Wang, Yucai

e13622 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized treatment of hematologic malignancies; however, severe toxicities like cytokine release syndrome (CRS) remain a limitation to broader utilization. Using a large dataset of patients treated with CAR-T, we developed a machine learning (ML) model leveraging multi-model patient characteristics to predict the risk of CRS onset with clinically meaningful lead times. Methods: A prospectively maintained dataset of CAR-T patients treated at Mayo Clinic was used. Baseline disease/patients characteristics, labs, ECG, echocardiogram, and vital signs (including data from remote patient monitoring program) were collected. A 24-hour rolling window was used to generate daily averages, maximum, minimum, and deltas for each parameter. ECG and echocardiogram data were forward-imputed; vital signs and labs were not imputed. Each day-post-infusion served as a potential event (CRS onset vs. no CRS). A gradient boosting classifier was trained and tested on a subset of patients (n = 351) using 1,000 bootstrap iterations, evaluating 24-, 48-, and 72-hour lead times. Shapley-based feature importance guided simplification to an 11-feature model, externally validated on an independent cohort (n = 51). Models’ performance assessed using the area under the receiver operating characteristic curve (AUC). Results: A total of 402 patients treated with CAR-T were examined. Median age was 64 years and 36% were female. Primary diagnosis was B-cell lymphoma (n = 240) or multiple myeloma (n = 162). A total of 226,332 vital sign measurements and 372,871 lab values, as well as ECG and echocardiogram data, were collected for 30 days post-infusion. Overall, 79.8% of patients experienced CRS within 30 days. The full ML model demonstrated AUCs of 0.90 (95% CI 0.86–0.93), 0.83 (95% CI 0.77–0.88), and 0.82 (95% CI 0.77–0.87) for 24-, 48-, and 72-hour predictions of CRS, respectively. Including “day of CRS onset post CAR-T” as a feature improved the 72-hour AUC to 0.87 (95% CI 0.83–0.90). A model restricted to vital signs alone showed AUCs of 0.88, 0.75, and 0.71 for 24-, 48-, and 72-hour horizons. An 11-feature model—focusing on temperature, blood pressure, fibrinogen, CRP, serum sodium level, QRS interval, and lymphocyte counts—maintained high accuracy at 24 hours (AUC 0.90, 95% CI 0.86–0.93) and was validated externally using an independent dataset with an AUC of 0.92. Conclusions: Our ML model provides a reliable approach for predicting if/when CRS will occur, with up to three days of lead time before clinical manifestation, offering an opportunity for proactive management. The robust performance of a parsimonious 11-feature model supports practical adoption across clinical settings and real-time risk stratification to enhance patient safety. Prospective validation and integration into clinical workflows will be critical to translating these findings into practice.

e15003 Background: Antibody-drug conjugates (ADCs) have shown substantial promise as therapies for metastatic breast cancer (mBC). However, direct comparisons of different ADC-based regimens are limited. We assessed survival outcomes in mBC patients treated with ADCs. Methods: Randomized controlled trials (RCTs) published before October 2024 were searched in Medline, Embase, ClinicalTrials.gov, and Cochrane Library. Progression-free survival (PFS) and overall surcvival (OS) outcomes were extracted from the most updated publications. Participants were stratified based on molecular subtypes, hormone receptor (HR) status, duration of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and sensitivity to endocrine therapy (ET). Bayesian frameworks were deployed, presenting the synthesized outcomes of indirect comparisons using the surface under the cumulative ranking curve (SUCRA), hazard ratio (HR), and 95% credible interval (Crl). This study was prospectively registered on the International Platform of Registered Systemic Reviews and Meta-analysis Protocols (INPLASY) (INPLASY2024110021). Results: A total of 6449 patients from 12 RCTs of ADCs ado-trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), and datopotamab deruxtecan (Dato-DXd) were included in the analysis. Compared to chemotherapy, T-DXd significantly improved PFS (HR 0.35, 95% Crl 0.15-0.84) and OS (HR 0.56, 95% Crl 0.32-1.0). SG also significantly extended OS (HR 0.65, 95% Crl 0.43-0.97) but not PFS. In HER2+ mBC, pooled analyses revealed T-DXd was the most effective treatment in terms of PFS, with a SUCRA of 94.2%, followed by T-DM1 (58.9%), and chemotherapy with HER2-directed therapy (34.2%). Synthesized outcomes of OS mirrored the PFS outcomes. In HR+/HER2- mBC (some of which was HER2-low), Dato-DXd (76.1%) showed slightly superior efficacy over SG (67.4%) for PFS, while SG (85.1%) was advantageous over Dato-DXd (49.1%) in terms of OS. Among patients with HR+/HER2+ mBC, T-DXd (80.0%), SG (55.5%), and chemotherapy with HER2-directed therapy (53.1%) were the most effective therapies for prolonging PFS. Regarding OS, SG (70.3%) and T-DM1 (60.3%) were the most effective, with comparable efficacy observed between chemotherapy with HER2-directed therapy (52.1%) and T-DXd (52.0%). In HR-/HER2+ mBC, T-DXd (78.1%), SG (56.1%), and T-DM1 (51.5%) significantly prolonged PFS, while SG (69.4%) had the most substantial benefit for OS, followed by T-DXd (62.8%) and chemotherapy with HER2-directed therapy (57.6%). Dato-DXd showed an advantage over SG in mBC patients received CDK4/6i for > 12 months. Conclusions: This network meta-analysis showed prominent survival benefits with ADC-containing regimens for mBC. Our results provide valuable insights into personalized treatment strategies for mBC patients.

7073 Background: The Optimized HLH Inflammatory (OHI) index (Zoref-Lorenz et al., Blood , 2022), based on serum soluble CD25 (sCD25) and ferritin, is a prognostic tool identifying inflammation in the hemophagocytic lymphohistiocytosis (HLH) spectrum and early mortality risk. Prior studies were retrospective and enriched with HLH-suspected cases. We hypothesized that the OHI index would predict outcomes in unselected diffuse large B-cell lymphoma (DLBCL). Methods: 670 newly diagnosed DLBCL patients from a prospective cohort (2002–2015) were analyzed: 335 for discovery and 335 for validation. Pre-treatment serum sCD25 and ferritin levels were quantified via ELISA, and we evaluated original thresholds (sCD25 ≥ 3,900 U/mL; ferritin ≥ 1,000 ng/mL) and developed DLBCL-optimized thresholds (using receiver operator curves) for predicting 500-day mortality. We also evaluated event-free survival (EFS), EFS at 24 months (EFS24), and overall survival (OS). Results: The median age was 64, and 51% were male. Using original thresholds, 4.2% (n=14) of patients were OHI+, with a 5.6-fold higher risk of 500-day mortality (95% CI 1.6–17; p<0.001). Optimized thresholds identified 23.6% (n=78) as OHI+ with a 9.2-fold higher 500-day mortality risk (95% CI 4.0–24; p<0.001). Optimized OHI+ also had a higher risk of EFS24 failure and inferior EFS and OS (Table). OHI+ patients had higher rates of B symptoms (35% vs. 20%; p=0.027), elevated LDH (76% vs. 34%; p<0.001), worse performance status (ECOG ≥2: 38% vs. 12%; p<0.001), and advanced-stage disease (Stage IV: 57% vs 38%; p<0.001), though IPI scores (3–5) were not significantly different (44% vs 36%; p=0.28). Adjusting for age and IPI, OHI+ independently predicted 500-day mortality (OR=5.0; CI 1.9–13; p=0.001), EFS24 failure (OR=3.2; CI 1.5–6.5; p=0.0018), and inferior long-term EFS (HR=2.2; CI 1.1–4.3; p=0.030) and OS (HR=2.0; CI 1.0–4.0; p=0.040) at a median follow up of 9.8 years in living patients. In validation, optimized OHI predicted 500-day mortality, EFS24 failure, and long-term OS and EFS (Table). Cytokine profiling revealed elevated inflammatory markers in OHI+ patients, including IL1a (p=0.008), CCL2 (p=0.03), CXCL10 (p<0.001), and CXCL9 (p<0.001), reflecting systemic hyperinflammation. Conclusions: The OHI index is a powerful predictor of early and long-term outcomes in DLBCL patients. Optimized thresholds identify a larger OHI+ group, highlighting hyperinflammation’s critical role in poor outcomes. These findings support its use in routine management and clinical trial design for novel therapies. Odds ratios or hazard ratios and p-values for optimized OHI+ and DLBCL prognosis. Outcome Discovery Validation OR for 500-day mortality 9.2; p<0.001 4.0; p=0.002 OR for EFS24 failure 5.2; p <0.001 6.3; p<0.001 HR for OS 2.3; p<0.001 1.8; p=0.006 HR for EFS 2.4; p<0.001 2.5; p<0.001

7052 Background: Secondary central nervous system lymphoma (SCNSL) is a rare but serious complication that occurs in 2-10% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). The CNS-International Prognostic Index (CNS-IPI) is a validated tool used to assess the risk of CNS relapse. However, with advancements in molecular profiling and treatments, the predictors of SCNSL, including the predictive ability of CNS-IPI combined with other molecular markers and treatment regimens, have become uncertain. This study evaluates new prognostic markers for CNS relapse in DLBCL, focusing on cell-of-origin (COO), gene rearrangements, and treatment types. Methods: DLBCL pts enrolled from 2002-2015 in the Mayo Clinic and University of Iowa Lymphoma Molecular Epidemiology Resource were prospectively followed for incidence of CNS relapse. Pts with primary CNS lymphoma or CNS involvement at diagnosis, and pts treated with high-dose methotrexate containing regimens were excluded. COO classification (GCB vs non-GCB) was determined using Hans algorithm and/or NanoString data. Multivariate Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for predictors of SCNSL. Survival analysis was performed from time of DLBCL diagnosis using Cox proportional hazards model. Results: Among 1278 newly diagnosed DLBCL pts included (median age: 63 years; 43.6% female), SCNSL occurred in 46 (3.6%) pts. Pts with SCNSL were more likely to have intermediate/high CNS-IPI scores (80.4%) than pts without SCNSL (63.9%, p=0.02). The 3 yr SCNSL incidence was 0.016 (0.008-0.0033) in low CNS-IPI vs 0.043 (0.031-0.0060) in high CNS-IPI. Those with SCNSL were significantly more likely at baseline to have non-GCB COO (56.3% vs. 36.5%, p=0.02), and advanced stage (76.1% vs. 59.9%, p=0.03) compared to those without SCNSL. The incidence of SCNSL was not influenced by MYC, BCL2, or BCL6 rearrangements, nor by treatment with R-CHOP, R-EPOCH, or other immunochemotherapy regimens. MVA showed that intermediate CNS-IPI (HR 2.32, 95% CI 1.09-4.92, p=0.029), high CNS-IPI (HR 3.59, 95% CI 1.49-8.62, p=0.004), and non-GCB COO (HR 2.19, 95% CI 1.08-4.42, p=0.0029) were independently associated with increased SCNSL risk. After a median follow-up of 12 years (IQR 9–15), overall survival (OS) was 52.1% for the cohort, with OS significantly worse for SCNSL pts (17.4% vs. 53.4%, p<0.001). Conclusions: This large cohort with extensive follow-up highlights the role of COO as an additional prognostic factor for SCNSL while reinforcing CNS-IPI’s prognostic value. Non-GCB COO pts had a higher risk of SCNSL even when adjusted by CNS-IPI risk. Despite advancements in management, SCNSL pts continue to have poor outcomes. Strategies to reduce the incidence of CNS relapse in high-risk pts require further investigation. MER CNS relapse hazard ratios (95% CI). Characteristics Hazard Ratio 95% CI P-Value CNS-IPI Group 0-1 Low Ref Ref Ref 2-3 Intermediate 2.32 1.09 - 4.92 0.029 4+ High 3.59 1.49 - 8.62 0.004 Cell of Origin* GCB Ref Ref Ref non-GCB 2.19 1.08 - 4.42 0.029 Double Hit* non-DHL Ref Ref Ref DHL 1.08 0.14 - 8.3 0.941 Not Done/Missing 1.38 0.76 - 2.51 0.297 Double Expressor* Negative Ref Ref Ref Positive 2.36 0.71 - 7.85 0.162 Not Done/Missing 1.91 0.89 - 4.08 0.097 IC Group* R-CHOP R-EPOCH Ref 1.63 Ref 0.71 - 3.74 Ref 0.249 Other IC 1.18 0.57 - 2.46 0.660 Any EN Involvement* No Ref Ref Ref Yes 0.98 0.51 - 1.88 0.946 Albumin Group* >=Normal Ref Ref Ref <Normal 1.70 0.75 - 3.85 0.201 Head & Neck Involvement* No Ref Ref Ref Yes 0.35 0.048 - 2.63 0.310 *Adjusted by CNS-IPI risk group.

7032 Background: The impact of immune cell counts pre LD and during immune reconstitution on CAR T therapy outcomes is poorly understood. We investigated the association between CD4, CD8 and NK cell counts and CAR T therapy outcomes in patients with LBCL. Methods: Retrospective study of R/R LBCL patients who received CAR T cells between 2016-24 at Mayo Clinic, Rochester, were included in this analysis. Peripheral blood CD4, CD8 and NK counts were measured pre LD and at M1 post CAR T infusion. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff for pre LD and M1 immune cells to predict patients who were alive and in remission at 6 months (M6) post CAR T infusion. Patients who progressed or were lost to follow up prior to day 30 were excluded from M1 ROC analysis. Results: Of 140 patients, 81 were alive and in remission at M6 (Group A), while 59 had relapse or death (Group B). Axicabtagene ciloleucel was the CAR T product given in 81% of patients (114/140). Median pre LD CD4 counts were significantly lower in Group B compared to group A (143 vs 280 cells/µL, p = 0.001). No significant difference was observed in median pre LD CD8 counts (205 vs 221 cells/µL, p = 0.8). ROC analysis identified an optimal pre LD CD4 count of 124.5 cells/µL for M6 alive+remission. Lower pre LD CD4 counts (<124.5) predicted worse progression free survival (PFS) in univariate (HR = 3.02, 95% confidence interval [CI]: 1.73–5.27, p< 0.01) and multivariable analysis (MVA) adjusted for IPI and the number of prior lines (aHR = 2.54, 95% CI: 1.39–4.62, p< 0.01).Lower pre LD CD4 counts also predicted inferior overall survival (OS) in MVA (aHR = 2.27, 95% CI: 1.08–4.77, p = 0.03). (Table 1) On day 30 landmark analysis, ROC identified M1 optimal CD4 count of ≥ 99.5 cells/µL to be associated with a trend toward superior PFS (P=0.09), but not OS (p=0.90) in MVA. Median pre LD NK cell counts were significantly lower in Group B (73 vs 98 cells/µL, p = 0.04). ROC analysis identified an optimal pre LD NK count of 151 cells/µL for M6 alive + remission. Lower pre LD NK counts (<151) predicted worse PFS, both on univariate (HR = 4.17, 95% CI: 1.29–13.47, p = 0.02) and MVA (aHR = 4.64, p< 0.01). The lower pre LD NK cell count group had worse OS in MVA (aHR = 5.69, 95% CI: 1.16–28.1, p = 0.01). (Table 1) On D30 landmark analysis, M1 NK cell count of ≥ 128.5 cells/µL was associated with a trend toward superior PFS (P=0.08), but not OS (p=0.30) in MVA. Conclusions: Pre LD CD4 and NK cell counts are significantly associated with PFS and OS post CAR T therapy in patients with R/R LBCL. Pre-treatment immune subset levels may identify patients at higher risk of relapse or death after CAR-T therapy. Groups Median PFS 2 Year PFS Median OS 2 Year OS CD4 ≥124.5 cells/µL (N=75) NR 58% 3.31 years 67% CD4 <124.5 cells/µL (N=30) 2.2 months 22% 1.59 years 45% NK ≥151 cells/µL (N=17) NR 77% NR 84% NK <151 cells/µL (N=82) 10.6 months 44% 3.31 years 62%

e19008 Background: Cytokine release syndrome (CRS) is typically reversible in CAR-T therapy, while hyperinflammatory syndromes like macrophage activation-like syndrome (MAS-L) and high-grade immune effector cell-associated hemophagocytic syndrome (IEC-HS) are associated with significant morbidity and mortality. Early interventions are critical for improving outcomes. We aim to analyze clinical cytokine assays and cellular phenotypes early in hyperinflammatory syndromes to identify profiles for severe cases to inform management decisions. Methods: This study included 113 CAR-T patients (pt) (September 2019-March 2024) with cytokine profiles (CP) performed at the second tocilizumab dose or with suspected hyperinflammatory states (CP1), followed by assessments at 24 hours (CP24) and 48 hours (CP48). 52 pts consented to blood (PB) and bone marrow (BM) cell immune phenotyping at pre-treatment (pre-LD) and day 1 for PB. Results: Among the 113 pts, CRS pts (N=74), when compared to MAS-L(N=19) & IEC-HS (N=20) at CP1, had lower levels of TNF (median in pg/mL; 31, 62.9, 47.7) , IL-18 (794, 1353, 2011), and MCP-1 (689, 2722, 2485.5). While MAS-L and IEC-HS had similar CP1 profiles, CP24 and CP48 differed between them: TNF & MCP-1 levels decreased in MAS-L but remained elevated or increased in IEC-HS. IL-18 was stable in MAS-L but increased steadily daily in IEC-HS. Infections were more frequent in IEC-HS (CRS: 43%; MAS-L: 58%; IEC-HS: 85%; p=0.002). Notably, patients who died with persistent E. faecium bacteremia had higher IL-18 in CP48. In the 52 pts with cell phenotypes available by flow, 33 had CRS, 18 MAS-L and 8 IEC-HS. The correlation between cell phenotypes and cytokine levels showed that elevated TNF at CP1 correlated with increased non-classical monocytes in pre-LD BM and higher NK and NK-T cells in pre-LD PB. Similarly, elevated IL-18 CP48 levels correlated with increased CD8 T-cells, NK-T cells, and intermediate monocytes in pre-LD PB, as well as increased NK cells at both pre-LD and day 1 (Table). Conclusions: We report distinct cytokine profiles in IEC-HS early in the inflammatory course post-CAR-T therapy. These elevated cytokines correlate with specific immune cell subsets, including BM-resident monocytes, intermediate monocytes with heightened cytokine trafficking and inflammatory capacity. This study demonstrates the feasibility for identifying potential biomarkers for early risk stratification and targeted interventions. Cytokine Sample source Immune cells R P value TNF CP1 BM pre-LD Non-classical monocytes (CD14loCD16+) 0.38 0.025 PB pre-LD Monocytes (All) 0.47 0.022 NK cells (CD56+CD16+) 0.34 0.024 NK-T cells (CD3+CD56+CD16-) 0.29 0.04 IL-18 CP48 PB pre-LD CD8+ T-cells 0.59 0.0093 NK-T cells (CD3+CD56+CD16-) 0.53 0.023 Intermediate monocytes (CD14+CD16+) 0.58 0.012 PB pre-LD NK cells (CD56+CD16+) 0.56 0.49 0.015 0.024

Abstract Family history of hematologic malignancy (FHHM) is an established risk factor for developing lymphoma, but studies examining associations between self-reported FHHM and lymphoma prognosis during the recent treatment era are limited. Utilizing a prospective cohort study, we evaluated associations between FHHM and prognosis for common lymphoma subtypes, including diffuse large B-cell (DLBCL), follicular (FL), marginal zone (MZL), mantle cell (MCL), Hodgkin (HL), and T-cell (TCL) lymphomas. We used the Mayo Clinic component of the Molecular Epidemiology Resource, a prospective cohort study of newly diagnosed lymphoma patients enrolled from 2002 to 2015. Self-reported FHHM (HL, NHL, leukemia, or multiple myeloma) in a first-degree relative was obtained via questionnaire. Primary outcomes were overall survival (OS) and event-free survival (EFS; time from diagnosis to disease progression, initiation of second-line therapy, or all-cause death). Secondary outcomes were failure to achieve 24 months of event-free survival (EFS24; associated with aggressive disease and poor outcomes) and lymphoma-specific survival (LSS; time from diagnosis to death from lymphoma or lymphoma treatment-related complications). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of FHHM with OS, EFS, and LSS, and logistic regression to estimate odds ratios (ORs) and 95% CI for the association with failure to achieve EFS24. All models were adjusted for sex and a lymphoma subtype specific prognostic index. The cohort consisted of 650 DLBCL, 679 FL, 291 MZL, 178 MCL, 254 HL, and 196 TCL patients. The prevalence of FHHM ranged from 9.7% in TCL to 14% in FL. FHHM was not associated with OS in any subtype, but MCL patients with FHHM showed an inferior EFS (HR=1.70, 95% CI 1.02-2.85; p=0.04). For EFS24, FHHM was associated with failure to achieve EFS24 only in FL (OR=1.57, 95% CI 0.99-2.48; p=0.05). Similarly, FHHM was associated with inferior LSS in FL patients (HR=1.98, 95% CI 1.11-3.53; p=0.02). In a treatment subgroup analysis of FL patients, the FHHM associations with failure to achieve EFS24 (OR=2.48, 95% CI 1.04-5.74; p=0.04) and inferior LSS (HR=2.68, 95% CI 1.09-6.58; p=0.03) strengthened among those treated with frontline immunochemotherapy (IC). In summary, there were no evidence of associations between FHHM and OS across lymphoma subtypes, but MCL patients with FHHM displayed inferior EFS. FL patients with FHHM were more likely to not achieve EFS24 and to ultimately die of their lymphoma or a lymphoma treatment-related complication. This finding was stronger in more aggressive FL requiring frontline IC. This novel finding would suggest that genetic or environmental factors associated with FHHM may underlie pathways that impact disease aggressiveness and early clinical failure in FL. Citation Format: George Cholack, Raphael Mwangi, Thomas M. Habermann, Verena Hinder, Rosalie Griffen, Dennis Robinson, Andrew L. Feldman, Thomas E. Witzig, Stephen M. Ansell, Brian K. Link, Yucai Wang, Carrie A. Thompson, Susan L. Slager, Matthew Maurer, Anne J. Novak, James R. Cerhan. Family history of hematologic malignancy and prognosis across lymphoma subtypes: Novel association with poor outcomes in follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7344.

Purpose Venetoclax-based treatment for chronic lymphocytic leukemia (CLL) can be a logistically burdensome regimen due to extensive required monitoring of tumor lysis syndrome (TLS). The purpose of this study was to evaluate the feasibility and safety of pharmacist and registered nurse (RN) driven management of venetoclax ramp-up in CLL. Methods This was a prospective, pilot program for patients receiving venetoclax-based therapy for CLL. Patients had nine weekly visits during the first three cycles of therapy, of which five visits were independently performed by a pharmacist or RN. Laboratory tests to evaluate TLS were ordered and monitored independently by the RN in collaboration with clinicians (physician, nurse practitioner, physician assistant). Results Thirty CLL patients, median age 67 years, 73% treated in the frontline setting, started venetoclax between May 2022 and January 2023. After the initial three weeks of obinutuzumab treatment, TLS risk prior to venetoclax initiation had improved to low (93%), medium (3%), and high (3%). There was zero incidence of laboratory or clinical TLS by Howard criteria during the venetoclax ramp-up for all patients. Pharmacist and RNs performed 139 independent visits and monitored 197 sets of TLS labs. Conclusion Use of independent pharmacist and RN visits for toxicity checks and TLS monitoring during weekly venetoclax dose ramp-up did not lead to increased incidence of TLS in patients with CLL. These visits increased both access and efficiency within the CLL clinic. This concept has the potential to be applied in other cancer care settings with a variety of treatment regimens.

ABSTRACT Rituximab, gemcitabine, and oxaliplatin (R‐GemOx) is a commonly used chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), but there are limited real‐world data. In a multicenter retrospective study from a cohort of eight US academic centers (LEO CReWE), we evaluated 183 patients with R/R DLBCL and high‐grade B cell lymphoma treated with R‐GemOx, including subgroups treated without intent for consolidation with autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T cell therapy ( n = 100), those utilizing R‐GemOx as a bridge to ASCT or CAR T ( n = 83), and those aged 70 and older ( n = 71). Overall response rates (ORRs) for all patients treated with R‐GemOx were 45% with a complete response (CR) rate of 29%. The median event‐free survival (EFS) was 2.3 months, and the median overall survival (OS) was 13.5 months. Patients receiving R‐GemOx without intent for ASCT or CAR T had ORR and CR rates of 33% and 18%, respectively, with median EFS and OS of 2.0 and 9.5 months, respectively. Patients receiving R‐GemOx as a bridge to ASCT or CAR T had ORR and CR rates of 57% and 36%, respectively, with median EFS and OS of 3.5 and 17.4 months, respectively. Patients receiving R‐GemOx aged 70 and older had ORR and CR rates of 53% and 33%, respectively, with median EFS and OS of 2.2 and 13.9 months, respectively. These data provide a benchmark for R‐GemOx in the rapidly evolving landscape of R/R DLBCL therapies.