 2) and cyclophosphamide (total 1000 mg/m 2) followed by infusion of VCAR33 on Day 0. Each study arm will enroll and escalate independently according to a standard 3+3 trial design, starting at 1 x 10 6 CAR T cells/kg for Dose Level 1. The dose limiting toxicity monitoring period is 28 days, at which time patients will undergo evaluation of disease response. Secondary endpoints include incidence of cytokine release syndrome, graft-vs-host disease, and clinical response. Exploratory endpoints aim to correlate VCAR33 properties with clinical response by characterizing T cell phenotypes within the VCAR33 product and by examining VCAR33 expansion and persistence after infusion. Follow up on trial will continue for up to 2 years after infusion followed by long term monitoring for up to 15 years. Patients may undergo second alloHCT for consolidation of remission or for rescue of prolonged cytopenia due to on-target off-tumor effects of VCAR33. *NCT number pending. Clinical trial information submitted to CT.gov on July 19, 2023.

Evaluating the Impact of Cryopreservation of PBMCs on CAR-T Therapy Efficacy and Safety in DLBCL Patients: An Informative Approach to Optimize Manufacturing Strategies

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a pivotal treatment modality for relapsed/refractory (R/R) B-cell malignancies. However, some patients are unable to receive CAR-T therapy due to challenges in obtaining sufficient lymphocytes through leukapheresis, often resulting from intensive prior treatments or impaired lymphocyte function after repeated tumor reductions under high tumor burden. This issue underscores the need to explore strategies such as advance collection and cryopreservation of peripheral blood mononuclear cells (PBMCs), which could provide enhanced flexibility in the pre-CAR-T treatment planning process and potentially widen the accessibility of CAR-T therapy. Aims: This retrospective study compares the safety, efficacy, and adverse reactions of anti-CD19 CAR-T cell therapy for Diffuse Large B-Cell Lymphoma (DLBCL) patients, using cryopreserved versus freshly harvested PBMCs. Methods: A total of 162 R/R DLBCL patients treated with an anti-CD19-CD3zeta-4-1BB CAR-T cell therapy from January 2019 to April 2023 were included in this study, excluding those who received concurrent autologous stem cell transplants. The median age was 52 (15-78) years old, and the majority (87.7%) patients had stage III-IV disease. With a median IPI score of 2 (range, 0-5), 71.0% (115/162) had extranodal lesions and 18.0% (29/162) had bulky disease > 7 cm. Among these, 136 patients received CAR-T cells derived from cryopreserved PBMCs, which were frozen with a controlled rate freezer and CryoSure-DEX40 cryoprotectant and stored in the liquid phase of liquid nitrogen. The remaining 26 patients received CAR-T cells that were directly cultured from freshly collected lymphocytes without any cryopreservation. For all patients, CAR-T cells were freshly infused post-manufacture. The study primarily explores the attainment of CAR-T cell infusion dose (achieving 2x10 6 cells/kg), in vivo expansion of CAR-T cells, and the persistence of CAR-T cells in the body. Secondary aims include assessing overall survival (OS), progression-free survival (PFS), 3-month complete response (CR) rate and objective response rate (ORR). The incidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and levels of cytokines were also recorded. In addition, baseline characteristics of both groups were taken into analysis, including factors such as Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, age, gender, presence of bulky disease, and extranodal lesions. For statistical analysis, either chi-square test or Fisher's exact test was employed for categorical variables, whereas continuous variables were assessed using the rank-sum test. Survival curves between groups were compared using the log-rank test. All P-values were two-tailed. Results: Baseline characteristics between the cryopreserved and fresh groups showed no significant differences in age, gender, IPI score≥3, ECOG score≥3, and extranodal lesions (P all > .05), while bulky disease prevalence was higher in the cryopreserved group (20.6% vs. 3.85%, P = .049). Metrics of CAR-T cell expansion, including meeting the infusion dosage benchmark of 2x10 6 cells/kg (46.1% vs. 44.9%, P = .90), in vivo CAR-T cell persistence (median duration: 21 days for both groups, P= .48), and the peak proportion of CART19 cells in lymphocytes (median peak: 49.6% vs. 35.2%, P = .41), revealed no significant differences between the fresh and cryopreserved groups. Assessments of CAR-T therapy safety revealed no significant differences in the incidence of grade 3 or higher ICANS and CRS, or peak levels of cytokines including interferon gamma, IL-6, IL-10, soluble CD25, and TNFα (P all > .05) between the two groups. Clinical efficacy measurements (3-month CR and ORR, 1-year OS and PFS) were similar between the two groups, with no statistically significant differences in CR (46.2% vs. 45.5%), ORR (69.2% vs. 61.9%), 1-year OS (75.4% vs. 64.1%, Fig 1), and 1-year PFS (52.1% vs. 44.5%, Fig 2) (P all > .05). Conclusion: Our study affirms that cryopreservation of PBMCs has no significant influence on the safety and efficacy of anti-CD19 CAR-T therapy for patients with R/R DLBCL. These findings widen the therapeutic flexibility and accessibility of anti-CD19 CAR-T therapy for DLBCL patients. Key words: PBMC Cryopreservation, CAR-T, DLBCL

“Defining the Optimal Post-CART Monitoring Period in Recipients of Axicabtagene Ciloleucel and Tisagenlecleucel”

Background: Rigorous monitoring for approximately 4 weeks after chimeric antigen receptor T-cell therapy (CART) is mandated due the potentially fatal toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndromes (ICANS) during this period, and to allow early appropriate interventions. The US Food and Drug Administration implemented the Risk Evaluation and Mitigation Strategy (REMS) program for approved CART that mandates patients remain within the proximity of the authorized treating center for the monitoring period. The physical and financial burden of stringent monitoring may pose a barrier to CART access, especially for minorities and patients from rural areas and low-income groups. Therefore, evaluating the optimal duration of monitoring and causes of non-relapse mortality (NRM) is an area of unmet need. We evaluated safety outcomes for commercial axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) recipients. Methods: Patients (pts) ≥ 18 yrs who received an axi-cel or tisa-cel infusion for large B-cell lymphoma between April 2016 and July 2022 at nine academic US medical centers were identified from the Cell Therapy Consortium registry. Descriptive analysis was used to report outcomes. NRM was death due to causes other than disease progression. New-onset CRS and ICANS were reported as a percentage of pts at risk (alive with no prior CRS/ICANS). Results: A total of 374 pts were included with 216 (58%) receiving axi-cel, and 158 (42%) tisa-cel. Demographics are in Table 1. Median follow-up was 12.4 mo (0.3-58) Safety: Any grade CRS occurred in 63% pts, more common in axi-cel recipients (80%) compared to tisa-cel (41%), p<0.0001. During week 1 (Day 0-7), new-onset CRS occurred in 60.4% of the total population including 75.4% of axi-cel and 39.8% of tisa-cel recipients. New CRS onset in week 2 (Day 8-14) was seen in 6.1% of pts (15.4% axi-cel vs 1% tisa-cel). There was no new onset CRS in Week 3 or beyond. The median time to CRS onset was 3 days (0-13). (Figure 1) Unresolved CRS beyond Day 14 occurred in 7.2% (8.7% of axi-cel vs 3.1% of tisa-cel recipients), of which only 1.7% of pts (all axi-cel recipients) had unresolved CRS beyond Day 28. The median time to resolution was 4 days (IQR 25-75%: 2-7). 98.3% of CRS resolved by Day 28. Any grade ICANS was seen in 35% of pts, more common in axi-cel (52%) compared to tisa-cel (10%), p<0.0001. During Week 1, new-onset ICANS was seen in 27% of of the total population including 40.7% of axi-cel and 8.2% of tisa-cel recipients. New ICANS in week 2 was seen in 9.5% of pts (18.8% of axi-cel vs 2.8% of tisa-cel recipients). During week 3, new-onset ICANS occurred in only 1 tisa-cel recipient (0.4%). There were no new cases in week 4 and beyond. The median time to ICANS onset was 5 days (1-21). Unresolved or ongoing ICANS beyond Day 14 occurred in 32.8% of pts (34.8% of axi-cel: vs 18.7% of tisa-cel recipients), and beyond Day 28 in 7% of pts (7.1% of axi-cel vs 6.3% of tisa-cel recipients). The median time to ICANS resolution was 12 days (IQR 25-75%: 9-16). 93% of ICANS resolved by Day 28. Toxicity Management: Tocilizumab was utilized in 47% of pts (axi-cel 62% vs tisa-cel 26%) and 33% of pts received steroids (axi-cel 50% vs 10% tisa-cel) for management of CART-related toxicities. Other Complications: Infectious complications from Day 0-28 were seen in 18.5% of the total population and more commonly in axi-cel (22%) compared to tisa-cel (13.9%) recipients, p=0.006. Grade ≥4 neutropenia from Day 0-28 days was seen in 66% of the total population (81% axi-cel vs 46% tisa-cel). 82% of the total population did not have Grade ≥4 neutropenia beyond Week 2, and 93% had no Grade ≥4 neutropenia beyond Week 4. NRM: Day 0-28 NRM included 4 deaths (3 related to ICANS and 1 infection), and Day 29-90 NRM included 7 deaths (3 infections, 1 ICANS, 1 cardiac, 2 other). Conclusions: This large multicenter retrospective analysis evaluates patterns of CRS, ICANS, and NRM in recipients of axi-cel and tisa-cel. While NRM is mainly due to infections and ICANS, our study suggests that beyond 2 weeks following CART infusion, the incidence of new onset CRS and ICANS is low. This data supports further investigation into individualized monitoring strategies for stable patients. A flexible monitoring period may help to decrease the financial and physical burden for patients and make CART more accessible and feasible, especially for those with limited socioeconomic support.

Efficacy and Safety of Interleukin-6-Knockdown CD19-Targeted CAR T Cells(ssCART-19) for Relapsed/Refractory B-ALL

Background： Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are significant challenges in the use of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory B-type acute lymphoblastic leukemia (r/r B-ALL). These complications limit the widespread adoption of CAR-T therapy. To address this issue, we developed a novel approach using anti-CD19 CAR T-cells incorporating a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene (ssCART-19). By reducing IL-6 expression levels in ssCART-19 cells, we aimed to decrease monocyte activation and pro-inflammatory cytokine release, thereby mitigating the incidence of severe CRS and neurotoxicity. In this phase 1/2 clinical trial conducted at two centers, we compared the efficacy and safety of ssCART-19 to classical CART-19 cells (cCART-19) in patients with r/r B-ALL (NCT03919240). Methods： Peripheral blood mononuclear cells were collected from patients through leukapheresis. ssCART-19 cells were generated by transducing anti-CD19 CAR with a shRNA-IL-6 gene silencing element into bulk peripheral T lymphocytes using a lentivirus vector. In contrast, cCART-19 cells were only transduced with an anti-CD19 CAR. Both cell types contained 4-1BB and CD3ζ co-stimulatory domains. Lymphodepletion (fludarabine at 30 mg/m 2/day and cyclophosphamide at 300 mg/m 2/day) was conducted on days -5, -4, and -3 before infusion. Each patient received a dose of 5×10 6CAR +/kg. The primary endpoint was safety, with efficacy as the secondary endpoint for both ssCART-19 and cCART-19. Results: A total of 121 patients who had received at least two prior lines of treatment were screened for this study. A total of 47 patients received ssCART-19 and 40 patients received cCART-19 were included in the analysis. The median patient age of group ssCART-19 and group cCART-19 was 33(9-64) years and 24(2-68) years. At enrollment, ssCART-19 patients and cCART-19 patients had a median percentage of BM blasts of 4.0(0.01-86.0) % and 4.0(0.02-98.0) % by flow cytometry. ssCART-19 patients and cCART-19 patients had a median of 3 (2-8) and 4（2-9）prior lines of therapy(table 1). The transfection efficiency was 44.66% (range: 13.70-84.66%) for ssCART-19 and 39.98% (range: 14.0-65.0%) for cCART-19. Adverse events within 28 days included grade 3-4 neutropenia in 14 patients (29.79%), thrombocytopenia in 17 patients (36.17%), grade 1-2 CRS in 25 patients (53.20%), grade 3-4 CRS in 7 patients (14.89%), and grade 1 ICANS in 2 patients (4.26%) in the ssCART-19 group. In the cCART-19 group, adverse events within 28 days included grade 3-4 neutropenia in 20 patients (50%), thrombocytopenia in 18 patients (45%), grade 1-2 CRS in 19 patients (47.5%), grade 3-4 CRS in 15 patients (37.5%), grade 1-2 ICANS in 4 patients (10%), and grade 3 ICANS in 2 patients (5%). The incidence of neutropenia, thrombocytopenia, grade 3-4 CRS, and ICANS in the ssCART-19 group was significantly lower than that in the cCART-19 group (p < 0.05)(Table 2). Furthermore, the peak levels of IL-6, IL-2 and TNF-α were significantly lower in the ssCART-19 group compared to the cCART-19 group (p < 0.05)(Fig.1). No significant differences were observed between the two groups in terms of the start time, peak value, duration and killing efficacy of CART cells (p > 0.05)(Fig.2). As of the data cutoff on December 25, 2020, the median follow-up time was 12 months (range: 0.5-41.33). On day 28, with 91.49% of patients achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) in ssCART-19, compared to 85% in the cCART-19 group. Median overall survival (OS) was not available for ssCART-19, while it was 32.93 months for cCART-19 (p=0.575). The median progression-free survival (PFS) was 14.17 months for ssCART-19 and 15.33 months for cCART-19 (p=0.339). Although no significant differences were observed in terms of 3-year OS and PFS, the 3-month PFS was higher in the ssCART-19 group compared to the cCART-19 group (82.3% vs 66.9%, p=0.045)(Fig.3). Conclusion： Our clinical studies demonstrated the safety and high efficacy of ssCART-19 with IL-6 gene silencing in patients with relapsed/refractory B-ALL. These findings support the potential of ssCART-19 as a promising therapeutic approach for this challenging patient population.

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.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

Bendamustine Lymphodepletion (LD) Prior to Idecabtagene Vicleucel (Ide-cel) Is Associated with Inferior Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Background Chimeric antigen receptor therapy (CART) has revolutionized the management of RRMM. LD prior to CART cells modulates the immune environment creating optimal conditions for T cell expansion and subsequent efficacy. Fludarabine/cyclophosphamide (FLU/CY) is an effective LD regimen, and its use has been adopted widely prior to CART cells for all indications. Since the safety of FLU/CY is not established in patients with substantial renal impairment and given recent nationwide fludarabine shortage, alternative lymphodepletion strategies have been explored. Bendamustine (BENDA) has been shown to be a safe alternative with equivalent efficacy and reduced toxicity in non-Hodgkin's lymphoma (NHL). While its use has been extrapolated to RRMM, efficacy and long-term outcomes have not been examined. Methods We retrieved and analyzed data on sequential patients (pts) with RRMM treated with commercial Ide-cel at a single institution from its approval in 3/2021 until 5/2023. We captured baseline patient, disease and treatment characteristics. We used IgG (with monoclonal component deducted) and uninvolved FLC as indirect surrogate of CAR-T expansion and on target, off tumor killing of non-malignant plasma cells. We assessed cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) based on the American Society for Transplantation and Cellular Therapy criteria and disease responses using the International Myeloma Working Group response criteria. We graded hematologic toxicity using the Common Terminology Criteria for Adverse Events version 5.0. We compared efficacy between the cohorts using overall response rate (ORR) and progression-free survival (PFS), since overall survival is expected to be affected by choice of subsequent, often experimental therapies. Results We identified 28 pts with RRMM who met the inclusion criteria. Nine pts received alternative LD with BENDA (2 pts - renal dysfunction with creatinine clearance <30ml/min; 7 - fludarabine shortage) and 19 received FLU/CY as LD. Baseline characteristics are summarized in Table. Prior autologous stem cell transplant (ASCT) and prior B cell maturation antigen (BCMA) targeting therapy were more frequent in the FLU/CY cohort. Median absolute lymphocyte count (measured in 10^3/ cmm) prior to LD chemotherapy was similar in both cohorts (0.85 in BENDA vs 0.80 in FLU/CY). Median duration of absolute neutrophil count <1,000/μL was shorter in the BENDA cohort. The incidence of any grade CRS (56% vs. 90%, p=0.06) and tocilizumab use (56% vs. 84%, p=0.16) was lower with BENDA compared to FLU/CY. In the absence of ide-cel expansion data, we used nadir polyclonal IgG and uninvolved free light chain (uFLC) in the initial 90 days post CART cell infusion as surrogate of non-malignant plasma burden and therefore ide-cel expansion. We noted lower median uFLC and median IgG with FLU/CY vs. BENDA. The overall response rate was lower with BENDA (22%) vs. FLU/CY (79%, p=0.01). With median follow up of 4.8 mo., all pts in the BENDA cohort progressed with median PFS of 1.6 months vs 7.8 months for FLU/CY (p<0.001, Figure). The median OS for both cohorts is not yet reached. Conclusion: BENDA LD prior to ide-cel infusion results in suboptimal lymphodepletion and subsequent inferior outcomes including low rate of objective responses and decreased progression free survival. The inferior efficacy of BENDA as LD likely results from inferior ide-cel expansion and persistence resulting in less frequent and severe CRS and cytopenias and less suppression of unaffected immunoglobulins. Future efforts to study alternative lymphodepletion approaches is essential given inability to use fludarabine in patients with severe renal dysfunction and periods of critical drug shortages. While there is a need to develop alternatives for LD prior to ide-cel, BENDA is an inadequate substitute of FLU/CY.

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.

Itacitinib for Prevention of Graft-Versus-Host Disease and Cytokine Release Syndrome with T-Cell Replete Peripheral Blood Haploidentical Transplantation

Introduction: Haploidentical peripheral blood allogeneic hematopoietic cell transplantation (PB haplo-HCT) can be complicated by graft-versus-host disease (GVHD) and cytokine release syndrome (CRS). Acute GVHD rates are higher with PB grafts compared with bone marrow, affecting 35-45% of patients and outcomes are poor in steroid refractory cases. Severe CRS occurs in 10-15% of patients receiving PB haplo-HCT and is associated with high non-relapse mortality and one-year overall survival between 25-30%. As interferon-γ and IL-6 are important mediators in both acute GVHD and CRS, we hypothesized that JAK1 inhibition with itacitinib could prevent these toxicities without impairing engraftment. Here we report outcomes from our study of itacitinib with haplo-HCT (NCT03755414). Methods: Patients with AML, MDS, ALL, or NHL in remission undergoing PB haplo-HCT were treated with itacitinib 200 mg/day on days -3 through +100 (first 20 patients) or 180 (second 22 patients), followed by a taper. Myeloablative and reduced intensity conditioning were allowed. GVHD prophylaxis was tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide. Primary outcomes were incidence of primary graft failure and incidence of grade III-IV acute GVHD. Secondary outcomes included incidence and severity of CRS, relapse, GRFS, and overall survival. Results: Forty-two patients were enrolled and underwent transplantation on study between November 2019 and December 2022, median days of follow up was 453 days (range 142-1259). The patient population had a median age of 60 years (20 - 73 years) with the majority of patients having AML (AML 60%, ALL 21%), MDS 10%, MF 5%, NHL 4%). All patients with AML, MDS, or ALL were in a complete morphologic remission, although 45% had disease by either cytogenetics, next generation sequencing, or measurable residual disease assay (flow cytometry for AML/MDS, NGS for ALL). There were no cases of grade III-IV acute GVHD. The cumulative incidence of grade II acute GVHD on day 100 was 17.3% (95% CI, 7% - 31%), day 180 was 20.5% and day 365 was 20.5%. There were no cases of severe CRS with 90% of patients having grade 1 CRS and 10% having no CRS. No anti-IL6R or steroid therapy was used. There were no cases of primary graft failure. The cumulative incidence of relapse at 1 year was 10% (95% CI, 3% to 22%) and at 2 years was 14% (95% CI, 5% to 29%). In patients who survived without relapse to day 100, the 1-year cumulative incidence of moderate or severe chronic GVHD was 5% (95% CI 1% - 17%). The refined GRFS at day +180 was 85% (95% CI 69% - 93%) and at day +365 was 79% (95% CI 62% - 89%). Overall survival at 180 days 87% (95% CI 72% - 94%) and at 1 year was 80% (95% CI 63% - 90%). Analysis of peripheral blood mononuclear cells at day +28, +60, and +100, revealed that patients on itacitinib, compared with control haplo-HCT patients, had lower numbers of CD4 and CD8 central memory T cells, lower numbers of CD4 and CD8 naïve T cells, and higher numbers of classical monocytes, nonclassical monocytes, and both myeloid and plasmacytoid dendritic cells. In itacitinib treated patients, T-cell subsets expressed lower LAG3 and PD-1 and higher TIGIT, while monocytes expressed higher HLA-DR, CD80, and CD86. Conclusions: Itacitinib with PB haplo-HCT was safe with low rates of acute and chronic GVHD, without increased risk of relapse or transplant related mortality. Severe CRS was not seen in this trial, and no anti-IL6 or steroid therapy was used. The addition of Jak inhibition to standard PtCy based GVHD prophylaxis was associated with encouraging rates of GRFS and OS on this pilot and expansion study. Patients on itacitinib have unique immune reconstitution characteristics both in terms of PBMC counts and signaling markers within subsets.

Prophylactic Tocilizumab to Prevent Cytokine Release Syndrome (CRS) with Teclistamab Administration

Introduction: Teclistamab is a T-cell redirecting bispecific antibody that targets both CD3 on the T-cell surface and B-cell maturation antigen (BCMA) expressed on myeloma cells. Teclistamab gained accelerated approval for RRMM patients that had previously been treated with 4 prior lines of therapy including a PI, IMID and a CD38 monoclonal antibody. This approval was based on the results of the MajesTEC-1 study demonstrating an ORR of 63%. Cytokine release syndrome (CRS), a known complication of T-cell engaging therapies, occurred in 72% patients which required a REMS program to monitor the patients in hospital for 48 hours post both priming doses and the target dosing. Several approaches are in place to minimize the risk of CRS to allow for the administration of teclistamab safely as an outpatient. We have evaluated the role of administering tocilizumab prophylactically to mitigate the incidence and the severity of CRS. Methods: A total of 48 patients were admitted to the Emory University hospital from December 2022 until July 2023 as mandated by REMS program for teclistamab step-up dosing followed by the first full dose at least 48 hours apart (0.06, 0.3, and 1.5mg/kg) with premeds per institutional guidelines (Benadryl 50 PO, Tylenol 650 PO, and Dexamethasone 16mg PO 30 minutes prior to each dose). Upon evaluation of our first 15 patients, the median time to CRS from the administration of the first-priming dose was 48 hours. We subsequently administered tocilizumab 8mg/kg IV over an hour (max dose of 800 mg) prophylactically at 44 hours (4 hours prior to the second step-up dose level) for the next 33 patients. CRS was graded per the American Society for Transplantation and Cellular Therapy criteria and managed according to institutional guidelines. Results: The median age of the patients was 66 years (range, 44-82). All patients were IMID, PI and CD38 mab refractory. The rate of all grade CRS amongst the entire cohort was 21 of 48 patients (43.8%). CRS occurred in 10 of the 33 patients (30.3%) who received prophylactic tocilizumab, compared to 11 of 15 (73.3%) of patients that did not. The majority the events in the prophylactic tocilizumab group are grade 1 [8 (24.2%)]. 1 patient had grade 2 and another had grade 3 CRS (patient with an aggressive relapse at time of teclistamab administration, requiring 3 doses of tocilizumab every 8 hours). The median number of tocilizumab doses was 1 (range, 1-3). The median duration of CRS was 1 day (range, 1-3). 1 dose of steroids (outside of premeds) was administered in the 1 patient who experienced grade 3 CRS but in no additional patients treated with prophylactic tocilizumab. Concurrent immune effector cell neurotoxicity syndrome (ICANS) was also decreased with the incorporation of prophylactic tocilizumab (20% vs 6.1%, respectively). All ICANS in the prophylactic cohort were grade 1 and managed symptomatically. The median duration of ICANS was 1 day. The non-prophylactic cohort experienced 3 of 15 (20%) patients with readmissions, with 1 additional patient going to hospice. None of the patients in the prophylactic cohort were readmitted to the hospital within 14 days of discharge. Conclusion: Prophylactic tocilizumab prior to the second priming dose has decreased the incidence and severity of CRS in heavily refractory RRMM patients receiving teclistamab. These results are lower in absolute incidence and severity when compared to the MajesTEC-1 trial where CRS was seen in 72% of patients. Prophylactic tocilizumab prevented usage of steroids, prevented dose delays, prevented readmission to the hospital, and possibly reduced the occurrence of ICANS. These data make a case for early incorporation of prophylactic tocilizumab and support outpatient administration of teclistamab in most patients.

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (>5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

Model-Based Exploration of the Impact of Prophylactic Tocilizumab on IL-6 Dynamics in Multiple Myeloma Patients Receiving Teclistamab Treatment

Introduction: Teclistamab is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody (BsAb) with personalized, weight-based dosing for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM).In the MajesTEC-1 study (NCT03145181 and NCT04557098), the incidence of all grade (mostly grade 1 or 2) cytokine release syndrome (CRS) was 72.1% (Moreau et al. 2022). The cytokine interleukin-6 (IL-6) is found to be increased in the serum of patients with CRS (Shimabukuro-Vornhagen et al. 2018). Tocilizumab is a humanized IL-6 receptor-inhibiting monoclonal antibody. As a competitive antagonist, tocilizumab inhibits the IL-6 pathway by competing with IL-6 for binding to IL-6 receptor (IL-6R), resulting in lower IL-6R receptor occupancy (RO) by IL-6, thereby blocking IL-6 signaling. By blocking IL-6R, tocilizumab also reduces IL-6R-mediated IL-6 clearance, which leads to an increase in serum IL-6 levels (Uchiyama et al. 2008). It has been published previously that a single dose of prophylactic tocilizumab reduced the overall incidence of CRS to 26% after teclistamab administration, which represents a 64% reduction compared to the CRS incidence observed in MajesTEC-1 (van de Donk et al. 2023). A mechanism-based PK/PD model was used to evaluate the impact of tocilizumab prophylactic treatment on the soluble IL-6R (sIL-6R), IL-6 and the duration of the blockade of IL-6 signaling pathway in the patients following teclistamab treatment. Methods: A mechanism-based PK/PD model was built by using reported tocilizumab PK parameters and sIL-6R target engagement. The time course of IL-6R RO for patients receiving prophylactic tocilizumab following teclistamab treatment was estimated from the PK profiles of tocilizumab and competitive binding kinetics. Among the patients with evaluable serum IL-6 levels, the highest peak serum IL-6 concentration in the patients who didn't have CRS (N=9) from prophylactic tocilizumab cohort of MajesTEC-1 was selected as the worst-case scenario. The IL-6R RO in patients receiving prophylactic tocilizumab in the worst-case scenario was characterized by model simulations and the results were compared to the calculated IL-6R RO in the cohorts following teclistamab treatment without prophylactic tocilizumab (N=40). Results: Time course of serum IL-6 levels following teclistamab treatment showed higher and earlier induction in the cohort with tocilizumab prophylaxis compared to the cohort without tocilizumab prophylaxis. Among the patients who received tocilizumab prophylactic treatment, the median peak serum IL-6 level was 208.6 pg/mL and the highest peak serum IL-6 level was 1701.8 pg/mL in patients who didn't have CRS. The model simulation results showed that a single dose of tocilizumab at 8 mg/kg IV given prophylactically could lower the IL-6R RO by IL-6. In a patient with 1700 pg/mL of serum IL-6 treated with tocilizumab, IL-6R RO was maintained below the level of RO achieved with 10 pg/mL of serum IL-6 in the absence of tocilizumab for approximately 10 days. An IL-6 level of 10 pg/mL was considered as a representative value in the patients who did not have CRS following teclistamab at the approved dosing regimen without prophylactic tocilizumab, as more than half (58%) of these patients showed peak serum IL-6 level below 10 pg/mL. The duration of IL-6R RO reduction covers the two step-up doses (SUD) and the first full treatment dose according to the teclistamab approved dosing schedule. Conclusions: The modeling and simulation results showed that a single dose of tocilizumab given prophylactically at 8 mg/kg could block IL-6R RO for approximately 10 days following the 1 st step up dose of teclistamab. The results further support this approach for lowering overall risk of CRS during the SUD schedule in multiple myeloma patients treated with teclistamab.

Balancing Monitoring and Access: Optimal Duration of Monitoring for CD19 and BCMA CART Recipients for Lymphoma and Myeloma

Background: Due to the risks of cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndromes (ICANS), a four-week monitoring period near the authorized treating center (ATC) is a requirement for all currently approved chimeric antigen receptor T cell (CART) therapies, as part of the required Risk Evaluation and Mitigation Strategy (REMS) programs. The purpose of the REMS program is to facilitate prompt administration of tocilizumab within 2 hours in the event of life-threatening adverse events . Most ATCs require patients to stay within a 30-60-minute radius of the ATC and require a dedicated caregiver. While monitoring is essential for safety, the optimal duration of monitoring post-CART has not been studied. It is an area of need as there is a known financial burden of relocation, which may increase gaps in access to care, especially for underserved populations. We evaluated real-world safety outcomes of patients receiving CD19 and BCMA CART for non-Hodgkin lymphoma (NHL) and relapsed refractory multiple myeloma (RRMM). Methods: Patients (pts) with NHL and RRMM who received commercial CD19-directed (axi-cel, tisa-cel, liso-cel, brexu-cel) and BCMA-directed CART (ide-cel, cilta-cel) respectively, from 1/2017 to 1/2023, at the University of Kansas Health System and Medical University of South Carolina were included. Based on each patient's 5-digit zip code, travel distance to the ATC, median household income, and rural or urban residence were estimated. Patients were divided into two groups: those who had either first or recurrent CRS or ICANS occurring at Day 7 or later (Events≥ D7) and the group with no CRS/ICANS ≥ Day 7 (No Events ≥ D7). Chi-square test and proportion tests were calculated. Results: 185 patients (pts) including 127 NHL pts (59% axi-cel, 19% tisa-cel, 13% liso-cel, 8% brexu-cel) and 58 RRMM pts (75% ide-cel and 25% cilta-cel) were included. Most patients (65%) lived beyond 30 minutes of the ATC, and only 23.2% were from rural neighborhoods. (Table 1) 150 pts were in the “No Events ≥ D7” while 35 pts were in the Events≥ D7 group. There were no differences in baseline characteristics of these groups (Table 1). 151 pts (81.6%) and 70 (39%) pts developed new-onset CRS and ICANS respectively on D0-28. Median time to onset for CRS vs ICANS: 2 (IQR 25-75%:1-4) vs 5 (IQR 25-75%:3-8). Median time to CRS vs ICANS resolution relative to infusion was 6 days (IQR 25-75%: 3-7) vs 11 days (IQR 25-75%: 8-15). 137 (91%) had onset of CRS D0-6, 12 (26% of at-risk at D7) developed CRS D7-14. There was no new onset CRS D15 onwards, although one pt (axi-cel recipient) developed CRS recurrence D15-28, and another axi-cel recipient developed CRS recurrence D43. Only these 2 pts had ongoing CRS beyond D14. 45 (64%) had onset of ICANS D0-6, 20 (14% of at-risk at D7) developed ICANS D7-14. Of the 119 at risk, 4 pts (1 axi-cel, 1 tisa-cel, 2 ide-cel) developed ICANS D15-28 and one pt (cilta-cel recipient) experienced new ICANS onset beyond D28. 30 pts had ongoing ICANS beyond D14 and 5 beyond D28. There was no significant association with disease, early vs no early event, product, co-stimulatory domain (CD28 vs 4-1BB), year of infusion (2021 onwards vs prior), or SDOH with CRS or ICANS on multivariate analysis. Resource Utilization: Tocilizumab (toci) was administered in 67% pts, median 2 doses (1-4). Median time to first dose toci was 3 days (0-11) and median time to last dose was 4 days (0-43). 44% pts received steroids, and all had first dose prior to D15. 14 pts had infections requiring admission D15-28. Other outcomes and resource utilization are shown in Table 2. Mortality:There were 15 deaths D0-90, mostly due to progression (9), 4 due to infection, and 1 “other” cause. No deaths were attributable to CRS or ICANS. Of these, one death occurred D0-28 (in an axi-cel recipient) due to progression. Conclusions: Despite differences in patterns of CRS and ICANS with CART products, there is a low incidence of CRS and ICANS onset beyond 2 weeks, but persistent risk of other fatal complications, mostly infectious, even beyond the mandated monitoring period. Our study suggests a flexible monitoring period proximal to the ATC for CRS/ICANS may be safe for select patients and will likely be more feasible especially for disadvantaged populations with limited support. Exploring hybrid models and earlier partnership of referring centers and ATCs for monitoring, may allow personalized continuum of care and improve outcomes.

Simvastatin with Intrathecal Dexamethasone Reduces Neurotoxicity in Adults Receiving Chimeric Antigen Receptor (CAR) T-Cells Treatment

Background Chimeric antigen receptor (CAR) T-celltherapy has become the standard of care for many relapsed/refractory hematological malignancies. There are significant associated side effects, most importantly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can limit its use in older and vulnerable populations. The rate of ICANS with axicabtagene ciloleucel (axi-cel) in the pivotal studies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) was approximately 60% with grade 3 or higher (≥ G3) in the range of 19-28%. Similarly, with brexucabtagene autoleucel (brexu-cel), ICANS also occurred in approximately 60% with ≥ G3 occurring in 26-31% of patients. The mechanism underlying ICANS remains unclear. The current hypothesis is that endothelial injury caused by systemic immune activation leads to the breakdown of the blood-brain barrier with the influx of pro-inflammatory cytokines into the CSF and subsequent activation of resident immune cells and neuroglial cells leading to local production of cytokines and the clinical syndrome observed. ICANS is treated with systemic steroids that have good central nervous system (CNS) penetration. Statins have been shown to stabilize the endothelium and have anti-inflammatory effects. We are currently evaluating the safety and feasibility of administering simvastatin in addition to intrathecal dexamethasone to decrease the incidence and/or severity of neurotoxicity in CAR-T recipients and we are herein reporting preliminary results. Methods This is a feasibility study (NCT04514029) combining simvastatin 40 mg daily, starting 5 days prior to apheresis and continuing through day +30 with dexamethasone (8 mg) delivered intrathecally (IT) on days -1 and +6 in relation to CAR T-cell infusion. Adult patients (age ≥18 years) receiving axi-cel or brexu-cel for FDA-approved indications are included. The primary endpoint is the percentage of patients who complete 80% of this therapy (pills and intrathecal). Secondary endpoints include the incidence of CRS and ICANS as well as overall response rates (ORR). Results At the time of data cutoff, a total of 15 patients who received treatment with axi-cel or brexu-cel and completed follow-up were enrolled. Baseline demographics and clinical characteristics are summarized in Table 1. Among patients who received axi-cel, 10 patients had DLBCL and 1 patient had FL. For brexu-cel, 2 patients had mantle cell lymphoma (MCL) and 2 had B-acute lymphoblastic leukemia (B-ALL). Median prior lines of treatment was 3 (range 2 to 7) and 11 patients (46.7%) had progressive disease at the time of the treatment. Analysis of baseline inflammatory markers prior to the cell infusion showed that 2 patients (13.3%) had elevated lactate dehydrogenase (LDH; upper limit normal 250 U/L; median 180, range 100 to 279). Eight patients (53.3%) had elevated C-reactive protein (CRP; median 9.24 mg/L, range <3 to 67.8). Ferritin was elevated in 6 patients (40%) (median 382, range 34 to 1749). All patients received > 80% of the total assigned doses. One patient was unable to receive intrathecal therapy due to thrombocytopenia with platelet transfusion refractoriness. All evaluable patients completed oral simvastatin with no patients requiring dose reductions. CRS occurred in 13 patients (86.7%), with ≥ G3 occurring in 1 patient (6.7%). Tocilizumab (8 mg/kg) was administered to 11 patients (73.3%) with the median number of doses being 1 (range 1 to 4). ICANS occurred in 4 patients (26.7%), with ≥ G3 occurring in 2 patients (13.3%) - one G3 and one G4 in the patient who was unable to receive IT therapy. Glucocorticoids were used in 3 patients (20%) for the management of ICANS. There were no grade 4 CRS events and no deaths related to CRS or ICANS. One patient had a vasovagal syncopal episode prior to the beginning of a lumbar puncture. There were no other ≥ G3 AEs associated with the administration of simvastatin or IT dexamethasone. One patient with Richter's had progressive disease at day 30, 4 patients had partial remission, and 10 patients had a complete remission for an ORR of 93%. Conclusions Preliminary results show that simvastatin and intrathecal dexamethasone appear to be feasible, safe, and effective in reducing the incidence and severity of ICANS in patients receiving axi-cel and brexu-cel.

Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients

BackgroundChimeric antigen receptor T (CAR-T) cell therapy, a new adoptive cell therapy, has been widely used to treat lymphoma patients. Immune checkpoint blockade may improve the cytotoxicity of CAR-T cells by reducing the failure of CAR-T cells and improving antitumor activity. It has shown promising efficacy.MethodWe searched PubMed, the Cochrane Library, Embase and Web of Science from January 2012 to August 2022 to find data reporting the results of CAR-T cells therapy combined with PD-1 in tumor patients. An updated search was conducted in October 2023. The partial response rate (PR), complete response rate (CR), objective response rate (ORR), mortality rate, and incidence of adverse reactions were calculated.ResultsWe analyzed 57 lymphoma patients from 5 clinical trials. The pooled partial, complete and overall response rates were 21% (95% CI 0.06–0.39, I2 = 0.37%), 27% (95% CI 0.03–0.60, I2 = 60.43%) and 65% (95% CI 0.23–0.98, I2 = 76.31%), respectively. The pooled incidence of cytokine release syndrome, neutropenia, fever, and fatigue was estimated to be 57% (95% CI 0.08–0.99, I2 = 85.20%), 47% (95% CI 0.14–0.81, I2 = 74.17%), 59% (95% CI 0.27–0.89, I2 = 60.23%), and 50% (95% CI 0.13–0.87, I2 = 73.89%), respectively.ConclusionCAR-T-cell therapy combined with anti-PD-1 immunotherapy in the treatment of lymphoma patients has efficacy, and the most common adverse effect is fever.RegistrationThe protocol was registered in prospero, with the registration number CRD42022342647.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40months, whereas CD19+ FTCs vanished in 8 patients 3months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

Negative Prognostic Impact of High-Dose or Long-Term Corticosteroid Use in Patients with Relapsed or Refractory B-Cell Lymphoma Who Received Tisagenlecleucel

The prognostic impact of corticosteroid therapy in patients receiving tisagenlecleucel (tisa-cel) treatment who are more likely to develop cytokine release syndrome (CRS) remains unclear. This study aimed to evaluate the clinical impact and lymphocyte kinetics of corticosteroid administration for CRS in 45 patients with relapsed and/or refractory B cell lymphoma treated with tisa-cel. This was a retrospective evaluation of all consecutive patients diagnosed with relapsed and/or refractory diffuse large B cell lymphoma, follicular lymphoma with histologic transformation to large B cell lymphoma, or follicular lymphoma who received commercial-based tisa-cel treatment. The best overall response rate, complete response rate, median progression-free survival (PFS), and median overall survival (OS) were 72.7%, 45.5%, 6.6 months, and 15.3 months, respectively. CRS (predominantly grade 1/2) occurred in 40 patients (88.9%), and immune effector cell-associated neurotoxicity syndrome (ICANS) of all grades occurred in 3 patients (6.7%). No grade ≥3 ICANS occurred. Patients with high-dose (≥524 mg, methylprednisolone equivalent; n = 12) or long-term (≥8 days; n = 9) corticosteroid use had inferior PFS and OS to patients with low-dose or no corticosteroid use (both P < .05). The prognostic impact remained even in 23 patients with stable disease (SD) or progressive disease (PD) before tisa-cel infusion (P = .015). but not in patients with better disease status (P = .71). The timing of corticosteroid initiation did not have a prognostic impact. Multivariate analysis identified high-dose corticosteroid use and long-term corticosteroid use as independent prognostic factors for PFS and OS, respectively, after adjusting for elevated lactate dehydrogenase level before lymphodepletion chemotherapy and disease status (SD or PD). Lymphocyte kinetics analysis demonstrated that after methylprednisolone administration, the proportions of regulatory T cells (Tregs), CD4+ central memory T (TCM) cells, and natural killer (NK) cells were decreased, whereas the proportion of CD4+ effector memory T (TEM) cells was increased. Patients with a higher proportion of Tregs at day 7 had a lower incidence of CRS, but this did not affect prognosis, indicating that early elevation of Tregs may serve as a biomarker for CRS development. Furthermore, patients with higher numbers of CD4+ TCM cells and NK cells at various time points had significantly better PFS and OS, whereas the number of CD4+ TEM cells did not impact prognostic outcomes. This study suggests that high-dose or long-term corticosteroid use attenuates the efficacy of tisa-cel, especially in patients with SD or PD. Additionally, patients with high levels of CD4+ TCM cells and NK cells after tisa-cel infusion had longer PFS and OS.