Yang, Xi

Abstract Introduction: Primary mediastinal B-Cell lymphoma (PMBCL) is a rare form of large B-Cell lymphoma (LBCL) with around 90% of patients (pts) cured with first line (1L) treatment. For pts with relapsed or refractory (RR) PMBCL, the optimal treatment is unclear. Prior retrospective analysis in the rituximab (R) era have shown high response rates to platinum salvage and high-dose chemotherapy followed by autologous stem cell transplant (HDT/ASCT) in second line (2L) RR PMBCL (Bakos et al. ASH 2023 and Dumke et al. ASCO 2024). The pivotal phase III LBCL trials in early relapsing pts that compared CD19 chimeric antigen receptor-T cell (CAR-T) with HDT/ASCT as 2L treatment had few PMBCL pts: none on ZUMA-7 and 17 PMBCL on TRANSFORM, of whom only 8 were randomized to 2L CAR-T. This study aims to evaluate outcomes of 2L therapies for RR PMBCL, including pts treated with 2L CAR-T. Methods: We performed a multicenter retrospective study in pts with RR PMBCL treated between 2001 and 2025. Clinical and pathologic characteristics, treatment regimens, and efficacy outcomes were collected and analyzed. Results: 139 pts were included with 43% male, 69% Caucasian, 7.9% Black, 8.6% Asian and 79% Non-Hispanic. R-EPOCH (64%) and (32%) were the most common 1L treatments and all pts received R. Consolidative radiation was used in 21 pts (15%) as part of 1L therapy, 28% after RCHOP. Primary refractory disease with relapse ≤6 month (mo), or early relapse ≤12 mo, occurred in 83% (N = 115) and 93% (N = 129 pts), respectively. At relapse, median age was 34 years (yrs), 44% had advanced stage disease, 31% had bulky disease (≥ 7.5cm). CNS relapse occurred in 8.6% of pts. Overall and complete response rate (ORR and CR) to any 2L treatment was 44% and 27%, respectively. At median follow-up of 40 months (mo) from the start of 2L treatment, median PFS of the entire cohort was 3.2 mo with a 3 yr OS of 70%. For 2L treatment, N=93 (67%) pts were treated with platinum salvage with intention to proceed with HDT/ASCT. Most commonly used platinum salvage regimens were ICE± R (n= 53, 38%), R-DHAP (n=23, 17%), R-GemOx (n= 5, 3.6%), and GDP ± R (n= 10, 7.2%), and the majority (95%) of pts received R with 2L therapy. ORR and CR to platinum salvage was 46% and 15% respectively. With a median follow up of 30 mo from start of 2L therapy, median PFS was 2.6 mos, and 3 yr PFS and OS was 15% and 64%, respectively. Of the 93 pts treated with platinum salvage, only 25 pts (27%) proceeded with HDT/ASCT- of whom, N = 17 (68%) achieved a CR after ASCT. In patients that proceeded to ASCT, relapses occurred in 10 pts (40%) with a 3 yr PFS and OS 56% and 83%, respectively. CAR-T was used as 2L in 20 pts (14%)- most commonly either axi-cel (N =7) or liso-cel (N = 8). ORR and CR to CART was 89% and 55% respectively, median PFS and OS was NR after CAR-T infusion and 3 yr PFS and OS was 55% and 95%, respectively. Other 2L treatments included pembrolizumab (N =3), brentuximab vedotin (BV) + nivolumab (N= 4) or single agent BV (N=2). Radiation was given as part of 2L treatment in 25.9% of pts. 2L CAR-T therapy was associated with improved ORR (OR 7.60, 95% CI 1.68 – 34.55, p = 0.002), improved CR rate (OR 4.15, 95% CI 1.49 – 11.53, p = 0.008) and improved PFS (HR 0.18, 95% CI 0.06 – 0.57, p = 0.004) compared to pts treated with 2L platinum salvage. There was no difference in OS between pts treated with platinum salvage or 2L CAR-T. A total of 96 patients progressed on 2L therapy, and 92 pts (95.8%) received third-line (3L) treatment. Third line treatments included chemoimmunotherapy +/- HDT/ASCT (N= 23), CD19 CAR-T (N = 35), clinical trial (N=7), check point inhibitor-based regimen (N= 11), BV based regimen (N= 8), allogeneic stem cell transplant (N = 3) or other (N = 5), with 7 pts receiving radiation as part of 3L therapy. Median PFS and OS from start of 3L therapy was 6.7 mo and 6.4 mo, respectively. Conclusions: We report the largest cohort of pts with RR PMBCL treated in the rituximab era and the largest number of PMBCL pts treated with 2L CAR-T. This is the first analysis, to our knowledge, to show a statistically significant benefit in PFS, ORR and CR rate of CAR-T compared to platinum salvage followed by HDT/ASCT as 2L treatment in a study of exclusively RR PMBCL pts. Our dataset was largely (93%) compromised of pts with primary refractory or early relapsing disease and provides support for using CAR-T as 2L treatment in this high-risk subset of RR PMBCL patients.

Abstract Introduction: Targeted therapy yields deep and durable response in histiocytic neoplasms.However, relapse rate following interruption is high at 75-77%, with a median time to relapse 6-9 months in previous studies. Outcomes after discontinuation in those who have already achieved a durable response are not well understood and are the focus of this study. Methods: We performed a multicenter retrospective study, including 4 US centers, including patients with histiocytic disorders treated with BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or combination BRAF/MEKi, and whose therapy was interrupted after ≥12 months of therapy following a best response of partial (PR) or complete response (CR). Progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier method. Cox regression was performed to identify clinical and molecular factors that are associated with PFS. Results: 26 patients were included (median age 55 [range 12-72]; male 53.8%; Caucasian 69.2%). Most predominant histology was Erdheim-Chester Disease (ECD) (n=15, 57.5%), followed by mixed histiocytosis (n=5, 19.2%). Rosai-Dorfman Disease (RDD) (n=4, 15.4%), and Langerhans Cell Histiocytosis (LCH) (n=2, 7.7%). All had BRAF V600E analysis and 10 (38.5%) were positive. 19 patients underwent additional molecular testing; alternative mutations identified included MAP2K1/2 (n=6, 23.1%), NRAS (n=1, 3.8%), RAF1 (n=1, 3.8%), ASXL1 (n=1, 3.8%), and SRSF2 (n=1, 3.8%). Targeted therapy was given as frontline therapy (n=8, 30.8%) or in the relapsed refractory setting (n=18, 69.2%) with median 1 prior line of therapy (range 0-7). Targeted therapies include BRAFi (n=5, 19.2%; 2 dabrafenib, 3 vemurafenib), MEKi (n=17, 65.4%; 14 cobimetinib, 3 trametinib), and BRAF/MEKi (n=4, 15.4%; 3 dabrafenib/trametinib, 1 vemurafenib/cobimetinib). PR and CR occurred in 8 (30.8%) and 18 (69.2%) patients, respectively. The median duration of treatment was 32 months (range 13-60) (12-24 months: 9 [34.6%]; 24-36 months: 7 [26.9%]; >36 months: 10 [38.5%]). Median time from initiation of targeted therapy to best response was 6 months (<6 months: 14 [53.8%]; 6-12 months: 5 [19.2%]; >12 months: 7 [26.9%]). Median duration from best response to drug discontinuation was 19 months (12-24 months: 14 [53.8%]; 24-36 months: 7 [26.9%]; >36 months: 5[19.2%]). Reasons for drug discontinuation include toxicity (n=8, 30.8%), patient preference (n=13, 50.0%), cost prohibition (n=1, 3.8%), and other critical medical conditions (n= 4,15.4%). Eleven patients (42.3%) experienced disease progression after discontinuation of targeted therapy, 5 patients progressed within 6 months. Systemic and CNS progression were captured by PET/CT and MRI brain, respectively. At median follow-up of 33.0 months (95%CI 24.3-47.1), median PFS, defined by time from targeted therapy discontinuation to progression or death, was 29 months (95% confidence interval [CI] not estimable). Median OS was not reached. In Cox regression model, BRAF V600E mutation (hazard ratio [HR] 4.16, 95% CI 1.10-15.70, p 0.036) and CNS involvement (HR 4.64, 95% CI 1.21-17.67, p 0.025) were associated with inferior PFS. MEKi containing regimen trended toward improved PFS (HR 0.35, 95%CI 0.10-1.21, p 0.097). There was no difference in PFS when assessing demographics, histology, prior therapies, best response to targeted therapy, treatment duration, or time from best response to discontinuation. Of the 11 patients with progression, 9 were re-challenged with targeted therapy (7 switched class), 2 did not receive next line therapy (1 transitioned to hospice and passed from progression, 1 has pending evaluation for next line therapy). Of 6 with response assessments, all recaptured response (1 CR, 5 PR), and none had progressed by data cutoff. Conclusions: In patients with histiocytic neoplasm and prior durable response to targeted therapy, ~40% experienced disease progression after treatment discontinuation. BRAF V600E mutation and CNS disease are associated with inferior PFS, suggesting these subgroups may not be appropriate for limited duration of treatment. Novel approaches are needed in these high-risk patients.

Abstract Introduction: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic neoplasm, with approximately 90% of patients exhibiting alterations in the MAPK pathway. BRAF and MEK inhibitors have shown promising results in treating MAPK pathway-altered LCH. However, treatment interruptions due to adverse effects are common, and limited access to targeted therapies complicates care globally. While chemotherapy remains a common treatment for LCH, the outcomes for patients with MAPK pathway-altered LCH specifically receiving chemotherapy are still unclear. Methods: This multi-institutional international retrospective cohort study analyzed adult patients with BRAF or MAP2K (gain-of-function, GOF) altered LCH that were consecutively seen at Mayo Clinic, MN, AZ, and FL, University of Alabama at Birmingham, and Peking Union Medical College Hospital in China between 2007 and 2024. All patients who were included in this study were treated with chemotherapy, and those who have received targeted therapies or other modalities of frontline treatment were excluded. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Progression-free survival (PFS) included death and progression as events and was measured from the time of treatment initiation. The response assessment was based on radiographic evaluation in accordance with the most recent Histiocyte Society consensus guideline. Risk organ involvement was defined as disease involving the liver, spleen, bone marrow or central nervous system. Results: A total of 63 patients with LCH were included. The median age of the population was 34 years (range: 27-43), and males were 59%. Risk organ involvement was seen in 44 (70%) of patients and multisystemic LCH was observed in 48 (76%) patients. Among the 63 patients, BRAF gain-of-function alterations were observed in 79%, MAP2K mutations in 19%, and BRAF fusions in 2%. Of the BRAF gain-of-function alterations, BRAFV600E mutation was seen in 64% patients and [p.N486_P490del] deletion in 36%. There was no significant difference in organ involvement (single-system versus multisystem) or risk organ involvement between patients with BRAF and MAP2K alterations. All 63 patients received systemic therapy with chemotherapy and the regimens included Cytarabine (n=43), Cladribine (n=5), Etoposide (n=1), Methotrexate (n=1), and combined Methotrexate and Cytarabine (n=13). The median follow-up for the entire cohort was 3.8 years (range 3.2–5.0 years), with similar durations observed in patients with single-system vs. multisystem involvement and those with risk-organ involvement vs. no risk-organ involvement. The overall response rate among patients who received chemotherapy was 89%, with complete responses in 15 patients (26%) and partial responses in 40 patients (64.5%). The median progression-free survival (PFS) for the entire cohort was 2.61 years (95% CI: 2.06–NA). The 3-year PFS did not significantly differ based on risk organ involvement: 50.6% (95% CI: 36–71) for patients with risk organ involvement versus 47.4% (95% CI: 28–81) for those without, p=0.52. Patients with single-system disease experienced longer PFS compared to those with multisystem disease; the 3-year PFS was 80.2% (95% CI: 58.7–100) versus 42.2% (95% CI: 29–61.5), respectively, p=0.04. Conclusions: Our results indicate that LCH patients with a GOF alteration in the MAPK pathway derive significant clinical benefit from chemotherapy, achieving deep and durable responses. Therefore, patients should not be excluded from treatment due to the absence of targeted therapies, as they can still attain substantial responses and clinical improvement with chemotherapy, even in the context of MAPK pathway-driven disease.

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 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: Autoimmunity in Rosai-Dorfman disease (RDD) has been reported in several case reports and small case series. The recent consensus RDD guidelines even classify “immune-related RDD” as a distinct entity, but little is known about the prevalence and patterns of autoimmune conditions in this rare disease. We conducted this study to evaluate a large cohort of patients with RDD for concomitant autoimmunity. Methods: We conducted a retrospective review of cases diagnosed with RDD from five referral centers globally. Data pertaining to autoimmunity were captured in terms of serology and a clinical diagnosis of autoimmune disease (AID) and compared to previously reported prevalence of AID and autoimmunity in the general population and in patients with other lymphomas. Results: We included 157 patients diagnosed with RDD from 2003-2023. Median age at the time of RDD diagnosis was 48 years, IQR 35.5-60. This included 103 females (65.6%) and 54 male (34.4%). Racial distribution included 54 Black (34.4%), 52 White (33.1%), 40 Asian (25.5%), 7 Middle Eastern (4.5%) and 4 other (2.5%). 83 patients had multi-systemic disease (52.8%) and 74 had single organ involvement (47.2%). Most common organs involved were skin/subcutaneous tissue (78, 49.7%), lymph nodes (63, 40.1%), bone (54, 34.2%). Tissue next generation sequencing data was available for 100 patients (63.7 %) and showed KRAS mutation (19, 19 %), MAP2K/MEK (13, 13%), other mutations (27, 27 %), and no mutations (41, 41%). Mean ESR at diagnosis of RDD was 28.42 mm/Hr and mean CRP was 19.5 mg/L. In our cohort, 28 patients (17.8%) were diagnosed with an AID. 19 (67.8%) were diagnosed with the AID prior to the diagnosis of RDD. Most common AID was systemic lupus erythematosus (6, 21.4%), rheumatoid arthritis (5, 17.8%), autoimmune hemolytic anemia (3, 10.7%), polymyalgia rheumatica (2, 7.1%). AID was more common in female vs male (64.3% vs 35.7%, p 0.8) and were more commonly seen in patients with multisystem compared to single organ RDD (60.7% vs 39.3%, p 0.3). Mean ESR and CRP at the time of RDD diagnosis in patients with AID were 40.63 mm/Hr and 37.04 mg/L respectively. Autoimmune antibodies were tested in 90 patients (57.3%), of which 43 (47.8%) were positive for atleast one autoantibody which included 15 patients (16.7%) with AID and a positive autoantibody and 6 (6.6%) with AID and negative antibodies (p 0.01). Most common antibodies were ANA (29/83, 34.9%), 42.3% with a titer higher than 1:160. Other antibodies include RF (10/60, 16.67%), anti-neutrophilic cytoplasmic antibody (3/19, 15.8%), double stranded DNA (6/56, 10.7%). Positive Antibodies were more common in female compared to male patients (72% vs 23%, p 0.04) and in patients from China compared to North America (45.7% vs 22.6%, p 0.007). Autoantibody positivity was common in multi-system vs single organ RDD (53.5% vs 46.5%, p 0.9). Mean ESR and CRP in this group of patients were 34.54 mm/Hr and 23.93 mg/L respectively. Median duration of follow up for our cohort was 32 months (IQR 14-65). Five-year survival was 93.4%. There were a total 8 deaths reported in the cohort, none of which were in patients with underlying AID. In a multivariable analysis, AID was associated with race (odds ratio [OR] for Middle Eastern compared with Chinese, OR 7, p=0.02) but other factors like organ involvement, mutational status, sex and age at diagnosis were not significant. Conclusions: Our study reveals a high prevalence of autoimmunity in RDD, both in terms of AID (17.8 %) and positive autoantibodies (47.8 %), which is much higher than the general population rates of approximately 3% and 16% respectively, and higher than patients with non-Hodgkin lymphoma, 7.6% and 39%, respectively. There was a trend toward association of AID with multisystem RDD and among individuals from North America and Middle East compared to China, although auto-antibody positivity was more common in Chinese patients. Mean ESR and CRP at the time of diagnosis of RDD was higher in the patients who had AID. We did not find any statistically significant association between AID and autoantibody positivity with the underlying driver mutation. Nearly half of the patients with RDD who also had AID did not have a positive autoantibody, thereby implying the need of clinical evaluation for rheumatological symptoms rather than empiric serological testing. Overall, this study also highlights the need to explore the biological link between RDD and autoimmunity.

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.