Abstract Introduction: Despite the growing success of chimeric antigen receptor (CAR) T cell therapy in treating previously incurable cancers, toxicities remain a major concern. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the most common and potentially life-threatening adverse events (AEs) associated with CAR-T cell therapy and are related to a heightened immune effector state. We explored a previously unidentified role of B-cell activating factor (BAFF), a cytokine that plays a prominent role in B-cell tumor microenvironments, in the pathophysiology of these AEs. Methods: A Luminex multi-analyte assay was used to measure serum levels of BAFF and known CRS cytokines in patients who experienced CAR-T CRS. To identify the cell types contributing to the release of BAFF in vitro, monocytes, CD19 CAR-T cells, and Jeko-1 cancer cells were incubated alone or at a 1:1:1 ratio, and a multiplex assay was performed on the supernatant. After IFN-γ stimulation of monocytes, BAFF secretion and expression of the BAFF receptors (BAFF-R, TACI, BCMA) were measured by ELISA and flow cytometry, respectively. To determine the impact of BAFF on cytokine release, this tri-culture was co-incubated in the presence of a BAFF or BCMA neutralizing antibody, and cytokine release was measured by multiplex assay (IL-6, IL-1β, GM-CSF, IL-10, CXCL8, CCL2). To determine if BAFF neutralization interferes with CAR-T cell function, cancer cells were cocultured with CD19 CAR-T cells in the presence of monocytes and a BAFF-neutralizing antibody. Cytotoxicity was measured by propidium iodide uptake in cancer cells, and activation and degranulation of CD3+ cells was measured by percent positivity of CD69 and CD107a by flow cytometry. Results: First, we observed that patients who experienced CAR-T cell-related CRS have elevated serum BAFF levels that coincide with increased IL-6 and other known CRS and ICANS-associated cytokines. In the tri-culture system of monocytes, cancer cells, and CAR-T cells, monocytes were the primary cellular producer of BAFF. Mechanistically, we show that IFN-γ, produced by activated CAR-T cells, stimulates monocytes to release BAFF. Additionally, monocytes derived from CRS patients express BCMA, which is further induced by IFN-γ stimulation. In the tri-culture system of cancer cells, monocytes, and CD19 CAR-T cells, neutralization of BAFF or BCMA significantly reduces production of various CRS and ICANS-related cytokines without impairing CAR-T cell function. Conclusion: We demonstrate that BAFF plays a role in CAR-T-cell-related AEs, and that its neutralization may be a novel strategy for treating both CRS and ICANS. In our model, we suggest that activated CAR-T cells secrete IFN-γ, which can increase the expression of BCMA on monocytes as well as the secretion of BAFF. BAFF binds to BCMA and induces increased release of cytokines that contribute to CRS and ICANS. Citation Format: Claire Fritz, Leland Metheny, David N. Wald, Paolo Caimi, Reshmi Parameswaran. B-cell activating factor plays a critical role in CAR-T cell-associated cytokine release syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1543.

Introduction: Chimeric antigen receptor (CAR) T-cell therapies have radically changed the treatment paradigm of patients (pts.) with relapsed/refractory (r/r) hematologic malignancies. Despite their remarkable efficacy, health care disparities can impact outcomes of pts. in the real-world setting. Living in a disadvantaged neighborhood has been associated with inferior outcomes after allogenic hematopoietic stem cell transplantation (HSCT), independent from individual-level socioeconomic (SE) factors. Our study aimed to identify the impact of neighborhood adversity on survival outcomes of recipients of CAR T-cell therapies, as this has not been yet described. Methods: We retrospectively identified consecutive adult pts. with r/r B-cell non-Hodgkin lymphoma (B-NHL) and multiple myeloma (MM) who received CAR T-cell therapies at our center from May 2018- January 2023. Neighborhood disadvantage was defined by Area Deprivation Index (ADI), a validated tool that allows for ranking of census block groups based on SE domains (income, education, employment, and housing quality) at a national level. The 2021 national ADI percentile ranks (1-100) were obtained for each pt. using the 9-digit zip code of place of residence, with a higher rank corresponding to higher level of disadvantage. We compared overall survival (OS) and progression free survival (PFS) between pts. with high vs. low ADI. We also examined survival outcomes in relation to estimated distance from place of residence to treatment center (DTC). Time dependent outcomes were calculated from date of CAR T infusion. Pts. with B-NHL and MM were analyzed separately. Baseline variables were compared between groups using chi-squared, t-test, and Wilcoxon rank sum tests as appropriate. Survival estimates were calculated with Kaplan-Meier method, and hazard ratios were generated using cox proportional hazards model. Results: CAR T therapy was administered in 124 and 45 pts. with B-NHL and MM, respectively. Median ages were 65 and 62 yrs., 68% and 51% were male, 94% and 84% were White, 47% and 20% had high-risk disease (based on IPI/MIPI for B-NHL, and FISH for MM), 30% and 69% had prior HSCT, and median number of prior therapies were 3 (range 1-6) and 6 (range 4-14), among pts. with B-NHL and MM, respectively. B-NHL subtypes included DLBCL (84%), MCL (6%), FL (5%), and PMBCL (5%), and CAR T products for B-NHL were axi-cel (52%), tisa-cel (24%), liso-cel (18%) and brexu-cel (6%). Ide-cel (82%) and cilta-cel (18%) were used in pts. with MM. We treated pts. from 169 census block groups over 8 states, although 89% pts. were from Ohio. For the entire cohort, median ADI rank was 62.5 (range 1-100) and median DTC was 42.5 (range 1-4559) miles (m). Pts. were categorized (based on median) as having high (> 62.5) or low (≤ 62.5) ADI, and long (> 42.5m) or short (≤ 42.5m) DTC. Longer DTC was significantly associated with higher ADI ( p<0.001). Baseline characteristics (age, sex, prior therapies, prior HSCT, high risk disease, CAR T product) were similar across groups with low vs. high ADI and short vs. long DTC. Median follow up time up was 12 (range 4-60) and 9 (range 4-22) months for living pts. with B-NHL and MM, respectively. For pts. with B-NHL, objective response rates (ORR) (85% vs. 80%; p=0.4), relapse rates (RR) (66% vs. 66%; p=0.9), median OS (19 vs. 14 months; HR of death: 1.2; 95% CI 0.7-1.8; p=0.5) ( Fig.1), and median PFS (10 vs. 5 months, HR of relapse: 1.1, 95% CI 0.7-1.7; p=0.6) were similar for pts. with low vs. high ADI. For pts. with MM, there were no differences in ORR (77% vs. 87%; p=0.3), RR (77% vs. 70%; p=0.5), median OS (14 vs. 18 months; HR of death: 0.8; 95% CI: 0.3-2; p=0.6) ( Fig.2), and median PFS (7 vs. 9 months, HR of relapse: 0.7, 95% CI 0.3-1.4; p=0.3) between those with low vs. high ADI. There were no differences in median OS of pts. with short vs. long DTC for NHL (19 vs. 14 months; HR: 1.2, 95% CI 0.7-1.9, p=0.4) or MM (14 vs. 20 months; HR: 0.9, 95% CI 0.3-2.5; p=0.9), or when DTC was analyzed as a continuous variable. Conclusion: In patients with r/r B-NHL and MM who received CAR T-cell therapies, response rates and survival outcomes were comparable regardless of neighborhood disadvantage level or distance to treatment center. Pts. living in more disadvantaged neighborhoods travelled longer distances for treatment. These findings prompt future investigation into referral patterns and access barriers to cellular immunotherapy, especially in disadvantaged neighborhoods.

Introduction BMS-986353 is a CD19 CAR NEX-T cell therapy (Fig 1) that expresses the same CAR as lisocabtagene maraleucel, manufactured via minimally expanded manufacturing process optimized to improve scalability and global patient access. BMS-986353 is being studied in autoimmune indications. Objective Safety and preliminary efficacy of BMS-986353 in multiple severe refractory autoimmune diseases. Methods Two phase 1 studies are evaluating BMS-986353 in severe refractory systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM) (Breakfree-1, NCT05869955), and highly active relapsing multiple sclerosis (haRMS), progressive multiple sclerosis (PMS), and refractory myasthenia gravis (MG; Breakfree-2, NCT06220201).Immunosuppressive therapies (ISTs) were discontinued before lymphodepletion. Patients (pts) received a single BMS-986353 infusion at the recommended phase 2 dose (10 × 106 CAR+ T cells). Primary endpoint: safety. Results As of August 20, 2025, all treated pts (N = 83; SLE, 26; SSc, 25; IIM,14; haRMS, 6; PMS, 9; MG, 3) were safety evaluable. Median follow-up: 92 (range, 2−644) days.Pts had active inflammatory disease: SLE (recent British Isles Lupus Assessment Group Category A), SSc (progressive skin/lung), IIM (severe muscle/skin), haRMS (breakthrough activity), PMS (disability progression), and MG (class II-IV) and highly refractory disease with failed prior ISTs (median): SLE, 7; SSc, 3; IIM, 6; haRMS, 2; PMS, 2.All inflammatory AEs were brief and reversible (Table). Cytokine release syndrome occurred in 59.0% pts; most were grade 1 (Gr; Gr1, 48.2%; Gr2, 8.4%; Gr3, 1.2%), resolving in median 3 days. Immune effector cell-associated neurotoxicity syndrome occurred in 12.0% of pts; most were Gr 1 (Gr1, 7.2%; Gr2, 1.2%; Gr3, 3.6%), resolving in median 3 days. Cytopenias occurred in only 53% of patients and no prolonged high-grade cytopenias were observed.At 6 mo, pts showed median (range) improvement in: SLE, SLE Disease Activity Index 2000 by 10 points (18 to 0); SSc, modified Rodnan skin score (skin thickness) of 8.5 points (-20 to -2) and predicted forced vital capacity by 6.4% (2.9–14.0); and IIM, muscle manual test-8 score (muscle strength) of 27 points (17-42). 91.6% of pts across indications remained off ISTs.All pts achieved complete peripheral B-cell depletion and robust cellular expansion. Median time to B-cell repopulation was 113 days and were predominantly naive (Fig 2). Conclusion CD19 NEX-T CAR T cell therapy demonstrates a manageable safety profile with only transient and reversible CRS and ICANS in the largest dataset in non-malignant indications to date. Preliminary clinical efficacy, robust CAR T cell expansion, complete B-cell depletion, re-emergence of naive B cells, and IST-free responses suggest immune reset potential.

Sexual dysfunction (SD) is reported as one of the most distressing survivorship concerns of cancer patients, impacting quality of life, intimate relationships, and overall well-being. Despite significant evidence that survivors of allogeneic hematopoietic cell transplant (HCT) experience SD, there are significant gaps in addressing sexual health and supportive interventions. The Cleveland Clinic Blood and Marrow Transplant program collects patient-reported data including SD symptoms at Day 100, 1 year, 2 years and 5 years post-HCT. This single institution study aims to describe the prevalence of SD in our HCT patient population, number of patients who underwent further evaluation of SD, and referral and treatment of SD symptoms.Patient reported SD symptoms collected include: difficulty getting/maintaining an erection, difficulty with ejaculation and difficulty with libido/desire (male) and difficulty with libido/ desire and vaginal dryness or pain (female). Referrals included: urology, gynecology, endocrinology, and fertility clinic. Hormonal evaluation included testosterone, FSH, LH, Estradiol-17B, and anti-mullerian hormone. Treatments include phosphodiesterase 5 (PDE5) inhibitor, hormone replacement therapy (HRT), and prescription topicals.We identified 104 adult patients who underwent first allogeneic HCT between July 2019 and March 2022 and had at least one survivorship clinic visit containing patient-reported SD data entered into our RedCap database. Of these, 58 were male and 46 female. Median age at time of transplant was 63 years (range 20-76). SD data was available for 97 patients at Day 100, 69 at 1 year, 43 at 2 years and 16 at 5 years post-HCT.Overall, 30% (N=31) of female patients and 39% (N=47) of male patients reported having at least one or more symptoms of SD. Vaginal dryness or pain was the most common symptom in females (23%). Difficulty getting or maintaining an erection was the most reported male symptom (39%) (Table 1). Except for male patients at 5 years post-transplant, patient-reported SD symptoms increased over timeConsult to gynecology, including women’s sexual health subspecialities, was recommended for 52% of patients who did not have a GYN exam in the last year regardless of symptoms and in 45% of female patients reporting 1 or more SD symptoms. Consult to men’s urology was recommended in 43% of male patients reporting 1 or more SD symptoms. 32% of female patients and 30% of male patients with 1 or more symptoms was started or continued on a therapy. Hormone labs were rarely drawn, including patients reporting symptoms.In this study, we report a significant number of patients who report SD dysfunction post transplant. Despite the use of patient-reported symptom assessment of SD, there are still several gaps in addressing these issues. Further work to improve evaluation and referral to SD care, tracking outcomes, and the development of carepaths is needed.

Background Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are common, potentially life-threatening toxicities after CAR T-cell therapy. Elevated IL-6 is mechanistically linked to CRS, yet most studies have retrospectively assessed static or peak cytokine levels. We hypothesized that real-time IL-6 measurement is feasible and that early IL-6 kinetics could predict CRS and ICANS. Methods We prospectively enrolled 42 patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) treated with commercial CAR T-cell products. Serum samples were collected at predefined timepoints [apheresis, day −5 of lymphodepletion (LD), day 0 (infusion), 12 h post-infusion (day 0.5), and days 1, 2, 4, and 7] for real-time IL-6 assay (Beckman Coulter). IL-6 log-slope was calculated using log-transformed values from day 0 to the last sample before toxicity onset, excluding samples drawn after CRS onset or tocilizumab/steroid use. CRS and ICANS were graded per ASTCT criteria. Associations were analyzed using nonparametric tests, logistic regression, and ROC analysis; optimal cutoffs were derived via Youden's index. Results Of 42 pts, 18 (43%) had MM and 24 (57%) NHL; median age was 67 y (39–84), 19% ECOG ≥2, and 36% had prior autologous transplant. CAR T-cell products included cilta-cel (43%), liso-cel (24%), axi-cel (21%), and brexu-cel (12%); 71% received fludarabine/cyclophosphamide LD. CRS occurred in 30 pts (71%) and ICANS in 13 (31%), with grade ≥2 events in 53% and 62%, respectively. Median time to onset was 5 d for CRS and 6 d for ICANS. Median IL-6 turnaround time was 1.7 d (IQR 0.6–3.5). Day 1 IL-6 was higher in ≥G2 CRS (20 vs 8 pg/mL, p=0.013), and peak IL-6 correlated with CRS (33 vs 12 pg/mL, p=0.002) and severity (p=0.005). IL-6 log-slope was higher in CRS (0.77 vs 0.30, p<0.001) and ≥G2 CRS (0.92 vs 0.47, p=0.009). ROC analysis demonstrated that IL-6 log-slope predicts CRS with an area under the curve (AUC) of 0.88. An optimal log-slope cutoff of 0.64 -corresponding to a daily IL-6 increase of ≈90% per day-yielded 89% sensitivity and 92% specificity. For ICANS, ROC analysis demonstrated that IL-6 log-slope predicts ICANS with an AUC of 0.72. A cut-off of 0.25 (increase by ≈29% per day)- yielded sensitivity and specificity of approximately 67% for predicting ICANS. Conclusions Early IL-6 kinetics over the first 4–7 days post-infusion, are significantly associated with the development and severity of CRS, and potentially predictive signal for ICANS. A slope threshold of 0.058, corresponding to a modest ∼6% daily rise, identified patients at high risk for CRS with high specificity. Incorporation into real-time monitoring could enable preemptive tocilizumab use, guide outpatient vs inpatient management, and improve safety in high-risk patients. Further prospective validation in larger cohorts is warranted.

Introduction CD19.CART is highly effective for B-cell non-Hodgkin lymphomas (NHL). However, CRS and ICANS remain a challenge. Interleukin-6 (IL-6) is a mediator of CRS/ICANS. Siltuximab (siltux), an IL-6 antagonist, has efficacy in treating CRS/ICANS (Bajwa, Blood Advances, 2025) and has been shown to reduce checkpoint inhibitor toxicity while improving anti-tumor T-cell differentiation (Hailemichael, Cancer Cell; Speake et al. JCI, 2022). Objectives Here we sought to evaluate if prophylactic (ppx) siltux prior to CD19.CART would be safe, mitigate severe CRS/ICANS, and lead to unique CART differentiation. Methods This phase I, investigator-initiated, single-center trial evaluated the safety of siltux before standard of care CD19.CART for patients (pts) with NHL. Adult pts received a single dose of siltux (11mg/kg) 1 hour prior to CART. The primary endpoint was estimation of safety. Secondary endpoints included clinical outcomes (efficacy and toxicity). Exploratory endpoints included evaluation of CART phenotype by high dimensional spectral flow cytometry and cytokine analysis by 32 plex semi-custom Luminex panel. A cohort of patients who received SOC CD19.CART within 6 months of study pts was used as a control. Results 10 pts were treated from 1/2023 to 8/2023 with characteristics shown in Table 1. No DLTs were observed. Rates, severity and duration of CRS and ICANS are reported in Table 2. One pt had grade (gr) 4 ICANS (seizure) who notably was not on seizure ppx prior to ICANS and who rapidly recovered. ORR was 80% (95% CI, 44-97) with 70% complete responses (CR). Median follow-up was 1.9 yrs (1.5-2.2), 2-yr PFS and OS were 60% (95% CI, 25-83) and 70% (95% CI, 33-89).High-dimensional flow cytometry analysis of 10 siltux pts vs 26 non-siltux control pts at D+14 post-CART revealed broad differences in CAR+ T-cell phenotype and function (Figure 1). Increased CAR+ CD8+ memory T-cells (CD45RO+/CD28+; p=.03), and a trend towards less senescent effector CAR+ CD8+ T-cells (Granzyme B+/CD57+; p=.08) occurred with siltux ppx. Longitudinal cytokine analysis demonstrated improved inflammatory parameters typically associated with CRS/ICANS with siltux ppx. On D+14, median cytokine levels were lower with siltux: TNF-a (p=.02), IFN-g (p=.04), CXCL10 (p=.04), and MIP1-a (p=.02). No significant differences were observed for IL-2, or the homeostatic cytokines IL-15 and IL-7. Conclusion Siltux was safe as ppx prior to CD19.CART. No gr > 3 CRS occurred and only 1 pt developed gr > 3 ICANS which rapidly resolved. ORR and CR rate were excellent and responses were durable. In addition, siltux ppx resulted in a favorable phenotypic and functional differentiation of CAR+ T-cells post-infusion and reduction in cytokines typically associated with CRS/ICANS. This is the first study to demonstrate the ability of IL-6 blockade in human subjects to safely alter CD19.CART cell differential expansion.

ABSTRACT:Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Background T-cell engaging bispecific antibodies (BsAbs) have shown promising activity in patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), including those that have progressed after chimeric antigen receptor (CAR) T-cell therapy. Bispecific antibodies have unique side effect profiles related to robust activation of the immune system. Although the rates of severe cytokine release syndrome (CRS) and neurotoxicity are significantly lower with BsAbs than CAR T, hematological toxicity is increasingly recognized as a common adverse event, with reported rates of grade ≥ 3 neutropenia ranging from 15 to 65% in pivotal trials. We sought to further characterize the incidence of cytopenias in patients receiving BsAbs, evaluate their impact on outcomes and identify predisposing risk factors. Methods We collected baseline, treatment and outcome information from our institutional databases, identifying patients with r/r NHL or MM treated with a BsAb as a single agent between 2020–2024. To test differences between groups, Wilcoxon rank sum test was used on numerical variables, and Fisher's exact test or Pearson's Chi-squared test for categorical variables. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan–Meier methods, with log-rank test used for comparisons between groups. Median follow-up time was estimated using the reverse Kaplan-Meier method. All tests were performed as two-tailed tests, with p < 0.05 considered statistically significant. “Cytopenia” was defined as any grade neutropenia and/or grade ≥3 anemia/thrombocytopenia. Results We identified 199 patients treated with single-agent BsAb, 56 (28%) NHL and 143 (72%) had MM. BsAbs prescribed included teclistamab (n = 80, 40%), talquetamab (n = 38, 19%), epcoritamab (n = 34, 17%), elranatanab (n = 25, 13%), mosunetuzumab (n = 14, 7%), odronextamab (n = 6, 3%) and glofitamab (n = 2, 1%). Median age at initiation of therapy was 68 years (IQR 61 – 76 years), 45% of patients were women, 74% were White, and 22% were Black. Cytopenia was observed in 152 patients (76%). Neutropenia (any grade) occurred in 125 (63%) patients, severe neutropenia (SN; ANC <500 cells/µL) in 51 (26%), grade ≥3 anemia in 84 (34%) and grade ≥3 thrombocytopenia in 66 (34%). The incidence of cytopenia was similar among patients on all BsAbs (p=0.4), ranging from 62% with epcoritamab to 100% with glofitamab. Pre-treatment characteristics associated with development of cytopenia included lower albumin (median 3.7 vs. 3.95 g/dL, p <0.05), higher CRP (median 2.2 vs. 0.4 mg/L, p <0.05), and lower baseline WBC (median 4.4 vs. 6.7x103/µL, p < 0.05), ANC (2.7 vs. 4.5x103/µL, p < 0.05), hemoglobin (9.7 vs. 12.4 g/dL, p < 0.05) and platelets (median 136 vs. 207 x103/µL, p<0.05), when compared to the group with no cytopenias. Previous CAR T cell treatment was not associated with higher incidence of cytopenia (79% vs. 77%, p=0.79), even when CAR T was received in the preceding six months (p = 0.99). Patients experiencing severe neutropenia (SN) had higher rates of CRS (75% vs. 54%, p=0.01), longer time on BsAb therapy (median 5.8 vs. 2.7 months, p=0.01), and higher overall response rate (91% vs. 73%, p=0.01). However, we observed a numeric trend towards higher rates of treatment discontinuation due to BsAb toxicity in patients with SN (25 vs. 14%, p = 0.06). Median follow-up did not differ between patients with SN (13.4 mo, 95% CI 9.9 - 24.8) and no SN (12.6 mo, 95% CI 10.7 - 15.9). The presence of SN was not associated with statistically significant differences in survival outcomes [median PFS: SN 10.4 mo (95% CI 8.1-25.4) vs. no SN 8 mo (95% CI 4.6-12.9); and median OS: SN 24.9 mo (95% CI 14.5-not reached) vs. no SN 14.1 mo (95% CI 11.4-27.4)]. Conclusions In our cohort of patients with r/r NHL and MM treated with a variety of single agent T-cell engaging BsAbs we observed a high incidence of all-grade and severe cytopenias. Higher rates of CRS and disease response in patients experiencing SN suggest the mechanism underlying hematologic toxicity is related to immune activation and possibly anti-tumor immune response. The absence of improved survival outcomes could be due to higher rates of toxicity-related treatment discontinuation. Future studies aimed at prevention and mitigation of BsAb-associated cytopenias while avoiding impacting disease control could improve outcomes of patients treated with this modality.

Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with multiply relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Though response rates are relatively high, most patients (pts) eventually experience progression of disease (POD). We sought to investigate the treatment patterns and clinical outcomes following POD post-BsAb for r/r LBCL Pts, as this has not previously been described. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCL receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAb, of whom a total of 168 (53.8%) pts experienced POD [104 of 193 (53.8%) treated with prior epco and 64 of 119 (53.8%) treated with prior glofit]. Pts with POD had a median age at BsAb start of 67 years (interquartile range [IQR] 58-76), most were male (68.4%), and the most common histology was diffuse large B-cell lymphoma not otherwise specified (n=122 [71.8%]). Sixty-seven of 168 pts (39.9%) with POD after BsAb had experienced primary refractory disease defined as failure to achieve PR or CR to frontline therapy. A total of 102 (60.7%) pts with POD to BsAb had received chimeric antigen receptor (CAR) T-cell therapy prior to BsAbs, with 33.3% of these pts being refractory to CAR T and 30.4% progressing within 6 months of CAR T-cell infusion. The median time to progression following BsAb start was 48 days. Following POD, 70 pts received no further anti-lymphoma therapy. Among 98 pts receiving subsequent therapy, 85 initially received systemic therapy and 13 initially received local therapy with radiation (concurrently with systemic therapy in 8 pts). The most commonly-used next line of systemic therapies included: loncastuximab tesirine in 19 pts (ORR 16.7%, all PR); commercial CAR T in 11 pts (ORR 50% [CR 36.4%, PR 18.2%); tafasitamab with lenalidomide in 7 (no responses); and other chemotherapy in 46 pts (ORR 27.6% [CR 24.1%]). The median follow-up time from POD was 9.2 months among survivors (95% confidence interval [CI] 7.8-13.3). Among those who initiated subsequent-line therapy following BsAbs, the median progression-free survival (PFS2) was 1.9 months (95% CI 1.5-2.4) and median overall survival (OS) from initiation of subsequent-line therapy was 3.9 months (95% CI 2.4-5.5). The estimated 1-year OS following initiation of next therapy was 12%. Conclusions: We report the outcomes of largest cohort of pts with POD post-BsAbs in r/r LBCL. Progression events occurred early after initiation of single agent BsAbs, and almost half of pts who progressed did not receive subsequent therapy. For those who received standard subsequent-line therapy after POD, response rates and survival outcomes were poor. Pts with POD after BsAB should be strongly considered for clinical trials of novel therapeutics or combination therapies.

R-CHOP as first-line (1L) therapy for LBCL has a cure rate of ~60%. However, ~10% of patients (pts) have refractory LBCL (Coiffier B et al, NEJM 2002) and ~30% of responders relapse within 2 years (Padala SA & Kallam A, In StatPearls. StatPearls Publishing; 2023). Autologous CAR T-cell therapies have been revolutionary in the treatment of relapsed/refractory (R/R) LBCL and they are considered standard second-line treatment but might not be an option due to aggressive disease, pt comorbidity, access barriers, or manufacturing issues/delays. Identifying responders to 1L therapy who are at high risk of relapse and rapidly administering an off-the-shelf CAR T-cell therapy for remission consolidation may improve outcomes. Presence of circulating tumor DNA (ctDNA)–based MRD, measured by an ultrasensitive MRD test at the end of 1L therapy, is highly prognostic for relapse. Cema-cel is an immediately available, off-the-shelf, HLA-unmatched allogeneic CD19 CAR T-cell product that utilizes Cellectis technologies has shown potent antitumor activity and manageable safety in phase 1 studies of pts with R/R LBCL and is a promising agent for consolidation in this treatment setting. The pivotal, randomized, open-label, phase 2 ALPHA3 study (NCT06500273) was designed to evaluate the efficacy and safety of consolidation with cema-cel compared with standard-of-care (SOC) observation in pts with LBCL who are in response after 1L immunochemotherapy but have detectable MRD by ctDNA-based testing. We report the updated study design.Study Design and Methods: Adults with histologically confirmed diffuse LBCL (DLBCL; includes DLBCL not otherwise specified, Epstein-Barr virus–positive DLBCL, DLBCL with IRF4/MUM1 rearrangement), high-grade B-cell lymphoma (HGBCL; includes HGBCL not otherwise specified, or with MYC and BCL2 and/or BCL6 rearrangements), or primary mediastinal B-cell lymphoma per WHO 2017 classification and ≥1 of the following clinical criteria at diagnosis—International Prognostic Index score of 2-5; Ann Arbor stage III/IV disease; and history of equivocal response at interim or end-of-therapy positron emission tomography (PET)/computed tomography (CT)—will be prescreened. Eligible pts must have completed a full course of standard 1L therapy that included an anthracycline and an anti-CD20 monoclonal antibody; achieved complete response (CR) or partial response (PR) suitable for observation at the end of 1L therapy per PET/CT evaluation by Lugano 2014 criteria and without evidence of progression by randomization; MRD positivity per ctDNA-based testing; Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. The study consists of a 2-part seamless design. In Part A, pts will be randomly assigned 1:1 to SOC observation or to cema-cel (120×106 CAR T cells) after a 3-day LD with fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) (FC). Second cema-cel arm that utilized 3-day LD with FC plus the anti-CD52 monoclonal antibody ALLO-647 (30 mg/day) was closed in August 2025 because of a grade 5 hepatic failure event caused by a disseminated adenovirus infection that was attributed to ALLO-647. Part A will conclude with interim safety and surrogate biomarker–based efficacy analyses. In Part B, pts will continue to be randomly assigned 1:1 to cema-cel after FC or SOC observation. Randomization in Parts A and B will be stratified by best response to 1L therapy (CR vs PR). The primary endpoint is event-free survival per Lugano 2014 criteria by independent review committee (IRC), with hierarchical testing of key secondary end points of progression-free survival per Lugano 2014 criteria by IRC and overall survival. Other secondary end points include rate of MRD clearance and safety of cema-cel. Enrollment in Part A is ongoing. Pts randomly assigned to the treatment arm or followed up in observation during Part A will be included in the inferential testing in Part B. Approximately 110 pts will be enrolled in each arm across academic- and community-based centers. The study was initiated in June 2024.

The treatment landscape of B-cell lymphomas has significantly evolved in recent years with approval of novel targeted therapies. CD3 × CD20 bispecific antibodies and CD19-directed monoclonal antibodies and antibody-drug conjugates have demonstrated efficacy in relapsed/refractory follicular lymphoma (FL). Bruton tyrosine kinase (BTK) inhibitor-based regimens are emerging as effective treatment options for patients with TP53-mutated classical mantle cell lymphoma (MCL). Results from ongoing clinical trials suggest that the addition of CD3 × CD20 bispecific antibodies to chemoimmunotherapy improves outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). These NCCN Guideline Insights highlight significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, MCL, and DLBCL.

e24032 Background: Despite recent advances in treatment paradigms for diffuse large B-cell lymphoma (DLBCL), a subset of patients (pts) continues to face a poor prognosis, with survival measured in months following diagnosis. Previous reports indicate high rates of hospitalization and intensive care unit utilization amongst aggressive lymphoma pts prior to death (Johnson, Journal of Palliative Medicine 2022), despite evidence suggesting that many cancer pts prioritize spending their final days at home (Fereidouni, Frontiers in Psychology 2021). Limited research exists on these pts' goals of care and circumstances of death. We conducted a single institution analysis to evaluate patterns of care and end of life events for patients who experienced early mortality after DLBCL diagnosis. Methods: We identified adult pts who died within 100 days of DLBCL diagnosis between 2008 and 2023 using the Lymphoma Data Registry at Cleveland Clinic. This survival cutoff reflects prior SEER findings showing untreated pts have a median survival of about 3 months (Diamond, ASH 2022). The analysis included demographics, disease characteristics, treatment details, code status and outcomes such as cause and location of death. Results: Of 462 newly diagnosed DLBCL patients, 84 (18.2%) had early mortality (Table). These pts were predominantly women (55%), white (88% vs. 7.1% black), married (63% vs. 18% single, 15% widowed), and insured by Medicare (69% vs. 22% private, 2.9% Medicaid, 5.9% uninsured). Median age at diagnosis was 74.9 years, with a median survival of 37 days. Before death, most pts were designated to receive Comfort Care (n = 44, 65%), with lower proportions having DNR/DNI status (n = 6, 9.5%) or remaining Full Code (n = 9, 14%). CPR was performed in 6.6% (n = 4) of cases. Pts with poor survival outcomes most often died either in the intensive care unit (n = 19, 29%) or at home with hospice care (n = 19, 29%), followed by inpatient hospice (n = 9, 14%) and home without hospice (n = 7, 11%). Notably, 4.6% (n = 3) of pts died on a regular nursing floor. Conclusions: Our study reveals that pts with poor survival outcomes in DLBCL often have code statuses aligned with their clinical condition, allowing them to avoid interventions with limited meaningful benefit. However, these pts experience aggressive healthcare utilization, including the intensive care unit as their final treatment location and infrequent hospice care independent of setting, which are inconsistent with most cancer pts’ preferences. These findings highlight the importance of balancing the curative potential of DLBCL therapies with their toxicities and the prognosis of untreated disease by transitioning to a palliative approach at the appropriate stage in the clinical course. Characteristic/Outcome % ECOG 0-2 36 ECOG 3-4 38 Stage IV 58 R-IPI Poor 85 Untreated 33 Death due to Sepsis 47 Death due to Tumor Lysis 11 Death due to GIB Bleed 11 Death due to Other Causes 28

IntroductionCD19-directed CAR T-cell therapy has transformed the therapeutic landscape for relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL), offering durable responses in a subset of patients. However, durable remissions are seen in <40% of the patients, highlighting the need for predictive biomarkers to identify the likely responders and non-responders. Although post-infusion parameters such as CAR T-cell persistence, phenotype, and in vivo expansion, as well as tumor burden and immune microenvironment are known correlates of CAR T-cell efficacy, reliable baseline or pre-lymphodepletion biomarkers that could predict clinical response after CAR T-cell infusion remain largely undefined. Such biomarkers would be invaluable in guiding patient selection and treatment decisions. Decentralized CAR T-cell manufacturing offers a promising solution to enhance global accessibility and reduce costs, yet immune correlates of response and resistance from such real-world settings remain underexplored. MethodsWe conducted a comprehensive immunophenotypic and proteomic analysis of peripheral blood mononuclear cells (PBMCs) and plasma samples from R/R B-NHL patients (n=27) enrolled in a phase I clinical trial using decentralized CD19 CAR T-cell manufacturing (Ghobadi et al., eClinicalMedicine 2025). Samples were collected at pre-lymphodepletion (day –6, referred henceforth as baseline), infusion (day 0), and serial post-infusion timepoints. Immune cells subset evaluation and T cell characterization such as differentiation, activation and exhaustion were done with 24-marker and 34-marker spectral flow cytometry panels respectively, while plasma protein levels were quantified using a 92-plex immuno-oncology panel (Olink®). Statistical comparisons were performed using Mann-Whitney and Kruskal-Wallis tests. ResultsAmong the 27 patients, 26 were evaluated for response, and 1 patient died withing two weeks of infusion. Among these, 19 achieved complete remission and 3 patients achieved a partial remission as their best response in the first 6 months following infusion. Manual gating and unsupervised clustering of the T cells from the baseline samples showed a significantly higher frequency of early memory T cells (naive and central memory) in the responders, observed in both CD4+ and CD8+ populations. In contrast, non-responders had a significantly higher proportion of effector memory and terminal effector cells expressing KLRG1 and CD244. This difference was more pronounced in the CD4+ T cells compared to CD8+ T cells and was also identified at the early post-infusion (day 6) timepoints. Consistent with our earlier finding in B-cell acute lymphoblastic leukemia (Bai Z et al, Nature 2024), T cells (CD4+>CD8+) with type 2 function (CCR4+ non-regulatory T cells) were significantly enriched in the responders, a finding not described before in lymphoma. Regulatory T cells (Tregs) were notably reduced in non-responders, potentially reflecting their migration to lymphoid tissues, supported by elevated plasma CCL20 levels in non-responders.Proteomic analysis at baseline and early post-infusion timepoints revealed higher plasma concentrations of LAMP3 and ANGPT1 in responders and increased CCL20 in non-responders. Non-responders also exhibited elevated IL-6, GZMB, GZMH, CD40, and TNFRSF12A at baseline, indicating a pre-existing pro-inflammatory and immunosuppressive tumor microenvironment. Manual and unsupervised clustering of the other immune cells revealed a higher frequency of circulating monocytes (classical and non-classical) in the non-responders and a trend towards increased NK cells in the responders at baseline. Single-cell RNA sequencing from the baseline PBMCs is currently underway to further validate these findings. ConclusionOur study demonstrates that distinct baseline immune and plasma protein profiles can predict response and resistance to CD19 CAR T-cell therapy in R/R B-NHL patients treated in a decentralized manufacturing setting. These findings highlight the importance of integrating baseline biomarker profiling into clinical workflows to improve patient selection, predict relapse, and optimize outcomes of CAR T-cell therapy in lymphoma.

Background and Significance: Despite major therapeutic advances including BTK and BCL2 inhibitors, patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) face limited treatment options after targeted therapy failure. Anti-CD19 CAR T cells show modest activity in CLL, with lisocabtagene maraleucel demonstrating only 57% overall response and 18% complete response rates in BTK/BCL2 inhibitor-treated patients. CLL cells express BAFF receptors (BAFF-R, TACI, BCMA) universally, and BAFF signaling promotes CLL cell survival through BTK-independent pathways. Additionally, CLL-associated T cell dysfunction limits CAR-T efficacy which may be overcome by pre-apheresis B cell depletion. We are conducting a trial with LMY-920, a BAFF ligand-based chimeric antigen receptor (CAR)-T cell therapy targeting all three BAFF receptors, manufactured using the TcBuster transposon system for improved manufacturing efficiency and safety with obinutuzumab intended to improve T cell quality and enhance CAR-T product function. Study Design and Methods: This is an open-label, dose escalation study (NCT 06916767) conducted at Cleveland Clinic, University Hospitals of Cleveland and The Ohio State University. Dose escalation of LMY-920 (2 - 8 x 106 cells/kg) is done using a 3+3 design to determine the maximum tolerated dose and recommended phase 2 dose. Major inclusion criteria include histologically confirmed CLL/SLL relapsed after ≥2 prior therapies including both BTK and BCL2 inhibitors (i.e. “double refractory”), active disease per iwCLL criteria, ECOG performance status ≤2, and adequate organ function. Key exclusion criteria include CNS involvement, active malignancy, cardiovascular instability, active infection, and autoimmune disease requiring immunosuppression. The treatment protocol involves: (1) pre-apheresis B cell depletion with obinutuzumab (100mg day 1, 900mg day 2) starting 14-21 days before leukapheresis; (2) standard leukapheresis and LMY-920 manufacturing over 8-11 days using transposon technology; (3) lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (500 mg/m²/day) for 3 days beginning on day -5; and (4) LMY-920 infusion on day 0 at escalating doses from 2×10⁶ to 8×10⁶ BAFF CAR-T cells/kg. Up to 18 patients will be enrolled across dose escalation and expansion cohorts. Primary endpoints include determination of recommended phase 2 dose and safety profile. Secondary endpoints assess objective response rate, complete response rate, duration of response, progression-free survival, and overall survival per iwCLL criteria. Correlative studies will evaluate BAFF CAR-T persistence, cytokine profiles, T cell functionality, receptor expression, circulating tumor DNA, and the impact of pre-apheresis obinutuzumab on T cell populations and CAR-T product characteristics. Long-term safety follow-up continues for 15 years per gene therapy guidelines. Conclusion: Targeting ubiquitously expressed BAFF receptors with optimization of the starting T cell material through pre-apheresis B cell depletion for patients with double refractory disease is designed to overcome current limitations of CAR-T therapy for CLL/SLL

Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T <6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p < 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.

We performed a phase I/II trial to explore the safety and efficacy of carfilzomib (K) in combination with R-CHOP (KR-CHOP) in patients with diffuse large B cell lymphoma (DLBCL). A total of 48 patients were enrolled and 47 were treated. The overall response rate (ORR) was 89% (70% complete response). At a median follow-up of 31 months, 3-year Kaplan-Meier estimates of PFS and OS were 79% and 87%, respectively. Treatment with KR-CHOP for non-GC DLBCL was associated with a decreased risk of disease progression and death relative to standard of care treatment with R-CHOP with hazard ratios (HR) of 0.16 [95% confidence interval (CI) 0.04-0.58, p = 0.002] and 0.31 [(95% CI, 0.09 - 0.99), p = 0.02], respectively. The most common grade 3 or 4 adverse events (AEs) were anemia (13%), thrombocytopenia (9%) and febrile neutropenia (9%). KR-CHOP is safe and may have preferential activity in non-GC DLBCL.