Citations

ABSTRACT The initiation and sustained expression of motivated behaviour is strongly regulated by mesolimbic dopamine (DA) release within the nucleus accumbens (NAc). Deep brain stimulation (DBS) has demonstrated efficacy in treating refractory psychiatric disorders characterised by dysfunctional motivated drive and related behaviours. However, the neurobiological mechanisms underlying DBS effects at the local and circuit levels remain unclear. This study aimed to investigate the effects of NAc DBS on effort‐based decision‐making and local phasic DA neurotransmission in male Wistar rats. Male Wistar rats ( N = 8) were trained on a concurrent fixed ratio 5/chow effort‐related choice task (ERCT) until stable baseline performance was reached. On the test day, animals underwent a 2‐h session of high‐frequency NAc DBS (130 Hz; 90 μs pulse width; 500 μA) immediately prior to behavioural testing, with additional testing conducted on subsequent days to assess prolonged effects. In a separate experiment, the effects of identical NAc DBS parameters (or sham) on ventral tegmental area (VTA)‐evoked (120 pulses; 60 Hz; 2 ms pulse width; 200–500 μA) DA release in the NAc core were quantified using fast‐scan cyclic voltammetry in urethane‐anesthetised rats ( N = 12). Acute bilateral NAc DBS transiently reduced overall food‐related motivation while maintaining effort‐based choice bias. In parallel, NAc DBS significantly suppressed VTA‐evoked NAc DA release compared to sham, although a moderate reduction was also observed in sham controls. DA reuptake kinetics remained unchanged across groups. NAc DBS transiently suppresses overall food‐related motivation while maintaining effort‐based decision‐making. Attenuated phasic DA neurotransmission with active DBS may contribute to this behavioural effect. image

Background: High-grade intracranial atherosclerosis (ICAS) is associated with an elevated risk of recurrent ischemic stroke, particularly in patients with severe stenosis (70–99%). Identifying predictors of early recurrence can inform risk stratification and guide treatment strategies. Methods: The Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) study is a multicenter, international, retrospective cohort analysis pooling data from 35 comprehensive stroke centers. We included hospitalized adult patients with symptomatic ICAS, defined as 50–99% stenosis of an intracranial artery (intracranial vertebral, basilar, distal ICA, or M1 MCA), confirmed by vascular imaging and associated with a qualifying ischemic event. Patients with only high-grade stenosis (70-99%) were included in this analysis. The primary outcome was to determine predictors of recurrent ischemic stroke in the territory of the symptomatic artery within 90 days of the index event. Baseline demographic, clinical, and imaging characteristics were recorded. Multivariable Cox proportional hazards regression with stepwise selection (p < 0.1) was used to identify independent predictors of recurrence; model discrimination was assessed using Harrell’s C-statistics. Results: Among 2,050 patients, 1,476 had high-grade (70-99%) symptomatic ICAS. The mean age was 67 ± 12.5 years, and 767 (55%) were male. Most patients were non-Hispanic (90.1%), taking dual antiplatelet therapy (77.8%), and statins (94.5%). Recurrent stroke occurred in 160 patients (10.8%) within 90 days. In multivariable Cox model, independent predictors of recurrence included atrial fibrillation (HR 2.05; 95% CI, 1.26–3.33; p = 0.004), hyperlipidemia (HR 1.57; 95% CI, 1.10–2.24; p = 0.014), diabetes mellitus (HR 1.36; 95% CI, 0.98–1.88; p = 0.064), and home use of dual antiplatelet therapy (HR 1.60; 95% CI, 1.01–2.54; p = 0.043)(Harrell’s C-statistic=0.62). In patients who underwent perfusion(n=402), mistmatch >10seconds were associated with increased recurrence (HR 1.80; 95% CI 0.95-3.38, p=0.07) and atrial fibrillation (HR 2.06: 95% CI 0.03-4.60, p=0.78) though did not reach statistical significance. Conclusion: In this population, diabetes, hyperlipidemia, atrial fibrillation, and prior use of dual antiplatelet therapy were associated with increased risk of 90-day recurrent ischemic stroke. Perfusion imaging may help identify high-risk patients who could benefit from intensified secondary prevention.

Introduction: Intracranial atherosclerosis (ICAS) is a leading cause of ischemic stroke (IS) worldwide and carries a high risk of recurrence. Current guidelines favor 90 days of dual antiplatelet therapy (DAPT) for severe symptomatic ICAS, but recurrence remain high. Limited data suggest possible benefit of single antiplatelet plus anticoagulation (SAPT+AC). We compared the effectiveness and safety of DAPT versus SAPT+AC. We hypothesized that DAPT would lower 90-day recurrent IS risk without significantly increasing bleeding. Methods: This substudy of the Biomarkers and Recurrence Risk in Symptomatic Intracranial Arterial Stenosis (BIORISK-ICAS) included patients from 35 centers (Jan 2019–Jun 2024) with symptomatic 50–99% ICAS in the intracranial internal carotid, vertebral, basilar, or M1 segment of the MCA, presenting ≤72 hours from last known well. The primary efficacy outcome was recurrent IS in the same vascular territory at 90 days; the primary safety outcome was severe bleeding (symptomatic intracranial hemorrhage or major extracranial bleeding). Categorical variables were compared using χ 2 and continuous variables with the Student's t test; multivariable Cox regression adjusted for key covariates. Results: Of 2050 BIORISK-ICAS patients, 1658 met criteria (DAPT n=1499; SAPT+AC n=159). Mean age was 67 vs. 73 years, and 44% were women. At 90 days, recurrent IS occurred in 121 DAPT patients (8.07%) vs. 13 SAPT+AC patients (8.17%); unadjusted HR 0.83 (95% CI, 0.50–1.36; p=0.46). After adjustment for age, diabetes, coronary heart disease, atrial fibrillation, active smoking, and borderzone infarct, the adjusted HR was 0.99 (95% CI, 0.52–1.86; p=0.97). Severe bleeding occurred in 34 DAPT patients (2.26%) and 5 SAPT+AC patients (3.14%); unadjusted HR 0.79 (95% CI, 0.28–1.85; p=0.50), adjusted HR 0.66 (95% CI, 0.21–2.09; p=0.47). Conclusions: In patients with symptomatic ICAS, DAPT and SAPT+AC were associated with similar risks of 90-day recurrent ischemic stroke and severe bleeding. Well-powered randomized trials are needed to determine the optimal antithrombotic regimen in this high-risk population.

Abstract The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary ( de novo ) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (46%), post-myelodysplastic syndrome (MDS) (19%), post-myeloproliferative neoplasm (MPN) (12%), post-MDS/MPN (6%), therapy-related (17%) and AML with myelodysplasia-related genetic abnormalities (AML-MR; 46%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1 MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including in AML-MR (60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2 MUT (86% vs. 44%; p = 0.02), or CEBPA MUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1 MUT (not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.

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.

Abstract Introduction Management of acute leukemia (AL) during pregnancy remains challenging. In the first trimester, chemotherapy is toxic to the fetus, while delaying treatment may endanger maternal health, often prompting recommendations for pregnancy termination. In later trimesters, although the risk of congenital malformations decreases, complications such as preterm labor remain prevalent. Delivery prior to chemotherapy may be considered in advanced gestation. This study aimed to describe maternal and fetal outcomes of patients diagnosed with AL during pregnancy. Methods Following institutional review board approval, we retrospectively identified pregnant patients diagnosed with AL between 1995 and 2025 across Mayo Clinic sites (Minnesota, Arizona, Florida). We recorded leukemia subtype, treatment course, maternal and fetal outcomes. Results We identified 18 patients diagnosed with AL during pregnancy, including 11 with acute myeloid leukemia (AML) and 7 with acute lymphoblastic leukemia (ALL). Ten were diagnosed in the first trimester, 3 in the second, and 5 in the third. In the AML group (n=11; median age 30 years, range 18-42), one patient had acute promyelocytic leukemia (APL). ELN 2022 risk stratification was favorable in 5 (45%), intermediate in 4 (36%), and adverse in 2 (18%). In the ALL group (n=7; median age 23 years, range 19-34), 5 had B-ALL (one Philadelphia chromosome-positive) and 2 had T-ALL. All ALL cases were diagnosed in the first trimester. Among first-trimester AMLs, 2 of 3 had core-binding factor (CBF) AML. All eight patients diagnosed in the second and third trimesters had AML (1 APL, 2 CBF AML, 1 KMT2A-rearranged, 1 with DEK::NUP214 fusion, 1 complex karyotype including t(8;21), 2 with normal karyotype). Overall, 15 (83%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) after initial induction. One patient had refractory disease and achieved partial remission after salvage, another had refractory disease and achieved CR after multiple lines of therapy, and a third achieved CR after FLAG-idarubicin and revumenib. Five patients received chemotherapy during pregnancy (3 in the first trimester, 1 in the second, 1 in the third); two of these resulted in live births. Among the 10 patients diagnosed in the first trimester, all underwent therapeutic or spontaneous abortion. Of the 3 second-trimester diagnoses, 2 underwent spontaneous or therapeutic abortion at 15 weeks. The third received 7+3 induction at 24 weeks for KMT2A-rearranged AML, followed by preterm delivery at 26 weeks and re-induction with FLAG-idarubicin plus revumenib, achieving CR. Among the 5 third trimester diagnoses, 4 delivered preterm infants (median gestational age 33 weeks) prior to chemotherapy. One patient received 7+3 at 29 weeks and delivered a viable preterm infant at 36 weeks. At a median follow-up of 6.5 years, 5 of 11 patients with AML (45%) and 3 of 7 patients with ALL (43%) died, mostly due to disease progression. Median overall survival was not reached in either group. Causes of death were as follows: 1 of AML, 1 of ALL, 3 of acute stem cell transplant (SCT) complications, 1 of chronic SCT complications, 1 of Hodgkin lymphoma, and 1 of pneumonia. Among patients diagnosed in the second and third trimesters (n=8, all with AML), 6 (75%) resulted in live births: 5 of 5 (100%) third-trimester diagnoses and 1 of 3 (33%) second-trimester diagnoses. All received intensive induction: 7+3 (n=5), 7+3 + ATRA (n=1), 7+3 + gilteritinib (n=1), and 7+3 + nilotinib (n=1). Of the second-trimester group, only one received induction prior to delivery; she later achieved CR with FLAG-ida and revumenib. Among the third-trimester group, one patient received chemotherapy prior to delivery and achieved CR followed by SCT. All but one of the 8 AML patients achieved CR after initial therapy. Conclusions Successful pregnancy outcomes were achieved in 75% of patients diagnosed with AML during the late second or third trimester. Notably, 5 (28%) of patients received chemotherapy during pregnancy. Larger, multi-institutional cohorts are warranted to further characterize the incidence and outcomes of AL in pregnancy.

Abstract Venetoclax (Ven) in combination with hypomethylating agents (HMA) is widely used as frontline treatment in older or unfit patients with acute myeloid leukemia (AML). Liposomal cytarabine and daunorubicin (CPX-351) is FDA-approved for the treatment of secondary AML, including therapy-related (t-AML) and AML with myelodysplasia-related changes (AML-MR). The current study aimed to provide a comprehensive comparison between the two treatment strategies to better inform clinical decisions. Methods The current retrospective analysis was performed under an institutional review board approved minimal risk protocol at Mayo Clinic (MN, AZ, FL). AML-MR gene mutations or cytogenetic abnormalities were categorized according to the International Consensus Classification (Arber et al. Blood 2022;140:1200). Treatment response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Dohner et al. Blood 2022;140:1345). Overall survival (OS) analysis was censored for allogeneic stem cell transplant (ASCT). Statistical analyses were performed using JMP Pro (Version 18.0.0). Results A total of 600 patients with newly diagnosed AML (ND-AML) treated with CPX-351 (N-112, 19%), or Ven-HMA (N=488, 81%) were included. AML subtypes included de novo (N=277, 46%), post-myelodysplastic syndrome (post-MDS, N=114,19%), post-myeloproliferative neoplasm (post-MPN, N=70, 12%), post-MDS/MPN (N=36, 6%), t-AML (N=103, 17%) and AML-MR (N=274, 46%). Compared with those treated with Ven-HMA, patients receiving CPX-351 were younger (median age 65 vs 73 years; p&lt;0.01), more likely to be female (50% vs 38%; p=0.02), more frequently diagnosed withsecondaryAML (68% vs 51%; p&lt;0.01), and less likely to have NPM1MUT (5% vs 12%; p=0.02) whereas ELN 2022 cytogenetic risk distribution was similar between the two (adverse risk; 43% vs 40%; p=0.5). Comparison of treatment response and survival Complete response rates with (CR) or without (CRi) count recovery were similar between CPX-351 and Ven-HMA overall (55% vs 60%) as well as specifically in patients with AML-MR (60% vs 63%), adverse karyotype (44% vs 44%), NPM1MUT (100% vs 89%), TP53MUT(32% vs 45%), IDH1MUT (60% vs 76%), IDH2MUT (63% vs 77%), SF3B1MUT(71% vs 45%), and CBLMUT (33% vs 69%) [p&gt;0.05 in all instances]. Compared to those with CPX-351, CR/CRi rates with Ven-HMA were superior in males (60% vs. 45%; p=0.04) and in patients with de novo AML (68% vs. 50%; p=0.03), STAG2MUT (86% vs. 44%; p=0.02), or CEBPAMUT (88% vs. 50%; p=0.03); infectious complications were significantly more frequent with CPX-351 (83% vs 62%, p&lt;0.01). At a median follow-up of 12 months (range; 1-88), 416 (69%) deaths, 179 relapses (44% in CPX-351 and 52% in Ven-HMA responders) and 149 ASCTs (53% in CPX-351 and 18% in Ven-HMA) were documented. OS rates were similar between CPX-351 and Ven-HMA, in general (median 10 vs 13 months), as well as in patients with adverse karyotype, TP53MUT, IDH1MUT, and IDH2MUT (p&gt;0.05 in all instances). By contrast, OS was superior in Ven-HMA-treated patients with post-MDS AML (median 12 vs. 7 months; age-adjusted p=0.02) and in CPX-351-treated patients harboring SF3B1MUT(median not reached vs 14 months; age-adjusted p&lt;0.01). In addition, a borderline-significant OS advantage for CPX-351 was apparent in patients with PTPN11MUT (13.5 vs 8 months; p=0.08). Comparison in ICC defined AML-myelodysplasia-related CR/CRi and OS rates were comparable between patients treated with CPX-351 (N=57) or Ven-HMA (N=217), with response rates of 60% vs 63% (p=0.68) and median OS of 10 vs 14 months (p=0.61), respectively. However, OS was superior with Ven-HMA in patients with post-MDS AML (15 vs 8 months; age-adjusted p=0.02) and with CPX-351 in those with SF3B1MUT (NR vs 14 months; age-adjusted p=0.02). Conclusions: The current study suggests that Ven-HMA was as effective and possibly less toxic than CPX-351 for the treatment of ND-AML, including AML-MR, despite the bias for younger and fitter patients treated with the latter regimen. Observed differences involving patients with SF3B1MUT or post-MDS AML require validation in prospective studies and provide parameters for developing treatment-specific predictive models that will be presented at the meeting.

Abstract BACKGROUND: DNA methyltransferase inhibitors (DNMTi) are US FDA approved for the management of CMML. These agents are associated with an overall response rate (ORR) of 40-50%, with a true complete remission (CR) rate of &lt;20%. TET2 mutations are seen in 60% of CMML, with TET2 being a ferrous and oxoglutarate dependent DNA-dioxygenase that oxidizes 5mC to generate 5hmC, 5fC and 5caC. Ascorbic acid (AA) is critical for TET activity and can enhance TET 1/2/3 dioxygenase function by binding to the catalytic domain and when given in high doses, can result in glutathione depletion and free radical induced cell death. In a pilot study (Xie et al. Blood 2024), we demonstrated that high dose IV AA can be clinically effective and induce changes in differentially methylated regions (DMR) involving hematopoietic enhancers and improve cytopenias in TET2-mutant (mt) patients [CCUS]. We expanded this study to combine high dose IV AA with DNMTi to enhance the demethylation effect and produce durable responses in new diagnosed, treatment requiring, TET2mt CMML patients. METHODS: At Mayo Clinic, the LS1781 (NCT03418038) clinical trial was amended to include Arm E, combing high dose IV AA with standard of care decitabine in newly diagnosed TET2mt CMML patients that needed therapy. IV AA was dosed at 1 g/kg on days 1, 3 and 5 (per 28-day cycle, max dose 100 gm) through a central line, based on demonstrated safety from phase 1 studies. Standard dosing was adopted for decitabine, and patients were then asked to take oral AA, 1 gm daily from days 6-28. Key inclusion criteria included a WHO-defined diagnosis of CMML with at least one detectable TET2 mutation requiring therapy with adequate performance status (ECOG PS &lt;2) and organ function (creatinine clearance &gt; 55 mL/min). Response was evaluated by the MDS/MPN International Working Group Criteria (Savona et al. Blood 2015). We measured pre- and post-therapy (4 cycles) bone marrow variant allele fractions (VAF) through next generation sequencing assays, transcriptomic changes through RNA seq, and DNA methylation changes using the Illumina Methylation EPIC array. RESULTS: Between February 2024 and July 2025, a total of six patients were enrolled. The median age at enrollment was 73 years (range: 65-80); all Caucasian with 3 (50%) males. All patients had a diagnosis of CMML-1 with a median bone marrow (BM) blast percentage of 3 (0-10), median hemoglobin 13 (9.5-14.5) g/dL, median WBC count of 5.7 (2.1-12.6) x 109/L, absolute monocyte count 1.4 (0.7-2.7) x 109/L, and platelet count of 92.5 (32-123) x 109/L. TET2 (100%, 4 patients &gt; 1 TET2 mutation at mean VAF of 36%), SRSF2 (67%), and KRAS (33%) were the most frequent molecular abnormalities. Neutropenia (without infection/sepsis) was the only treatment-associated adverse effect seen in 3 (50%, all grade 3) patients. Response was assessed in patients who completed at least 4 cycles (n=5) of therapy, with all (100%) patients meeting criteria for either a complete response (n=2, 40%), optimal marrow response (n=1, 20%) or clinical benefit (platelet response, n=2, 40%). In five patients who had NGS assessment pre-and post-therapy, there was a &gt;50% reduction in TET2mt VAF, with one patient loosing the KRAS G12D clone in its entirety. Furthermore, we identified significant changes in DNA methylation associated with treatment with &gt;85% of the CpGs being hypomethylated post-treatment. RNA-sequencing on patients pre- and post-treatment, identified key transcriptomic changes, with a decrease in expression of leukemogenic genes. Integration of the differential methylation data with transcriptomic changes identified several genes in which changes in DNA methylation correlated with a change in gene expression. These genes include regulators of blood cell development and inflammatory response including GATA2, BCL2, and HLA-DPA. Several leukemia-associated genes were downregulated including MEIS1, TCL1A, and SETBP1. CONCLUSION: In TET2mt CMML, high dose IV AA acid enhances TET activity and synergizes with DNMTi with encouraging clinical responses in all patients and with no new safety signals. On completion of this study, we plan a randomized phase 2 trial comparing high dose IV AA with decitabine vs decitabine alone in newly diagnosed TET2/IDHmt CMML.

Abstract Background: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a hemato-inflammatory syndrome due to somatic mutations in UBA1 gene. Recently, DNA methyltransferase inhibitors (specifically, 5-azacitidine) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have shown success in eradication of UBA1 clones and clinical remission in some patients. This study aims to provide a comparative efficacy analysis between DNA methyltransferase inhibitors (hypomethylating agents/HMA) versus alloHSCT in VEXAS syndrome patients. Methods: This is a multi-center, retrospective cohort study. UBA1 mutations were detected either through next generation sequencing [NGS, limit of detection (LOD) 2% variant allele fraction (VAF)] or quantitative droplet digital polymerase chain reaction testing (ddPCR, LOD 0.5% VAF). Outcomes of interest included overall survival (OS), glucocorticoid (GC) discontinuation/reduction in dose (prednisone &lt; 10 mg/day), and complete molecular remission (CMR, defined as an undetectable UBA1 mutation). OS was calculated from the time of diagnosis to death or last follow up. Cumulative incidence of reduction in GC dose was calculated using competing risk analysis after accounting for death. Results: Between years 2020-2024, a total of thirty-nine male patients (median age 67, range 45-82 years) with VEXAS syndrome, necessity for therapy (GC-refractory inflammation and/or progressive marrow failure/myeloid neoplasm) and confirmed UBA1 pathogenic mutation were included. Of these, 18 (46%) received HMA therapy (5-azacitidine 72% and Decitabine 28%) with a median of 4 (range 1-36) cycles. and 21 (54%) underwent alloHSCT (MSD=4, MUD=12, MMUD=2, and haploidentical=3), all received reduced intensity conditioning (Flu/Mel =11, Flu/Bu=5, Flu/Cy/TBI=2, and TBF=3) and 91% received post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis (only 2 patients in alloHSCT group received prior HMA without benefit). Baseline characteristics were well-balanced between HMA and alloHSCT groups; age at treatment (median 70 vs 65 years, p=0.2), and UBA1 M41V subtype (25% vs 40%, p=0.3), cytogenetic and non-UBA1 mutation abnormalities (p=0.4), prior lines of therapy (median 4 in both, p=0.5), time from diagnosis to therapy (median 7 vs 13 months, p=0.15), indication for therapy (p=0.12), Charlson CI scores (median 4 in both, p=0.4) and HCI-CI scores (median 4 in both, p=0.7). At a median follow-up of 45 (range 7-57) months, 11 (28%) deaths (alloHSCT=3 and HMA=8) were documented. Causes of death included infections (n=6), cardiac disease (n=2), poor graft function (n=2) and pulmonary GVHD (n=1). Compared to HMA therapy, alloHSCT group demonstrated higher rates of GC discontinuation (52% vs 6%, p&lt;0.01) and CMR (evaluable= 22, 100% vs 50%, p&lt;0.01). In the HMA group, 50% (n=9) discontinued therapy after a median of 4 months due to infectious complications or lack of benefit. In the alloHSCT group, 3 (14%) patients developed grade 2 acute GVHD (1-skin, 2-gut, no grade 3-4 acute GVHD) and 4 (19%) experienced moderate to severe chronic GvHD (2-lung, 2-mucocutaneous). In multivariable analysis (MVA) adjusted for age and HCT-CI, alloHSCT was identified as the strongest favorable predictor for OS (HR 0.18 95% CI 0.04-0.8) with similar results when analysis was restricted to transplant-eligible patients &lt; 75 years of age (HR 0.1, 95% CI 0.03-0.6). In a 6-month post-treatment landmark analysis (n=31 evaluable), patients who underwent alloHSCT (n=17) exhibited numerically superior GC discontiuation rate (29% vs 14%, p=0.049) and subsequent OS compared to HMA (2-years OS: 84% vs. 61%, median not reached vs 25 months, 95% CI: 0.06–1.7). In a post-treatment competing risk [GC dose reduction (death)] analysis alloHSCT was associated with superior 2-, and 3-year rates of 57% (10%), and 76% (10%), compared to HMA 22% (24%), and 31% (42%) [p&lt;0.01 (0.04)]. AlloHSCT was also associated with higher rate of CMR (evaluable= 21, alloHSCT N=16 and HMA N=5, 100% vs 60%, p=0.01). At the last follow up, none of the patients who achieved CMR had re-emergence of the UBA1 clone (despite early mixed chimerism). Conclusions: This study represents the largest comparative analysis of alloHSCT versus HMA therapy in VEXAS syndrome, and confirms superiority of alloHSCT in achieving molecular remission, GC discontinuation/dose reduction, and overall survival. Prospective clinical trial confirmation is warranted.