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Abstract Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

Abstract Introduction Approximately 40% of patients with DLBCL will experience relapse after initial treatment with standard-of-care chemo-immunotherapy. Effective treatment options are limited for patients who experience first-line treatment failure, particularly for those with R/R disease following CAR T-cell therapy or those not able to receive CAR T-cell therapy (Sehn et al, N Engl J Med. 2021). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R DLBCL (Bachy et al, ICML 2025, #148). Here, we provide longer follow-up in patients with R/R DLBCL from Part B of the study. Methods Patients with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients after ≥ 1 line of therapy were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 77 patients with R/R DLBCL were enrolled in Part B Cohort C (GOLCA 0.2 mg + R, n = 39; GOLCA 0.4 mg + R, n = 38). Median age was 66 years (range, 20–86). Patients were heavily pre-treated; median number of prior treatments was 4 (range, 1–11), 55% of pts had prior CAR T-cell therapy, 38% had prior bispecific antibody treatment, and 44% were refractory to last treatment. Ten patients (13%) were ongoing, 4 completed 2 y of treatment, and 63 (82%) had discontinued treatment, mostly due to PD (n = 48 [62%]). The most common any-grade (G) treatment-emergent adverse events (AEs) in the 0.2- and 0.4-mg cohorts, respectively, were neutropenia (54% and 84%), an on-target side effect of GOLCA, and anemia (44% and 45%). G3/4 neutropenia was reported in 49% of patients with 0.2 mg and 79% with 0.4 mg, and febrile neutropenia (FN) in 5% and 16%, respectively. Granulocyte colony-stimulating factor was used in 81% and 88% of patients with neutropenia and 50% and 100% of patients with FN in the 0.2-mg and 0.4-mg cohorts. Dose interruptions (mainly due to infections/neutropenia) occurred in 49% and 53% of patients and discontinuations due to AEs occurred in 10% and 3% with 0.2 and 0.4 mg. One G5 pneumonia was considered related to study treatment (0.2 mg). The median follow-up was 11.8 months (range, 3.1–35.1) with 0.2 mg and 16.2 months (range, 3.8–31.4) with 0.4 mg. The overall response rate (ORR) in efficacy evaluable patients was 34% (complete response rate [CRR], 20%) with 0.2 mg (n = 35) and 58% with 0.4 mg (n = 36), including a CRR of 44% with this dose. In patients with prior T-cell–redirecting treatment, the ORR was 33% (CRR, 22%) with 0.2 mg (n = 18) and 56% (CRR, 38%) with 0.4 mg (n = 16). Seven of 35 (0.2 mg) and 14 of 36 (0.4 mg) patients experienced durable response > 12 months. The median time to response with both 0.2 and 0.4 mg was 1.8 months. In patients with durable responses (remained in response [CR or partial response] for more than two consecutive efficacy assessments) to GOLCA, circulating tumor DNA reduction from baseline continues to deepen over time. Response was similar across clones/tumor variants. Conclusions With additional follow-up, GOLCA + R continued to demonstrate a predictable and manageable safety profile, with no new safety signals observed at longer follow-up. Durable responses were shown in heavily pretreated patients with R/R DLBCL, including those with prior T-cell–redirecting therapy. GOLCA + R induced a decrease in circulating tumor DNA across tumor variants. These data support the ongoing development of GOLCA + R in patients with R/R non-Hodgkin lymphoma.

Abstract Diffuse Large B Cell Lymphoma (DLBCL), the most common subtype of aggressive B-cell Non-Hodgkin Lymphoma (NHL), accounts for 30-40% of newly diagnosed NHL cases. Despite recent progress improving our understanding of molecular features of DLBCL, there is still a high relapse rate (~45%) among patients who undergo standard treatment (R-CHOP). Several groups have identified reproducible molecular clusters of DLBCL although, the biologic significance of many of the specific gene mutations within these clusters is poorly understood. DTX1 mutations are a feature of the BN2/C1 DLBCL classifiers and are among the mutations with unknown significance. BN2/C1 DLBCL are a mixture of ABC, GCB, and Unclassified cell of origin (COO) with a common signature being the presence of genetic alterations in genes known to regulate the NOTCH pathway; yet, these tumors lack transcriptional signatures of traditional NOTCH activation, suggesting a unique and undefined biology driven through non-canonical NOTCH pathway activation. DTX1 is an E3 ubiquitin ligase which directly binds the intracellular domain of the NOTCH receptor (NICD), targeting it for degradation, resulting in suppression of NOTCH pathway activity. We therefore hypothesize that DTX1 mutations lead to NOTCH pathway dysregulation and are a critical driver for a subset of BN2/C1 DLBCLs. Using whole exome sequencing (WES) data from 404 newly diagnosed DLBCL patients, we found 8% of patients with mutations in DTX1. Alterations in DTX1 were localized to the NICD binding domain, WWE1. In silico Alphafold modeling of DTX1 WWE1-interaction with NICD revealed that patient mutations clustered within predicted interacting surfaces with NICD. These findings lead to the hypothesis that mutations in the DTX1 WWE1 domain suppress its ability to bind to and degrade NICD, enhancing NOTCH pathway activation in DLBCL. To address this question, we first compared DTX1 protein expression by immunoblot in DTX1 WWE1 mutant (OCI-Ly3 and SUDHL2) and wildtype (WT) (OCI-Ly7, OCI-Ly19, SUDHL6, and U2932) DLBCL cell lines. We found higher expression of NICD1 (p=0.03) in OCI-Ly3 and NICD2 (p<0.0001) in SUDHL2 cell lines compared to WT. This increase was accompanied by an increase in NOTCH surface expression with higher NOTCH1 (p<0.0001) and NOTCH2 (p<0.0001) expression on OCI-Ly3 and SUDHL2 cells, respectively, compared to WT. To remove variability across cell lines we next used CRISPR to generate DTX1 knock out (KO) models using WT DTX1 DLBCL cell lines U2932 and OCI-Ly19. Analysis of NICD and NOTCH receptor protein expression confirmed our initial finding, showing an 8.5 and 4.8-fold increase of NICD1 and a 6 and 2.5-fold increase of NICD2 expression in the U2932 and OCI-Ly19 DTX1 KO cell lines, respectively, compared to empty vector (EV) controls. An increase in surface NOTCH1, and to a lesser extent NOTCH2, was seen in U2932 (p=0.01 and p=0.07, respectively) and OCI-Ly19 (p=0.001 and p=0.2, respectively) KO cells compared to EV controls. To identify pathways affected by DTX1 mutations, we next performed RNAseq on U2932 EV and KO cell lines. Of interest, we did not detect any significant changes in classical NOTCH driven genes (Hes1, Hey1, etc.), supporting prior studies on BN2/C1 tumors. However, we did identify potential non-canonical NOTCH-target genes that may contribute to lymphomagenesis. Gene expression in KO cells showed upregulation of genes involved in germinal center (GC) processes (AICDA, IRF4; p<0.001) and cellular growth and survival (IL6R, CCND2, STAT5B, BCL2; p<0.0001). Measurement of IL6R by flow cytometry and CyclinD2 by immunoblot further verified DTX1-mediated upregulation of IL6R (p<0.01) and CyclinD2 (p<0.01) for U2932 KO cells compared to EV control. We also observed downregulation of genes contributing to cell death (ex. BAX, CASP8, FAS; p<0.05) in KO cells compared to EV. Together, these novel findings support our hypothesis that DTX1 WWE1 mutations lead to dysregulation of the NOTCH pathway by driving overexpression of NICD and NOTCH, resulting in dysregulated expression of proteins involved in cell cycle, GC reaction, and apoptosis. We further provide new biologic insight into BN2/C1 DLBCL, ultimately highlighting a path toward novel therapeutic targets and the advancement of personalized medicine, as patients harboring these mutations may benefit from new therapies targeting inflammatory pathways, such as CELMoDs.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs). Their use is associated with relatively high response rates, with some patients experiencing prolonged remission. It is unclear whether continuous treatment beyond 12 months for pts in remission is beneficial, as continued immunosuppression may result in additional toxicity. We sought to report the outcomes of pts with prolonged remission and survival following BsAb administration. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCLs receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates. Pts who responded to BsAbs and had ≥365 days of follow-up from initiation of BsAb treatment were included in the analysis. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAbs (epco n=193, glofit n=119) with a median age of 66 years (interquartile range [IQR] 59-73) at BsAb start. Most were male (64.5%), had advanced stage disease (77.4%) and had ECOG performance status of ≤1 (93.3%) at BsAb start. Of 207 pts who had initiated treatment with BsAb ≥12 months prior to data cutoff, we identified 31 pts (15.0%) who had a response to BsAbs (19 epco, 12 glofit) and were alive without progression at 12-months post-BsAb initiation and included them in this landmark analysis. Of the cohort of 19 pts treated with epco, 6 discontinued due to reasons other than disease progression including CAR-T cell therapy (n=2), secondary malignancy (n=2), allogeneic transplant (n=1), or other reasons (n=1). Thirteen of 19 pts received ≥12 months of epco treatment, and, with a median follow-up of 16 months from the start of BsAb, 12 of 13 pts continued receiving epco beyond 12 months with one pt discontinuing after 12 months (observed for an additional 41 days prior to censoring). Of the cohort of 12 pts treated with glofit, 8 pts were observed after completing all planned therapy and 4 patients underwent allogeneic transplant. Among all 31 BsAb-treated patients alive and in remission at 12 months, at the time of data cutoff, 5 pts (12.9%) had progressed (2 previously treated with epco and 3 with glofit). Three of the 4 pts who underwent allogeneic transplant after prior glofit treatment experienced disease relapse. A total of 24 pts (77.4%) were alive at the time of last follow-up, with the causes of death being disease progression (n=1), secondary malignancy (n=1), infection (n=1), and unknown cause (n=4). Conclusions: In this large cohort of r/r LBCL pts treated with BsAbs monotherapy in the standard of care setting, a relatively small proportion of pts (15%) achieve the 12 month PFS landmark. In the absence of robust evidence for what constitutes best practice, different strategies are employed, including continuation of BsAb, observation as well as consolidation with allogeneic transplant or CAR T-cell therapy. Additional follow-up will be reported to help guide clinical decision making regarding the optimal management strategy for this high risk pt population.

Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.

Abstract Introduction: BTK inhibitors are effective treatments for CLL/SLL; however, treatment intolerance and resistance to BTK inhibitors are major clinical challenges for many patients. BGB-16673 is an orally available protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway, leading to tumor regression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing open-label, phase 1/2 study evaluating BGB-16673 monotherapy in patients with B-cell malignancies. Here, updated phase 1 safety and efficacy data are reported for patients with relapsed/refractory (R/R) CLL/SLL. Methods: Eligible patients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2 (0-1 in the EU), and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). Patients received BGB-16673 once daily orally. The primary phase 1 objectives were to assess safety/tolerability (NCI-CTCAE v5.0; iwCLL hematologic toxicity criteria) and to establish the maximum tolerated dose and recommended dose for expansion. A secondary objective was to assess overall response rate (ORR) per iwCLL 2018 criteria with partial response with lymphocytosis (PR-L) modification and per 2014 Lugano criteria for SLL, with the first response assessment after 12 weeks of treatment. Results: As of May 23, 2025, 67 patients with CLL/SLL were enrolled and treated (50 mg, n=1; 100 mg, n=22; 200 mg, n=17; 350 mg, n=15; 500 mg, n=12). Patients had a median age of 70 years (range, 47-91 years) and a median of 4 prior lines of therapy (range, 2-10), including cBTKis (n=63 [94.0%]), BCL2is (n=55 [82.1%]), and noncovalent BTK inhibitors (ncBTKis; n=14 [20.9%]). At study baseline, 65.7% (44/67) of patients had CLL/SLL with del(17p) and/or TP53 mutation, 77.6% (38/49) with unmutated IGHV, 38.1% (24/63) with BTK mutation, and 15.9% (10/63) with PLCG2 mutation. Median study follow-up was 18.0 months (range, 0.3-31.0 months); 39 patients (58.2%) remained on treatment at the data cutoff. Overall, 95.5% of patients had any-grade treatment-emergent adverse events (TEAEs); any-grade TEAEs in ≥25% of patients were fatigue (37.3%), contusion/bruising (31.3%), diarrhea (28.4%), and neutropenia (28.4%). Grade ≥3 TEAEs occurred in 62.7% of patients; grade ≥3 TEAEs in ≥5% of patients were neutropenia (23.9%), pneumonia (10.4%), and thrombocytopenia (6.0%). Eight patients (11.9%) had a TEAE leading to dose reduction. TEAEs led to treatment discontinuation in 12 patients (17.9%), three (4.5%) of whom had treatment-related TEAEs (subdural hemorrhage, maculopapular rash, and disseminated aspergillosis). Four patients (6.0%) had TEAEs that led to death (all due to infections, including 1 fungal infection); no deaths were deemed related to treatment. In 66 response-evaluable patients (1 patient on treatment did not reach the first assessment by the data cutoff), ORR (PR-L or better) was 86.4% (n=57), with a 4.5% (n=3) complete response (CR)/CR with incomplete marrow recovery rate. At 200 mg, ORR was 93.8% (15/16), including 1 CR. The median time to first response was 2.8 months (range, 2.0-19.4 months). Thirty-three patients (49.3%) remained on treatment for ≥12 months. Responses deepened over time: of 22 patients with initial PR-L, 15 transitioned to partial response (PR); of 16 patients with initial stable disease, 1 transitioned to PR-L and 10 to PR. Responses were seen in patients previously treated with a cBTKi (53/62 [85.5%]) or ncBTKi (10/14 [71.4%]), with double (cBTKi and BCL2i; 39/42 [92.9%]) and triple exposure (cBTKi, BCL2i, and ncBTKi; 9/12 [75.0%]), with (18/24 [75.0%]) and without (36/39 [92.3%]) BTK mutations, with del(17p) and/or TP53 mutation (35/43 [81.4%]), and with PLCG2 mutation (9/10 [90.0%]). The 12-month progression-free survival rate was 79.2%; 15 patients (22.4%) had progressive disease (2 associated with Richter transformation to diffuse large B-cell lymphoma), and 4 (6.0%) died. Further exploratory analyses will be presented at the meeting.Conclusions: Data from the ongoing CaDAnCe-101 study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows robust and deepening responses in patients with heavily pretreated R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK mutations. The 200-mg dose of BGB-16673 is being evaluated in phase 2 and 3 studies in patients with R/R CLL/SLL.

Abstract Background: Given a potential risk of extravasation with vesicants and irritants, central venous catheters (CVCs), such as port-a-cath or peripherally inserted central catheters (PICC), are commonly used for the administration of anthracycline-based chemotherapy. However, CVC placement can result in treatment delay, deep vein thrombosis (DVT), catheter malfunction, and added burdens (eg, financial, travel, etc), partly due to the need for regular flushing. Peripheral intravenous (PIV) access is often utilized in the academic setting with select frontline chemotherapy regimens. However, there is limited data reporting on the safety of PIV in this setting. This large, multicenter RWA evaluated the use and associated complications of PIV and CVC for administering CHOP- or ABVD-based chemotherapy in patients (pts) with lymphoma. Methods: We conducted a retrospective RWA across 8 U.S. centers among pts aged ≥18 years with non-Hodgkin lymphoma and Hodgkin lymphoma who were consecutively treated with ABVD or CHOP-based anthracycline chemotherapy via PIV or CVC access between 2010-2024. Choice of catheter placement was at the discretion of the pt's treating physician. Detailed baseline and safety data were collected. The primary outcome was extravasation; secondary outcomes included infiltration, DVT, cellulitis, erythema, and pain. Standard definitions of extravasation and other complications were used (Jackson-Rose J. CJON 2017). Rates of complications were compared via Fischer exact testing. Results: A total of 1,414 pts were included in the analysis: 790 in each arm (ie, PIV vs CVC). Of these, 624 were unique to each group, while 166 pts received chemotherapy via both modalities (PIV and CVC during the treatment course). Overall, 78.9% of pts completed all treatment as planned via PIV. Median age was 63 years (IQR 45–75) in the PIV group and 61 years (IQR 40–73) in the CVC group. Male sex comprised 57% vs 51%, ECOG 0–1 performance status was 83% vs 76%, and advanced-stage disease (stage III/IV) was present in 51% vs 62%, respectively. Lymphoma subtypes were comparable: DLBCL/high-grade/B-cell NOS (54.5% vs 56.1%), Hodgkin lymphoma (27.2% vs 27.5%), T-cell lymphoma (12.4% vs 6.6%), and indolent/mantle cell lymphoma (5.6% vs 6.7%). Among those receiving chemotherapy via CVC, 78.5% were treated through a port-a-cath and 21.5% via PICC. CHOP-based and ABVD-based regimens were administered to 68% and 32% of PIV pts, and 69.6% and 30.4% of CVC pts, respectively. A total of 4,084 (PIV) vs 3,859 (CVC) treatment cycles were delivered, corresponding to 4,347 (PIV) vs 4,884 (CVC) anthracycline infusion days. There was 1 documented case of extravasation in the CVC group and 2 suspected cases in the PIV group (p=0.9); for PIV, this translates to a per pt risk of 0.3% (or 0.05% of infusion days). The two PIV cases involved elderly women with DLBCL receiving CHOP. Both developed localized symptoms post-infusion and were treated conservatively (DMSO/warm compresses or dexrazoxane/ice), with full symptom resolution within 1 week and 1 day, respectively. No tissue or vascular injury occurred. Additionally, there were no significant differences between the PIV and CVC groups in the rates of induration/swelling (1.8% vs 2.0%, p=0.85), phlebitis/cellulitis (2.4% vs 2.4%, p=0.9), venous thromboembolism (VTE; 1.4% vs 2.0%, p=0.32), or erythema (3.8% vs 5.1%, p=0.27). Pain or tenderness at the infusion site (8.5% vs 2.9%, p=0.001) and infiltration (1.4 vs 0.13%, p=0.006) were more frequent in the PIV group. Chronic vascular complications related to prior VTE was slightly lower in the PIV group (0.13% vs 0.9%, p=0.06), but not significant. Additional details from a propensity score-matched analysis will be presented at the meeting. Conclusions: This is the largest known analysis to date evaluating the safety of PIV access for anthracycline-based chemotherapy in >1,500 lymphoma pts over a recent 15-year period, representing >9,000 total treatments with CHOP or ABVD. PIV access was found to be safe and associated with a low rate of serious complications. Moreover, extravasation was rare and there was not a significant difference observed between PIV and CVC use. While PIV use was associated with higher rates of local pain/tenderness and infiltration, the events were uncommon and self-limited. Despite the widespread default to CVC placement in many centers, these findings support the selective use of PIV in appropriate pts as elucidated here.

Abstract Background Chimeric antigen receptor T-cell (CAR-T) and bispecific antibody (BsAb) therapies are both effective for patients with relapsed/refractory (R/R) follicular lymphoma (FL), but differ in treatment schedules and associated “time toxicity,” or contact days spent physically interacting with the healthcare system. While contact days can be estimated from clinical trials, real-world data provides a more nuanced depiction of treatment-related time burden, which may guide treatment decision-making. The comparative time toxicity of CAR-T vs BsAb in R/R FL is not defined. Methods We conducted a multicenter retrospective study of adults with R/R grade 1-3A FL who received standard-of-care CAR-T (axi-cel, tisa-cel, liso-cel) or BsAb (mosunetuzumab, epcoritamab) in the third-line or later setting before Jan 1, 2025. Time toxicity was defined as outpatient or inpatient days with physical health care system contact, counting multiple visits on the same day as only one day. All days after treatment initiation were counted, regardless of disease progression, therapy completion, or relation to FL therapy. Median contact days over 1-year time horizon were compared, stratified by CAR-T vs BsAb, prior lines of therapy (LOT, 2 vs 3+), and time intervals (0-1, 1-3, 3-6, 6-9, and 9-12 months). Progression-free survival (PFS) and overall survival (OS) were calculated from day of CAR-T infusion or day 1, cycle 1 for BsAb. Cox regression and propensity matching (by age, ECOG, refractory to prior LOT, POD24) were used to assess predictors and survival associations with contact days. Results Among 209 patients from 15 U.S. academic centers, median age was 64, 37% were female, 61% received CAR-T (80% axi-cel, 7% liso-cel, 13% tisa-cel) and 39% BsAb (93% mosun, 7% epcor). Most had Grade 1-2 FL (72%), advanced stage (84%), and extranodal disease (51%). Median prior LOT was 3 (range 2-15), 41% were refractory to prior LOT, and 52% had POD24. Median number of BsAb doses was 10 (range 1-36). Patients receiving BsAb were significantly older (p<.01) and had higher CIRS comorbidity scores (p<.02) in both 2 and 3+ prior LOT cohorts, and had higher ECOG scores (p=.01) and were less likely to be refractory to prior LOT (p=.029) in 3+ LOT cohort. There were no differences in POD24 rates between CAR-T and BsAb. Median PFS for the entire cohort was 3.6 yrs; median OS was not reached. In the 2 prior LOT cohort (N=75), 60% received CAR-T and 40% BsAb. With median follow-up of 1.5 years, median PFS was not reached for CAR-T and 1.6 yrs for BsAb (p<.0001). In the 3+ prior LOT cohort (N=134), 62% received CAR-T and 38% BsAb. With median follow-up of 2 yrs, median PFS was 3.6 yrs for CAR-T and 1.6 yrs for BsAb (p=.0044). In propensity matched analysis, PFS was shorter for BsAb in both 2 LOT (HR 9.0, 95% CI 1.14-71.04, p=.037) and 3+ LOT (HR 3.25, 95% CI 1.06-9.97, p=.039) cohorts as compared to CAR-T. There were no significant differences in OS between CAR-T and BsAb. Median contact days were significantly higher for CAR-T vs BsAb in the 0-1 month interval: 19 vs 8 days in 2 LOT (p<.0001) and 18 vs 7 days in 3+ LOT (p<.0001) cohorts. There were no differences in contact days between CAR-T vs BsAb in subsequent time intervals. Over 1 year, CAR-T had significantly more time toxicity than BsAb: median 51 vs 36 contact days in 2 LOT (p<.0001) and 64 vs 38 days in 3L+ LOT (p<.0001) cohorts; these remained significant in the matched analysis. B symptoms (p=.04) and Grade ≥3 cytopenias (p=.007) were associated with higher contact days in 3+ LOT cohort in univariable analysis. Higher contact days were associated with inferior PFS (HR 1.01, 95% CI 1.00-1.02, p=.032) and OS (HR 1.01, 95% CI 1.00-1.02, p=.038) in 3+ LOT cohort regardless of treatment type. Discussion In this large real-world cohort of patients with R/R FL, CAR-T therapy resulted in better PFS but more time toxicity over the first year as compared to BsAb therapy. Excess time toxicity from CAR-T was driven by more contact days in the first month of treatment. This study provides benchmark data for counseling patients about expected time burden of CAR-T (51-64 days) and BsAb (36-38 days) over the first year of these therapies. Further, with superior PFS of CAR-T in this study and minimal impact of time toxicity on survival outcomes, these data can be used to better support shared decision-making in R/R FL by addressing patient preferences regarding both contact days as well as duration of disease control.