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Abstract Background Red blood cell (RBC) transfusion may be lifesaving, however transfusion-transmitted infections (TTI) and transfusion-associated graft-versus-host disease (TA-GVHD) still pose a threat despite current donor selection and testing requirements. Amustaline (S-303)/glutathione (GSH) pathogen reduction (PR) is designed to inactivate infectious microbes and leukocytes in RBCs. The RedeS study evaluates the safety and efficacy of amustaline/GSH PR-RBCs compared to conventional RBCs in a broad spectrum of patients requiring acute and/or repeated RBC transfusion support. Methods RedeS is a Phase 3, prospective, multi-center, randomized, double-blind, active-controlled, parallel-design study, with a 6-month extension option to evaluate patients requiring repeated transfusions including red cell exchange (RCE).Eligible subjects will be stratified according to site, baseline bleeding status and participation in the extension period. The study arms include a transfusion period of 28-days for anemia with any bleeding or non-bleeding patients or a 28-day+6-month extension for non-bleeding patients with chronic anemia requiring repeated simple transfusions, or for patients with sickle cell disease (SCD) expected to receive three RCE procedures. The study will seek to enroll 600-800 subjects in the overall safety analysis, including ~140 repeatedly-transfused subjects in the 6-month extension including up to 30 subjects receiving three RCE procedures. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days after the last study transfusion, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to PR-RBCs. The primary efficacy endpoint is the hemoglobin (Hb) increment in subjects who are non-bleeding at baseline, adjusted for the grams of Hb transfused and averaged over multiple transfusions. With 352 evaluable transfused non-bleeding subjects (176 per treatment group) from either arm, the study will have 80% power to demonstrate non-inferiority, defined as a Hb increment treatment difference of no more than 15% of the Control group mean, assuming a Control arm coefficient of variation of 50%. Discussion RedeS will characterize the safety of amustaline/GSH PR-RBCs and is designed to demonstrate the non-inferiority of PR-RBCs to conventional RBCs with respect to Hb increment, a common pragmatic clinical assessment of RBC transfusion effectiveness.

Circulating tumor DNA (ctDNA) testing is a minimally invasive alternative to tissue biopsy and is ideal for inaccessible tumors or limited samples. It captures tumor heterogeneity over time and different anatomic locations, unlike the static snapshot provided by a biopsy. In this report, we describe a 68-year-old female with an initial diagnosis of metastatic pancreatic adenocarcinoma (a pancreas head mass with multiple bilateral lung nodules). Mutation profiling of the pancreatic mass biopsy using a comprehensive cancer next-generation sequencing (NGS) panel was unsuccessful due to insufficient tissue. Consequently, ctDNA testing using a pan-cancer NGS panel was performed, and an EGFR p.L858R variant at 2.15% was identified. Interestingly, this activating variant is highly specific to non–small cell lung cancer (NSCLC), which raised the possibility of a synchronous tumor unrelated to the pancreatic mass. Immunohistochemistry showed the EGFR variant in station 7 lymph nodes but not in pancreatic biopsy tissue, supporting the inference that the variant originated from the lung mass. Droplet digital PCR on the limited pancreatic biopsy identified a KRAS p.Q61 variant, which was absent by ctDNA testing, suggesting a pancreatic primary with low ctDNA levels. In addition to diagnosing a primary lung cancer, ctDNA testing guided treatment decisions. With a primary EGFR p.L858R–mutant NSCLC, osimertinib was administered, resulting in a partial response within 10 months. In addition, given the synchronous primary pancreatic adenocarcinoma, germline testing was performed, revealing a CDKN2A p.I49T variant consistent with melanoma-pancreatic cancer syndrome, prompting comprehensive cancer surveillance and familial testing. This case illustrates how ctDNA testing enabled a comprehensive evaluation by clarifying the diagnosis, identifying actionable biomarkers, and facilitating genetic risk assessment, ultimately having a significant impact on the patient’s clinical management.

Background: Accurate characterization of tumor stiffness and adhesion is crucial when surgically resecting meningiomas. Currently, such determinations are difficult to ascertain through standard preoperative imaging diagnostics and clinical experience. Herein, we explored magnetic resonance elastography (MRE) as a means of assessing these parameters and thereby improving neurosurgical resections. Methods: This prospective study of 193 patients with meningiomas involved three distinct patient subsets (cohort 1, 88 [2017–2021]; cohort 2, 55 [2022–2023]; cohort 3, 50 [2023–2024]. We analyzed preoperatively obtained MRE data on meningioma stiffness (cohorts 1 and 2) and adhesion (cohort 2) for accuracy, while matching subjects with or without MRE studies (cohort 3, 1:1 ratio) to define the role of preoperative MRE in improving operative outcomes. Results: Areas under the curve (AUCs) for MRE in gauging meningioma stiffness and adhesion were 0.87 and 0.89, respectively. Both parameters significantly surpassed empiric predictions of stiffness and adhesion rendered by surgeons and radiologists, based on routine magnetic resonance imaging (MRI). MRE-determined stiffness measures independently correlated with prolonged resection duration, whereas MRE-assessed adhesion showed independent associations with increased blood loss, longer duration of tumor resection, and higher risk of pial injury. Ultimately, results based on cohort 3 demonstrated that MRE has great potential in this setting to improve neurosurgical procedures by significantly reducing intraoperative bleeding, resection duration, and risks of pial injury. Conclusion: MRE is a promising, noninvasive tool for accurately assessing meningioma stiffness and adhesion, standing to improve the precision and safety of needed surgical intervention.

Traditional solvents face limitations in environmental friendliness, biocompatibility, and functional tunability, which restrict their use in pharmaceuticals, biocatalysis, and biosensing.

Abstract Background We performed a prospective study evaluating a baseline GA battery and clinical outcomes in fit older adults (age ≥60 years) with AML and normal cardiac and renal function in the recent E-A NCTN E2906 phase 3 study. A patient-reported outcomes (PRO) assessment of Depression, Activities of Daily Living (ADL), Cognitive Function, Social Support (SS) domains, and comorbidity was performed at study registration to evaluate the prevalence of vulnerabilities and their impact on overall survival (OS) and 30-day induction mortality rates (IM) in this cohort selected for fitness to receive IC. Methods E2906 study design and results have been presented previously [n=727, age ≥60 years, randomized 1:1 to ‘standard 7&3‘ & high dose cytarabine (Arm A) vs. single agent clofarabine (CLO, Arm B), as remission induction (Step 1) and consolidation (Step 2)]. There was no difference in composite complete remission (CCR, 50%) or IM (8.5%), and CLO was inferior for OS. A baseline GA was a key secondary protocol objective, offered to all patients, and n=532 (73%) participated. We assessed Geriatric Depression Scale (GDS, none vs. any depressive symptoms, n=524); cognitive screen using Mini-Mental Exam Section (MMES, score 8/8 vs. <8, n=516); ADL & Instrumental ADL (iADL), (need for assistances vs. not n=526); a Medical Outcomes Study SS Survey (MOS-SS, measured as per unit increase, n=527); a Comorbidity survey ( ≤4 vs. ≥5 patient-reported comorbidities, n=530), patient-reported prescription medications use (PM, 0-3 vs. ≥4, n=519); and a survey of Sexual Desire (n=491) and Sexual Activity (n=477) within 4 weeks of AML diagnosis. Association of GA domains with OS, IM, and achievement of CCR was evaluated using the Chi-squared, Fisher's exact, and Wilcoxon rank sum test. Survival analysis was performed using the Cox proportional hazards models, adjusted for treatment arm. All p-values are 2-sided. Results The median age among those participating in GA battery was 67 yrs (range 60-85), including 38% age ≥70. There were 42% females, and ECOG performance status was 0 (28%), 1 (54%), 2 (16%), or 3 (2%). Central Cytogenetic review was classified (ELN2017) as Favorable (3%), Intermediate (66%), and Adverse (31%) risk. There was a notable rate of GA scores outside ‘normal’ clinical cutoff, including Depression (GDS 31%), cognitive and functional impairment [MMSE (37%), ADL (25%) and iADL (32%)], ≥5 Comorbidities (23%), and ≥4 PM's (44%). 81% & 76%, respectively, reported no sexual activity and low/none sexual desire. MOS-SS tended to be high in this cohort [mean (SD) score 87 (17)]. We observed a significant association of GA domains with OS & IM. For OS, absence of depressive symptoms [GDS, Hazard Ratio (HR) 0.79, 95% confidence Intervals (CI) 0.64-0.97, p=0.025)], MMES 8/8 (HR 0.78, 95%CI 0.64-0.96, p=0.016), requiring no assistance with ADLs (HR 0.65, 95%CI 0.52-0.82, p<0.001) and iADLs (HR 0.69, 95%CI 0.57-0.85, p<0.001), and ≤4 Comorbidities (HR 0.68, 95%CI 0.54-0.84, p=0.001) were significant for superior OS; use of ≥4 PM's was associated with inferior OS (HR 1.32, 95%CI 1.09-1.61, p=0.005). There was no association of sexual activity/desire, BMI ≥30 kg/m2, or MOS-SS with OS. IM was significantly higher among those with any depression symptoms (GDS, p=0.005), any ADL (p=0.010) or iADL (p=0.013) impairment, ≥5 comorbidities (p=0.037) and ≥4 PM's (p=0.001); there was no association with MOS-SS or MMES. There was no significant association of GA scores with cytogenetic risk group or with CCR rates. Only ADL independence (p=0.048), and possibly Comorbidity ≤4 (p=0.071), were associated with proceeding to Step 2. Conclusions In this large prospective cohort of fit older adults with AML selected to receive IC, we observed high rates of PRO-assessed GA vulnerability, which was significantly associated with inferior OS and higher IM rates, and (for ADL impairment) lower rates of proceeding to consolidation therapy. This suggests that functional and cognitive impairments are prevalent and can significantly impact outcome even in fit older adults. Despite potential long-term OS advantages of IC previously observed in E2906, efforts to systematically recognize those at higher risk based on GA PROs are needed to help identify patients who may be more appropriate for study of lower intensity treatment options to mitigate impact on IM and OS. SImilarly we plan to evaluate the potential benefit of GA-driven supportive care to improve patients' outcomes.

Abstract Background Etentamig is a second-generation B-cell maturation antigen (BCMA) x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Etentamig possesses a unique combination of 2 high-affinity BCMA binding domains, coupled to a low-affinity CD3 binding domain that have been shown to reduce the negative impact of soluble BCMA (sBCMA), decrease risk for cytokine release syndrome (CRS), and drive sustained T-cell activation with reduced immune exhaustion in preclinical models of MM (Blood 2023;142 [suppl 1]:4666). Here, we describe correlative biomarker analyses from Phase 1 (NCT03933735) and Phase 1b (NCT05650632) clinical trials of etentamig in RRMM designed to assess the impact of sBCMA on clinical response and pharmacodynamic changes in proinflammatory cytokines, and T-cell redistribution, activation, proliferation, and exhaustion. Methods Peripheral blood and serum samples from patients with RRMM enrolled in Phase 1 and Phase 1b open-label studies who received etentamig monotherapy were collected at baseline, on treatment, and at disease progression. The Phase 1b study consisted of dose-optimization (DO) and dose-expansion (DE) phases. During DO, patients received a single step-up dose (SUD) of intravenous etentamig (2 or 4 mg) on Cycle (C) 1 Day (D) 1, followed by the target dose of 60 mg on D4. In DE, based on DO findings, patients received the recommended etentamig SUD (2 mg) on C1D1, followed by 60 mg on D4 with modified dexamethasone predosing. Samples were analyzed by flow cytometry for immune cell populations, Luminex® for cytokines, and electrochemiluminescence for sBCMA. Peripheral blood mononuclear cells and bone marrow mononuclear cells (BMMC) at baseline and on-treatment were subjected to single-cell Cellular Indexing of Transcriptomes and Epitopes sequencing (scCITEseq) and single-cell T-cell receptors (scTCR) / B-cell receptors clonality analyses. Results While baseline serum sBCMA levels did not correlate with clinical response to etentamig at the selected dose level of 60 mg every 4 weeks (Q4W) with 2 mg SUD, a reduction in sBCMA levels over time was associated with best International Myeloma Working Group response. Etentamig treatment led to a rapid and transient increase of proinflammatory cytokines and promoted T-cell redistribution, activation, and proliferation. Maximum reduction in peak levels of CRS-related cytokines, including (interleukin [IL]-6, IL-8, IL-10, tumor necrosis factor–a), were observed in DE compared with DO and 60 mg Q4W without SUD. Peak induction levels of proinflammatory cytokines during C1 correlated with occurrence of CRS (≥Grade [G] 1) as well as clinical response across dose levels. A modified dexamethasone premedication schedule of 2 mg/60 mg Q4W cohort for C1 resulted in significantly reduced baseline levels of IL-6 and key macrophage-associated cytokine/chemokines (eg, monocyte chemoattractant protein-1 and macrophage inflammatory protein-3 beta). Incidence of CRS was lowest in the 2 mg/60 mg Q4W cohort (26% G1, 4% G2, 0% ≥G3). Higher T-cell to myeloma cell ratio in BMMCs at baseline correlated with better response to etentamig. scCITEseq and scTCR analysis revealed that at baseline, responders also had greater CD8+ T-cell cytotoxic activities, increased TCR clonality, and elevated inflammatory signatures in T-cells from both peripheral blood and bone marrow. Etentamig at a dosage of 60 mg Q4W resulted in significant clonal expansion of CD8+ effector T-cells and enhanced gene expression signatures related to activation and cytotoxicity in both CD8+ T effector and natural killer cells. Along treatment cycles, responders maintained their T-cell fitness, high clonality, and low T-cell exhaustion levels. Frequency of baseline CD4+ or CD8+ T-cell exhaustion (programmed cell death receptor 1+/ T cell immunoglobulin and mucin-domain containing-3 +) did not impact clinical response at optimal dose level of 2 mg/60 mg Q4W etentamig. Conclusions Responses to etentamig were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation indicating that the optimal dose of etentamig (2 mg/60 mg Q4W) maximizes its clinical potential as a convenient, safe, and effective therapy for MM.

Abstract Background Patients with myeloproliferative neoplasms (MPNs) are at risk of splanchnic vein thrombosis (SVT). Prior studies failed to demonstrate a benefit of hydroxyurea in preventing SVT extension/recurrence, but these were limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. We therefore investigated the role of cytoreduction as a time-dependent covariate on thrombosis recurrence in a large, international cohort of MPN-SVT patients. Methods We performed a retrospective cohort study of MPN-SVT patients included in the international GASTRO-MPN consortium. Patients diagnosed with MPN at any time before, concurrently with, or up to 60 days after initial SVT were included. Primary outcome was time from initial SVT to first thrombosis recurrence, defined as the composite of SVT extension/recurrence, transjugular intrahepatic portosystemic shunt (TIPS) thrombosis, or venous/arterial thrombosis outside the splanchnic veins. Secondary outcomes included SVT extension/recurrence, TIPS thrombosis or extra-SVT thrombosis individually, clinically relevant bleeding (composite of major and clinically relevant non-major bleeding), MPN progression to myelofibrosis or blast phase, and death. Cytoreductive therapy was treated as a time-dependent covariate to account for discontinuation and therapy changes. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results A total of 757 patients were included for this analysis. Median age was 51 years (IQR 38-62), 59% were female. SVT involved the portomesenteric veins in 558 (77%) patients, hepatic veins in 95 (13%), and both in 54 (7.4%). MPN was known prior to initial SVT in 316 patients (42%) and diagnosed concurrently or up to 60 days after SVT in 441 (58%). Polycythemia vera (PV) was the most common MPN subtype (43%), followed by essential thrombocythemia (ET) in 24%, and primary myelofibrosis in 14%. JAK2V617F mutation was present in 86% and CALR in 2.9%. 13% had prior non-SVT thrombosis. 607 patients (83%) were treated with cytoreduction. At time of SVT, 131 patients (17%) were already on cytoreduction; in those who started after SVT, median time to initiation was 54 days after SVT, and median duration of cytoreduction per patient was 63 months. Cytoreductive therapies used at any point in treatment included hydroxyurea in 504 (69%), ruxolitinib in 182 (25%), and interferon-based in 85 (12%) patients. Anticoagulation (AC) was started within 30 days after SVT in 504 (68%) patients. Median duration of any AC per patient was 24.6 months. During a median follow up of 7.4 years, 245 patients (33%) had thrombosis recurrence; 143 (20%) had SVT extension/recurrence/TIPS thrombosis, 129 (18%) extra-SVT thrombosis (of which 74% venous), 237 patients (32%) experienced clinically relevant bleeding, and 163 (22%) died. After adjusting for age, sex, timing of MPN diagnosis relative to SVT diagnosis, AC within 30 days of SVT, PV/ET vs other MPN, JAK2 mutation, previous thrombosis, non-MPN cancer, and cirrhosis, cytoreductive therapy was associated with a significantly decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). Age was associated with an increased risk of recurrent thrombosis (p=0.01). When considering types of recurrent thrombosis, cytoreduction was associated with a decreased risk of SVT extension/recurrence/TIPS thrombosis (HR 0.62 95%CI 0.42-0.90, p=0.01), but not thrombosis outside the splanchnic veins (HR 0.97 95%CI 0.72-1.30, p=0.82). There was no association between cytoreduction and bleeding (HR 1.10 95%CI 0.82-1.47, p=0.52). Similarly, there was no association between cytoreduction and time to MPN progression (p=0.24) or overall survival (p=0.30). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=271), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.10, p=0.09) for recurrent thrombosis. Limited sample size and low event-rate precluded evaluation of the impact of individual cytoreductive therapies. Conclusions In the largest cohort of MPN-SVT patients to date, we show for the first time that cytoreductive therapy is associated with a decreased risk of thrombosis recurrence, driven largely by decreased SVT extension/recurrence/TIPS thrombosis. Collectively, these findings support use of cytoreductive therapy in individuals with MPN-SVT to prevent recurrent thrombosis.

Abstract Introduction Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients <30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary <36m; isolated extramedullary <18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p<0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised >40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

Abstract Description In the tumor microenvironment of glioblastoma, myeloid cells act as a double-edged sword—they are a major cellular component suppressing the immune response while serving as a promising therapeutic target. Our study sheds light on the voltage-gated proton channel Hv1, predominantly expressed in myeloid cells, as a pivotal regulator of their physiological functions. Elevated Hv1 expression correlates strongly with poor prognosis in glioblastoma patients, underscoring its clinical significance. Using a glioma mouse model, we demonstrated that Hv1 depletion markedly extended survival. To overcome the limitations of existing tools, we engineered novel transgenic mouse lines optimized for Hv1 research. Our findings revealed tumor-induced Hv1 upregulation, with glioma-associated macrophages identified as the principal contributors. Crucially, we identified that Hv1 in infiltrating macrophages as the major driver of survival phenotype differences. Through a multi-faceted approach combining in vivo two-photon imaging, spectral flow cytometry, and spatial transcriptomic sequencing, we discovered that Hv1 depletion limits macrophage infiltration and enhances antigen presentation, ultimately fostering a stronger adaptive immune response. These findings establish the Hv1 channel as a crucial new immune regulator within the brain tumor milieu, offering a promising target for reprogramming macrophage function to combat glioblastoma. Funding Sources Supported by NIH R35NS132326 (LJW); Mayo Clinic Cancer Center and Mayo Clinic Center for Biomedical Discovery. Topic Categories Neuroimmunology (NEUR)

Abstract Objective To evaluate 2-year cost to insured patients treated with Roux-en-Y gastric bypass (RYGB) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for type 2 diabetes (T2D) and obesity. Methods Using the 2017 to 2023 Merative™ claims database, we identified adult patients with severe obesity and T2D who were treated with a RYGB or GLP-1 RAs. Patients with RYGB had no treatment with GLP-1 RAs, and those who received GLP-1 RA therapy with tirzepatide or semaglutide for ≥ 2 years had no metabolic and bariatric surgery (MBS) procedures. The study cohorts were matched on demographics including obesity, associated medical problems, and baseline direct or out-of-pocket (OOP) costs to patients in the year prior to treatment initiation. Direct costs included those from outpatient services, inpatient admissions, and outpatient prescription filled that were paid directly by patients. We compared this cost up to two years after treatment initiation using paired t-tests. Results 1012 matched RYGB and GLP-1 RA patients were analyzed, including 35% male. At 1-year after treatment initiation, healthcare costs paid directly by patients were similar for the RYGB ($2,301) and GLP-1 RA ($2,179) (delta = $122, p = 0.15) cohorts. From one to two years after index treatment date, OOP costs were significantly lower in the RYGB treatment group ($1,277 vs. $2,104, p < 0.01). Two years after treatment initiation, RYGB patients spent $704 less in OOP costs than similar patients treated with GLP-1 RA medications (p < 0.01). Conclusions Direct OOP healthcare costs were lower for RYGB compared to GLP-1 RA use patients 2-years after treatment initiation.