ABSTRACT:Chimeric antigen receptor T-cell therapy has revolutionized the treatment of relapsed/refractory (R/R) follicular lymphoma (FL). Real-world efficacy and toxicity data are needed because clinical trial populations are often unrepresentative. Therefore, we conducted a multicenter retrospective study of R/R FL patients undergoing commercial axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between 2021 and 2024. End points included efficacy measures (overall response rate [ORR], complete response rate [CRR], progression-free survival [PFS], and overall survival [OS]) and toxicity (rates of cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS]). Among 136 patients, 100 (74%) received axi-cel and 36 (26%) received tisa-cel. Axi-cel patients were younger than tisa-cel patients (median age, 60 vs 68 years; P = .001) and received bendamustine lymphodepletion less often than them (9% vs 33%; P< .001). Median follow-up was 14.4 months (range, 0.8-72.0 months). In the unweighted analysis, compared with tisa-cel, axi-cel was associated with higher ORR (96% vs 80%; P = .007), CRR (88% vs 71%; P = .024), and longer median PFS (30.5 months vs 11.9 months; P = .021). Median OS did not differ significantly between the 2 products (not reached vs 23.6 months; P = .061). The rates of CRS were comparable (75% vs 75%; P = .99), whereas ICANS occurred more frequently with axi-cel than with tisa-cel (42% vs 17%; P = .008). After inverse probability of treatment weighting, efficacy outcomes were largely similar, but axi-cel remained associated with significantly higher toxicity. In real-world settings, both axi-cel and tisa-cel demonstrated efficacy in patients with R/R FL, although PFS was inferior to that reported in clinical trials.

Introduction: Sézary Syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma involving diffuse erythroderma (T4) and leukemic disease (B2). Prognosis is poor, with 5-year overall survival ranging from 30-50%. A unique cohort of patients diagnosed with B2 (high blood tumor burden) leukemic disease without erythroderma has previously been described. However, little is known about these patients' clinical features and prognosis. Methods: A retrospective study of SS patients diagnosed after 1/1/2010 was conducted at the University of Pennsylvania. Patients with B2 disease with or without T4 disease at diagnosis were identified. B2 disease was defined as positive blood T-cell receptor clonality and Sézary cell count ≥1,000 cells/µl by flow cytometry (CD4+/CD7- or CD4+/CD26-). T4 was defined as erythroderma involving ≥80% body surface area (BSA). Fisher's exact test and Wilcoxon rank-sum test were used for statistical significance. Patients with HTLV-I/II and B2 disease utilizing only percentages of lymphocytes/elevated CD4:CD8 ratio criteria were excluded as per modified ISCLC/USCLC/EORTC criteria. T0/B2 patients were diagnosed based on Sézary immunophenotype and were ruled out for other diagnoses (e.g. T-PLL, T-LGLL, ATLL). Results: Two cohorts of patients with B2 disease were identified: 21 patients without erythroderma (non-erythrodermic SS, neSS) and 79 classic SS patients (T4/B2 stage at diagnosis, cSS). There were no significant differences in age (70 and 71.5 years), race (76% and 74% white, 24% and 25% black) or absolute Sézary cell count at diagnosis (2,225 vs 2,812 cells/µl) for neSS versus cSS, respectively. A significantly greater proportion of neSS patients were female (76.2% vs 44.3%, p = 0.0034), but significantly fewer had N2/3 nodal disease (4.8% vs 43.4%, p=0.0002). One neSS patient had visceral disease pathologically confirmed in the liver (M1) at diagnosis. This did not occur in the cSS patient cohort. Of the neSS patients, 3 had no skin involvement (T0), 6 had patch/plaque disease <10% BSA (T1a/b), and 13 had patch/plaque disease >10% BSA (T2a/b). Pruritus was reported in 55% (11/20) of patients at diagnosis. With a median follow-up of 5 years, 3 patients later developed erythroderma (T4). Among these patients, the median time to T4 disease was 1.9 years after B2 diagnosis. Median follow-up for the 18 patients who never developed erythroderma was 4.5 years. Interrogation of 9 neSS patient samples for cancer-associated mutations showed known disease-associated variants in TP53 (n=3), PTEN (n=1), DNMT3A (n=1) and EGR2 (n=1). The median number of systemic treatments for neSS patients was similar to cSS patients (3.5 vs 3). Among the neSS patient cohort, systemic treatments included extracorporeal photopheresis (ECP)(n=16), bexarotene (n=11), interferon (IFN)(n=8), mogamulizumab (n=8), romidepsin (n=4), brentuximab vedotin (BV)(n=3), pembrolizumab (n=3), chemotherapy (n=1), methotrexate (n=1) and clinical trial (n=1). None underwent hematopoietic stem cell transplant. Four underwent surveillance/topical-only treatment without systemic therapy. Radiation was commonly used, with 4 patients receiving localized radiation, 4 receiving total skin electron beam therapy, and 4 receiving narrow-band UV phototherapy. ECP was the most common first-line therapy. Of the 3 patients who later developed erythroderma, treatments prior to developing T4 disease included ECP (n=3), IFN (n=3), bexarotene (n=3), BV (n=2) and mogamulizumab (n=1). When compared to the cSS patients, outcomes were significantly better for neSS patients. 2-year overall survival (OS) for neSS vs cSS was 100% (18/18) versus 74% (54/73) (p = 0.0275). 5-year OS was 100% (11/11) versus 34.5% (19/55) (p<0.0001). Conclusions: Non-erythrodermic patients with B2 disease (T0-2/B2, neSS) had a significantly better prognosis compared to classic SS patients with erythroderma (T4/B2, cSS). neSS patients received multiple systemic treatments; however, 4 patients with minimal skin disease were managed with surveillance or skin-directed therapy alone. Only 3 neSS patients (9.6%) later developed erythroderma. Although neSS patients were more often women and less likely to have nodal disease at diagnosis, other clinical characteristics including age, race and Sézary cell count at diagnosis were similar to cSS patients. Further exploration into mechanisms driving these clinical differences and the optimal management of this unique cohort of patients is needed.

Marginal zone lymphoma (MZL) is a heterogeneous indolent B-cell malignancy comprising splenic (SMZL), nodal (NMZL), and extranodal (EMZL) subtypes. Owing to its low incidence and variable presentation, prospective randomized data are limited. Most NMZL regimens mirror those for follicular lymphoma, while localized EMZL is frequently treated with local therapies or antibiotics for Helicobacter pylori-associated gastric disease. The IELSG-19 trial remains the only histology-specific phase 3 study of systemic first-line therapy in MZL, demonstrating longer progression-free survival (PFS) with rituximab plus chlorambucil versus either agent alone, but no overall survival (OS) benefit.

Background: Bispecific antibodies (BsAbs) have changed the treatment paradigm in aggressive B-cell lymphomas, but these agents carry risks of cytokine release syndrome (CRS) and neurotoxicity (NT). These risks are most pronounced during the first cycle, requiring careful monitoring and hospitalization which may limit community use. Our aim was to explore risk factors for CRS and NT during the first cycle of BsAb administration. Methods: Fourteen institutions contributed to a shared database of patients (pts) with aggressive B-cell lymphoma receiving BsAbs. Data around demographics, histology, treatment history, laboratory values at administration, and incidence of CRS and NT following Cycle 1 were collected. A chi-square test of independence was used to assess differences in CRS and NT rates across glofitamab (glofit), mosunetuzumab (mosun), and epcoritamab (epcor). Continuous laboratory measures were binned into abnormally high, normal range, and abnormally low based on reference ranges from the American Board of Internal Medicine. A series of univariate logistic regressions was performed between variables of interest and the following: 1) any grade CRS, 2) Grade 2+ CRS, 3) Grade 3+ CRS, and 4) any grade NT. Results: A total of 262 pts received a BsAb. Median age was 67; pts were 59% male, 76% white, and 90% non-Hispanic. Prevalent histologies were de novo diffuse large B-cell lymphoma (73%), transformed follicular lymphoma (12%), and transformed marginal zone lymphoma (5%). BsAb products were glofit (45%), mosun (29%), epcor (23%), and other (3%). Products were administered as monotherapy or with steroids alone (66%), with systemic chemotherapy (7%), with targeted therapy (21%), or with XRT (5%). Line of therapy was known for 242 pts: 14% received 1st line, 45% received 2nd or 3rd, and 41% received 4thor later. Of the 244 pts with available CRS data, 79 (32%) experienced any grade CRS; 19 (8%) had G2 and 12 (5%) had G3+. Of the 231 pts with available NT data, 20 (9%) had any grade NT and 4 (2%) had G3+. CRS rates by BsAb product were 33%, 25%, and 34% for glofit, mosun, and epcor respectively (p =.43), while NT rates were 10%, 3%, and 11% respectively (p=.19). All grade CRS was more commonly seen in female pts (OR=1.79, 95% CI:1.04-3.09, p=.035), pts with high LDH (>225 IU/L, OR: 2.14, CI:1.14-4.0, p=.017), and pts receiving concurrent systemic chemotherapy (OR=5.18, CI:1.86-14.5, p=.002). Odds of any grade CRS did not vary by: (1) presence of extranodal or bulky (>5cm) disease, (2) bone marrow involvement, (3) CNS disease, (4) concurrent receipt of targeted therapy or XRT, or (5) abnormalities in other baseline lab values (ALC, ANC, platelets, CD4 count, albumin). G2+ CRS was increased in pts with high ferritin (>336 ng/mL, OR=2.90, CI:1.01-8.33, p=.048). All patients who developed G3+ CRS with sCRP data available (n=6, 100%) exhibited very high sCRP (≥15mg/L). Ferritin was also available for 5 of these pts; all of whom exhibited high ferritin (>336). Conversely only 12% pts without G3+ CRS exceeded both those thresholds. Of note, sCRP was only available for 57% of pts and ferritin for 61%. G3+ CRS was more common in pts receiving concurrent systemic chemotherapy (OR=10.8, CI:2.78-41.8, p<.001). Any grade NT was increased in pts with high ferritin (OR=6.45, CI:1.32-31.6, p=.022), high ANC (>8.25 /µL, OR=4.32, CI:1.26-14.8, p=.02), and high LDH (OR = 4.8, CI:1.08-21.3, p=.039), and increased but not significantly with high sCRP (>3mg/L, OR=3.8, CI:0.81-17.9, p=.09). Conclusion: This study represents one of the largest multi-institution analyses of risk factors for CRS or NT in patients treated with BsAbs for B-cell lymphoma. It serves as confirmation of low incidence of G3+ CRS and any grade NT, mirroring results from clinical trials. We identified sCRP ≥15 mg/L and ferritin >336 ng/mL as possible thresholds for screening for patients requiring closer observation during drug ramp up, but these values require increased acquisition and validation. Notably, we did not reproduce previously reported associations with extranodal disease or high tumor burden and found increased risk of CRS with concurrent systemic chemotherapy, and increased risk of any CRS and NT among patients with LDH >225 IU/L. These findings require further investigation. This evidence supports the growing initiative to understand which patients are suitable for an entirely outpatient ramp-up of BsAbs and their expanded use in the community setting.

TPS7087 Background: Autologous CART options for patients with relapsed or refractory (R/R) T-cell lymphomas (TCL) have faced challenges such as T-cell fratricide during CART manufacture and safety concerns regarding depletion of normal T cells. To overcome these obstacles, we proposed a dual cell population CART product, which contained both autologous 4-1BB costimulated CART cells against CD5 and healthy T-cells, with both populations knocked out for CD5 (CRISPR-Cas9 CD5 short-guide RNA to delete CD5 - Senza5). In vivo experiments using the dual population product of (Senza5 CART5) demonstrated increased CART5 expansion and enhanced antitumor efficacy in TCL xenograft models compared to wild-type (WT) CART5. For clinical use, a novel 5-day manufacturing process was designed to obtain a less differentiated and less exhausted product, with enhanced in vivo expansion and fitness. Methods: A human phase I trial was designed to determine the safety, effectiveness and recommended phase 2 dose (RP2D) of Senza5 CART5 cells in participants with R/R TCL with ≥50% expression of CD5 on malignant cells, and no circulating CD5+ cells. Participants must have a suitable backup stem cell product or donor identified in the unlikely event of T-cell aplasia. Patients with prior allo HCT are currently excluded. Cohorts of patients are treated with escalating doses of Senza5 CART5 cells (3x10 6 to 1.25x10 8 ) using a Bayesian Optimal Interval design following lymphodepletion. The study will enroll and treat participants until a maximum of 9 participants are infused and evaluable for dose limiting toxicity (DLT) assessments at a given dose level, or a maximum of 30 DLT-evaluable participants from all dose levels are infused. The RP2D will be determined based on both safety and biological evidence of efficacy. Study objectives include frequency and severity of treatment-related adverse events, as well as efficacy by assessing overall and complete response rates, duration of response, progression-free and overall survival. Manufacturing feasibility will be determined by the frequency of product release failures and occurrence of dose failures (inability to meet targeted dose). Exploratory objectives will evaluate the persistence and trafficking of Senza5 CART5 cells in blood and tumor by characterizing the kinetics of the infused cells by flow cytometry and qPCR gene expression. We will perform profiling of the tumor microenvironment and measure systemic soluble cytokines before and after treatment. We will also assess the impact of CART5 on normal T cells, and the persistence of CD5KO untransduced T cells that are infused as part of the Senza5 CART5 product by multicolor flow cytometry and qPCR. The trial is sponsored by Vittoria Biotherapeutics and is registered at clinicaltrials.gov as NCT06420089. Enrollment in this trial has begun. Clinical trial information: NCT06420089 .

Diagnosis-to-treatment interval (DTI) is an important prognostic factor in patients with newly diagnosed aggressive lymphomas, however the impact of DTI on outcomes in marginal zone lymphoma (MZL) is unknown. In this multicenter retrospective cohort study, we included adult patients with MZL who received first-line immunochemotherapy within 120 days of diagnosis at 10 US medical centers. Patients who received treatment within 60 days from their diagnosis were classified into the short DTI group and those who received treatment beyond 60 days into long DTI group. The primary objective was progression-free survival (PFS), while secondary objectives included overall survival (OS) and cumulative incidence of histologic transformation (HT) between the two groups. Of the 870 patients with newly diagnosed MZL, 177 patients met the inclusion criteria and were included in this analysis. Among these 144 (81

Background: CD19-directed CAR T-cell therapy (CAR-T) has improved outcomes and altered the treatment landscape for patients with relapsed/refractory large B-cell lymphomas (r/r LBCL). Despite these improvements, 60-70% of patients do not have long term remissions after CAR-T. CD20 x CD3 bispecific antibodies (BsAbs), such as mosunetuzumab and glofitamab, have demonstrated efficacy in LBCL relapsing after CAR-T (Chong Blood Advances 2025). We hypothesized that BsAbs could enhance the efficacy of CAR-T by reducing antigen-negative escape and enhancing CAR-T cell activation and persistence. To evaluate this hypothesis, we designed a phase IIa trial of early administration of mosunetuzumab or glofitamab within 31-45 days of CAR T-cell infusion. Methods: This is a multi-center clinical trial of early administration of BsAb for patients with r/r LBCL who receive standard of care CAR-T and have a partial response (PR), stable disease (SD), or progressive disease (PD) at day 30 post CAR-T infusion. BsAb is administered day 31-45 post CAR-T. Patients receive 2 cycles of BsAb (Cohort 1, mosunetuzumab; Cohort 2, glofitamab) and are assessed for response. Patients with complete response (CR) or PD after 2 cycles of BsAb discontinue BsAb; patients with PR or SD are continue BsAb every 3 weeks for up to 1 year and every 24 months during the second year. Efficacy is measured by the CR rate at 24 weeks after initiation of BsAb. CAR-T expansion in blood is assessed by qPCR. Enrollment to Cohort 1 (mosunetuzumab) is complete and Cohort 2 (glofitamab) enrollment is ongoing (NCT04889716). Results: Eight patients, 5 male and 3 female, with a median age of 63 years (range 47-78) were enrolled between January 2022 and May 2025, and included 7 patients with diffuse large B-cell lymphoma NOS (GCB-like [n=4], ABC-like [n=2]) and 1 patient with high grade B-cell lymphoma (double-hit). Patients had a median of 3 prior lines of therapy (range 2-7); 5 patients were primary refractory, 6 patients had extranodal disease, and 5 patients had elevated LDH at CAR-T infusion. Prior CAR-T products included tisagenlecleucel (n-2) and lisocabtagene maraleucel (n=6). The median time from CAR-T cell infusion to BsAb treatment was 42 days (range 33-45). Pre-BsAb responses to CAR-T at Day 30 included 4 PR, 1 SD, 3 PD. Within 30 days after CAR-T infusion and prior to treatment with BsAb, three patients had cytokine release syndrome (CRS) (n=2, grade 1; n=1, grade 2); no ICANS was observed. Mosunetuzumab (n=6) was generally well tolerated; CRS occurred in 3 of the 6 (50%) patients and was low grade (n=2, grade 1; n=1 grade 2). One patient received corticosteroids. One patient had a grade > 3 adverse event related to mosunetuzumab (2 episodes of grade 4 neutropenia, which responded to G-CSF and delay of mosunetuzumab). No CRS occurred in the 2 patients who received glofitamab. No patients developed ICANS. No unexpected adverse events have occurred. The best overall response rate (ORR) in the mosunetuzumab cohort (n=6) was 67% (1 CR, 3 PR, 2 SD, 1 PD). Four patients improved their CAR-T response status after the addition of mosunetuzumab (1 PD to SD, 2 SD/PD to PR, and 1 PR to CR). At 24 weeks, the best ORR was 50% (1 CR, 2 PR, 3 PD). With median follow-up of over 3 years, 1 year progression-free survival is 33% (95%CI 5-68); 1 year duration of response is 50% (95%CI 6-84). Response assessment in the glofitamab cohort is forthcoming. We also assessed changes in T cells and CAR-T cells in both cohorts. After starting BsAb, CAR-T cells in peripheral blood increased between cycle 1 day 1 and cycle 1 day 8 in 5/7 patients with available data; median fold change in CAR-T expansion was 0.25 (25% increase) copies/ug gDNA (range -0.42-12.62). Two patients with responses to mosunetuzumab had undetectable CAR-T at baseline and developed detectable CAR-T by cycle 1 day 8. All patients who continued to receive bispecific antibodies (5/7), had detectable CAR transgene at 12 weeks to 3 months. Two patients underwent biopsy at PD; both tumors expressed CD19 and CD20 and had minimal to no infiltration by T cells. Additional samples are undergoing evaluation and will be presented at the meeting. Conclusions: Early administration of CD20 x CD3 bispecific antibodies after CAR-T appears safe and may enhance CAR-T expansion. The sequential combination of CD19 and CD20 targeted therapies may improve clinical responses in certain patients with r/r LBCL.

Introduction: Bispecific CD20-directed/T cell-engaging antibodies (BsAbs) are FDA approved for treatment (tx) of patients (pts) with relapsed/refractory (r/r) large B-cell lymphomas (LBCL) and follicular lymphoma (FL). For LBCL, pivotal trials report durable remissions for those pts who achieve complete response (CR); however, progression-free survival (PFS) is short and real-world evidence suggests inferior CR rate, PFS, and overall survival (OS) compared to pivotal trials (Brooks et al. Blood 2025). We performed a retrospective, single-center analysis to better characterize the timing and clinical characteristics predictive of BsAb failure. Methods: This retrospective analysis included pts with histologically confirmed r/r LBCL or FL who received at least one dose of a commercially available BsAb at the University of Pennsylvania between February 2023 and January 2025. Results: As of January 13, 2025, we identified 109 pts who received BsAb meeting study criteria; 68 (62%) pts had LBCL. Among LBCL pts, 31 (45.6%) received glofitamab (glofit), 31 (45.6%) epcoritamab (epco), and 6 (8.8%) mosunetuzumab (mosun). Forty-one pts had FL of whom 40 pts (97.6%) received mosun and 1 pt (2.4%) epco. Fourteen pts (12.8%) did not complete BsAb step-up to dosing (SUD). Among SUD failures, 13/14 pts (92.9%) had LBCL and 1 pt (7.1%) FL; 7 pts received epco, 6 pts glofit and 1 pt mosun. Of 55 LBCL pts who completed SUD, the median age was 68 years (IQR 60.5-75), 36 of 55 pts (65%) had Ann Arbor stage III-IV (advanced stage) disease and median prior lines of tx (LOT) was 3 (range 1-10). The median number of cycles completed for epco was 4 (range 0.75–20), glofit 8 (range 1-17), and mosun 4 (range 2-8). Of 31 pts treated with epco, 4 (12.9%) continue on tx and 4 (12.9%) used epco as a bridge to CAR-T; other reasons for epco discontinuation included progressive disease (PD; 9 pts, 29.0%), infections (4 pts,12.9%), Grade 5 CRS/ICANS (1 pt, 3.2%), and secondary malignancy (1 pt, 3.2%). One pt was lost to follow-up (FU). Of 31 pts who received glofit, one (3.2%) continues tx; 8 pts (25.8%) completed prescribed course; 12 pts (38.7%) discontinued due to PD, 2 pts (6.5%) bridged to CAR-T, and 2 pts (6.5%) after CR prior to completing the prescribed course. Of 6 transformed FL pts treated with mosun, 3 pts (50%) discontinued after CR, 2 pts (33.3%) bridged to CAR-T, and 1 pt (16.7%) had PD. Of the 13 pts with LBCL who did not complete SUD, median age was 73 years (IQR: 67-80) and 12 pts (92%) were advanced stage. Median prior LOT was 2 (range 1-8). 12 of 13 pts (92.3%) are deceased at data cut, with a median time to death 17 days (range 6-39) after initiating BsAb. Causes of death included PD (n=8), multi-system organ failure (n=2), infection (n=1) and CRS/ICANS (n=1). Generalized linear model univariate analysis of LBCL pts (n=68) indicated the following variables were significantly associated with SUD failure: LDH > 2 x upper limit of normal [ULN] (p<0.001); high/high-intermediate IPI score and longest recorded lymph node diameter as a continuous variable (each p<0.01); age (continuous variable), elevated ECOG PS score (> 2) and stage III/IV disease (each p<0.1). In a multiple regression model, pts with LDH > 2x ULN were at higher risk of not completing SUD (p < 0.05). Of 13 LBCL pts who did not complete SUD, 11 pts (84.6%) had LDH > 2 x ULN, while 8 of 53 pts who completed SUD had LDH > 2 x ULN (15.1%; 2/55 pts had no LDH available). No FL pt had LDH > 2 x ULN. For the entire LBCL cohort, median FU was 8.7 months (mo); median PFS was 9.4 mo (95% CI, 5.9-not reached [NR]) with median OS NR (95% CI, 10.5-NR). The overall response rate (ORR) was 57.3%; CR 32.3%, stable disease (SD) 7.4%, and PD 25% (7 pts [10.3%] did not have response assessment). For the entire FL cohort, median FU was 16.2 mo, median PFS and OS NR (95% CI, 8.0-NR and 95% CI, 26.7 mo-NR, respectively). The ORR was 80.5%; CR 56.1%, PR 24.2%, SD 2.4%, and PD 17.1% Conclusion: Our findings suggest a substantial percentage (20%) of pts with LBCL do not make it to the full dose of BsAb therapy. Risk factors, such as elevated LDH and LBCL histology, characterize a subset of pts, at high-risk for not completing SUD and early mortality, which may necessitate an alternative tx strategy. Efficacious “bridging” or pre-BsAb therapy could be a reasonable approach to improving outcomes for these high-risk pts. A prospective clinical trial is planned to explore this approach.

Introduction Bispecific antibodies (BsAbs) have added to the treatment landscape for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), achieving complete response (CR) rates of ~ 40% in pivotal trials as monotherapy. BsAbs in combination with other agents that target distinct components of malignant B-cell biology are being explored to improve response and survival. We present real-world data comparing clinical characteristics and outcomes for BsAb monotherapy (B-M) vs BsAbs in combination with targeted therapy (B+T) in patients (pts) with R/R LBCL. Methods We developed a multicenter cohort of pts with R/R LBCL treated with B-M vs B+T across 15 US institutions from 2022-2025, excluding those treated on clinical trials. Differences in clinical and treatment characteristics were investigated using Pearson's Chi-squared test, Fisher's exact test, and Wilcoxon rank sum test. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier curves. Variables of clinical significance in univariate analyses (UVA) were included in multivariable regression analyses (MVA) using Cox Proportional Hazards Models to examine impact on PFS and OS. Results A total of 157 pts received BsAbs: 137 (87%) received B-M and 20 (13%) received B+T. For B+T pts, 9 (45%) were treated with lenalidomide, 6 (30%) with polatuzumab, 2 (10%) with a BTK inhibitor, and 3 (15%) with other targeted agents. For B-M vs B+T cohorts: there was no difference in median age (66 vs 66 years, p=0.8), male sex (62 vs 56%, p=0.6), Caucasian race (74 vs 70%, p=0.5), de novo DLBCL (68 vs 55%) or transformed follicular lymphoma (15 vs 15%; p=0.3), double hit status (DHL, 16 vs 6%, p=0.5), primary refractory disease with frontline therapy (PRD, 36 vs 45%, p=0.3), prior bendamustine (17 vs 21%, p=0.7), or prior CART (60 vs 80%, p=0.08). At time of BsAb initiation, rates of elevated LDH (63 vs 65%), extranodal disease (76 vs 89%), and bulky disease (36 vs 25%) were similar for each cohort (p ≥0.3). The B+T cohort included more pts with progression/relapse within 6 months of CART infusion (75 vs 44%, p=0.009). For B-M vs B+T: median time from diagnosis to BsAb infusion was 20 vs 13 mo (p=0.03) and median line of therapy was 4 for both (p=0.5). Glofitamab was more commonly used for B-M (n=83, 61%) and just as often as epcoritamab for B+T (n=8 for each, 40%; p=0.2). Median cycles of BsAb therapy were 4 in each cohort (p=0.8). Rates of any grade or ≥ grade 3 cytokine release syndrome and neurotoxicity were comparable across both groups (p>0.9), with no toxicity related deaths. For B-M vs B+T: median follow-up was 10.8 vs 17.1 mo. CR rates were 37 vs 31% (p=0.14). Although relapse rates (53 vs 65%, p=0.3) were similar, median duration of CR was not reached (7.4, NR) vs 3.2 mo (2.3, NR; p=0.009). Median PFS (mPFS) was 3.4 vs 4.9 mo (p=0.7), and median OS (mOS) was 10.1 vs 10.4 mo (p=0.6). From time of B-M vs B+T relapse, with next line therapy, mPFS was 1.6 vs 3.3 mo (p=0.4) and mOS was 2.6 vs 5.1 mo (p=0.6). On UVA, age >60, age >80, PRD, DHL, prior bendamustine or CART exposure, BsAb treatment within 3 mo of CART, LDH, bulky disease, and absolute lymphocyte count (ALC) ≤0.3 at time of BsAb did not impact PFS or OS in either B-M or B+T cohorts (p≥0.2). On MVA, choice of B-M vs B+T had no impact on PFS (p=0.6) or OS (p=0.4). ALC ≤0.3 negatively impacted PFS [HR=2.75, (95% CI 1.38-5.48), p=0.006] but not OS (p=0.2). Elevated LDH at time of BsAb was independently associated with worse PFS [HR=3.36, (95% CI 1.64-6.86), p<0.001] and OS [HR=3.39, (95% CI 1.37-8.43), p=0.005]. PRD and BsAb within 3 mo of CART trended towards negative impact on PFS (p<0.07) but not OS (p=0.2). Age >60 years, DHL, and bulky disease had no impact on PFS and OS in pts treated with BsAb +/- T. ConclusionsIn real world practice, there is a tendency to consider B+T rather than B-M in pts with quicker relapses after CART. B-M vs B+T may yield similar response rates and survival. However, the optimal combination partner for BsAbs remains unclear and requires further study. Low ALC and elevated LDH negatively impacted PFS with BsAb +/- T suggesting a need to balance disease burden and lymphotoxicity of treatments prior to the use of BsAbs. Elevated LDH also negatively impacted OS with BsAb +/- T and may serve as a key prognostic marker for treatment with BsAbs. In pts who relapse post-BsAb +/- T, survival is dismal underscoring the need for novel treatments in this population.

Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL), with a median age at diagnosis of 55 years old. However, many patients (pts) are older, and its incidence is four-fold increased among pts over 70. As life expectancy rises, octogenarians will comprise an increasing proportion of the CTCL population; however, there are currently no consensus guidelines for managing this older demographic. Mogamulizumab (moga), a monoclonal antibody targeting C-C chemokine receptor 4 (CCR4),demonstrated remarkable efficacy in CTCL in the phase 3 MAVORIC trial. We sought to evaluate the effiacy and tolerability of moga-based regiments in patients aged 80 and older that were under-represented within this trial cohort. Methods: This single-center retrospective observational study included CTCL pts aged ≥80 who initiated moga therapy between December 2017 and December 2024, with at least 6 months of follow-up.Global treatment response was assessed by 2022 consensus criteria, and toxicity per CTCAE v5.0. Baseline characteristics were analyzed using independent t-tests, Fisher's exact tests, or Pearson's chi-square tests. Overall survival (OS) and progression-free survival (PFS) were co-primary endpoints analyzed via Kaplan-Meier log-rank and Cox proportional hazards models. Results: Nineteen pts were identified (13 SS [68%], 6 MF [32%]); median age was 82 (range:80–94). Ten (53%) were male and 16 (84%) were White. Thirteen (68%) had ECOG 0-1 and 15 (79%) had advanced stage disease. LDH was elevated in 15 pts (79%) and 8 (42%) had a history of large cell transformation. Median lines of treatment prior to moga was 3 (range:1-8). All pts received moga at 1 mg/kg on days 1, 8, 15, and 22 of cycle 1, then biweekly; 8 pts (42%) later transitioned to 3–4-week intervals. Combination therapy was used based on institutional practice in 13 pts (68%) including interferon alpha (6/13,46%), bexarotene (6/13,46%), interferon gamma (7/13,54%) and extracorporeal photopheresis (8/13, 62%). Two pts (11%) received total skin electron beam therapy during their treatment course. Median duration of moga treatment was 9 months (range 2-51 months). Seventeen pts (89%) achieved a global response (6/17 [35%] complete, 11/17 [65%] partial), while two (11%) had stable disease. Compartmental responses were highest in blood (15/16, 94%), followed by skin (17/19,89%) and nodes (2/3,67%). No pts exhibited visceral disease. Median length of follow up was 14.4 months (range: 6-72 months). Median duration of response was 10 months (range 3-49 months). Median PFS was 12.6 months (95% CI 6.8-32.3 months). Thirteen pts (68%) were alive at last follow-up; and median OS was not reached. Cause of death was attributable to CTCL in only one patient (5%) and there were no treatment-related deaths. Six pts (32%) experienced grade 1-2 infusion reactions, all manageable with subsequent additional premedication. Cytopenias were observed in 15 pts (79%) with 7/15 ( 46%) having grade 3 or 4 cytopenias. Biopsy confirmed moga-associated rash (MAR) was observed in 9 pts (47%) all of which resolved with topical corticosteroids (7/9, 78%) and/or oral methotrexate (2/9, 22%). Other notable non-hematologic adverse events included grade 2 thyroiditis in one patient (5%) and Grade 1-2 diarrhea in two pts (10.5%). Reasons for cessation of moga therapy included MAR (4,21%), progression of disease (5/19,26%) or patient preference (4/19, 21%). Six pts (32%) remained on therapy at last follow-up. Discussion: To our knowledge, this is the first real-world study to evaluate moga-based regimens in patients 80 or older with MF/SS. Notably, this patient population was largely not represented within the MAVORIC trial which led to moga approval for MF/SS. Our results suggest that moga-based treatment regimens have a significant therapeutic role in elderly pts with MF/SS, with an observed response rate of 89%, in line with our previously reported institutional experience. Given its safety and efficacy profile, moga -based regimens can play an important role in CTCL in elderly pts. However further investigation in prospective clinical trials is warranted to more clearly delineate efficacy in this patient population.

Background: Anti-CD19 chimeric antigen receptor T-cell therapy (CART) is an effective therapy for relapsed or refractory (R/R) large B-cell lymphoma (LBCL) with 3 FDA approved CART constructs: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), & lisocabtagene maraleucel (liso-cel). Clinical trials report variability in manufacturing, efficacy, & treatment related toxicities, but limited data exists directly comparing these treatments. Here we report the largest real-world comparison of all 3 CART constructs for the treatment of R/R LBCL. Methods: Patients (pts) >18yr treated with CART for R/R LBCL were identified across 15 academic institutions. Wilcoxon rank-sum test, Kruskal-Wallis, & pooled t-test were utilized (p<.05) to determine the statistical significance of differences between variables. Time-to-event curves were estimated from time of CART infusion using Kaplan-Meier, & Cox regression was performed to determine the impact of variables on survival. Results: 925 pts were identified: axi-cel (61%), tisa-cel (19%), liso-cel (20%). There was no difference in disease stage, histology, presence of c-MYC/BCL-2 gene rearrangement (DHL), primary refractory disease (PRD), or pre-infusion performance status among pts for each construct. Pts treated with liso-cel were older (median age 68, range 19-85) compared to axi-cel (60, 21-86) & tisa-cel (64, 22-89; p=0.001) & received more bridging therapy liso-cel (61%) compared to axi-cel (50%, p=0.01). Axi-cel had the lowest incidence of out of specification (OOS) product (2.5%) vs tisa-cel (16.6%) & liso-cel (12.6%; p=0.001) but did not account for recent changes in defined OOS criteria for liso-cel. Time from apheresis to CART infusion (vein-to-vein) was shorter with axi-cel (28 days (d), range 9-250) vs tisa-cel (40d, 12-180) & liso-cel (40d, 24-393; p=0.001). There was a higher incidence of CRS (78%) with axi-cel compared to tisa-cel (53%, p=0.001) & liso-cel (52%, p=0.001). Liso-cel was associated with the lowest incidence of grade 3-4 CRS (n=1, 0.5%) vs axi-cel (n=61, 11%) & tisa-cel (n=17, 10%, p=0.001). Axi-cel also had a higher incidence of ICANS (50%) vs tisa-cel (29%) & liso-cel (22%, p=0.02) with tisa-cel having the lowest incidence of grade 3-4 ICANS (n=12, 6.8%) vs axi-cel (n=116, 20%) & liso-cel (n=22, 12%, p=0.011). There was no difference in 30-day mortality post-CART: axi-cel (2.1%), tisa-cel (2.8%), & liso-cel (1.6%, p=0.73). At a median follow up of 469d (IQR 941), there was no difference in incidence of microbiologically confirmed infection, hypogammaglobulinemia, secondary malignancy, or administration of IVIG across the 3 CART constructs. Tisa-cel was associated with a lower CR rate (41%) vs axi-cel (51%) & liso-cel (57%; p=0.002) & this difference persisted when examined in the 3L+ only (p=0.001). Tisa-cel was also associated with inferior median progression free survival (mPFS) at 147d (95% CI 105-218) vs axi-cel 582d (95% CI 339-1352) & liso-cel 332d (95% CI 184-926; p=0.001) & with inferior median overall survival (mOS) at 550d (95% CI 423-723) vs axi-cel 1154d (95% CI 866-1853) & liso-cel 722 d (95% CI 524-1630; p=0.001). Results were similar when stratified by 3L+. There was no significant difference in CR rate between axi-cel or liso-cel overall (p=0.62) or when stratified by 2L or 3L+ therapy. There was also no significant difference in mPFS or mOS between axi-cel & liso-cel overall (p=0.29 & 0.50, respectively) or when stratified by lines of therapy. In a multivariate analysis, after adjusting for pt age, LDH, PRD, use of bridging therapy, line of therapy, & vein-to-vein time, axi-cel had higher OS when compared to pts treated with tisa-cel (HR 1.46, 95% CI 1.14-1.86, p=0.003) but comparable OS to liso-cel (HR 1.08, 95% CI 0.82-1.42, p=0.602). Additionally, multivariate analysis demonstrated a higher PFS in pts treated with axi-cel compared to tisa-cel (HR 1.6, 95% CI 1.25-2.04, p=0.001) but this was not statistically significant when compared to liso-cel (HR 1.2, 95% CI 0.93-1.55, p=0.17). Conclusions: In the largest, real-world comparison study of FDA approved CART constructs for R/R LBCL, tisa-cel was associated with inferior response rates & survival outcomes. Despite differences in manufacturing, treatment timelines, & toxicity profiles, there was no statistically significant difference in response rates or survival outcomes with axi-cel compared to liso-cel, in contrast to previously published reports.

Introduction: Mantle cell lymphoma (MCL) is usually an incurable lymphoma with no standard frontline therapy. Increasingly, Bruton tyrosine kinase inhibitors are utilized in frontline therapy, especially in older patients, but data remain limited in younger patients. We report our experience with a cohort of patients with MCL who received frontline second-generation BTKi +/- rituximab. Methods: We reviewed all patients treated at our institution with either acalabrutinib or zanubrutinib (BTKi) +/- maintenance rituximab who had therapy initiated by July 10, 2024. Adverse events (AEs) were graded based on CTCAE v5. We defined patients as either younger or older: patients <65 years old were considered younger unless noted to be autologous hematopoietic stem cell transplant (ASCT) ineligible. Patients ≥70 years were considered older. Patients aged 65-70 were assessed for ASCT eligibility; ASCT-ineligible patients were considered older. A cohort of patients who had frontline standard-of-care chemotherapy (R-HyperCVAD or R-CHOP/R-DHAP) was also collected for comparison to the younger BTKi-treated cohort. Results: Thirty patients received frontline second-generation BTKi. Eleven (37%) were younger and 19 (63%) were older. Twenty-three patients (77%) received acalabrutinib (10 with rituximab maintenance) and 7 patients (23%) received zanubrutinib (4 with rituximab maintenance). Twenty (67%) were male, 27 (90%) were white, and 3 (10%) were black. Median age was 70.9 years (range 44.8-93.4). Twenty-five (83%) had ECOG performance status (PS) 0-1. Twenty-seven patients had advanced stage disease (90%). MIPIb was high risk in 21 (70%); Ki-67 was ≥ 50% in 6/26 (23%) and ≥ 30% in 12/26 (46%). Three (10%) patients had blastoid MCL. Five of 26 (19%) patients had a TP53 aberration. Between younger and older cohorts, there were no significant differences in sex, ECOG PS, blastoid MCL, or presence of TP53 aberrations. MIPIb was significantly higher in older patients (6.3 vs. 7.2, p=0.003). Overall, 24 patients (80%) had an AE related to BTKi, with 7 (23%) experiencing a serious AE (SAE). The most common AEs were bleeding/bruising (33%), infections (n=8, 27%; 1 URI, 4 pneumonia, 1 bacteremia, 1 urinary tract infection, 1 cellulitis; 3 were SAEs), and rash (20.0%). There was no significant difference between rate of any AE or SAE between older and younger patients. Five patients discontinued BTKi due to toxicity (recurrent neutropenia, rash, cellulitis, pneumonitis, dysgeusia) and one due to patient preference. Thirty-two patients were included in the frontline chemotherapy cohort. Twenty-five patients (78.1%) were male, 29 (90.6%) were white, two (6.3%) were black, and one (3.1%) was Hispanic. Median age was 60.3 years (range 27.3-74.5 years). Twenty-eight (87.5%) patients had an ECOG PS 0-1. Median stage was 4 (range 2-4) and median MIPIb was 6.8 (range 5.4-9.6). Nineteen (59.4%) of patients had classical MCL and 13 (40.6%) had blastoid/pleomorphic MCL. Five of 28 (18%) patients had a TP53 aberration. Comparing younger patients who received frontline BTKi and younger patients who received frontline chemotherapy, there were no significant differences in sex, ECOG PS, MIPIb, or presence of TP53 aberrations or proportion of patients who received maintenance rituximab; however, the younger BTKi cohort did have a significantly lower incidence of blastoid MCL (10% vs. 37%, p=0.02). Median follow-up for the entire cohort (n=62) was 58 months; estimated 3-year PFS for the BTKi (n=30) and chemotherapy cohorts (n=32) was 57% (95%CI 34-74%) vs. 43% (95%CI 26-60%). Median follow-up for the younger BTKi and younger chemotherapy cohorts was 35 and 102 months, respectively. Estimated 3-year PFS for the younger BTKi cohort (n=11) vs. younger chemotherapy cohort (n=27) was 52% (95%CI 20-77%) vs. 48% (95%CI 25-61%). Conclusions: Second-generation BTKi with and without rituximab appear safe and effective frontline therapy for MCL regardless of patient age. We also observed excellent BTKi outcomes in younger patients comparable to standard-of-care chemotherapy. Limitations include a higher proportion of patients in the frontline chemotherapy group with blastoid MCL as well as relatively short follow-up in the BTKi cohort. Nevertheless, second generation BTKi may represent an effective frontline therapeutic approach for patients with MCL. Further studies are needed to determine the role of chemotherapy with BTKi vs chemotherapy-free regimens in this setting.

Introduction: Bruton tyrosine kinase inhibitors (BTKi) are highly efficacious oral agents FDA-approved for treatment of specific B-cell malignancies. BTKi are generally administered until disease progression, intolerable toxicity, or death. The emergence of cardiovascular adverse events (CVAE) including hypertension (HTN), arrhythmias, heart failure, and sudden death have limited the use of ibrutinib (Ibr), the first-in-class BTKi FDA-approved in 2013. Hypertension (HTN) is a frequent and cumulative toxicity of Ibr that is associated with increased risk of major adverse cardiac events. Alternate covalent BTKi (acalabrutinib, zanubrutinib) and non-covalent BTKi (pirtobrutinib) have lower rates of CVAE in clinical trials compared with Ibr. The objective of this study was to analyze the real-world incidence of HTN and CVAE in patients (pts) on Ibr and the outcome of pts with new or worsening HTN on Ibr who were then transitioned to an alternate BTKi. Methods: We conducted a retrospective electronic medical record review of pts with hematologic malignancies treated with Ibr from January 2013 to July 2024 at the University of Pennsylvania. Blood pressure (BP), cardiovascular medications, comorbidities, and CVAE were analyzed prior to Ibr (baseline), while on Ibr, and while on subsequent BTKi (acalabrutinib, zanubrutinib, or pirtobrutinib). Eligible pts had at least 3 BP measurements available during each of the following periods: 1) within 12 months of Ibr initiation; 2) while on Ibr; and 3) while on subsequent BTKi. All available BP values were used to calculate medians and means for each therapy period. HTN was defined as elevated systolic BP (SBP) ≥130 and/or diastolic BP (DBP) ≥80 on more than one occasion with physician confirmation of the diagnosis. Worsening HTN was defined as pts with antecedent HTN with an increase in the number or doses of prescribed antihypertensives. Graphpad/R 4.4.0 were used for statistical analysis. Results: A total of 114 pts received Ibr for 408.7 patient-years and 77 (68%) of pts had CLL. The median age was 67 (range 27-86) and 81 (71%) pts were men. On Ibr, 109 (96%) pts had systolic HTN and 100 (88%) had diastolic HTN. Across all BTKi, 74 (65%) pts had a CVAE. CVAE led to Ibr discontinuation in 58 (51.5%) pts, including HTN (n = 20, 18%), atrial fibrillation (n = 25, 22%), other arrhythmia (n = 1, 0.9%), palpitations (n = 2, 1.8%) and hemorrhage (n = 10, 8.8%). Among all pts on Ibr, 67 (59%) had either new onset HTN (n = 49, 43%) or developed worsening HTN with an increase in anti-HTN medications (n = 18, 16%). The median time on Ibr to first elevated SBP and maximum SBP were 32 (95% CI: 24 – 49) and 342 (95% CI: 229 – 604) days, respectively. The median time on Ibr to first elevated DBP and maximum DBP were 114 (95% CI: 83 –199) and 335 (95% CI: 250 – 465) days, respectively. Among the 109 pts with HTN on Ibr, transition to acalabrutinib (n = 67, 61%) or zanubrutinib (n = 33, 20%) resulted in a mean reduction in SBP of -9 mm/Hg (95%CI: -13 to -5.1) and -6 mm/Hg (95%CI: -11 to -0.8), respectively, without a change in number of antihypertensive medications. There were no observed differences in SBP, DBP, or the number of anti-HTN medications among pts with HTN on Ibr who transitioned to pirtobrutinib (n = 9, 8%). Among pts with HTN on Ibr, 45 (41.3%) had resolution of HTN with a median time to resolution (mTTR) of 2,277 days (95% CI: 1,996 – 2,463), although this time estimate is biased by infrequent follow-up. Among 55 pts with documented HTN on Ibr who transitioned to acalabrutinib, 20 (36.4%) had resolution of HTN with mTTR of 1,463 days (95% CI: 976 – NE). Among pts with documented HTN on Ibr who transitioned to zanubrutinib (n = 26) and pirtobrutinib (n = 8), HTN resolved in 8 (30.8%) and 2 (25%) with mTTRs of 683 (95%CI: 606 – NE) and NR (95%CI: 158 – NE) days, respectively. Conclusion: BTKi are associated with increased risk of CVAE; 43% of pts on Ibr developed new onset HTN and 52% of pts discontinued Ibr due to a CVAE. Among pts with HTN on Ibr, transition to alternate covalent BTKi was associated with a reduction in mean SBP as well as resolution of HTN, in some patients, without an increase in number or dose of antihypertensive medications. Despite the development of HTN on Ibr, BP can improve after replacing Ibr with an alternate BTKi.

Background Previous work has linked the inferior prognosis of patients with newly diagnosed large B cell lymphoma (LBCL) of activated B cell (ABC) cell of origin (COO) by gene expression profiling (GEP) with both double expressor (DE) features (PMID 23449635) and MCD genetic subtype (PMID 32289277 and 34739844). However, it is unknown whether these findings apply to LBCL tumors diagnosed in routine clinical practice, for which COO is typically assigned by immunohistochemistry (IHC) and genetic subtype based upon targeted next generation sequencing (NGS) panels. Methods We retrospectively compiled patients with newly diagnosed LBCL from multiple data sets (PMID 32780847, 30523716, and Hematological Oncology, 43: e180_70094). Inclusion criteria were cases with non-GCB COO by Hans algorithm, treatment with R-CHOP, known DE status (cutoffs MYC IHC ≥40% and BCL2 IHC ≥50%), known MYC rearrangement (MYC-R) status, calculable International Prognostic Index (IPI) score of <3 vs ≥3, available NGS data, and >12 months of follow-up without evidence of disease progression. MCD-like subtype by LymphPlex (PMID 37032379) and MYD88 subtype (PMID 34378195) were assigned based upon available variant data. Results Of 689 total cases, 218 met inclusion criteria and were analyzed. Baseline characteristics included IPI score ≥3 46%, MYC-R 6%, DE 43%, TP53 mutation 24%, any MYD88 mutation 31%, MYD88 L265P mutation 22%, PIM1 mutation 33%, ETV6 mutation 14% (tested in 83 cases), TBL1XR1 mutation 16% (tested in 83 cases), MCD-like subtype 16%, and MYD88 subtype 22%. Of note, for 138 cases for which COO was also reported by Lymph2Cx, 72% were assigned ABC, 9% GCB, and 19% unclassified. DE was associated with the presence of MYC-R (p=0.046), MCD-like subtype (p=0.09), and MYD88 subtype (p=0.02), but no other baseline characteristic. As was the case for DE, neither MCD-like nor MYD88 subtype were associated with IPI score. Neither MCD-like nor MYD88 subtype was associated with MYC-R, and MYD88 subtype was not associated with TP53 mutation (noting cases with TP53 mutation were assigned to an independent cohort by LymphPlex). For the entire cohort, with a median length of follow-up was 70 months (range 37-123 months across cohorts), the 3-year progression-free survival (3yPFS) was 65% (95% confidence interval [CI] 58-71%) and estimated 3-year overall survival (3yOS) was 71% (95% CI 64-77%). Inferior 3y PFS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.008), DE (p=0.002), TP53 mutation (p=0.07), MYD88 mutation (p=0.02), and MYD88 L265P mutation (p=0.004) by univariate analysis (UVA) with significance level p<0.10; however, only IPI score ≥3 (hazard ratio [HR] 2.2, 95% CI 1.4-3.5, p=0.001) and DE (HR 1.9, 95% CI 1.2-3.0, p=0.007) remained significant on multivariate analysis (MVA) with significance level p<0.05. On UVA, inferior 3yOS was associated with IPI score ≥3 (p<0.001), MYC-R (p=0.001), and DE (p<0.001), with all remaining significant on MVA: IPI score ≥3 (HR 3.1, 95% CI 1.8-5.4, p<0.001), DE (HR 2.3, 95% CI 1.4-3.9, p=0.002), and MYC-R (HR 2.3, 95% CI 1.1-5.0, p=0.03). For patients with vs without DE, 3yPFS was 53% (95% CI 42-62%) vs 74% (95% CI 65-81%) (p=0.001) and 3yOS 57% (95% CI 47-67%) vs 81% (95% CI 77-87%) (p<0.001). Finally, one cohort (PMID 30523716) reported genetic classification by LymphGen, in which 16% of cases were classified as MCD genetic subtype. Subgroup analysis of this cohort (n=122) revealed an association between DE and MCD genetic subtype by LymphGen (p<0.001). Additionally, MCD genetic subtype by LymphGen was associated with inferior 3yPFS on UVA (p=0.06), but not MVA (HR 1.4, 95% CI 0.7-2.7, p=0.32) when incorporating IPI score and DE, both of which remained significant. MCD genetic subtype by LymphGen was not significantly associated with 3yOS on UVA (p=0.20). Conclusions DE is a biomarker of inferior 3yPFS and 3yOS independent of IPI score or genomic features analyzed in this multi-national cohort of newly diagnosed non-GCB LBCL patients. MCD genetic subtype as well as genetic subtypes approximating MCD are associated with DE but are not independently prognostic in this patient population. These findings have implications for non-GCB LBCL patients diagnosed in routine clinical practice, and support further exploration of common molecular features that predict for chemoresistance, as well as evaluation of the efficacy of targeted therapies, in newly diagnosed non-GCB DE LBCL patients.

Background: CART and bispecific antibodies (BsAb) are both effective treatments for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). In prospective trials, BsAbs demonstrate similar response rates regardless of prior CART exposure. However, the impact of BsAb exposure on subsequent CART efficacy is unknown and the appropriate sequencing of these therapies has not been studied. In this real-world analysis, we compare outcomes in pts who received CART and/or BsAb for R/R LBCL to understand the impact of sequencing on survival. Methods: We identified 1031 adult pts with R/R LBCL treated with a CD20-directed BsAb and/or CD19-CART at 15 US cancer centers from 2015-2024. De novo DLBCL, transformed FL, and other LBCL histologies were included. Pts were grouped according to sequence of therapy received. Baseline characteristics were compared with the Pearson Chi-squared test and included: demographics (age, race, ethnicity, sex), disease features [cell of origin (COO), histology, double hit lymphoma (DHL), LDH at treatment], and treatment characteristics [primary refractory disease (PRD) defined as progression on or relapse within 12 months of start of frontline therapy, BsAb or CART product, line of therapy, prior ASCT or bendamustine]. Median duration of complete response (mDOCR), progression free survival (mPFS) & overall survival (mOS) were estimated by Kaplan-Meier method and assessed from time of treatment start in months (mo). A p-value <0.05 was significant. Results: We compared BsAb pts with prior CART (group 1, n=121) vs those without prior CART (group 2, n=109): Glofitamab was the most common BsAb in both group 1 and group 2 (56% vs 45%). Cohorts did not differ by sex, race, histology, bendamustine exposure, or drive time to center. For group 1, median time from CART relapse to BsAb administration was 43 days. Pts in group 2 were older (> age 60, 69 vs 56%, p=0.04), less fit (ECOG PS 0-1, 74 vs 91%, p<0.001), more often GCB subtype (70 vs 48%, p=0.002), more often with elevated LDH (67 vs 53%, p=0.03), and received fewer prior lines of therapy (BsAb 3rd vs 5th line, p<0.001). We examined outcomes following BsAb between groups. There was no difference in rate of best response, including CR rate (32 vs 38%, p=0.3), mDOCR (34.4 mo vs NR, p=0.2), time to relapse (4.3 vs 4.9 mo, p=0.7), or rates/severity of CRS or neurotoxicity (NT). Pts with DHL had superior mDOCR in group 2 (21.7 vs 5.1 mo, p=0.025). There was no difference in mPFS (3.4 vs 4.3 mo, p=0.7) or mOS (13.2 vs 10.4 mo, p=0.3), including among patients age > 60 or with PRD, DHL, or elevated LDH. BsAb product had no impact on mPFS or mOS. For group 1, time from CART relapse to BsAb treatment (< 90 days, 90-180 days, >180 days), did not impact mPFS or mOS. We compared CART pts with prior BsAb (group 3, n=12) vs those without prior BsAb (group 4, n=922): Groups did not differ by sex, race, histology, DHL, LDH, stage, extra-nodal disease, prior bendamustine, or prior ASCT. Pts in group 4 were younger (> age 60, 56 vs 91%, p=0.03), more fit (PS 0-1, 90 vs 64%, p=0.02), had lower baseline IPI (IPI 3-4, 51 vs 90%, p=0.04), more non-GCB subtype (45 vs 0%, p=0.002), and fewer prior lines of therapy (3rd vs 4h line, p=0.005). We examined outcomes following CART between groups. There was no difference in rate of best response, including CR rate (58 vs 61%, p=0.3), mDOCR (43 mo vs NR, p>0.9), time to relapse (11.2 vs 7.9 mo, p=0.6), or rates/severity of CRS or NT. There was no overall difference in mPFS (2.6 vs 2.1 mo, p=0.4) or mOS (30.4 vs 15.2 mo, p=0.15), including among pts age > 60, with DHL, or with elevated LDH. However, mOS among PRD pts was superior in group 4 (25.4 vs 5.9 mo, p=0.03). Conclusions: In pts with LBCL, those treated with BsAb without prior CART are often older and have worse performance status. Among PRD pts, CART without prior BsAb offers a survival advantage to CART with prior BsAb exposure. Otherwise, sequencing of CART and BsAb does not appear to impact mPFS and mOS following each therapy, including among older, DHL, and high LDH subsets. In DHL pts, mDOCR with BsAb may be improved if not preceded by CART. Results are skewed by retrospective assessment, including unbalanced cohort characteristics and ineligibility for subsequent therapy due to worsening clinical status or death. As CART is potentially curative, based on this analysis, we favor CART over BsAb, particularly as BsAb appears similarly effective following CART.

Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive non-Hodgkin lymphoma. Given its infrequency, there are few randomized trials to guide induction and consolidation strategies, with no consensus on optimal treatment. Most centers will offer high-dose methotrexate-based induction chemotherapy followed by either autologous stem cell transplant, whole-brain radiation, or prolonged chemotherapy. The preferred strategy at our institution has been 6 doses of methotrexate, temozolomide, and rituximab (MTR) induction with methotrexate on day 15 until complete response for induction followed by 6 monthly cycles of MTR. We conducted a retrospective analysis of patients diagnosed with PCNSL at the University of Pennsylvania from 1 April 2008 to 1 October 2024, identifying 153 patients who received this regimen. With a follow-up of 63 months, the median overall survival (OS) in the entire cohort was 65 months, with a median relapse-free survival (RFS) of 36 months. In the cohort of patients who were able to complete 6 months of MTR induction and proceed with MTR consolidation, median OS and RFS were 143 and 122 months, respectively. Although 13% of patients discontinued therapy because of toxicity, there was no treatment-related mortality. These results indicate that prolonged MTR is a safe treatment option and an alternative to intensified consolidation strategies. Further randomized studies are necessary to determine the optimal treatment strategy in newly diagnosed PCNSL.

T-cell non-Hodgkin lymphomas (NHL) are a heterogenous group of malignancies that represent a minority of all NHL cases world-wide. Outcomes with traditional chemotherapy-based regimens remain poor with notably dismal outcomes in the relapsed/refractory setting. The power of immunotherapy has revolutionized treatments and outcomes for hematologic malignancies and has already made significant strides in addressing the treatment needs in T-cell NHLs. Given the heterogeneity of T-cell lymphoma subtypes and biology, a wide variety of innovative immunotherapies have been evolving to treat these various malignancies. Here, we review the promising advancement of various immunotherapies in T-cell NHLs including antibody-based therapies targeting T-cell surface antigens and checkpoint signaling, as well as the expanding strategies for chimeric antigen receptor T-cell (CAR-T) therapy in this difficult to treat disease space.

Introduction: All FDA-approved chimeric antigen receptor (CAR) T-cell therapies targeting CD19 (CART19) for relapsed/refractory (r/r) large B-cell lymphoma (LBCL) utilize the FMC63-derived single-chain variable fragment. However, they differ in co-stimulatory domain (CD28 in axi-cel versus 4-1BB in tisa-cel and liso-cel) which influences T-cell expansion and persistence. Whether these design differences affect the biology of the relapse following CART19 or the efficacy of subsequent therapies remains unclear.Methods: We conducted a retrospective, single-center study of LBCL patients (pts) who were r/r to commercial CART19 products. Data cutoff was June 2025. Clinical data, relapse tumor characteristics, and outcomes of subsequent therapies were collected from pt records. CD19 status was assessed by flow cytometry and/or immunohistochemistry; genomic profiling was retrieved by institutional assay (PENNSEQ hematological panel). Progression-Free Survival-2 (PFS2) was defined from the first post-CART progression to the next event (progression, new therapy, death, or last follow-up).Results: Of 327 LBCL pts treated with CART19 (01/2018–12/2024), 77% (N=251) received a 4-1BB-based product (tisa-cel N=181; liso-cel N=70) and 23% (N=76) the CD28-based axi-cel. CART19 was given in 2nd line in 19.5% of pts (N=64; 29 liso-cel, 35 axi-cel). In the full cohort, median age was 63 years (21-86 yrs); 64% of pts were male, 8% had prior CNS involvement, and 95% had ECOG <2 at CART. The median number of prior therapies was 3 (1-12),14% of pts had prior autologous transplant, 83% received bridging, and 34% had elevated LDH. Baseline characteristics were similar between CART costimulation groups, though pts receiving CD28-based CART were younger (56 vs. 66 yrs; p<0.01), more often received fludarabine/cyclophosphamide lymphodepletion, and treated more frequently in 2nd line. With a median follow-up of 30.9 months (95% CI:24.9–36.02), 60.5% of pts (N=198) experienced disease progression, with no significant difference by CART costimulation (p = 0.34). Among those who progressed, 7% (N=13) had isolated CNS relapse, 45% (N=90; 70% of whom were stage IV at infusion) had extranodal progression, and 48% (N=95) had nodal relapse. Of all relapses, 47% (N=94) occurred during the first 3 months, 37% (N=73) during months 3-12, and 16% (N=31) after 12 months with no difference by construct. Among pts with available relapse biopsies (N=97), 68% (N=66) were CD19-bright, 18% (N=17) CD19-dim, and 14% (N=14) CD19-negative, with numerically higher CD19-negative cases in CD28-based CART (21% vs. 12%, p=0.3). Genomic profiling at relapse was available for 57 pts, revealing frequent mutations in KMT2D (34%), TP53 (30%), and CREBBP (25%). CIITA mutations that may lead to overexpression of PD-L1/2 were observed in 9% and were more common after CD28-CART (21% vs. 3%, p=0.04). Interestingly, LZRT1 and PIK3C2B mutations were detected at low frequencies (4/43) exclusively in pts relapsing after CART. The median PFS2 following CART progression was 3.88 months (95% CI: 3.26–5.83). Pts with extranodal relapse (3.4 vs. 5.6 months), elevated LDH (3.0 vs. 6.1 months), or high ferritin (1.9 vs. 6.4 months) at relapse had shorter PFS2 (p <0.01). In multivariate analysis, elevated LDH and ferritin remained independently associated with shorter PFS2. The frequency of these adverse features did not differ by prior CART subtype. PFS2 varied significantly by type of subsequent therapy (polatuzumab-based regimens, bispecific antibodies, lenalidomide-based regimens, radiotherapy /local therapy, targeted agents (Di Blasi et al. Blood 2022), and other treatments; p=0.012). Polatuzumab-based therapies achieved the longest median PFS2 at 7.6 months (bispecific 3.9, lenalidomide 2.7, local 3.1, targeted 4.2, other 2.3 months). However, within these treatment groups, outcomes were similar regardless of the prior CART constructs.Conclusions: In this study of LBCL pts relapsing after CART19, PFS2 was overall short for both 4-1BB and CD28 CART19. CD19-negative relapses and CIITA mutations were more frequent after axi-cel. Polatuzumab-based regimens achieved the longest PFS2. Ongoing analyses are assessing CART-cell persistence and CD19 mutational changes pre-/post-treatment to identify selective pressures. Better insight into relapse biology may inform personalized strategies post-CART in this high-risk population.

Although CD19-directed chimeric antigen receptor T-cell therapies (CAR-T) have improved the prognosis for patients (pts) with relapsed/refractory (r/r) B-cell lymphomas (BCL), only about 30% of pts achieve durable disease-free survival and late effects of this therapy are still being defined. Immunocompromised pts have high risk of developing non-melanoma skin cancers (NMSC), including cutaneous basal cell and squamous cell carcinomas (Hall et al, Am Soc Clin Oncol Educ Book. 2020). Thus, we examined the incidence of NMSC post CAR-T in r/r BCL pts as a potential marker of ongoing immunosuppression. In this single-center, retrospective study, we reviewed medical records of BCL pts who received CAR-T between May 2018 - October 2024 at the Hospital of the University of Pennsylvania. Eligible pts had no antecedent history of NMSC and routine immune system studies (e.g., absolute lymphocyte count [ALC], CD3 and CD4 T cell counts) and clinical follow-up (f/u) available. ALC recovery (ALC-R) post CAR-T was defined as ALC ≥ 1x10^3 cells/µL; recovery period was defined as time from CAR-T infusion to last f/u, progressive disease, or death. Kaplan-Meier and log-rank tests were used for survival analyses. Cox proportional hazard models and linear regression were used for univariate and multivariate analyses. Of 369 pts screened, 284 were eligible for analysis (22 excluded due to death before CAR-T, 63 due to prior NMSC). Of 284 pts, 21 (7.4%) developed NMSC post CAR-T. For 21 pts with NMSC post CAR-T, median age was 65 years (yrs; IQR 61-71); 16 pts (76.2%) were male; 19 (90%) had large B-cell (LBCL), 1 (5%) follicular (FL), 1 (5%) mantle cell (MCL) lymphoma; 12 pts (57.1%) received tisacel, 5 (23.8%) axicel, 3 (14.3%) lisocel, 1 (4.8%) brexucel. For 263 pts without NMSC post-CART, median age was 61 yrs (IQR 52-68); 166 pts (63%) were male; 210 (80%) had LBCL, 32 (12%) FL, 21 (8%) MCL; 141 (53.6%) pts received tisacel, 67 (25.5%) axicel, 34 (12.9%) lisocel, 21 (8.0%) brexucel. Of 154 pts (54.2%) with ALC-R, 8 pts (5.2%) had NMSC; ALC did not recover (ALC-NR) in 130 pts (45.8%) and 13 pts (10%) had NMSC. Median time to ALC-R was 28 days (IQR 9-189); median time for ALC-NR pts was 91 days (IQR 50-240). For ALC-R vs ALC-NR: median age was 60 yrs (IQR 51-68) vs 62 yrs (IQR 57-69); 93 (60.4%) vs 89 (68.5%) were males; CAR-T received tisacel 94 (61.0%) vs 59 (45.4%), axicel 31 (20.2%) vs 41 (31.5%), lisocel 16 (10.4%) vs 21 (16.2%), brexucel 13 (8.4%) vs 9 (6.9%); LBCL diagnoses (dx) were 119 (77.3%) vs 110 (84.6%). Bendamustine was lymphodepletion (LD) for 223 pts (78.5%) (NMSC, n=15 [71.4%]; no NMSC, n=208 [79.1%]; ALC-R, n=121 [78.6%]; ALC-NR, n=102 [78.5%]). Best complete response rates were numerically higher in pts with NMSC (16/21 pts [76.2%]) than pts without NMSC (147/263 pts [55.9%]) and in pts with ALC-R (102/154 [66.2%]) than ALC-NR (61/130 [47.0%]). For pts with ALC-R, 43 pts (27.9%) died of lymphoma (32/43 [72.1%]), infection (6/43 [14.0%]), cardiac event (1/43 [2.3%]) secondary malignancy (1/43 [2.3%]), and unknown (4/43 [9.3%]). For pts with ALC-NR, 50 pts (38.5%) died of lymphoma (39/50 [78%]), infection (6/50 [12%]), secondary malignancy (1/50 [2%]), and unknown (4/50 [8%]). Analysis for risk of developing NMSC post CAR, including age, dx, gender, race, LD, CAR-T product, and baseline lymphocyte counts, showed ALC-R vs ALC-NR and time to ALC recovery were significant (P<0.05 and P<0.001, respectively); pts with ALC-NR had an increased risk of NMSC (p=0.05). We evaluated whether pts with ALC-NR (n=130, 45.8%) had an increased risk of other secondary malignancies (n=11, 3.9%); although not statistically significant, a trend was noted (p=0.1). Further, we examined ALC-R and survival. Median f/u for ALC-R and ALC-NR pts was 751 and 558 days, respectively. Pts with ALC-NR had median PFS 162 days (95% CI, 115-272) and median overall survival (OS) not reached (95% CI, 796-not reached); pts with ALC-R had median PFS 690 days (95% CI, 413-1066) and median OS was not estimable (n=154, events=43). Both PFS and OS were statistically significant between groups with improved outcomes for ALC-R pts (HR 0.48, p<0.001 for PFS and HR 0.43, p<0.001 for OS). While infection is the primary concern for most clinicians in the immediate post CAR-T period, our retrospective study highlights additional risks related to prolonged lymphopenia, including decreased PFS and OS and increased risk of NMSC.