Citations

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Background Artificial intelligence (AI)–enabled electrocardiography has emerged as a tool for detecting cardiac dysfunction. The prognostic relevance of AI‐enabled electrocardiography–derived diastolic dysfunction (DD) in patients undergoing transcatheter aortic valve replacement had not been assessed. Methods We analyzed 3197 patients undergoing transcatheter aortic valve replacement for severe aortic stenosis between 2010 and 2023 with baseline 12‐lead ECGs processed by a validated AI model to classify diastolic function (grades 0–3). Multivariable Cox models and nested model comparisons assessed associations with all‐cause mortality, including a prespecified analysis in patients with indeterminate echocardiographic grading. Trajectories were defined by change in AI‐enabled electrocardiography DD grade (<2 versus ≥2) from baseline to 30‐day or 1‐year follow‐up. Results At baseline, 21% had grade 3, 57% had grade 2, 8% had grade 1, and 14% had grade 0 AI‐enabled electrocardiography DD. Higher grades were associated with adverse cardiac remodeling and comorbidities. Over a median follow‐up of 3.4 years, grade 3 AI‐enabled electrocardiography DD independently predicted mortality (hazard ratio [HR], 1.80 [95% CI, 1.47–2.20]; P <0.001). AI‐enabled electrocardiography DD improved prognostic discrimination beyond clinical and echocardiographic measures (ΔHarrell concordance statistic, 0.016; Δ χ 2 =57; P <0.001). Among 1259 patients with indeterminate echocardiographic grading, AI‐enabled electrocardiography added prognostic value (ΔHarrell concordance statistic, 0.02; Δ χ 2 =13; P =0.006). Worsening or persistently high‐risk trajectories were associated with increased mortality (HRs, 1.45–1.80; all P <0.05). Conclusions AI‐enabled electrocardiography–derived DD independently predicts mortality after transcatheter aortic valve replacement, adds value beyond echocardiographic grading, and enables dynamic risk stratification through longitudinal tracking.

Early allograft failure (EAF) after living donor liver transplantation (LDLT) remains a clinical challenge. Existing prediction models developed for deceased donor transplantation poorly apply to LDLT due to distinct surgical and physiological factors. This study identifies clinical determinants of EAF and develops an LDLT-specific prediction model. We conducted a multicenter retrospective cohort study from 17 high-volume LDLT centers (January 2016–December 2020) with external validation at a tertiary center in Saudi Arabia (January 2015–December 2022). The primary outcome was EAF (graft loss or patient death ≤90 d). Multivariable mixed-effects logistic regression identified preoperative/intraoperative risk factors. The EAGLE-LDLT model was constructed using postoperative laboratory values. Performance was compared against established models (EAD, MEAF, A2ALL) using ROC analysis and decision curve analysis. The development cohort included 2944 adult LDLT recipients (67.7% male; median age 55 y; median MELD 14) with a 5.5% EAF rate. External validation included 1020 recipients (median MELD 21, 6.7% EAF). Independent risk factors for EAF were MELD (OR 1.06, 95% CI 1.04–1.08), donor BMI (OR 1.05, 95% CI 1.00–1.10), portal vein thrombosis (OR 1.73, 95% CI 1.13–2.63), and hepaticojejunostomy (OR 1.58, 95% CI 1.06–2.36). The EAGLE-LDLT model incorporating peak ALT (>468 U/L), peak INR (>1.9), and bilirubin (>3.5 mg/dL) and INR (>1.3) at POD7, demonstrated superior discrimination (AUC=0.81) compared with MEAF (AUC=0.77, p =0.004), EAD (AUC=0.67, p <0.001), and A2ALL (AUC=0.65, p <0.001). EAGLE-LDLT achieved balanced sensitivity (75.0%) and specificity (73.7%), effectively stratifying patients into high-risk (15% of patients; 40.4% EAF incidence) and low-risk groups. Preoperative and intraoperative clinical factors predict EAF in LDLT. The EAGLE-LDLT model accurately identifies LDLT recipients at the highest risk for EAF postoperatively.

Objective: To establish international benchmark values for relevant outcome parameters in robotic Whipple. Summary Background Data: For safe adoption of surgical innovation, robust quality control is essential. Benchmarking is a validated tool for assessing surgical performance. Recent international consensus identified establishing benchmark values for robotic Whipple as top priority. Methods: We analyzed consecutive patients undergoing robotic Whipple between 2020-2023 with a minimum one-year follow-up. Reference centers were required to perform ≥15 cases/year, be scientifically active in the field, and maintain a prospective database. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Benchmarks were established for 13 outcome parameters. Result: The benchmark cohort comprised 418 patients from 12 centers across four continents. Benchmark values were: conversion rate ≤4.3%, transfusion rate ≤2.1%, 6-month mortality ≤2.2%, major complications ≤23.2%, and CCI® ≤20.9. Clinically relevant pancreatic fistula (grade B/C) and hemorrhage (grade B/C) rates were ≤23.6% and ≤12.7%, respectively. For pancreatic ductal adenocarcinoma (n=123), the benchmark for lymph node yield was ≥20. Higher surgical difficulty was associated with increased overall postoperative morbidity (R 2 =0.38, P =0.019), higher center caseload with reduced pancreas-specific complications (R 2 =0.28, P =0.044). Independent POPF predictors included duct diameter ≤4 mm (OR 1.37, 95% CI: 1.03, 1.82), anticoagulation (OR 2.45, 95% CI: 1.47, 3.99), and indication other than PDAC (OR 2.33, 95% CI: 1.68, 3.27). Conclusions: This study establishes the first international benchmarks for robotic Whipple, demonstrating oncologic outcomes and morbidity comparable to open surgery with the benefits of minimally invasive surgery.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

PURPOSE Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency. METHODS The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed–progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), and safety. RESULTS Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone. CONCLUSION The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

Abstract Introduction Obecabtagene autoleucel (obe-cel) and brexucabtagene autoleucel (brexu-cel) are CD19 targeted chimeric antigen receptor T cell (CAR-T) therapies, approved for the treatment of adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Mechanistic differences between obe-cel and brexu-cel including differing costimulatory domains (4-1BB vs. CD28), CD19 binding domains (intermediate vs. high affinity) and split dose (Days 1 and 10) vs. single infusion may impact in-vivo cellular kinetics that translate into variant clinical outcomes. In pivotal trials, obe-cel resulted in lower rates of severe cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) compared to brexu-cel with comparable efficacy (Roddie et al., NEJM 2025; Shah et al., Lancet 2021). Real-world utilization and outcomes with obe-cel are unknown given the relatively recent approval. Methods The ROCCA database, comprising real world data from patients (pts) with r/r ALL treated at 40 North American institutions was utilized in this analysis. Pts with r/r ALL were eligible if they were apheresed for obe-cel since its approval (11/8/2024) or brexu-cel over a comparable period (since 8/1/24) and had at least 30 days of follow up. Data cut off was 7/15/2025. CRS/ICANS were graded per ASTCT criteria. Measurable residual disease (MRD) was assessed by flow cytometry and/or next generation sequencing per institutional standards. Results 38 pts have undergone apheresis for obe-cel (36 infused, all received both infusions) and 54 (53 infused) for brexu-cel over the study period. Pts in the obe-cel and brexu-cel cohorts had the following baseline characteristics: median age, 47 vs. 39 years; ECOG 2+, 15% vs. 26%; Ph+ disease, 24% vs 13%; KMT2Ar, 0 vs. 4%; TP53m, 11% vs 11%, and hypodiploid karyotype, 5% vs 6%. The following prior treatment patterns were observed: median lines of therapy before CAR-T 3 vs. 3; prior SCT 24% vs. 30%, prior blinatumomab 68% vs. 46%, prior inotuzumab 45% vs. 30%. At apheresis, active disease (&gt;5% bone marrow blasts) was present in 47% vs. 55% of obe-cel and brexu-cel pts, respectively; the remainder were in CR (with 18% vs. 22% in MRD- CR, respectively). Among obe-cel (n= 35 [92% of cohort]) and brexu-cel (21 [38% of cohort] pts with disease re-assessment prior to lymphodepletion (LD), 31% vs. 43% had active BM disease, respectively; few pts (24% vs. 17%) had &gt;20% marrow disease burden prior to LD. CAR-mediated toxicity differed significantly between the cohorts. CRS occurred in 56% of obe-cel pts compared to 94% of brexu-cel pts (p &lt; 0.0001). There were no Gr3+ CRS events among the obe-cel pts; 3 (6%) brexu-cel pts had Gr3+ CRS (p = 0.27). ICANS occurred in 17% of obe-cel pts vs. 51% of brexu-cel pts (p = 0.001). Gr3+ ICANS occurred in 6% of obe-cel vs. 32% of brexu-cel pts (p = 0.0027). Among the obe-cel pts, CRS occurred in 31% after the first infusion and 46% after the second; ICANS occurred in 3% after the first infusion and 15% after the second. Prolonged Gr4 neutropenia (ANC &lt; 500 cells/uL beyond day 30 from infusion) occurred in 24% of obe-cel vs. 28% of brexu-cel pts (p = 0.73). Deaths within the first 28 days of infusion occurred in 0 obe-cel pts and 4 brexu-cel pts (2 of infection, 1 of infection/brain bleed, and 1 of liver failure in the setting of Gr4 CRS and HLH). Response rates were high and did not significantly differ between cohorts (p = 0.85). Among the 31 obe-cel pts with available response data, 25 (81%) achieved an MRD- CR/CRi, 3 (10%) had an MRD+ CR/CRi, 2 (6%) had a CR/CRi with unknown MRD, and 1 (3%) did not respond. Among 41 brexu-cel pts with available response data, 33 (80%) had an MRD- CR/CRi, 4 (10%) an MRD+ CR/CRi, and 4 (10%) CR/CRi with unknown MRD. Conclusion Pts selected for obe-cel apheresis were similar to those for brexu-cel over the study period (noting that not all centers had access to obe-cel during this time). Similar to clinical trial results, obe-cel was associated with lower rates of CRS/ICANS. Rates of MRD-negative CR were high and did not differ between cohorts. A larger sample and longer follow up are required for further analyses; we anticipate a cohort of ~75 obe-cel treated pts by the annual meeting and will provide updated data.

Abstract Introduction: Brexucabtagene autoleucel (Brexu-cel) is a CD19-targeted chimeric antigen receptor (CAR-)T cell therapy approved for treatment of relapsed/refractory (r/r) B-ALL. Brexu-cel's approval was founded on data from the ZUMA-3 trial, in which 78 patients (pts) were treated at the pivotal dose of 1x10e6 CAR-T cells/kg, resulting in a complete remission (CR) rate of 73%. Three-year follow-up from ZUMA-3 demonstrated median relapse-free and overall survival (RFS/OS) of 11.6 and 25.6 months (mos) for all treated pts. Amongst responders, the median OS was 60.4 mos for those who did not receive a subsequent allogeneic hematopoietic cell transplant (HCT) (n=43), but only 36.3 months for those who did (n=14). This has led some to conclude that HCT may not be beneficial following brexu-cel therapy for r/r B-ALL; however, it must be noted that 29 (37%) of the pts treated on ZUMA-3 received brexu-cel for post-HCT relapse. T cells collected from individuals who relapse in the post-HCT setting are largely of donor origin, making the CAR-T product comparable to a genetically modified donor lymphocyte infusion (DLI). The immunology at play in this scenario may be different from that in which CAR-T cells are of truly autologous origin. Methods: The Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database includes pt characteristics and outcomes of brexu-cel therapy given as standard-of-care across 41 US institutions. We identified pts who achieved an MRD negative (neg) CR by either flow cytometry (minimum sensitivity 10e-4) or NGS following brexu-cel for r/r Ph neg B-ALL and categorized them into three groups with regard to use of HCT: Never HCT, Pre-CAR HCT, or Post-CAR HCT. Pts who received second HCT following brexu-cel for post-HCT relapse (n=9) were excluded. Pt/disease characteristics, RFS, and OS were assessed for each group, landmarked at 73 days after brexu-cel infusion (the median time to consolidative allogeneic HCT). Results: In the ROCCA database we identified 165 pts who achieved MRD neg CR following brexu-cel, amongst whom 69 never underwent HCT, 49 were transplanted pre-CAR (ie, brexu-cel served as a genetically modified DLI), and 47 underwent post-CAR consolidative HCT while in CR. The median follow-up is 373 days. The median age was higher in the Never HCT group (49, range 19-83) in comparison with the Pre-CAR HCT (40, 24-72) and Post-CAR HCT (34, 18-70) groups. Thirty-five percent were &gt;60yo in the Never HCT group vs 20% in the Pre-CAR HCT and 9% in the Post-CAR HCT groups. Ph-like disease was present in 38%, 29%, and 43% of the Never HCT, Pre-CAR HCT, and Post-CAR HCT groups, respectively (p=0.35). No significant differences were observed in pre-apheresis bone marrow blasts, presence of CNS disease at apheresis, prior blinatumomab or inotuzumab treatment, or use of bridging therapy across the groups, though there was a higher prevalence of non-CNS extramedullary disease in the Pre- and Post-CAR HCT groups (32, 39%) vs the Never HCT group (13%) (p=0.004). A minority of pts in all groups were deemed to be in MRD neg CR prior to apheresis (6-20%). Median RFS was 260 days in the Never HCT group and not reached in the Pre- and Post-CAR HCT groups (p=0.002), with respective 1-yr RFS of 38%, 64%, and 67%. Median OS was not reached in any group and was similar for all at 1-yr at 68-79% (p=0.13). Characteristics of those in the Never HCT group who were least likely to relapse included age &gt;60 (OR 0.22, CI 0.07-0.73 vs age 18-39, p=0.024) and those with non-Ph-like B-ALL (OR 0.33, CI 0.12-0.94, vs Ph-like, p=0.037) in univariate analyses. Conclusions: Real-world data regarding outcomes following brexu-cel therapy allow evaluation of the role for consolidative allogeneic HCT, which remains one of the most important unresolved questions in the use of CAR-T therapy for r/r B-ALL. This analysis demonstrates that a first consolidative HCT after achieving MRD neg CR with brexu-cel is associated with a significant decrease in relapse. Additionally, use of brexu-cel for post-HCT relapse is also associated with a significantly lower risk of relapse compared with those who never received an allogeneic HCT. With the current duration of followup, OS is not significantly different across the three groups. These data suggest there is a benefit for relapse-free survival in pts receiving an allogeneic HCT at some point in the course of treatment for r/r Ph neg B-ALL.

Abstract Background: Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. Methods In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (&lt;10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (&lt;10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Results Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (&lt;10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. Conclusions At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.