Hill, Brian T.

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

Abstract The Bridging the Gaps (BTG) in Leukemia, Lymphoma and Multiple Myeloma Consensus Conference 2025 brought together a multidisciplinary group of oncology experts to address the complexities of lymphoma management, focusing on mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and diffuse large B‐cell lymphoma (DLBCL). This article presents consensus recommendations developed through a modified Delphi process, which emphasize the need for tailored therapeutic strategies in light of recent advancements in treatment options. Key recommendations include the screening for high‐risk features in MCL, use of the BOVen regimen (zanubrutinib, obinutuzumab, and venetoclax) for TP53 ‐aberrant cases, and integration of chimeric antigen receptor T‐cell therapy for patients with mantle cell lymphoma that is refractory to covalent Bruton tyrosine kinase inhibitors. For CLL, recommendations include consideration of time‐limited therapies for younger patients and a “watch and wait” strategy for asymptomatic patients despite the improved activity and safety of current treatment regimens. For DLBCL, this article highlights the challenges in treatment sequencing and the role of circulating tumor DNA and minimal residual disease testing in monitoring disease progression. Overall, the conference describes the importance of ongoing research to refine management strategies and improve patient outcomes in lymphoma care, addressing the gaps in clinical practice where high‐level evidence is lacking.

Objectives: To evaluate evolving management, ICU admission, and outcomes for critically ill chimeric antigen receptor (CAR) T-cell patients over a 6-year period. Design: Multicenter retrospective cohort study from January 2018 to September 2023. Setting: Eight U.S. centers. Patients: Adult CAR T-cell patients requiring ICU admission. Interventions: None. Methods: Summary statistics included mean, sd , median, and interquartile range (IQR). Fisher exact test or chi-square test were used to evaluate association between year treated and other categorical variables. Cochran-Armitage test was performed to assess significance of trends across years. Multivariable logistic regression was performed to assess covariates associated with mortality. Measurements and Main Results: Demographics, toxicity management, ICU admission, support modalities, toxicity severity, and survival (ICU, hospital, and 3-mo) were compared year-to-year. From 2018 to 2023, 2238 patients received CAR T cells, with increasing number of patients treated yearly; 398 (17.8%) required ICU care. Of those admitted to the ICU, 66.1% were male, 89.2% had lymphoma, and median age was 64 years (53–71 yr). ICU admission rates declined from 38.5% (95% CI, 31.6–45.8%) in 2018 to 16.4% in 2023 (95% CI, 13.5–19.7%; p < 0.0001). Cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was the reason for ICU admission in 87.9%. In 2023 vs. 2018, ICU patients were older (median, 65 yr [IQR, 55–73 yr] vs. 58 yr [48–67 yr]; p = 0.003) with higher comorbidity indices (4 [4–6] vs. 3 [2–4]; p = 0.005) and more severe toxicities (≥ grade 3: 90.1% vs. 69.9%; p = 0.004). Corticosteroid use for less severe toxicities (≤ grade 2 toxicity: 73.8% vs. 40.6%; p = 0.0001) and anakinra use (56% vs. 5.5%; p < 0.0001) increased throughout the years. Mortality from cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome remained low (5.5%). Age, Sequential Organ Failure Assessment greater than or equal to 10 at ICU admission, and ICU admission for noncytokine release/neurotoxicity syndrome reasons were associated with hospital mortality (odds ratios, 1.02 [95% CI, 1–1.04; p = 0.046], 4.69 [2.44–9.01; p < 0.0001], and 3.74 [1.91–7.3; p = 0.0001], respectively). Conclusions: ICU admission rates after CAR T-cell treatment are declining. Although ICU patients are older with higher severity of illness and toxicity grades, ICU mortality after CAR T-cell therapy remains low.

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P&lt; .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P&lt; .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P&lt; .001]; median OS, 136.1 vs 75.3 months [P&lt; .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Introduction: Lisocabtagene maraleucel (liso-cel) was approved in the United States for the treatment of CLL in 3/2024 for patients who have received two prior lines of therapy including a covalent BTK inhibitor and a BCL-2 inhibitor. Data regarding outcomes of liso-cel is limited to reports from the registrational TRANSCEND-CLL 004 clinical trial which had strict inclusion and exclusion criteria. This work investigates the real-world efficacy and safety of liso-cel for patients with CLL and its efficacy in specific sub-populations. Methods: This is a multi-institutional retrospective study (Collaborative Assessment of Real-World Evidence of Lisocabtagene Maraleucel in Patients with Relapsed/Refractory CLL/SLL [CARE CAR-T CLL]) of patients with CLL who received commercial liso-cel in the United States. Patients with Richter transformation were excluded. Response was defined by iwCLL criteria. Patients who did not undergo a marrow biopsy but met other criteria for a complete response (CR) were categorized as unconfirmed CR (CRu). CRS and ICANS were graded per ASTCT criteria. Results: A total of 30 patients were identified with a median age of 67 years (range 44 – 80). Twenty of thirty patients (67%) had either del17p and/or mutated TP53, and 8/30 (27%) had complex karyotype (≥ 3 abnormalities) at time of liso-cel infusion. Patients received a median of 6 prior lines of therapy (range 1 - 12), and 24 (80%) were previously treated with chemotherapy. All patients had previous exposure to a covalent BTK inhibitor and a BCL-2 inhibitor. Twenty-seven (90%) of patients had prior exposure to pirtobrutinib. Twenty-nine patients (96.7%) received bridging treatment that was stopped after leukapheresis with 1 patient in CR and 25 patients in PR at time of liso-cel. Eighteen patients (60%) were treated with pirtobrutinib as the last line of treatment prior to liso-cel. Median length of time on pirtobrutinib prior to liso-cel infusion was 4 months (interquartile range [IQR], 2 – 8 months). Twelve (66.7%) patients stopped pirtobrutinib between leukapheresis and lymphodepletion, and 6 continued after liso-cel. Best CR/CRu rate was 60.0% (CR, n = 17/30; CRu, n = 1/30), and best overall response rate (ORR) was 83.3% (25/30) with median time to best response of 30 days (IQR, 28 – 30 days). Of the 18 patients who received pirtobrutinib as their last line of therapy, 13 (72%) achieved a CR/CRu. Meanwhile, of the 12 patients who did not receive pirtobrutinib as their last line of therapy, only 5 (28%) achieved a CR. Measurable residual disease testing (MRD) by flow cytometry was done in 14/30 patients, and 9 patients (64%) had achieved undetectable MRD (uMRD). MRD by next generation sequencing (NGS) was done in 17 patients, and 7 (41%) patients had uMRD. Twenty-seven of 30 patients (90%) were alive at time of data collection. Median follow-up was 3.3 months (IQR, 1.2 – 8.9 months). Twenty-six patients (87%) experienced any grade cytokine release syndrome (CRS), and 3 patients experienced grade 3 CRS (10%). Twelve patients (40%) experienced any grade immune effector cell-associated neurotoxicity syndrome (ICANS), and 4 patients (13%) experienced grade 3 ICANS. There were no grade 4 or 5 CRS or ICANS. One patient experienced grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). At day 30, patients had a median absolute neutrophil count of 1.7K/μL (IQR, 0.8 – 3.6K/μL), hemoglobin of 11.7 g/dL (IQR, 8.6 – 13.1 g/dL), and platelet count of 72K/μL (IQR, 29 – 119K/μL). Conclusion: Real-world analysis of liso-cel for patients with relapsed/refractory CLL showed CR and ORR of 60.0% and 83.3%, respectively. Despite having a heavily pre-treated and chemotherapy-exposed population and with over half the patients having high-risk features, these response rates are higher than what was described in the TRANSCEND-CLL 004 clinical trial. These results are limited by the short follow-up period and the variability in response assessment typical of a retrospective study. As we increase our sample size, we will also be interested if the use of the non-covalent BTK inhibitor pirtobrutinib prior to liso-cel is associated with a higher CR rate, mimicking the findings of the sub-cohort analysis of TRANSCEND-CLL 004 where the concurrent use of ibrutinib led to higher CR rates. Further updates and patients from additional collaborators will be presented at the meeting.

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p&gt;0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=&lt;0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

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

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

Abstract Background: Venetoclax (VEN)+obinutuzumab (VO) is an effective therapy for CLL/SLL requiring regular monitoring for tumor lysis syndrome (TLS) during VEN ramp-up. The CLL14 trial of VO reported no TLS during VEN ramp-up; however, there are limited real-world data on monitoring practices and TLS outcomes for different dose levels and monitoring timepoints. This study assessed VEN initiation prophylaxis and monitoring outcomes for patients (pts) with CLL/SLL starting VO in first line (1L) in an outpatient, real-world setting. Methods This interim analysis relied onretrospective observational data from 4 US sites of the CLL Collaborative Study of Real-World Evidence (CORE). Adult pts with CLL/SLL were eligible if they: (1) started VO per-label outside of a clinical trial in 1L, or immediately after exposure in 1L to agents with different mechanisms of action (i.e., BTKi, anti-CD20 only) of &lt;30 days; (2) prior to VEN start, had either (i) low physician-determined tumor burden (TB) (i.e., all lymph nodes [LN] &lt;5 cm and ALC &lt;25 x 109/L), or (ii) medium physician-determined TB (i.e., any LN ≥5-&lt;10 cm or ALC ≥25 x 109/L) with creatinine clearance ≥80 mL/min; (3) had no strong CYP3A inhibitors or prophylactic rasburicase from 3 days prior to VEN start until end of VEN ramp-up; and (4) had VEN ramp-up in an outpatient setting. TB-related labs/imaging was assessed from 2 months prior to obinutuzumab initiation (i.e., index date) until VEN start. VEN characteristics (i.e., dosing, duration), prophylaxis measures (i.e., antihyperuricemics and IV hydration), and TLS-related monitoring and management (i.e., lab results and interventions received) were collected per ramp-up week and TLS monitoring timepoint. Results Of 128 pts in CORE who initiated VO in any line, 72 pts met inclusion criteria (low TB: 57 [79.2%]; medium TB: 15 [20.8%]). Median (IQR) age was 62 (56.0, 68.5) years, 58.3% were male, and 81.9% had ECOG grade ≤1. Among pts tested, 7/68 (10.3%) had del(17p)/TP53 mutation and 43/66 (65.2%) had unmutated IGHV. Median (IQR) time from index to VEN start was 23.0 (22.0, 30.0) days. Most pts completed ramp-up (98.6% [71/72]) and followed a per-label regular dosing schedule (93.1% [67/72]). Prior to VEN ramp-up, all pts received prophylactic antihyperuricemics (allopurinol: 71 [98.6%]; febuxostat: 2 [2.8%]) and prophylactic hydration. In the 2 days prior to a dose escalation for at least 1 week of ramp-up, prophylactic IV hydration was reported for 27 (37.5%) pts based on physician determination. One pt stopped VEN after week 2 due to neutropenia (grade 3+). During ramp-up (median [IQR] of 9 [8, 12] blood tests per pt), no lab or clinical TLS was reported. Of 21 (29.2%) pts who received an intervention following a lab assessment, most had low TB at VEN start (16 [76.2%]). All interventions were either prophylactic or non-TLS-related. Following a lab assessment for at least 1 week of ramp-up, prophylactic IV or escalated oral hydration intervention was reported in 17/21 pts (81.0%) based on physician determination (e.g., to manage impaired baseline renal function in those with low TB, patient request, or institutional practice) (IV hydration: 15 pts; escalated oral hydration: 2 pts). By per-label monitoring timepoints, hydration intervention was given prophylactically following pre-dose lab tests for 7 pts (across weeks 1-5), 6-8 hours post-dose for 5 pts (weeks 1-2), and 24 hours post-dose for 10 pts (weeks 1-2). By per-label monitoring timepoints, other non-TLS-related interventions (i.e., blood transfusion for anemia, insulin for hyperglycemia, and potassium for non-TLS-related hypokalemia) were given following pre-dose lab tests for 2 pts (weeks 1-5) and 24 hours post-dose for 4 pts (weeks 1-2). Conclusion Consistent with the CLL14 trial, no TLS was reported in this real-world, interim analysis of pts with mostly low TB and good renal function at 1L VO initation. All interventions during VEN ramp-up were prophylactic or non-TLS-related, with prophylactic hydration commonly given based on physician preference. These results suggest that VO initiation is manageable in an outpatient setting. Consideration should be given for simplified monitoring requirements including potential removal of 6-8 hour post-dose lab in this population and be further explored in prospective studies. Data collection for this study is ongoing to further contextualize real-world VEN initiation prophylaxis and monitoring outcomes in a larger cohort.

Abstract Background: Glofit, a CD20/CD3 bispecific antibody, has shown efficacy in prospective trials, including the Phase III STARGLO study evaluating glofit plus gemcitabine/oxaliplatin (GemOx) in transplant-ineligible patients (pts) with R/R large B-cell lymphoma (BCL). However, concerns raised by the FDA's Oncology Drug Advisory Committee regarding the generalizability of the STARGLO data to U.S. pts underscore the need for real-world evidence. We report real-world outcomes of Glofit-GemOx in U.S. pts with R/R aggressive BCL. Methods: We conducted a multicenter retrospective review across 8 U.S. academic centers, identifying 31 pts with R/R aggressive BCL treated with Glofit-GemOx outside clinical trials. Baseline characteristics, treatment history, and outcomes were abstracted from medical records. Results: At Glofit-GemOx initiation: median age was 72 years (range, 34–88); 90% had stage III/IV disease. Histologic subtypes included DLBCL in 58% (n=18), high-grade BCL in 29% (n=9), PTLD/DLBCL in 6.5% (n=2), follicular lymphoma (FL) grade 3B in 3.2% (n=1), and Burkitt lymphoma (BL) in 3.2% (n=1). Germinal center B-cell phenotype was seen in 80% of evaluable cases. Double- (n=8) or triple-hit (n=1) cytogenetics were observed in 31% (n=9). Elevated LDH was present in 74%, and 16% had B symptoms. Median ECOG performance status was 1 (range, 0–3), and 23% (n=7) had received prior CAR T-cell therapy. Pre-treatment biopsy was performed in 77% (n=24) with CD20 expression tested in 74% (n=23). CD20 expression was negative in 3 pts by flow cytometry and/or immunohistochemistry. Pts received a median 1 prior line of therapy (range, 0-6); Glofit-GemOx was administered as 1L in 7% (n=2), and 2L in 58% (n=18). Median 4 cycles (range, 1-11); both 1L pts had prior FL (1 and 3 prior lines for FL). Twelve pts remain on therapy, 2 on Glofit monotherapy. Four pts were unevaluable (2 death pre-assessment; 2 pending evaluation). Among 27 evaluable pts, ORR was 78% (21/27) and CR rate was 41% (11/27). Among CD20- negative cases on pre- Glofit-GemOx biopsy (n=3), ORR was 33% (1/3), with 1 CR lasting 3.5 months. Of 11 pts who progressed on Glofit-GemOx, 6 were rebiopsied; 1 showed CD20 loss, 1 was previously CD20-negative. Among the 24 pts who received Glofit-GemOx as destination therapy, ORR of 75% (15/20 evaluable). Among pts with prior CAR T (n=7), the ORR and CR rate were both 43% (3/7). None received Glofit-GemOx within 30 days of CAR T-cell infusion; 4 received within 6 mo; 2 of whom achieved CR. Seven pts (24%) received Glofit-GemOx as bridging to CAR T. ORR pre-CAR T was 86% (6/7); 4 pt successfully proceeded to CAR T, 2 are pending infusion, and 1 progressed after 2 cycles and transitioned to alternate therapy. Three pts were evaluable post-CAR T with an ORR of 100% (3/3) and CR rate of 67% (2/3). At data cutoff, 23/31 pts were alive. Full PFS and OS data will be presented at ASH. Notable individual responses included a patient with relapsed BL post–DA-EPOCH-R who received Glofit-GemOx as 2L therapy and achieved a 6 mo CR without consolidation before progression. Another patient treated with Glofit-GemOx in the 7L setting after prior allogeneic transplant achieved a 3 mo CR prior to progression. CRS occurred in 58% (18/31), with grade ≥3 in 13% (4/31), including 2 possible treatment-related deaths. One occurred in a frail patient after the 1st dose, though neutropenic fever was present prior to Glofit administration. The second followed influenza A infection, respiratory failure, and possible grade 4 ICANS after the 2nd dose; attribution to CRS vs. infection was unclear. ICANS occurred in 10% (3/31), with one possible grade ≥3 case. Conclusions: This is the first U.S.-based real-world analysis of Glofit-GemOx, including more U.S. pts than the STARGLO trial, appear to demonstrate comparable response rates, potentially supporting its use as both bridging and destination therapy. Notable toxicities, including CRS, were observed, with 2 possible treatment-related deaths, with plausible alternate non-treatment related causes. Favorable responses were seen in bridging therapy and high-risk subgroups (transformed, HGBCL) which were excluded in the STARGLO trial. These findings support the real-world utility of Glofit-GemOx in the management of R/R aggressive BCL but underscore the need for caution due to associated toxicities. Further real-world and prospective evaluation are warranted, particularly in rare subgroups and as bridging therapy.