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Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aimed to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, lixisenatide, and albiglutide). Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Five-year incidence of pancreatic cancer was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with CP and T2DM and repeated this analysis. Results: We identified 89,596 patients with CP, including 3183 GLP-1 RA users and 86,413 non-users. After PSM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.30–0.80, p < 0.005). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (HR 0.53, 95% CI 0.31–0.91, p < 0.05). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP, as well as the subpopulation with both CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential beneficial effect of GLP-1RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

PURPOSE Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)–p16–Rb pathway, features shared with hormone receptor–positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

ABSTRACT Purpose Magnetic resonance elastography (MRE) of the heart has predominantly utilized breath‐held acquisitions with limited anatomic coverage. This work investigates the feasibility of 3D, free‐breathing cardiac MRE. Methods A 3D hybrid radial and EPI acquisition is utilized and combined with retrospective binning of k ‐space via physiologic monitoring, iterative reconstruction, MRE processing and inversions, and post‐processing specialized for cardiac imaging. Results Feasibility of free‐breathing stiffness mapping of the left ventricular myocardium was demonstrated in 11 participants. Myocardial stiffness estimates were obtained throughout the left ventricle for seven temporal states of the cardiac cycle. Stiffness estimates were presented in participant‐specific images, 17‐segment bullseye plots, and stiffness plots throughout the cardiac cycle. Results indicate increased stiffness in systolic states, with localized stiffness heterogeneity observed between participants, illustrating a key benefit of 3D cardiac MRE acquisition. Mean stiffness estimates obtained through 11 subjects were 4.44 ± 0.68 kPa (begin‐systole), 5.74 ± 0.94, 5.42 ± 0.87 (end‐systole), 3.84 ± 0.71 (begin‐diastole), 3.51 ± 0.74, 3.54 ± 0.52, and 3.55 ± 0.59 kPa (end‐diastole). Statistical testing indicated significant differences in stiffness across cardiac states with one‐way, repeated‐measures ANOVA ( p < 0.001) and Friedman's test ( p < 0.001). Experiments in scanning three participants with and without applied motion indicated that stiffness changes were more robustly detected in systole than in diastole, although patterns were subject‐specific. Comparison of free‐breathing stiffness measurements against reference breath‐held measurements yielded similar systolic stiffness estimates. Conclusions This study establishes the feasibility of free‐breathing, 3D cardiac MRE in healthy volunteers. With the current framework, stiffness estimation appears more robust in systole, and the reliability of diastolic estimates is limited and subject‐specific.

Abstract BACKGROUND Children exposed to poverty during frontline therapy for B-lymphoblastic leukemia (B-ALL) experience inferior overall survival (OS), higher relapse rates, and earlier relapse than their peers. Real-world data describing treatment patterns and survival after relapse of B-ALL are lacking and, as a result, the impact of poverty following relapse remains poorly understood. This study evaluated the association of poverty exposure, proxied by insurance status, with post-relapse survival and explored potential explanatory mechanisms, including disease biology and therapy utilization. METHODS Data from Retrospective Study of Contemporary Approaches to First Relapse in B-ALL (ReCALL-1), a multicenter retrospective cohort study of patients &lt; 30 years old with first relapse of B-ALL from 2018-2022, were used. The primary exposure was poverty, proxied by insurance status at relapse, categorized as any private insurance (poverty unexposed), public-only insurance (poverty exposed), no insurance, or unknown; the latter two were not included in comparative analyses due to low numbers. The primary outcome was OS. Secondary outcomes included measurable residual disease (MRD)-negative second complete remission (CR2), relapse after CR2, non-relapse mortality (NRM), with relapse treated as a competing risk, and receipt of cellular and immunotherapies. RESULTS Among 462 patients from 31 U.S. institutions, 41% had private insurance, 47% public-only insurance, 2% no insurance, and 10% unknown. Compared to privately insured patients, those with public insurance were more likely to be Hispanic (56% vs 19%, p&lt;0.001) and have non-English preferred language (30% vs 6%, p&lt;0.001). Non-Hispanic Black patients comprised 9% of those with public insurance and 5% of those with private insurance. Disease characteristics that differed by insurance status at relapse included: Ph-like cytogenetics, more common in publicly insured (23% vs 11%, p=0.002), and infant ALL, more common in privately insured patients (10% vs 5%, p=0.06). Publicly insured patients were more likely to have experienced major organ toxicity during frontline therapy (32% vs 18%, p=0.002) and very early relapse (&lt;18m from diagnosis: 43% vs 32%, p=0.07). Other demographic and disease characteristics, including relapse site and cytomolecular features, were similar by insurance status. With a median follow-up of 51 months from relapse, 4-year OS differed by insurance (log-rank p=0.02): 72% for private vs 56% for public insurance. After adjusting for race/ethnicity and language, public insurance increased the hazard of death by 65% (aHR 1.65 95% CI 1.13-2.42, p=0.004). The association remained, but was attenuated, when unbalanced disease characteristics (time to relapse, infant ALL, Ph-like cytogenetics, prior organ dysfunction) were included (aHR 1.47, 95% CI 1.00-2.16, p=0.05). Rates of MRD-negative CR2 were similar (85% public vs 87% private). However, point estimates suggested publicly insured patients had more relapse after CR2 (44% vs 37%, p=0.42) and higher 4-year NRM (16% vs 10%, Gray's test p=0.12), though neither were significant. Treatment choices for first relapse did not differ by insurance status. Utilization of intensive reinduction (91% vs 95% for public vs private, p=0.18) and clinical trial enrollment (22% for both) were similar. Receipt of cellular therapies did not significantly differ by public vs private insurance: Chimeric Antigen Receptor-T cells (CAR-T: 38% vs 34%, p=0.41), hematopoietic cell transplant (HCT: 42% vs 47%, p=0.32). Use of blinatumomab trended higher in those with private insurance (36% vs 45%, p=0.07), and inotuzumab was similar (11% for both, p=0.87). Median time from relapse to CAR-T or HCT was comparable (to CAR-T 102 vs 100 days, to HCT 117 vs 114 days). CONCLUSION This is the first study to demonstrate differential survival by insurance type, a proxy for poverty exposure, after first relapse of B-ALL. In this large multicenter, real-world cohort, patients with public insurance had worse OS after relapse than those with private insurance. The survival disparity existed independent of other SDOH factors. Adjustment for known high-risk disease features only partially accounted for the observed differences in OS. In contrast, rates of MRD-negative CR2 and receipt of CAR-T and HCT were comparable across insurance types. These findings highlight the urgent need to identify effective interventions that will ensure equitable outcomes after relapse.

Abstract Background The expansion of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow is universally associated with adverse outcomes and disease progression in all chronic myeloid neoplasms, to include chronic myelomonocytic leukemia (CMML). However, HSPCs are a heterogeneous cellular compartment and the impact of its composition on clinical outcomes remains poorly defined. Single cell RNA-sequencing (scRNA-seq) represents an optimal strategy to annotate cellular composition but no large clinically annotated scRNA-seq datasets are currently available. To address this, we have embarked to generate a clinically annotated 500 patient CMML scRNA-seq atlas from CD34+ enriched BMNCs to establish among the largest clinically and genetically annotated single cell references for any chronic myeloid malignancy. Here we report the interim analysis of 113 clinically annotated cases that demonstrates massive reshaping of HSPC composition that is independently a predictor of overall survival. Methods Single-cell RNA expression profiling was performed on 113 CD34-enriched CMML BMNC samples using 10x Genomics GEM-X Universal 3' Gene Expression v4 (4-plex) chemistry. Libraries were sequenced on NovaSeq S4 flow cells in two runs, and data were processed using Cell Ranger to generate gene expression matrices. A total of 502,659 single cells from 113 samples were processed using Seurat. The upper threshold for gene count was defined as the mean number of detected genes plus two standard deviations data normalization was performed using the log-normalization method. Batch correction and integration were conducted with Harmony to mitigate technical variation across pools. Descriptive statistics were used to tabulate clinical and genetic parameters. KM curves, log-rank test, and cox regression were used to calculate survival, test for statistical differences, and perform multivariate analysis, respectively. Results To derive high resolution cell annotations, we employed the SingleR algorithm using a large hematopoietic reference of over 300,000 single cells (Zhang, X. Nature Immunology, 2024). Using this approach a diverse set of cell types were identified that included HSCs, 23 myeloid progenitors, 18 erythroid progenitors, and 18 lymphoid progenitors. This diverse cellular repertoire displayed massive reshaping relative to the normal CD34 enriched reference including a &gt;53x expansion of multilineage GMPs and a &gt;100x depletion of B-cell progenitors consistent with the known myeloid skewing seen in this disease. To understand whether expansion of specific progenitors was associated with outcomes we iteratively evaluated key progenitor populations and observed that expansions of HSC (HR 0.468 p&lt;0.005) and MEP (HR 0.485, p&lt;0.005) were associated with improved survival while GMP (HR 1.729, p=0.029) expansions were associated with inferior survival when using a cut point derived with a maximally selected ranks statistics approach. To achieve a more comprehensive metric of HSPC composition we explored GMP ratios to include GMP/HSC ratios and GMP/MEP ratios and observed that both were associated with inferior survival in univariate and multivariate when considering clinical and genetic features such as the CPSS-molecular prognostic score and FAB classification. When considering both GMP/HSC and GMP/MEP ratios in a multivariate model only GMP/MEP ratios and CPSS molecular remained independently prognostic. As an orthogonal approach, pseudotime projections were carried out using a reference map from Setty et al., 2019 to calculate differentiation potential and branch probabilities. This approach enabled both cell identity assignment and placement of cells along the hematopoietic differentiation trajectory. Samples were classified as monocyte-biased, MEP-biased, or normal-like, as previously described (Ferrall-Fairbanks et al. 2022) and demonstrated that increased GMP ratios are associated with a monocytic biased trajectory and that this trajectory is also associated with overall survival. Conclusion This study represents an interim analysis of among the largest scRNA-seq cohorts generated in chronic myeloid malignancies. This enabled us, for the first time, to demonstrate that HSPC composition is independently prognostic even when considering modern CMML prognostic models. As this cohort continues to increase, validation of these findings and examining the impact of therapy on HPSC composition in serial samples will be prioritized.

Abstract BACKGROUND Hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder (IBD) worldwide, afflicting 1 in 5,000 people. HHT is likely the most morbid IBD of women. Severe, recurrent epistaxis, gastrointestinal (GI) bleeding, and solid organ arteriovenous malformations (AVMs) cause major clinical and psychosocial morbidity and reduced survival. In recognition of the serious morbidity of HHT as an IBD, in 2022 the U.S. Congress allocated funding to create CHORUS, the Comprehensive HHT Outcomes Registry of the United States (NCT06259292). Herein, we present the initial report from CHORUS. METHODS CHORUS is a prospective, multicenter, U.S. longitudinal registry enrolling unselected patients with HHT, collecting over 2400 data elements. Data were collected by trained research coordinators at enrollment and follow-up visits via the medical record and direct participant interviews. RESULTS Patients. 600 patients with genetically- or Curacao criteria-confirmed HHT were enrolled from November 2023 to April 2025 at 15 U.S. HHT Centers of Excellence. Median (range) age was 53 (0-88) years, and the cohort was 60% female. Despite most patients developing typical HHT disease manifestations by age 13, most HHT diagnoses (63%) were made during mid-to-late adulthood. Mucosal Bleeding. 568 patients (95%) developed recurrent spontaneous epistaxis, with 339 (60%) developing recurrent epistaxis prior to age 13; 43% had at least one nasal surgery/procedure and 22% had at least one medical therapy (e.g., antifibrinolytic or antiangiogenic) for epistaxis. 180 (30%) had a known diagnosis of chronic GI bleeding. Among post-menarche females, 124 (34%) had been diagnosed with heavy menstrual bleeding. 247 (41%) reported other clinically significant mucocutaneous oral or skin bleeding. 454 (76%) had developed moderate-to-severe HHT-associated mucocutaneous bleeding, defined as an Epistaxis Severity Score &gt;4, bleeding requiring targeted pharmaceutical or surgical intervention, IV iron, and/or red cell transfusion. This includes 334 (56%) with moderate-to-severe HHT-associated epistaxis. CNS and Pulmonary Hemorrhage. 16 patients (3%) suffered one or more intracranial hemorrhages (ICH), with 10 (63%) suffering a first ICH by age 25. 13 (2%) suffered one or more pulmonary hemorrhages. Iron Deficiency and Anemia. 408 patients (68%) had been diagnosed with anemia (351, 59%) or iron deficiency (381, 64%). Of those, 247 (61%) and 150 (37%) required IV iron and RBC transfusion, respectively. Solid Organ AVMs. Brain, pulmonary, and liver AVMs were diagnosed in 81 (15%), 268 (45%), and 128 patients (21%), respectively. Just 30 with brain AVMs (37%) had these diagnosed by age 25. 3 patients (2%) had undergone liver transplantation. Thrombosis. Venous and arterial thromboembolism occurred in 44 (7%) and 38 patients (6%), respectively, including 34 (6%) with ischemic stroke (94% of whom had pulmonary AVMs). Other Serious HHT Complications. These included heart failure in 41 patients (7%), pulmonary hypertension in 44 (7%), chronic liver disease in 17 (2.8%), epilepsy in 24 (4%), severe bacterial/deep-seated tissue infection in 35 (6%), and brain abscess in 15 (3%). 205 (34%) developed migraine. Notably, serious CNS manifestations of HHT (brain AVM, ischemic stroke, intracranial hemorrhage, and/or epilepsy) occurred in 128 (21%). 241 (40%) required emergency room visits and/or hospital admissions specifically to manage HHT complications. CONCLUSIONS This first-of-its-kind HHT registry reliably describes for the first time the incidence and severity of numerous HHT complications. Most patients develop moderate-to-severe recurrent epistaxis and/or chronic GI bleeding as well as iron deficiency anemia (usually requiring IV iron and/or RBC transfusion). Heavy menstrual bleeding, thromboembolism, severe cardiopulmonary complications, and serious CNS complications are all substantially more common in HHT than previously thought. Notably, ICH occurred in 3% of patients, which approximates the ICH incidence of hemophilia in the pre-factor prophylaxis era and is ~2-fold and ~9-fold higher than in hemophilia A treated with modern factor prophylaxis (1.6%) and modern non-factor prophylactic agents (0.3%), respectively, per the ATHN registry. This 3% number may be an underestimation given the known high ICH mortality rate, pervasive delay in HHT diagnosis, and the fact that survival post-ICH is necessary to enroll in CHORUS.

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 &lt;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 &lt;36m; isolated extramedullary &lt;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&lt;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 &gt;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 INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients &lt;30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (&lt;18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (&lt;0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed &lt;18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p&lt;.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses &lt;18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.