Citations

e19524 Background: Carfilzomib, a second-generation proteasome inhibitor, has emerged as one of the therapeutic agents in the treatment of relapsed or refractory multiple myeloma (MM). Despite its known cardiotoxicity, real-world data on its long-term cardiovascular outcomes remain limited. This study aimed to evaluate the real-world cardiovascular outcomes in patients with relapsed or refractory MM treated with carfilzomib. Methods: We utilized the TriNetX network to identify patients (≥18 years old) with relapsed or refractory MM between January 1, 2014, and January 1, 2019. We further categorized the patients into two groups: patients exposed to carfilzomib and patients not exposed to carfilzomib. Inclusion in the carfilzomib group required exposure to carfilzomib during the 5-year study period. Propensity score matching was performed to match these two groups based on comorbidities, medications, baseline hemoglobin A1c, low-density lipoprotein, and left ventricular ejection fraction to produce two comparable cohorts. The study outcomes were cardiovascular outcomes, including acute heart failure, acute myocardial infarction, cerebrovascular accident, acute venous thromboembolism, all-cause hospitalization, and all-cause mortality over the 5-year follow-up duration. Results: A total of 151,802 patients with relapsed or refractory MM were identified, including 6,386 patients (mean age 64.8 ± 10.6 years) who were exposed to carfilzomib and 145,416 patients (mean age 66.1 ± 12.7 years) who were not. After propensity score matching, there were 4,559 (65.3 ± 10.8 years of age, 44.7% female, 18.2% African American [AA]) patients who were exposed to carfilzomib and 4,559 patients who were not (65.2 ± 12.2 years of age, 45.1% female, 17.0% AA). Exposure to carfilzomib was associated with higher odds of acute heart failure (adjusted odds ratio [aOR]: 1.61; 95% CI: 1.48-1.77, P < 0.001), acute myocardial infarction (aOR: 1.24; 95% CI: 1.03-1.48, P = 0.020), cerebrovascular accident (aOR: 1.97; 95% CI: 1.47-2.64, P < 0.001), acute venous thromboembolism (aOR: 1.79; 95% CI: 1.58-2.03, P < 0.001), all-cause hospitalizations (aOR: 1.91; 95% CI: 1.75-2.09, P < 0.001), and all-cause mortality (aOR: 1.97; 95% CI: 1.80-2.16, P < 0.001). Conclusions: Patients with relapsed or refractory MM who were exposed to carfilzomib had poorer cardiovascular outcomes compared to those who did not.

e19515 Background: The prevalence of diabetes mellitus (DM) is significantly higher in patients with multiple myeloma (MM) compared to the general population. DM has been associated with worse outcomes in MM, including reduced overall survival and increased mortality. The impact of diabetes in patients with MM is further compounded by cardiotoxicity from proteasome inhibitors and the increased thromboembolic risk linked to immunomodulatory agents. Given the potential benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors, we hypothesized that their use in MM patients with DM could improve clinical outcomes and mitigate adverse events in this population. Methods: We utilized the TriNetX network to identify patients (≥18 years old) with MM and DM between January 1, 2013, and January 1, 2019. We categorized the patients into SGLT2 inhibitors users and SGLT2 inhibitors users. Inclusion in the SGLT2 inhibitors group required exposure to SGLT2 inhibitors for at least 1 year. 1:1 Propensity score matching was performed to match these two groups based on comorbidities, medications, baseline hemoglobin A1c, low-density lipoprotein, and left ventricular ejection fraction to produce two comparable cohorts. The study outcomes include all-cause mortality, all-cause hospitalization, acute venous thromboembolism (VTE), acute heart failure (HF), acute myocardial infarction (MI), cardiac arrhythmia, and cardiac arrest over the 5-year follow-up duration. Results: A total of 43,078 patients were identified, including 3,640 SGLT2 inhibitors users and 39,438 non-SGLT-2 inhibitors users. After 1:1 propensity-score matching, there were 3,379 SGLT-2 inhibitor users (68.9 ± 10.3 years of age, 38.0% female, 23.9% African American [AA]) and 3,379 non-SGLT-2 inhibitor users (68.9 ± 11.0 years of age, 35.9% female, 22.2% AA). SGLT-2 inhibitors users were associated with lower rates of all-cause mortality (odds ratio [OR]: 0.34, 95% confidence interval [CI]: 0.30-0.39) and all-cause hospitalization (OR: 0.52, 95% CI: 0.47-0.58). Lower odds of acute VTE (OR: 0.59, 95% CI: 0.49-0.70), acute HF (OR: 0.89, 95% CI: 0.81-0.98), acute MI (OR: 0.81, 95% CI: 0.69-0.95), cardiac arrhythmia (OR: 0.82, 95% CI: 0.70-0.97), and cardiac arrest (OR: 0.57, 95% CI: 0.44-0.74) were reported among SGLT-2 inhibitors users compared to non-SGLT2 inhibitor users. Conclusions: Our study revealed that only 8.4% of patients with DM and MM were prescribed an SGLT-2 inhibitor. Our study also demonstrated that SGLT2 inhibitor use was associated with lower odds of all-cause mortality and hospitalization, reduced risk of VTE, and favorable cardiovascular outcomes in this patient population.

e23024 Background: Efforts to address disparities in clinical trial participation have increased over the past 30 years. Strict eligibility criteria in phase III interventional trials may exacerbate these disparities, limiting access and raising concerns about generalizability. Chronic lymphocytic leukemia (CLL), the most common chronic leukemia in adults, primarily affects older individuals and those with comorbidities, emphasizing the need for inclusive research. This study aimed to explore changes in eligibility criteria for phase III interventional CLL trials over 15 years. Methods: Clinical trial data were obtained from ClinicalTrials.gov, focusing on Phase 3 interventional studies related to CLL. The search used "chronic lymphocytic leukemia," filtered for adults aged 18–64 and older adults aged 65+. Trials enrolling patients between January 1, 2004, and December 1, 2019, were included. Trial designs, endpoints, and eligibility criteria were primarily extracted from published protocols when available and supplemented with information from ClinicalTrials.gov. Studies not specific to CLL, those evaluating supplements or vaccines, lacking a control arm, being single-center, or without investigational products were excluded from the data analysis. Data were grouped into three periods (2004–2008, 2009–2013, 2014–2019), and one-way ANOVA was used to assess differences in average eligibility criteria across these periods. Results: A total of 103 clinical trials were identified, with 47 included in the final analysis. Most were industry-funded (37 trials, 81%), while 10 (19%) were non-industry-funded. Regarding treatment settings, 60% targeted untreated patients, 32% focused on relapsed/refractory patients, and 9% included both. Interventions included chemoimmunotherapy (40%), targeted therapies (21%), combined approaches (36%), and other types (2%). The average number of eligibility criteria increased over time: 23.86 (IQR 14; range 12–39) in Period 1, 32.05 (IQR 19; range 18–59) in Period 2, and 46.25 (IQR 26.5; range 13–70) in Period 3. One-way ANOVA confirmed a significant difference across periods (F = 7.35, p < 0.001), showing a significant increase in the average number of criteria over time. Conclusions: Over 15 years, the number of eligibility criteria in phase III interventional CLL trials significantly increased, nearly doubling from 23.86 (2004–2008) to 46.25 (2014–2019). While this may improve internal validity, it risks excluding older patients and those with comorbidities, who are most affected by CLL. These findings highlight the need to balance scientific rigor with equitable access to ensure generalizability.

7075 Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, aggressive peripheral T-cell lymphoma arising primarily from γδ T-cells. It carries a poor prognosis and resists conventional chemotherapy. Most reports on HSTCL are case-based. This study comprehensively analyzes a large cohort, evaluating treatment strategies and survival outcomes. Methods: This retrospective study included patients (pts) with pathologically confirmed HSTCL diagnosed between 2000-2024, consecutively seen at Mayo Clinic MN. Clinical, pathological, genomic, and treatment-related data were extracted when available. Descriptive statistics were used to summarize baseline characteristics. Time-to-event analyses, including Kaplan-Meier estimates, median overall survival (OS), and survival time estimates were conducted from the date of diagnosis. Results: A total of 20 patients with newly diagnosed HSTCL were included, with a median age of 57 years (range: 35-71). The cohort was predominantly male (70%) and non-Hispanic (93%). Molecular data was available for five patients, revealing abnormalities in STAT5B, MLL3 deletion, TP53, EZH2, TERT, and NF1 E291D . The median follow-up was 27.6 months (m) with a median OS of 17.6 m (95% CI: 11.2 - NA). First-line treatment was anthracycline-based in 68% of pts and non-anthracycline-based in 32%, with higher response rates in the latter group (50% vs.83%). Although non-anthracycline regimens showed a trend toward improved 3-year OS (100% vs. 29%) the difference was not statistically significant (p = 0.16). Achieving a complete response to first-line therapy was also associated with a trend towards a better 3-year OS compared to refractory disease (80% vs. 50%, p = 0.17). Most pts (79%) underwent hematopoietic stem cell transplant (HSCT), primarily allogeneic, with only one receiving autologous HSCT. First-line therapy before HSCT was evenly distributed between anthracycline (55%) and non-anthracycline (45%) regimens. HSCT recipients had significantly higher 3-year OS than non-recipients (83% vs. 33%, p = 0.017). Notably, the patient with a TP53 mutation has remained in remission for over a year post-allogeneic HSCT. Conclusions: HSTCL predominantly affects younger pts, with nearly half dying within a year. Allogeneic HSCT, rarely used in other NHL subtypes, improved survival. Non-anthracycline regimens and achieving CR trended toward better outcomes. Our study, leveraging a sizable cohort, highlights the need for targeted research and novel therapies to improve HSTCL management. Summary of survival outcomes in HSTCL. Characteristics Median OS (y) 3-Year OS (95% CI) 1.48 [0.93- NA] 46% [0.26 - 0.81] Transplant Transplant NA [NA - NA] 83% [0.58 - 1.00] No Transplant 1.02 [0.93 - NA] 33% [0.07 - 1.00] Treatment Anthracycline Based 1.02 [0.36 - NA] 29% [0.11 - 0.73] Non-Anthracycline Based 4.61 [NA- NA] 100% [1.00 - 1.00]

Abstract Introduction: Multiple myeloma (MM) is a B-cell-derived malignancy associated with immune dysregulation. Anti-CD38 monoclonal antibodies (mAbs) therapies have shown improved outcomes in patients with MM. Silbermann et al. showed that anti-CD38 mAb-containing therapies lead to profound hypogammaglobulinemia and reduction in Ig gene repertoire. The effect of modern therapies such as CAR-T and bispecific antibodies (BsAbs) on B-cell repertoire has not been well described. In this study, we sought to investigate the effect of these therapies on B-cell repertoire in patients with MM. Methods: This is a single-institution retrospective observational study evaluating MM patients treated with anti-BCMA CAR-T and BsAbs. Baseline characteristics, laboratory data, treatment history, were extracted from medical records. Total unique sequences (TUS) and total sequences of IgH, IgK, and IgL were identified and quantified using clonoSEQ. Patients were classified in two groups: CAR-T and BsAbs. The primary objectives were (1) characterize changes in TUS and total sequences within IgH, IgK, and IgL before and after treatment, and (2) examine how the sequences evolve over time following CAR-T. Results: 76 MM patients received CAR-T or BsAbs. Among those, 22 CAR-T and 5 BsAbs patients had pre- and post-treatment sequences available. Median age at initiation of treatment was 66 years in the CAR-T group (42-81 y) and 65 years in the BsAbs group (48-71 y). Based on mSMART v3 criteria, 72% of CAR-T and 60% of BsAbs recipients were classified as high-risk. Median number of prior lines of therapy was 5 (2-8) in the CAR-T group and 6 (5-13) in the BsAbs group.CAR-T recipients were classified into early (&lt;40 days) and late (&gt;40 days), based on when the post-CAR-T treatment clonoSEQ assay was performed. Changes in TUS and total sequences of IgH, IgK, and IgL were calculated, and the averages were assessed independently. The mean early and late change in total unique IgH sequences were (-75, 586 and 131, 038, p=0.052), unique IgK (-57, 797 and 52, 586, p=0.020), and unique IgL (-22, 354 and 25, 056, p=0.011). A subgroup of 8 patients with sequential MRD reports post-CAR-T therapy were identified, six patients showed improvement in B-cell sequence dynamics and two patients showed a decrease over time. For patients who received BsAbs, results indicated a similar pattern, with an early decrease in B-cell repertoires, characterized by reductions in sequence diversity and quantity. Conclusions: Our analysis of B-cell repertoires following CAR-T revealed changes before and after treatment. Patients receiving CAR-T therapy showed a decline in the number of TUS and total sequences of IgH, IgK, and IgL, likely due to the lymphodepletion regimen, followed by a gradual restoration reflecting immune recovery. Longer follow-up and a larger cohort will be necessary to assess the implications of these B-cell repertoire changes on patient outcomes. Citation Format: Feba Miriam Jacob, Rodolfo Garza-Morales, Joseph G Hentz, Alex Wonnaparhown, Julia E. Wiedmeier-Nutor, Mariano Arribas, Gabriela Alatorre, Sharene Best, Jayden Poulignot, Udit Yadav, Saurabh Chhabra, P. Leif Bergsagel, Rafael Fonseca, Talal Hilal. Dynamics of B-cell repertoires following CAR-T and bispecific antibody therapy in multiple myeloma [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 4537.

ABSTRACTBackgroundChimeric Antigen Receptor (CAR) T‐cell therapy has arisen as a revolutionary treatment for hematologic malignancies. Our study aimed to evaluate how sex differences affect outcomes and complications following CAR T‐cell therapy.MethodsUtilizing the Nationwide Readmissions Database (2018–2020), we identified patients and divided them into male and female groups. Hospital outcomes and complications were compared among these two groups after propensity score matching to match groups based on comorbidities, producing two comparable cohorts.ResultsWe analyzed 2928 patients (1832 males, 62.6%, mean age 60.3 ± 13.7 years; 1096 females, 37.4%, mean age 59.1 ± 13.8 years). After propensity score matching (1:1ratio), 1092 males and females were compared. There were no significant sex differences in early mortality (adjusted odd ratios (aOR): 1.04 [95% CI 0.69–1.57]), 30‐day readmissions (aOR: 1.05 [95% CI 0.86–1.30]), or nonhome discharge (aOR: 0.89 [95% CI 0.60–1.31]). Females had higher odds of leukopenia (aOR: 1.26 [95% CI 1.06–1.50]) but lower odds of acute kidney injury (aOR: 0.68 [95% CI 0.52–0.88]).ConclusionsNo sex differences were found in hospital outcomes, including early mortality, 30‐day readmission, and nonhome discharge after CAR T‐cell therapy.

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as &lt; 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p &lt; 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts &lt; 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p &lt; 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

INTRODUCTION Atrial fibrillation (AFib) is a recognized complication in patients with chronic lymphocytic leukemia (CLL) treated with Bruton tyrosine kinase inhibitors (BTKis). Early detection and management of AFib are critical due to its association with increased morbidity and mortality. Traditional detection methods, such as intermittent EKGs and wearable devices, often capture only brief snapshots of cardiac activity, potentially missing episodes. Recent advances in artificial intelligence (AI) have enabled the development of algorithms that analyze electrocardiograms (EKGs) to predict AFib risk. These algorithms can potentially identify patients with undetected AFib and assess risk at a single point, reducing the need for continuous monitoring. This study evaluates the utility of an AI-enabled EKG algorithm in predicting AFib in patients with CLL treated with ibrutinib and acalabrutinib. METHODS Patients with CLL treated with ibrutinib and acalabrutinib were identified from a single-center database. Patients with CLL who received BTKi therapy at Mayo Clinic between 2015 and 2024 with available EKGs in the EMR were included. Patients were excluded if they received BTKi for non-CLL indications or if patients with CLL had documented AFib without accompanying EKGs in their medical records. An AI-enabled EKG algorithm developed by Attia et al. (Lancet, 2019) was used to estimate AFib probability (AFibAI). EKGs were categorized into pre-treatment, during treatment, and post-treatment phases. Mean values of all EKGs within each phase were used for analysis to reduce heterogeneity. Paired t-test was used for continuous variables and ROC analysis was used to evaluate diagnostic performance. A p-value of &lt;0.05 was used for statistical analysis. RESULTS The analysis included 383 individual CLL patients (74% male, median age71; ace/ethnicity not available), of which 79 were treated with acalabrutinib and 304 with ibrutinib, with a total of 5844 EKGs analyzed. The AFibAI was significantly higher in EKGs with documented AFib compared to other EKGs, mostly normal sinus rhythm (0.5710 vs. 0.1857, p &lt;0.001). Pre-treatment AFibAI was higher in patients who ultimately developed AFib after starting BTKi treatment compared to those who did not. Mean AFibAI at baseline was 0.2176 for those who developed AFib and 0.0986 for those who did not (p &lt;0.001; difference between means: -0.1191 +/- 0.02005, 95% CI: 0.-0.1585 - 0.0796). Differences of baseline AFibAI were similar when stratified by BTKi. Trends in AFibAI scores indicated a significant increase during and after BTKi treatment in patients who developed AFib, with mean score of 0.2176 at baseline to 0.4064 post-treatment (p&lt;0.001). In patients who did not develop Afib during BTKi therapy, there was minimal increase of AFibAI scores from 0.1041 at baseline to 0.1620 post-treatment (p = 0.0002). The ROC analysis showed an area under the curve of 0.7280 (SE = 0.03911, 95% CI: 0.6514 to 0.8047, p &lt;0.001), indicating fair discriminatory ability. The sensitivity at the optimal threshold (0.1202) was 65.45% and the specificity was 74.59%, with a Youden's Index of 0.4004. To achieve a sensitivity of ≥90% for detecting patients who ultimately develop AFib, a threshold of 0.2368 was established (specificity of 41.82%). DISCUSSION Our study demonstrates the efficacy of an AI-enabled EKG algorithm in estimating atrial fibrillation risk among CLL patients treated with BTKis. We demonstrated that baseline AFibAI was notably higher in patients who ultimately developed AFib, suggesting that it could potentially identify patients at elevated risk before the onset of AFib. Early identification would allow for closer monitoring and timely intervention, potentially mitigating complications. Pending validation with an external cohort, the 90% sensitivity threshold could help identify the patients at highest risk, where other treatment options could be considered. The trend across different treatment phases revealed a significant increase in scores during treatment, indicating that AFibAI is responsive to changes induced by BTKi therapy and suggest its utility for patient monitoring. Practical questions remain about its impact on clinical decision-making and management. Future prospective studies should confirm the validity of identifying high-risk patients and its role in both treatment decisions and patient outcomes.

Background: Indolent non-Hodgkin lymphomas (iNHL) are incurable and disproportionately affect adults age &gt;65 in whom frailty and functional impairment can impact disease management. The Vulnerable Elders Survey (VES-13) is a 13-item screening tool that incorporates age, self-rated health, physical function limitations, and functional disabilities to identify vulnerable older community-dwelling adults. Adults with a VES-13 score of &gt;3 have a fourfold increased risk of death or functional decline over 2 years as compared to adults with a score &lt;3 (Saliba et al, JAGS 2001). Our team previously showed that VES-13 &gt;3 was associated with a higher risk of 1-year mortality in NHL (OR 3.26, 95% CI 2.15-4.96, Fama et al, ASH 2019), including in adults age &lt;65. In this study, we determined whether VES-13 scores &gt;3 were associated with quality of life (QOL) changes in adults with iNHL across the age spectrum. Methods: We used the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study to identify adults enrolled from 2015-2020 with grade 1-3A follicular and marginal zone lymphoma (FL, MZL) who completed the VES-13 at enrollment and QOL surveys at enrollment and follow-up. The LEO Cohort Study enrolls participants within 6 months of diagnosis and collects information on disease status, QOL, health behaviors, and patient-reported functional assessment. For this analysis we included QOL measured using the Functional Assessment of Cancer Therapy-General (FACT-G) at years 1 and 2 post-enrollment. The FACT-G total score was the sum of 4 subscales (range): physical (PWB, 0-28), social/family (SFWB, 0-28), emotional (EWB, 0-24), and functional (FWB, 0-28) well-being. A higher FACT-G total score (range 0-108) indicated better overall QOL. VES-13 scores ranged from 0 (lowest risk for death or decline) to 10+ (highest risk). Generalized linear mixed models evaluated changes in QOL from baseline based on VES-13 score &gt;3 (vulnerable) vs &lt;3 (non-vulnerable), within groups by age at enrollment &gt;65 and &lt;65. Results: Our study included 1,186 participants: 42% age &gt;65, 54% female, 84% non-Hispanic White, 10% Hispanic, 3.3% Black, and 1.4% Asian/Pacific Islander. Most (68%) were diagnosed with FL. FLIPI was high risk for 20%, and MALT-IPI was high risk for 23%. In the VES-13 &lt;3 group, the mean (SD) baseline FACT-G total score was 86.5 (12.0), PWB 21.0 (3.5), SFWB 24.3 (4.3), EWB 18.8 (3.7), and FWB 22.3 (4.9). In the VES-13 &gt;3 group, the mean (SD) baseline FACT-G total score was 70.4 (16.5), PWB 15.4 (5.6), SFWB 22.3 (5.5), EWB 17.5 (4.5), and FWB 15.3 (6.4); all significantly lower than the VES-13 &gt;3 group (all p&lt;0.01). In adults &lt;65, 63 (9%) had a VES-13 &gt;3, which was associated with a significant improvement from baseline in PWB at years 1 and 2 when compared to VES-13 &lt;3 (changes in baseline PWB were 2.1, 2.9 for VES-13 &gt;3 vs 0.2, 0.1 for VES-13 &lt;3, all p&lt;0.05). Similarly, we observed improvement in FWB from baseline at years 1 and 2 in the VES-13 &gt;3 vs &lt;3 group (2.4, 2.9 vs 0.4, -0.1, respectively all p&lt;0.05). The VES-13 &gt;3 group had a decline in their EWB at 1 year vs the VES &lt;3 group (-0.5 vs 1.2, respectively, p=0.003). At year 2, total FACT-G improved from baseline in the VES-13 &gt;3 group (5.6 for VES-13 &gt;3 vs -0.5 for VES-13 &lt;3, p=0.002). SFWB changes from baseline did not differ between groups. In adults &gt;65, 83 (17%) had a VES-13 &gt;3, which was associated with a significant improvement from baseline PWB (1.3, 1.5 for VES-13 &gt;3 vs. 0.1, -0.1 for VES-13 &lt;3), FWB (3.3, 2.2 for VES-13 &gt;3 vs. 0.5, 0.1 for VES-13 &lt;3), and total FACT-G score (5.2, 3.4 for VES-13 &gt;3 vs. 1.0, -0.4 for VES-13 &lt;3) when compared to VES-13 &lt;3 at years 1 and 2 (all p&lt;0.05). SFWB and EWB changes from baseline did not differ between groups. While there was improvement from baseline PWB and FWB in the VES-13 &gt;3 group, QOL scores across all subscales remained below the VES-13 &lt;3 group in the study period for both age groups. Statistical significance was maintained in models adjusted for baseline characteristics, including initial treatment strategy (observation, systemic, vs local) for both age groups. Conclusion: Although the vulnerable group reported worse QOL throughout the study period compared to the non-vulnerable group, survivors in the vulnerable group saw greater improvement in their physical and functional well-being at 1- and 2-years post-diagnosis. Additional analyses are underway to identify drivers of improvement in physical and functional well-being in vulnerable adults diagnosed with iNHL.

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts &gt;65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in &lt;60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (&gt;5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts &lt;60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts &lt;60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in &lt;60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and &lt;60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts &lt;60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts &lt;60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the &lt;60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts &lt;60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in &lt;60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in &lt;60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.