Citations

Abstract 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.

Abstract 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.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs). Their use is associated with relatively high response rates, with some patients experiencing prolonged remission. It is unclear whether continuous treatment beyond 12 months for pts in remission is beneficial, as continued immunosuppression may result in additional toxicity. We sought to report the outcomes of pts with prolonged remission and survival following BsAb administration. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCLs 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. Pts who responded to BsAbs and had ≥365 days of follow-up from initiation of BsAb treatment were included in the analysis. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAbs (epco n=193, glofit n=119) with a median age of 66 years (interquartile range [IQR] 59-73) at BsAb start. Most were male (64.5%), had advanced stage disease (77.4%) and had ECOG performance status of ≤1 (93.3%) at BsAb start. Of 207 pts who had initiated treatment with BsAb ≥12 months prior to data cutoff, we identified 31 pts (15.0%) who had a response to BsAbs (19 epco, 12 glofit) and were alive without progression at 12-months post-BsAb initiation and included them in this landmark analysis. Of the cohort of 19 pts treated with epco, 6 discontinued due to reasons other than disease progression including CAR-T cell therapy (n=2), secondary malignancy (n=2), allogeneic transplant (n=1), or other reasons (n=1). Thirteen of 19 pts received ≥12 months of epco treatment, and, with a median follow-up of 16 months from the start of BsAb, 12 of 13 pts continued receiving epco beyond 12 months with one pt discontinuing after 12 months (observed for an additional 41 days prior to censoring). Of the cohort of 12 pts treated with glofit, 8 pts were observed after completing all planned therapy and 4 patients underwent allogeneic transplant. Among all 31 BsAb-treated patients alive and in remission at 12 months, at the time of data cutoff, 5 pts (12.9%) had progressed (2 previously treated with epco and 3 with glofit). Three of the 4 pts who underwent allogeneic transplant after prior glofit treatment experienced disease relapse. A total of 24 pts (77.4%) were alive at the time of last follow-up, with the causes of death being disease progression (n=1), secondary malignancy (n=1), infection (n=1), and unknown cause (n=4). Conclusions: In this large cohort of r/r LBCL pts treated with BsAbs monotherapy in the standard of care setting, a relatively small proportion of pts (15%) achieve the 12 month PFS landmark. In the absence of robust evidence for what constitutes best practice, different strategies are employed, including continuation of BsAb, observation as well as consolidation with allogeneic transplant or CAR T-cell therapy. Additional follow-up will be reported to help guide clinical decision making regarding the optimal management strategy for this high risk pt population.

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.

Abstract Outcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL after brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received ≥3 previous lines of systemic therapy (or ≥2 if ineligible for hematopoietic stem cell transplant). Patients received 45 μg/kg Cami (IV, once every 3 weeks) in cycles 1 to 2, followed by 30 μg/kg IV once every 3 weeks for ≤1 year. The primary end point was overall response rate (ORR) per 2014 Lugano classification. Secondary end points included complete response rate (CRR), progression-free survival (PFS), and overall survival (OS). In total, 117 patients were enrolled with a median age of 37.0 years (range, 19-87). The ORR was 70.1% (95% confidence interval [CI], 60.9-78.2), with a CRR of 33.3% (95% CI, 24.9-42.6). The median PFS was 9.13 months (95% CI, 5.3-15.0); median OS was not reached. Thirty-three (28.2%) patients discontinued treatment because of treatment-emergent adverse events; the most common reasons were skin and subcutaneous tissue disorders (n = 10 [8.5%] patients), infections and infestations (n = 5 [4.3%]), and nervous systems disorders (n = 5 [4.3%]). Guillain-Barré–type or polyradiculopathy-type events occurred in 8 (6.8%) patients. Cami was efficacious in this heavily pretreated population; however, the efficacy was overshadowed by substantial issues with the safety profile. This trial was registered at www.clinicaltrials.gov as #NCT04052997.

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.

Introduction: The optimal induction for younger fit patients (pts) with mantle cell lymphoma (MCL) is unknown; though intensive chemoimmunotherapy (CIT) containing high dose cytarabine has been shown to prolong remission. Achieving molecular remission is an independent predictor of outcomes post induction therapy in patients with MCL. Incorporating undetectable measurable residual disease (uMRD) status into the primary endpoint may be preferable to progression-free survival (PFS), particularly when approaches following induction are varied (e.g., ASCT, maintenance treatment, observation). Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton's tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439). In 2019, the US Intergroup activated EA4181 to explore the efficacy with the addition of fixed duration BTKi, to BR or BR/CR for patients with MCL ≤ 70 years old. Patients and methods: Patients were randomized 1:1:1 (stratified by MIPI risk status) to 6 cycles of BR/CR (control arm), BR/CR-A, or BR-A. Cytarabine was dosed at 2 g/m2 Q12 hours x 4, with dose reductions based on age and creatinine clearance. Acalabrutinib was dosed at 100 mg BID continuously on BR cycles with the BR/CR-A and BR-A arms and at 100 mg BID on days 1-7 and 22-28 with CR cycles on the BR/CR-A arm to mitigate hematologic toxicity. Consolidation approaches following induction were at the discretion of the treating physician. The primary endpoint was a composite of PET/CT CMR and peripheral blood uMRD rate (< 1 in 105). ClonoSEQ (Adaptive Biotechnologies) was performed at baseline and MRD testing was obtained at the end of induction. Secondary clinical objectives included PFS and overall survival (OS) at 36 months (mo), objective response rates (ORR), and toxicity rates. With 108 patients per arm expected, there was 86% power to detect an increase in PET/CT CMR/uMRD rate from 60% in the control arm to 75% in either BR/CR-A or BR-A arms using a Z-test with a 10% alpha (1-sided). Results: Between October 2019 and March 2023, 359 participants were randomized to BR/CR (n = 128), BR/CR-A (n = 129), and BR-A (n = 102). BR-A was closed to further accrual by the DSMC based on interim futility analysis for superiority in Fall 2022. The median (range) age was 61 (25, 70), 30% were ≥ 65 years, 77% were male, 89% were white, 89% were non-Hispanic, 18%/43%/39% were low/intermediate/high risk MIPI. Baseline clonal sequence was identified in 308/326 (95%) among samples received. 281/308 were eligible and treated and 260/281 had an end of treatment MRD test result (BR/CR = 85, BR/CR-A = 98, BR-A = 77). This subset (n = 260) is the focus of the primary analysis; sensitivity analysis included 281 eligible and treated pts with trackable clonal marker. In the primary analysis subset, 94%, 91%, and 90% in BR/CR, BR/CR-A, and BR-A arms, respectively, completed 6 cycles of protocol therapy. The PET/CT CMR/uMRD rates were 82% (BR/CR), 82% (BR/CR-A; p = 0.55 vs BR/CR), and 78% (BR-A; p = 0.76 vs BR/CR). In the sensitivity analysis set, PET/CT CMR/uMRD rates were 74% with BR/CR (n = 94), 76% (p = 0.44) with BR/CR-A (n = 106), and 74% (p = 0.52) with BR-A (n = 81). ORR (CMR) rates were 94% (91%), 99% (90%), and 94% (91%) with BR/CR, BR/CR-A, and BR-A, respectively. At a median follow-up of 27.9 mo, estimated 12-mo PFS/OS were 86%/94% (BR/CR), 89%/98% (BR/CR-A) and 87%/95% (BR-A). The proportion of treatment-related grade 3 or higher adverse events (AE) was 78%/88%/73%, with neutropenia in 52%/58%/27%, anemia in 23%/32%/3%, thrombocytopenia in 55%/66%/6%, and febrile neutropenia in 11%/12%/4%; treatment discontinuation due to AE occurred in 5%/7%/8% in BR/CR, BR/CR-A, and BR-A arms, respectively. Conclusion: High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles. BR-A was found not superior and closed early by the DSMC; however, it is the least toxic arm with similar efficacy, and represents an appealing option to avoid high dose cytarabine.

Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes 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. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.

Introduction CD19 CAR T cell therapies are highly effective for several aggressive B-cell malignancies. Emerging data suggest that these therapies may lead to durable, treatment-free responses in multiple autoimmune diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIMs), systemic sclerosis (SSc), and multiple sclerosis (MS). BMS-986353 (CC-97540) is an investigational CAR T cell therapy expressing the CD19-targeting CAR used in FDA-approved lisocabtagene maraleucel (liso-cel). BMS-986353 is manufactured using the NEX-TTM process, which shortens manufacturing time and optimizes phenotypic attributes of the CAR T cell product. Here, we report updated data on BMS-986353 in severe, refractory autoimmune diseases. Methods Two phase 1, multicenter, open-label studies are investigating BMS-986353 in patients (pts) with severe, refractory SLE, IIM, and SSc (CA061-1001; NCT05869955), and relapsing or progressive forms of MS (CA061-1006; NCT06220201). CAR T cells were manufactured using the NEX-T process and autoimmune-directed therapies were tapered before BMS-986353 infusion. Two to 9 d after lymphodepletion (3 d of fludarabine [30 mg/m2/d], cyclophosphamide [300 mg/m2/d]), a single infusion of BMS-986353 was administered. Pts were treated with 5 × 106 (MS only), 10 × 106, or 25 × 106 CAR+ T cells according to dose level. Pharmacokinetics were evaluated using droplet digital PCR to detect transgene copy numbers, and pharmacodynamics were measured using flow cytometry. Results As of Jul 12, 2024, 7 pts were treated with BMS-986353 (SLE, n=5; SSc, n=1; relapsing-remitting MS [RRMS], n=1). Seven pts were evaluable for safety; 4 pts were evaluable for efficacy (median follow-up of 167.5 d [range, 68-240]). All 5 pts with SLE had history of renal organ system involvement (BILAG category A) and disease refractory to multiple prior therapies (range 5-8); at screening, scores were (median [range]): SLE Disease Activity Index 2000 (SLEDAI-2K), 12.0 (7.0-22.0); Physician's Global Assessment (PGA), 2.3 (1.5-2.5). The pt with SSc was aged 43 y, and had history of progression of diffuse cutaneous SSc after 2 therapies and a modified Rodnan skin score of 18; the pt with RRMS was aged 33 y, and had history of active clinical disease despite 3 prior anti-CD20 therapies and an Expanded Disability Status Scale score of 3.0. Cytokine release syndrome was reported in 1 pt with SLE (grade [gr] 1) and 1 pt with SSc (gr 2), both resolved within 1 d. ICANS was reported in 1 pt with SSc (gr 1) and resolved in 1 d. Gr 3/4 transient lymphodepletion-related cytopenia occurred in 4 pts with SLE and 1 pt with MS. There were no prolonged gr ≥3 cytopenias or dose-limiting toxicities reported. In all efficacy evaluable pts, significant improvements in SLEDAI-2K (median, 4.0) and PGA (median, 0.55) were observed. dsDNA seroconverted and complements normalized for all pts who had abnormal values at screening. All pts remain off autoimmune-directed therapies without evidence of disease flare. Pts with SLE treated with 10 x 106 CAR+ T cell dose of BMS-986353 showed complete B-cell depletion and similar robust cellular expansion compared with pts with diffuse large B-cell lymphoma treated with liso-cel (TRANSFORM; NCT03575351) at the recommended phase 2 dose (RP2D; 100 x 106 CAR+ T cells). At the time of B-cell reconstitution following BMS-986353, re-emerging B cells were predominantly naive. Conclusions BMS-986353, a NEX-T investigational CD19-targeted CAR T cell therapy, has a more rapid manufacturing time and optimized phenotypic attributes. In pts with severe, refractory autoimmune diseases, BMS-986353 demonstrates a low rate of low gr CRS and ICANS events. Preliminary data suggest promising efficacy in pts with SLE despite discontinuation of all lupus therapies. Robust CAR T cell expansion comparable to the RP2D of liso-cel and complete B-cell depletion were observed after BMS-986353 at a dose of 10 x 106 CAR+ T cells despite being 1/10 of the RP2D of liso-cel. The studies continue to enroll pts in all autoimmune indications. Updated safety, efficacy, and translational data will be presented.